Beruflich Dokumente
Kultur Dokumente
Hypomelanoses of
H air and Skin
1983
Acknowledgments
The authors wish to acknowledge the assistance of the many colleagues who
have inspired and assisted them in this endeavor. Particularly appreciated is
the editorial review of Dr. John A. Parrish and the assistance of Dr. Madhu A.
Pathak particularly in the areas of chemical leukoderma and vitiligo. Diane
Patry assisted with typing and copy preparation. We are particularly indebted
to Pat K. Novak for her tireless diligence as copy editor.
Preface
Leukoderma is a generic term for any pigmentary dilution, be it congenital or
acquired, circumscribed or generalized, devoid of or partially lacking in pigmentation. In the approach to the diagnosis of leukoderma, we have generally
first considered the age of onset, whether leukoderma was congenital or acquired, the extent and pattern of involvement, and the degree of pigmentary
dilution. The organization of this monograph reflects this approach. For example, we have separated the section devoted to various disease entities into
diffuse and circumscribed leukoderma and the latter into various etiologies
such as genetic, metabolic, infectious, and endocrinologic.
One of several justifications for this monograph is to present an approach
to the diagnosis of leukoderma, as detailed in Part II. In formulating a guide
for the physician, we have found some limitations to our previous approach;
we therefore offer the following new classification based upon a clinical-pathologic correlation. This could provide the means to describe both the
clinical and pathologic findings in one term.
I. Melanocytopenic leukoderma (reduction or absence of melanocytes)
A. Vitiligo
B. Piebaldism
C. Chemical leukoderma
D. Waardenburg's syndrome
II. Melanopenic leukoderma (reduction or absence of melanin)
A. Albinism
B. White macule of tuberous sclerosis
C. Nevus depigmentosis
In the melanocytopenic leukodermas, melanocytes are absent and the macules are usually pure white. However, in the melanopenic leukodermas, melanocytes are present, but there is a reduction of melanin, due to a defect in
melanosome formation, melanization of melanosomes, melanosome transfer,
or other process, so that mild to very marked pigmentary dilution is apparent.
Differential diagnosis of a melanocytopenic leukoderma that is congenital
and circumscribed would, for example, have to include piebaldism, whereas
if it were acquired and circumscribed, vitiligo and chemical leukoderma would
vii
viii
PREFACE
Contents
PART I. SKIN COLOR AND THE MELANIN PIGMENTARY SYSTEM
Melanins ............................................ .
Epidermal Dendritic Cells ............................ .
Origin of Melanocytes ................................ .
Biologic Basis of Melanin Pigmentation ................ .
Race, Light, Age, and Melanocytes ..................... .
Factors Controlling Pigmentation ...................... .
References ........................................... .
1
3
7
9
11
20
22
28
40
41
51
54
56
57
59
59
Introduction ......................................... .
Tyrosinase-Negative Oculocutaneous Albinism ......... .
Tyrosinase-Positive Oculocutaneous Albinism .......... .
Yellow-Mutant Oculocutaneous Albinism .............. .
Hermansky-Pudlak Syndrome ........................ .
Chediak-Higashi Syndrome ........................... .
Albinism and Immunodeficiency ...................... .
Cross-McKusick-Breen Syndrome .................... .
Oculocutaneous Albinoidism ......................... .
Ocular Albinism ..................................... .
59
65
69
74
75
79
87
88
89
89
ix
x
CONTENTS
92
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466
Kwashiorkor ..........................................
Generalized Dyschromia in a Malnourished Infant . . . . . ..
Pigmentary Changes in the Hair of Patients with
Nephrosis, Ulcerative Colitis, or Extensive Resection
of the Gut . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..
Severe Iron Deficiency ............................... "
Copper Deficiency .....................................
Vitamin B12 Deficiency (Pernicious Anemia) .............
References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..
467
469
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xi
CONTENTS
xii
CONTENTS
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Herpes Zoster. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..
Tinea Versicolor. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..
Onchocerciasis ........................................
Post-Kala-Azar Dermatosis. . . . . . . . . . . . . . . . . . . . . . . . . . . ..
Tuberculosis ..........................................
References. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ..
544
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xiii
CONTENTS
FIGURE 1. Components of skin color. Any variation in skin color arises from
different ratios of blue, red, brown. and yellow. (From: Quevedo WC Jr: The control
of color in mammals. Am Zool 9:531-540. 1969. Copyright. 1969. American Society
of Zoologists. Used with permission.)
I
Skin Color and the Melanin
Pigmentary System
The skin is a complex organ system endowed with the capacity to undergo a
wide array of color changes. Normal skin color arises from a mixture of red,
blue, yellow, and brown colored pigments (Fig. 1). In normal skin, melanin is
the major pigment or color determinant and imparts a color ranging from a
very light tan to a deep brown or black, depending on the quantity of melanin
in the epidermis. A yellow hue may be imparted by carotenoids, red by oxygenated hemoglobin in the capillaries, and blue by reduced hemoglobin in the
dermal venules and by pigment in the dermis.
Melanin is synthesized by a specialized cell, the melanocyte, which is a
dendritic cell found in the basal layer of the epidermis, though some melanocytes higher in the epidermis and a few in the dermis may be found. The
melanin pigmentary system consists of millions of such melanocytes, each of
which is functionally associated with 36 keratinocytes (Fig. 2); this cluster of
keratinocytes and the associated melanocyte is referred to as the "epidermal
melanin unit" [1-3] which appears to be a structural and functional entity.
Within each functioning melanocyte, melanin is synthesized and packaged in
specialized pigment organelles called "melanosomes." The dendritic processes
of the melanocytes project in between keratinocytes so that a single melanocyte
supplies melanosomes to its group of 36 keratinocytes. These melanosomes
migrate centrifugally along the dendritic processes of the melanocytes and are
then transferred to or captured by keratinocytes. Although the number of active
epidermal melanin units per unit area varies markedly over various regions of
the human skin [4-6], the keratinocyte/melanocyte ratio remains constant [7].
It has been suggested that the epidermal melanin unit is the functional integrator
of the multicellular system of melanin pigmentation in humans and animals
[1].
PART I
FIGURE 2. The epidermal melanin unit. Relationship of basal melanocyte high-level Langerhans
cells and keratinocytes in mammalian epidermis. (From: Quevedo WC Jr: The control of color in
mammals. Am Zo019:531-540. 1969. Copyright. 1969. American Society of Zoologists. Used with
permission.)
lanocytes as unicellular secretory glands; subcellular (electron microscopic)the melanosome as a metabolic unit of melanogenesis; and macromolecular
(biochemical)-tyrosinase, the enzyme, and melanoprotein, the end product of
melanogenesis. This chapter touches each of these levels but concentrates on
the cellular, subcellular, and macromolecular aspects.
MELANINS
There are three different melanins-eumelanin, phaeomelanin, and neuromelanin. Eumelanin is the brown-black pigment of skin and hair and most
responsible for skin color. Phaeomelanin is a red-yellow pigment found in
hair in humans. Neuromelanin is present in neurons of the central nervous
system, in adrenal medulla, and in other areas of the chromaffin system.
Eumelanin
Eumelanin is a high-molecular-weight polymer of which the precise molecular structure has yet to be determined, in part because eumelanin is insoluble in most solvents and resists most chemical alterations and degradations.
Observations based on the work of Raper [18] with plant tyrosinases and modified by Mason [19] led to the conclusion that melanin is a polymer of indole5,6-quinone units. Use of labeled precursors, however, showed this to be an
oversimplification [20,21]. Work of Nicolaus and Piatelli [22] with squid melanin showed melanin to be a complex heteropolymer composed of 5,6-dihydroxyindole and 5,6-hydroxyindole-2-carboxylic acid moieties at various oxidative levels. The proportion of various subunits, molecular chain length, and
molecular weight of eumelanin are still unknown. Blois et a1. [23] consider
melanin to be a highly irregular three-dimensional polymer joined by covalent
bonds. Melanin possesses a free radical character [24] related to a semiquinonoid form of 5,6-dihydroxyindole stabilized by resonance throughout the
highly conjugated polymer [23]. Melanin may be able to function as a mild free
radical quencher and may also have some weak acid cation exchange capabilities. Melanin has specific absorption peaks only in the infrared region at 3
and 6 J.L [23], but shows a rather nonspecific wide absorption band from 200
to 2400 nm.
Tyrosine-Melanin Pathway
4
PART!
OM
7
~
at - ....2
COOM
OM
oil/NOt
I'lOOtJC ,
OM
-s - ~~- at - COOM
s - Cllz - f" - ~
NM:z
~~
~ - II~
NM:z
COOM
S - S - CYSTD_
- S - cysn:l~
S.I . DIKYDIIOXYlllOOU
FIGURE 3. Metabolic pathway of eumelanin and phaeomelanin biosynthesis. Both begin with
the enzymatic (tyrosinase) conversion of tyrosine to dopa to dopaquinone. (From: Jimbow K et al:
Some aspects of melanin biology: 1950-1975. J Invest Dermoto! 67:72-89, 1976. Copyright, 1976,
The Williams & Wilkins Company. Used with permission.)
boxylic acid moieties at various oxidative levels; many different indoles combine to form this complex polymer, which becomes protein-bound to form
melanoprotein.
Tyrosinase
PART!
Phaeomelanin
Phaeomelanins are yellow and red sulfur-containing pigments found in
the hair of mammals. Unlike eumelanin, phaeomelanin is soluble in dilute
alkali. Phaeomelanins, like eumelanin, are derived from tyrosine via dopaquinone. But it is the interaction of cysteine with dopaquinone at this level which
results in phaeomelanin synthesis. With a 1,6 addition of cysteine to dopaquinone, 13-(5-S-cysteinyl-3,4-dehydroxyphenyl)alanine or 2-S-cysteinyldopa
is formed [47,48]. This is further oxidized to form phaeomelanin [49]. A minor
product of the 1,6 addition may be 2-S-cysteinyldopa [50,51]. Sulfhydryl compounds have a role in in vivo synthesis [52]; in fact, under some experimental
conditions, sulfhydryl compounds may induce pigment cells to produce yellow
pigment [53].
The curious genetic control affecting the common pathway of eumelanin
and phaeomelanin synthesis is reflected in the agouti mouse, which has only
a few subapical phaeomelanosomes, the rest being eumelanogenic. The follicular melanocytes initially produce brown-black eumelanin, temporarily switch
to yellow phaeomelanin production, and soon revert to the original eumelanin
synthesis. Guinea pig studies have shown melanosomes in red or yellow follicles to be spherical whereas those of black follicles are ellipsoidal [54].
Various differences in biochemical behavior have been observed between
eumelanin and phaeomelanin. It has been demonstrated that more sulfhydryl
compounds containing glutathione and cysteine are incorporated into phaeomelanogenic melanocytes and phaeomelanin than into eumelanic melanocytes
and eumelanin. In the presence of adequate reduced glutathione in vitro, melanocytes that in vivo synthesize only eumelanin elaborate phaeomelanin. It
has been suggested that the agouti band in the agouti mouse is derived from
cyclically changing patterns of competition by keratinocytes and melanocytes
for substrate common to hair growth and to melanogenesis. So it was suggested
that cyclic changes in the type of melanin synthesized may involve histochemical changes, not genetic intervention [52]. The failure of Knisely et al. [55] to
confirm these findings with yellow (AY/a) specimens in similar conditions and
in cultures of (A/A) agouti skin may relate to such histochemical factors not
extant in these systems. Although cysteine is an established substrate for phaeomelanogenesis, cysteinyldopa, and phaeomelanin may be produced by eumelanogenic melanocytes [56]. Furthermore, it has become clear that there is
a third melanocyte pigment, namely, trichochrome [57], which like eumelanin
and phaeomelanin has dopaquinone as a critical intermediate. The factors that
select one final pathway over another remain unclear.
Neuromelanin
The trigeminal and dorsal root ganglia, substantia nigra, locus caeruleus,
and the pigmented nuclei of the basal ganglia contain cytoplasmic organelles
containing a brown pigment called "neuromelanin." There appear to be important differences between eumelanin and neuromelanin. Since patients with
oculocutaneous albinism have normal amounts of neuromelanin, it seems unlikely that neuromelanin is formed by the action of tyrosinase. There are other
significant differences between melanin and neuromelanin. The pigment particles of the substantia nigra appear to have a higher electron density than
melanosomes, a size range from 0.5 to 2.5 f.L, a single limiting membrane, and
no longitudinal or cross-striations typical of eumelanin melanosomes [58]. The
presence of labeled tyrosine in the area of pigmented granules in neurons has
persuaded investigators that tyrosine must be present. The enzyme catalyzing
the hydroxylation of tyrosine to dopa is probably tyrosine hydroxylase [29],
and not the copper-requiring oxidase tyrosinase. Since tyrosine hydroxylase
catabolizes only CNS tyrosine, CNS abnormalities should not be expected with
disorders of eumelanin synthesis, and disorders of neuromelanin (such as Parkinson disease) would not be expected to have obligate aberrations of cutaneous
eumelanogenesis.
Melanocyte
Oval
Granular
Melanosome
(round to oval)
Langerhans cell
Indeterminate cell
Lobulated
Lobulated
Clear
Clear
Langerhans or Birbeck
None
(rod-disc)
Langerhans cells are dendritic cells found in the epidermis and once thought
to be related to melanocytes but demonstrated by Breathnach [59] not to be of
neural crest origin. These cells are characterized by a clear cytoplasm, a lobulated nucleus, absence of desmosomes, and presence of specific organelles
called "Birbeck" or "Langerhans" granules. These granules have a disclike form
and may appear under the electron microscope as rod-like bodies with rounded
ends and a central striated line. Some of these granules have a blown-out
boundary membrane at one end along with an enclosed clear zone; these assume
the general shape of a hand mirror or tennis racket. Langerhans cells arise in
the bone marrow from some precursor of the mononuclear phagocyte system
[59a]; but it does appear to be an immunologically significant cell and not just
a macrophage that has migrated from the dermis to the epidermis. Although
Langerhans cells can phagocytize melanin granules, these cells are not typical
macrophages. To dramatize its possible role in the epidermis, like that of the
osteoblast in bone, Prunieras [60] has suggested calling the Langerhans cell an
"epidermoclast. "
Further more recent evidence has illuminated the role of the Langerhans
cell. Langerhans cells have been shown to have a role in allergic contact reactions in which they lie in close apposition to lymphocytes [61]. The cellular
8
PART!
membrane has been shown to have Fc receptor sites for IgG, C3, and IgA antigens
[62,63]. It would appear that Langerhans cells are part of the monocyte-macrophage-histiocyte [64] line and have an important role in the afferent
limb of the immune system [65].
The "a-dendritic" or "indeterminate" cell is even more of a mystery. It
resembles a Langerhans cell without Langerhans granules. The origin and role
of this third type of dendritic cell are unknown. It may be a premelanocyte
with induction potential, an effete melanocyte, a displaced dermal phagocyte,
an undifferentiated cell capable of becoming a Langerhans cell or melanocyte,
or some totally unrelated cell. The work of Mishima and Kawasaki [66] and
Mottaz and Zelickson [67], in which for a time, in vitiligo, melanocytes and
indeterminate cell populations seemed inversely related quantitatively, certainly suggests some direct relationship between the a-dendritic cell and the
melanocyte.
Melanocytes are dendritic cells with a granular cytoplasm, an oval nucleus
with a nucleolus, cell-specific organelles called melanosomes, and no desmosomes (Fig. 4).
FIGURE 4.
epidermis.
ORIGIN OF MELANOCYTES
N!;~L
CR!;ST
M(;LANOBLAS TS
"M!;LANOGONIA"
M~LANO(VH.S
FIGURE 5. Development and migration of melanoblasts. Melanoblasts migrated from the neural
crest in early fetal development and appeared as undifferentiated melanocyte precursors in the
eighth week. Epidermal melanocytes usually first appear in the 11th week.
10
PART!
MISCEllANEOUS
SITES
Mucous mtm brone
Internal ear
Orb ital cavil,
Metenle"
FIGURE 6. The embryonic origin. dispersion. and development of melanocytes in humans. Retinal melanocytes (A); choroidal melanocytes (B). (From: Fitzpatrick TB. Quevedo WC Jr: Albinism.
in The Metabolic Basis of Inherited Disease. 2nd ed. Edited by JB Wyngaarden. DS Fredrickson.
Copyright. 1966. McGraw-Hill Book Company. Used with permission.)
Dermal melanocytes then precede the epidermal ones by about two weeks.
In early fetal development, the density of the skin melanocyte population is
reduced in a cephalocaudal direction corresponding to the anteroposterior wave
of migration observed by Rawles. This gradually disappears with time. The
number of dermal melanocytes decreases with development until only a few
remain after birth (Mongolian spots).
The differentiation of melanoblasts into melanocytes is a function of the
genetic constitution of the melanoblasts and the nature of the environment into
which they migrate. Weiss and Andres [72] injected melanoblasts of young
chick embryo of one breed into the circulation of another breed; they found
differentiation of the melanoblasts to melanocytes in the regions of the host
corresponding to those anticipated in the donor.
In humans, melanocytes are present not only in the skin but also in the
leptomeninges, inner ear, uveal tract, and retinal epithelium. The retinal cells
arise from the optic cup, not from the leptomeninges.
Melanocytes are present in the basal layer of the epidermis and around
hair follicles. These may be identified selectively with the split dopa technique *
in which the melanocytes appear as dark dendritic cells (Fig. 7).
11
12
PART I
13
SKIN COLOR AND
THE MELANIN
PIGMENTARY
SYSTEM
( Y5T{; IN[;
5 -S- CYSWNYlDOPA
FIGURE 8. Diagram summarizing major events in the early development of melanocytes, their
subsequent differentiation, and interaction throughout life. G, Golgi apparatus; E, endoplasmic
reticulum; N, nucleus; M, mitochrondia; PMS, early melanosomes; MS, fully melanized melanosomes; I, II, III, and IV, stages in melanosomal development shown in upper left corner in dendritic
process. (From: Jimbow K et al: Some aspects of melanin biology: 1950-1975. J Invest Dermatol
67:72-89,1976. Copyright, 1976, The William & Wilkins Company. Used with permission.)
FIGURE 7. a: Melanocytes in human epidermis. The epidermis was separated ("split") from the
dermis with trypsin and treated with dopa. The melanocytes are recognizable as dark cells with
dendrites meandering between the very slightly stained keratinocytes of the basal layer (x 500).
b: High-power view of split sheets of human epidermis. The dendritic nature of melanocytes is
well shown (x 1150). (a and b from Fitzpatrick TB et al: The biology of the melanin pigmentary
system, in Dermatology in General Medicine. Edited by TB Fitzpatrick et al. Copyright, 1971,
McGraw-Hill Book Company. Used with permission.)
14
PART I
Melanization of Melanosomes
Melanization is the gradual accumulation on developing melanosomes of
an electron-dense material, melanoprotein. The spherical vesicle gradually becomes elongated, loses its characteristic internal filamentous periodicity, and
becomes electron-opaque. Four stages of melanosome formation have been
characterized [86] (Fig. 9):
Stage I is a spherical membrane-limited vesicle which has a periodicity of
100
tyrosinase.
15
II
III
IV
active, tyrosinase is released and the vesicles break down to form "empty"
carriers within the melanosome. Although these "vesicoglobular bodies" may
be enzyme carriers in humans, their true role remains unknown. Phaeomelanosomes differ from eumelanosomes. They are spherical and contain coarse
granular material inside [94a].
16
PART!
Transfer of Melanosomes
Melanosomes synthesized by melanocytes are transferred to keratinocytes,
where they are packaged as singles (nonaggregated) or as groups (aggregated)
with membrane-limited vesicles. Melanosomes in the keratinocytes are present
FIGURE 10. Melanosome complexes from a Caucasoid, Mongoloid, and Negroid. a: Melanosome
complexes
from
a
malpighian cell of a Caucasoid.
The complexes are surrounded
by a membrane and contain small
particles in addition to Stage IV
melanosomes. b: Melanosome
complexes from a malpighian cell
of a Mongoloid (Chinese). There
is less ground substance between
the melanosomes in this specimen than in (a). c: Melanosomes
in the malpighian cell of a Negroid. Almost all melanosomes
are individually dispersed and are
much larger than those of a Caucasoid or Mongoloid (x 45,750).
(From: Szabo G et al: Racial differences in the fate of melanosomes in human epidermis.
Nature 222:1081-1082, 1969.
Copyright, 1969, MacMillan
Journals Ltd. Used with permission.)
17
SKIN COLOR AND
THE MELANIN
PIGMENTARY
SYSTEM
18
PART I
[17], but all normal cutaneous melanocytes have the capacity to transfer melanosomes.
The mechanism of this melanosome transfer, termed "cytocrine activity"
by Masson [108], is not clearly defined. Bubbling of the melanocyte cell membrane in the region of a melanosome does suggest the beginning of melanosome
transfer [1151. Based on electron microscopy studies [671 and cell culture experiments [60,116-118]' three mechanisms have been suggested. These mechanisms are not mutually exclusive.
The first possibility is that melanosomes are secreted by the dendrites of
the melanocytes into the extracellular space and subsequently the extracytoplasmic melanosome particles are picked up by the keratinocytes.
An alternative hypothesis is termed "cytophagocytosis," by which the den-
FIGURE 12. a: Epidermal melanin unit in Caucasians or Mongoloids. Melanosomes are aggregated
within the keratinocytes. b: Epidermal melanin unit in Negroes and Australian aborigines. Melano somes are packaged into "singles."
drite of the melanocyte approaches and contacts the cell membrane of a keratinocyte. The receptor keratinocyte pinches off the tip of the melanocytic
dendrite which contains the melanosome and encloses this within a phagocytic
vacuole. The observation of phagocytic vacuoles containing melanosomes surrounded by a double membrane provides support for this hypothesis [119], yet
most keratinocyte vacuoles have a single not a double membrane. It has been
suggested that the double membrane may be an artifact.
The third hypothesis also involves phagocytic action of the keratinocyte
in pinching off the tip of the melanocytic dendrite. However, this pinched-off
dendrite then disperses the melanosome within the keratinocyte. Packaging
may be a function of melanosome size. Studies of animal experiments using
melanosomes of varied sizes have demonstrated cytophagocytosis in which
large melanosomes are packaged as singles and smaller ones clustered [120].
None of these hypotheses explains the problem of packaging as singles or
aggregates within keratinocytes. By the first postulate, in which melanosomes
are extracytoplasmic particles, the melanosomes are seen as foreign bodies by
the keratinocytes and are phagocytized and packaged according to size. Since
"singles" are usually large melanosomes, whereas aggregates are composed of
small particles, it would seem that packaging of melanosomes within keratinocytes is a size-dependent phenomenon [109,121]. Intracutaneous injection of
various sizes of melanosomes into albino guinea pigs and subsequent phagocytosis by keratinocytes have shown that smaller melanosomes do indeed aggregate, whereas the larger ones remain "single" [120]. However, there is no
agreement as to the critical size above which melanosomes become single
within the keratinocytes, but estimates range from 0.4 to 1 fLm [122]. This does
not explain why then extracellular melanosomes are rarely observed or what
happens to the double membrane.
Degradation of Melanosomes
Melanosomes within keratinocytes are subject to degradation by lysosomes.
The membrane-limited vacuoles which contain aggregated melanosomes have
acid phosphatase activity [123] as well as fine grains of what seem to be degraded melanin and other melanosome components. At the level of the horny
layer, the limiting membrane is lost and the melanosomes disperse individually. The larger ellipsoidal melanosomes appear to resist degradation and,
particularly in deeply pigmented peoples, intact melanosomes appear to be
present in the stratum corneum. Clearly, then, some melanosomes are not
degraded within the epidermis [17].
Autophagocytosis or degradation of melanosomes within the melanocyte
may also occur. This is found in skin hyperpigmented from exposure to ultraviolet radiation and in hyperpigmented macules derived from malignant melanocytes [124-126]. Lysosomal hydrolases (e.g., acid phosphatase and aryl
sulfatase) are also found in melanocytes [127]. Autophagocytosis can also result
in hypomelanosis in animals. The tyrosinase-positive feathers of White Leghorn
chickens are hypomelanotic because the melanocytes are fewer and shorterlived than in normally pigmented chickens. Recent ultrastructural studies [128]
19
20
PART I
21
~
1220!10
FOREHEAO
-roiO'!2IO
140cr.1O
1 400!220!!!..~
~-'~1
Human melanocyte
density in average number of mel anocytes per square millimeter. S.
(From: Fitzpatrick TB, Szabo G: The
melanocyte: cytology and cytochemistry. J Invest Dermatol
32:197-209, 1959. Copyright, 1959,
The Williams & Wilkins Company.
Used with permission.)
FIGURE 13.
~ _ /I \
rsao:MOLV
ZtOO! tOO
12 101 120)
1110:40 UPP(A
~
~IIOOt.1O
.....-1120 ..-0
+--1000:1
~_
~ 11 30!1O ~
.....--
I~UO ! 110
22
PART!
The investigation of the physiology of normal pigment darkening is hampered by an inability to identify melanoblasts or by inactive melanocytes lacking characteristic organelles.
be available for melanin synthesis in such patients. Six chromosomes are also
involved, although in mice only one of two is metabolically active [145,146];
the one that is "switched off" occurs as a matter of chance. The mottled (mo),
dappled (Modp), and brindled (Mobr) are found on the X chromosome and are
lethal in the homozygous female or the male hemizygote. The role of the mottled
gene in melanogenesis is unknown but may influence the availability of copper
in the pigmentary pathway [147]. The molecular level of the genetic influence
needs scrutiny. No doubt DNA nucleotide sequences dictate primary provocative attributes of melanosomes, but these may be determined by regulation at
the level of gene transfer or translation or both [129,148]. The number of melanosomes synthesized and the shape, size, melanization, and internal structure
of individual melanosomes may be dictated by interplay of the latter two mechanisms. Congenital or inherited defects could result from abnormalities of the
primary structures of elementary melanosomic protein or from any aberration
in the presentation of melanosomes for assembly. The observation of macromelanosomes in various pigmentary disorders provides support for this theory
[8,149].
Melanosome size clearly is genetically determined, but other factors are
important; ultraviolet radiation, for example, has an effect on the size of melanosomes in the epidermal melanocytes [114,150]. The genetic milieu is the
stage on which these and environmental influences interact to result in macroscopic pigmentary changes.
23
24
PART!
Tissue Factors
Feedback Control of Melanocyte Function
It has become increasingly evident that there are cues arising from the
dermis throughout the complex functional levels of the epidermal melanin unit
and that these cues have an important influence on the biosynthesis of melanosomes. The arrival of melanosomes from melanocytes may alter the metabolic
activity of the keratinocytes and, by a feedback influence, affects the melanocyte
of that epidermal melanin unit. Also, it is possible that melanosome degradation
products may pass downward through or by the keratinocytes to exert some
sort of regulatory influence on melanocyte function [152,153].
Hormonal Factors
Various hormones are known to influence melanin pigmentation in human
skin and in other mammals [166]. MSH induces dramatic changes in the melanosome distribution of the melanophores of fish, amphibians, and reptiles.
In mammalian melanoma cells, MSH increases cyclic AMP levels and stimulates melanogenesis within normal melanocytes [167,168]. Considerable evidence suggests that cyclic AMP is the "second messenger" in MSH regulation
of melanosome movement in the melanophores of fish, amphibians, and reptiles. Cyclic AMP may stimulate tyrosinase synthesis as a primary step in
increased melanogenesis. In humans, administration of a-MSH results in a
marked diffuse hyperpigmentation of the skin; the melanocytes appear highly
dendritic and contain an increased number of melanosomes as do the keratinocytes. This suggests that MSH causes translocation of melanosomes within
melanocytes, and thereby enhances melanocyte "dendricity," transfer to keratinocytes, and melanogenic activity in mammals [165,168]. Increased tyrosinase activity has been associated with the darkening effect of MSH on the skin
or hair of humans, guinea pigs, hamsters, and mice [165]; Lerner [165] suggested
this results not simply from activation of tyrosine already present in the melanocytes, but rather from increased tyrosinase synthesis. More recent evidence
suggests that MSH-activated tyrosinase activity results from conversion of inactive tyrosinase to active tyrosinase through inactivation of an enzyme inhibitor [164]. Ultraviolet radiation-induced photoconversion of 7-dehydrocholesterol to cholecalciferol increases melanoma cell tyrosinase activity with resultant
increased melanogenesis [169].
Pituitary release of MSH is regulated by the hypothalamus, but the mechanism of MSH regulation and of the hypothalamic-pituitary apparatus is unclear. Both MSH-releasing factors and an inhibitor of MSH release [170,171]
have been described in mammalian hypothalamus.
ACTH, a-MSH, and [3-MSH are powerful stimulants of human melanogenesis and also cause dispersion of melanosomes in frog melanocytes in vitro
[129,172,173]. The hyperpigmentation seen in Addison disease may be due to
elevated MSH levels or elevated ACTH levels [166]. That male eunuchs have
pale skin and tan poorly suggests a yet undefined action of androgens on
melanin pigmentation. In vivo studies have shown that testosterone increases
cutaneous melanogenesis [174] but seems to have no consistent effect in humans [137] or animals [175].
In females, gonadal hormones, especially estrogen, are strong stimulants
of melanogenesis. Area-specific melanocytes are very sensitive to estrogens.
Abnormal hyperpigmentation in the pregnant human female occurs around the
nipples, and to a lesser extent on the face and on the midline anterior abdominal
wall and the genitalia [137]. Abdominal wall skin biopsies have shown the
25
26
PART!
Ultraviolet Radiation
"Tanning" is the pigment darkening resulting from increased melanin pigmentation of, or rearrangement of, melanin granules in human skin that follows
exposure to natural sunlight or to artificial ultraviolet radiation sources. The
two phases of this tanning phenomenon are immediate pigment darkening (IPD)
and delayed tanning (DT).
IPD, which may be induced both by UV A and to a lesser degree by visible
light and UVB, is an immediate process occurring during the exposure of the
skin to light. IPD is dose related, may occur within minutes of exposure, peaks
in one to two hours, may last longer than two hours, and is observed then to
decrease between two and three hours after the exposure. It may not occur in
normally unexposed Type I skin. IPD is probably an oxidation reaction involving generation of unstable semiquinone-like free radicals in melanin [206].
27
SKIN COLOR AND
THE MELANIN
PIGMENTARY
SYSTEM
28
PART I
While no recognizable changes in the ultrastructure of the melanogenic organelles have yet been reported, IPD is known to be characterized by changes in
the distribution pattern of melanosome filaments and microtubules [207].
DT is optimally stimulated by exposure to intermediate-wavelength ultraviolet radiation (UVB) and, to a lesser extent, to long-wave ultraviolet radiation
(UVA) and to visible light [208]. DT involves increased numbers of dopapositive melanocytes, synthesis of new melanosomes, an augmented functional
state of melanocytes (increased perikaryon size, increased dendrite arborization), and increased melanin content in the keratinocytes. Thus, at the ultrastructural level, there is an increase in the formation, melanization, and transfer
of melanosomes and a marked change in the contour of the nucleus and in the
size and the chromatin pattern of the nucleus and of the nucleolus [207].
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SYSTEM
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n,
35
SKIN COLOR AND
THE MELANIN
PIGMENTARY
SYSTEM
II
Approach to the Problem of
Leukoderma
"The skin calls for faculty of close observation and attention to detail."
Louis A. Duhring, Valedictory Address
University of Pennsylvania School of Medicine, 1894
The study of diminished skin color requires a special vocabulary. Various terms
have been used to refer to decreased melanin content in the skin. These terms
are intended to be purely descriptive and not to imply anyone particular
diagnosis or disease entity.
Leukoderma is a generic term which connotes a mild to marked decrease
in normal skin color. This decrease may be secondary to a disturbance of normal
melanogenesis, or, as in the case of nevus anemicus, to some other factor. Most
leukodermas are, in fact, defects of melanogenesis.
Hypomelanosis refers to a leukoderma characterized by reduced or absent
melanin content. The terms "pigmentary dilution" and "hypopigmentation"
are synonymous with hypomelanosis. Amelanosis refers to hypomelanosis in
which melanin pigmentation is totally absent.
Depigmentation implies a loss of preexisting melanin pigmentation. It is
incorrect to apply the term "depigmentation" to cases of congenital hypomelanosis. Leukomelanoderma refers to melanin disturbances characterized by
both hyper- and hypomelanosis in the same general area of skin.
Poliosis is a term applied to a localized hypomelanosis of hair, whereas
canities implies a more generalized pigmentary dilution of hair. Graying of
hair is a localized or generalized hypomelanosis in which there is an admixture
of normally pigmented and depigmented hair. Generalized graying of hair is a
form of canities. Whitening of hair is the endpoint of canities.
Vitiligo implies a specific leukoderma, and the term is correctly applied
only to that disorder.
Diagnosis of a leukoderma requires both a complete history and physical
examination of the skin. A hand lens, Wood's light, and biopsy equipment are
the tools which should be at hand.
A classification of hypomelanosis in humans is presented in Table 1. Hereditary leukodermas are distinguished from those of metabolic, endocrine,
37
38
PART II
Metabolic
Copper deficiency (d,h)
Iron deficiency (h)b
Endocrine
Hypopituitarism (d)
Hyperthyroidism (h)
Cushing syndrome (c)b
Nutritional
Chronic protein deficiency or loss
Kwashiorkor (c,h)
Nephrosis (h)
Ulcerative colitis (h)
Malabsorption syndrome (h)
Vitamin B'2 deficiency (h)
Chemical and pharmacologic agents
Hydroquinone (c)
Monobenzylether of hydroquinone and
other hydroquinone derivatives (c)
Paratertiary butyl phenol and paratertiary
amylphenol (c)
Paratertiary butyicatechol (c)
Alkyl phenols (c)
Arsenical intoxication (c)
Topical steroids (c)
DNCB (c)
5-Fluorouracil-methenamine mandelate (c)
Guanonitrofurazone (c,h)
Hydrogen peroxide (h)
Mephenesin carbamate (h)
Triparanol (h)
Fluorobutyrophenone (h)
Chloroquinone and hydroxychloroquine (h)
Physical agents
Burns: thermal, ultraviolet (c,h)
Ionizing radiation (c,h)
Trauma (c,h)
Infection
Treponematoses
Pinta (c)
Endemic nonvenereal syphilis (c)
Yaws (c)
Secondary syphilis (c)
Leprosy (c)
Tinea versicolor (c)
Onchocerciasis (c)
Post-kala-azar dermatoses (c)
Herpes zoster (h)
(Continued)
TABLE 1. (continued)
Inflammatory
Pityriasis alba (c)
Psoriasis (c)
Postinflammatory hypomelanosis, atopic
dermatitis, discoid lupus
erythematosus, chronic guttate
parapsoriasis (c)
Neoplastic
Leukoderma acquisitum centrifugum (c,h)
Halo nevus
Other benign pigmented tumors
Malignant melanoma (primary or
metastases)
Abbreviations: c, circumscribed hypomelanosis of the skin; d, diffuse hypomelanosis of the skin; e, eye involvement; h, hair involvement.
b Questionable (occasional reports).
Abbreviations: c, pigment decrease or loss is circumscribed (poliosis), d; pigment decrease or loss is diffuse.
Occasional reports.
39
APPROACH TO
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40
PART II
Genetic
Hereditary premature canities
"Bird-headed" dwarfism
Premature aging syndrome
Progeria
Werner syndrome
Rothmund-Thomson syndrome
Waardenburg syndrome
Book syndrome
Homocystinuria
Ataxia-telangiectasia
Myotonia dystrophica
Fisch syndrome
Prolidase deficiency
Endocrine
Hyperthyroidism
Nutritional
Vitamin B12 deficiency
Miscellaneous
Rapid or sudden whitening of hair
Cardiovascular disease (questionable)
The history of the time of onset and course of a hypo melanotic disorder
is important. A circumscribed hypomelanosis present at birth suggests nevus
depigmentosus, tuberous sclerosis, piebaldism, Waardenburg syndrome, Ziprkowski-Margolis syndrome, or some other rare hereditary hypomelanosis.
Vitiligo, the most common hypomelanosis in nonendemic leprosy areas, is
usually acquired but may in fact, very rarely, be present at birth. History can
be misleading because a congenital hypomelanosis may not be observed for
months or longer either because it simply is overlooked or because, in the
absence of sun-induced melanogenesis of normal skin, the lesion is inapparent.
Thus, the history of a lesion appearing at six months, for example, may mislead
one to conclude a congenital hypomelanosis is acquired. In temperate latitudes,
most hypomelanoses become more apparent in the late spring or summer, after
the patient has had a chance to tan his normal skin. Only tinea versicolor seems
to have a seasonal onset.
Not all congenital hypopigmentation represents hypomelanosis; nevus
anemicus is a vascular lesion and not a pigmentary lesion.
PHYSICAL EXAMINATION
Physical examination of the patient is the most useful tool for the clinician
in the diagnosis of leukoderma. The patient should be completely undressed
and fully examined. Every examination should include use of the Wood's light
(Table 5).
Extent
The extent of the leukoderma must first be noted. In universal leukoderma,
the entire cutaneous surface is affected. A circumscribed leukoderma with
identifiable borders between hypopigmented and normal skin can be either
generalized or localized.
Universally decreased pigmentation of the skin and hair suggests one of
only a few diseases in which the degree of hypomelanosis is moderate or marked
(Table 6). In some of these disorders (see Table 7), the degree of pigment dilution
is so subtle as to be apparent only when the skin or hair of the affected patient
is compared to that of an unaffected member of the same family or another
individual of the same ethnic group.
A circumscribed localized hypomelanosis suggests one of the conditions
listed in Table 8. The list of circumscribed generalized hypomelanoses is so
long that one needs to look for other clinical clues to the diagnosis. Symmetrical
distribution suggests vitiligo, piebaldism, Waardenburg syndrome, often chemically induced leukoderma, and occasionally leprosy. Incontinentia pigmenti
achromians is often symmetrical, whereas nevus depigmentosus is usually not.
41
APPROACH TO
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42
PART II
Autosomal dominant
Vitiligo
Dominant oculocutaneous albinism
Piebaldism
Waardenburg syndrome
Tuberous sclerosis
Incontinentia pigmenti achromians
Dyschromatosis
Pigmentary demarcation lines
Darier-White disease
Neurofibromatosis
Hypopigmentation with punctate keratosis of palms and soles
Tietz syndrome
Fisch syndrome
Book syndrome
Dystrophia myotonia
Hereditary premature canities
Seckel syndrome
Autosomal recessive
Tyrosinase-negative oculocutaneous albinism
Tyrosinase-positive oculocutaneous albinism
Yellow mutant
Hermansky-Pudlak syndrome
Cross-McKusick-Breen syndrome
CMdiak-Higashi syndrome
Werner syndrome
Progeria
Phenylketonuria
Homocystinuria
Histidinemia
Rozycki syndrome
Woolf syndrome
Xeroderma pigmentosum
Rothmund-Thomson syndrome
Sex-linked
Menkes syndrome
Incontinentia pigmenti
Ziprkowski-Margolis syndrome
Ocular albinism
Distribution
The distribution of hypomelanotic macules is important because several
disorders have characteristic cutaneous areas of involvement. A central white
forelock with associated hypomelanotic macules and the presence of a leukoderma of the ventral midline and the distal extremities suggest piebaldism
or the Waardenburg syndrome. The lesions of tuberous sclerosis are most common on the lower back, in contrast to tinea versicolor which most commonly
involves the upper anterior and posterior chest. Periorificial involvement and
43
APPROACH TO
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44
PART II
Phenylketonuria
Homocystinuria
Histidinemia
Menkes syndrome
Nutritional copper deficiency
Lance-ovate or "ash-leaf"
Polygonal or "thumbprint"
15)
Guttate
Bizarre or disorganized
TABLE 8. Conditions in
Which Circumscribed Areas of
Leukoderma are Usually
Localized to One Area of the
Skin
Nevus depigmentosus
Segmental or focal vitiligo
Tuberous sclerosis (segmental)
Pigmentary demarcation lines
Nevus anemicus
45
APPROACH TO
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46
PART II
nevus (resolved), idiopathic guttate hypomelanosis, tinea versicolor, chemically induced depigmentation, and occasionally vitiligo. Small lesions may
also be seen in pityriasis lichenoides chronica, vagabond's disease, and chronic
actinic skin damage without true poikiloderma (Fig. 16).
Number of Lesions
The number of lesions may vary from one to 100 or more. The presence
of only a few lesions suggests tuberous sclerosis, nevus depigmentosus, nevus
anemicus, and vitiligo. Idiopathic guttate hypomelanosis, vitiligo, and tinea
versicolor may have a few or many lesions.
Degree of Hypomelanosis
Observation of the degree of hypomelanosis is a very useful clinical parameter (Fig. 17). Hypomelanosis may be graded on the following four-step
scale:
Type
Type
Type
Type
0 hypomelanosis:
1 hypomelanosis:
normal pigmentation
barely perceptible hypomelanosis
2 hypomelanosis: definite but not complete amelanosis
3 hypomelanosis: totally absent pigmentation or amelanosis
47
APPROACH TO
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48
PART II
the skin, or poliosis may be the only cutaneous abnormality, as in the Waardenburg syndrome. The same can be said of canities.
Alopecia in the white macules is common in leprosy.
49
APPROACH TO
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LEUKODERMA
FIGURE 18. Nonpigmentary surface epidermal features of the hypopigmented macules. a: Pityriasis alba with powdery scale; b: Pityriasis alba with scaling; c: Postinflammatory hypopigmentosis;
d: Tinea versicolor with fine scaling, occasionally slightly raised surfaces.
and vitiligo with raised borders report pruritus or a burning sensation. Anesthesia or hypesthesia of the hypopigmented lesions is diagnostic of leprosy.
Nevus anemicus, which is not a pigmentary anomaly, can be distinguished
from hypomelanosis because, in contrast to normal skin, vigorous stroking and
application of heat or cold fail to produce erythema.
Certain postinflammatory hypomelanoses may have a blue-gray cast because of melanin incontinence (dermal melanosis).
50
PART II
51
APPROACH TO
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LEUKODERMA
5Z
PART II
Pigmentary abnormality
Disorder
Alezzandrini syndrome
Ataxia-telangiectasia
Chediak-Higashi syndrome
Cross-McKusick-Breen
syndrome
Histidinemia
Homocystinuria
Incontinentia pigmenti
achromians and
incontinentia pigmenti
Leprosy
Menkes syndrome
Phenylketonuria
Rozycki syndrome
Tietz syndrome
Tuberous sclerosis
Vogt-Koyanagi-Harada
syndrome
Waardenburg syndrome
Woolf syndrome
Ziprkowski-Margolis
syndrome
Hypomelanotic macules,
poliosis
White patches
Dilution of skin, hair, and iris
pigmentation
Dilution of skin, hair, and iris
pigmentation
Dilution of skin, hair, and iris
pigmentation
Dilution of hair and iris and
possibly skin pigmentation
Whorled hypomelanotic
macules
Hypopigmented macules
Dilution of skin and hair
Dilution of skin, hair, and iris
pigmentation
Hypopigmented macules
Dilution of skin and hair
pigmentation
Hypomelanotic macules,
poliosis
Hypomelanotic macules,
poliosis
White forelock, premature
graying of hair,
hypomelanotic macules
Hypopigmented macules and
hair depigmentation
Hyper- and hypomelanotic
macules
Neurologic manifestation
Deafness
Choreoathetosis, ataxia,
mental retardation
Signs of cerebral disease
Mental retardation, athetosis,
seizures, deafness
Mental retardation
Mental retardation, seizures
Mental retardation, seizures
Sensory disturbances
Mental retardation, seizures,
pyramidal signs
Mental retardation, seizures
Deafness
Deafness
Mental retardation, seizures
Signs of lymphocytic
meningitis
Deafness
Deafness
Deafness
Vitiligo
Vitiligo
Premature graying of hair
Paratertiary butylcatechol-induced
depigmentation
Vitiligo
Generalized hypopigmentation most
evident in the genital area
Hypopigmentation of genital skin
(controversial)
Vitiligo
Vitiligo
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APPROACH TO
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54
PART II
PATHOGENESIS
Leukoderma is a generic term for abnormally white skin. It implies no
specific etiology or mechanism, just as the term "anemia" does not explain low
hemoglobin. While leukoderma implies decreased or absent pigmentation, the
appearance of pale skin may also result from profound anemia, nevus anemicus,
or from vasoconstriction as in the Raynaud phenomenon.
The problem of leukoderma resulting from decreased melanin in the skin
must be viewed as a defect at some level of melanogenesis.
There are 11 possible mechanisms to explain hypomelanosis or leukoderma
in humans (see Fig. 19, Table 12).
Mechanism I: No melanocytes are present because of failure of melanoblasts to migrate from the neural crest to the skin or because of failure of
melanoblast or melanocyte survival.
Mechanism II: Melanoblasts fail to differentiate into melanocytes. The leukoderma observed in Waardenburg syndrome, piebaldism, Woolf syndrome,
and Ziprkowski-Margolis syndrome is characterized by an absence of melanocytes. Either Mechanism I or II may explain this observation.
Melanin Removal
w ith Loss of
Stratum Corneum
T
1I
10
Migration of
Melanoblasts
Melanosome
Degradation
t
1
Mitotic Division
of Melanocytes
1
MELAHOCYTE
Melanosome
Transfer
IMelanosome I
: Melanization ,
7
Melanoaome
Formation
6
Tyrosinase
Transport
5
Melanosome
Matrix
Synthesis
4
TyroslnMe
SynthNIs
Mechanism II
Mechanism III
Mechanism IV
Mechanism V
Mechanism VI
Mechanism VII
Mechanism VIII
Mechanism IX
Mechanism X
Mechanism XI
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APPROACH TO
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56
PART II
REFERENCE
1. Jimbow K et al: Ultrastructural investigation of autophagocytosis of melanosomes and pro-
III
Hypomelanotic Disorders
1
Genetic and Congenital Disorders
One purpose of any classification is to categorize, organize, and increase understanding of the disorders classified. For hereditary leukodermas, the presence or absence of certain common features permits a useful subclassification
(see Table 13, page 60). Those disorders with features of oculocutaneous albinism (3 + hypomelanosis) must be distinguished from those having a relative
(1 or 2 + hypomelanosis) generalized pigmentary dilution. In the latter, the
hypomelanosis may be apparent only in comparison to family members or
individuals of the same ethnic background, and these are readily distinguished
from entities usually featuring circumscribed hypomelanosis. The fourth category involves hereditary disorders in which pigmentation of the hair but not
of the skin is affected.
59
60
CHAPTER 1
eyes. The outstanding characteristics are the "milk-white" skin and hair color,
photophobia, and nystagmus.
Historical Background
The term "albino" is believed to have derived from the Latin adjective
albus, meaning "white," and was first applied by Balthazar Tellez to certain
"white" Negroes observed on the west coast of Africa [6]. The striking contrast
of albino skin with the darkly pigmented normal skin of Indians and Negroes
sets them apart, and many myths have featured these strange "moon-ey'd"
people. Several albino heroes are prominent in the mythology of the Cuna
Indians living on the San BIas Islands located off the coast of Panama.
Sir Archibald Garrod [7] considered albinism to be an inborn error of
metabolism. In 1908 he suggested three possible mechanisms: (a) the cells that
usually contain pigment fail to take up melanins formed elsewhere; (b) the
albino has an unusual power of destroying these pigments; or (c) the albino
fails to form melanin pigment. Garrod concluded:
Evidence available indicates that the pigment is formed in situ. probably by the action
of intracellular enzymes .... Only certain specialized cells appear to have the power
of forming melanin .... Taking all the known facts into consideration, the theory that
what the albino lacks is the power of forming melanin which is normally possessed
by certain specialized cells is that which has most in its favour and is probably the
true one. If so, an intracellular enzyme is probably wanting in the subject of this
anomaly.
Through the ages albinos have been social curiosities, and even today
albinos may be exploited for their "carnival" value.
Definition
The metabolic defect which presents as albinism may involve the melanocytes at a specific site (ocular albinism) or the entire melanocyte system (oculocutaneous albinism). The term albinism should be restricted to congenital
heritable hypomelanoses limited to the eye (ocular albinism) or to the eye and
integument (oculocutaneous albinism). The basic defect is expressed as a partial
or total reduction of melanin deposition in the melanosomes.
Classification
The six types of oculocutaneous albinism (OCA) include tyrosinase-negative OCA, tyrosinase-positive OCA, yellow-mutant OCA, Hermansky-Pudlak
syndrome (HPS), Cross-McKusick-Breen syndrome (CMBS), and CMdiak-Higashi syndrome (CHS). This group of autosomal recessive disorders is
characterized by congenital absence or reduction in melanin pigment of the
skin, hair, and eyes, nystagmus, photophobia, and decreased visual acuity [8,9].
61
GENETIC AND
CONGENITAL
DISORDERS
62
CHAPTER 1
X-linked
ocular albinism
X-linked
Forsius-Eriksson
A-R ocular
albinism
Normal to slight
lightening
Normal
Present
Normal
Normal
Normal
Present
Normal
Present
No
No
No
Normal range
Males, cartwheel;
females,
diaphanous
Present, males
Males, 0; females,
mosaic fundus
++to++++
+ + to + + +
Moderate to severe
decrease; 20/50
to 20/400
Unknown
Unknown
Normal Stage IV
Normal range
Females, normal;
males,
diaphanous
Present, males
Males, 0
Normal range
Cartwheel to normal
Pigmentation
X-linked. Severe
affecting males;
in carrier
females, mosaic
retina
++to++++
+ + to + + + +
Moderate
Unknown
Unknown
Unknown; probably
normal
Unknown; probably
normal
X-linked. Males
protanopia;
females, no
mosaic retina
Present, males
Males and females,
o to +
+ + + to + + + +
++to+++
Moderate to severe
decrease; 20/60 to
20/400+
Unknown
Unknown
Normal Stage IV
Pigmentation
Autosomal
recessive. Males
and females
equally involved
Source: Quevedo WC Jr et al: Albinism, in The Metabolic Basis of Inherited Disease, 4th ed. Edited by JB
Stanbury et al. New York, McGraw-Hill, 1976. Used with permission.
63
GENETIC AND
CONGENITAL
DISORDERS
FIGURE 20. These two black albino parents have a normally pigmented daughter. Biologic examination showed that the father had ty-neg oculocutaneous albinism while the mother had typos oculocutaneous albinism. This indicates that genes at separate loci are involved in the production of the two forms of oculocutaneous albinism. These genes appear to be completely complementary in the double heterozygote. (From Witkop CJ Jr: Albinism, in Advances in Human
Genetics. Edited by H Harris, K Hirschhorn. Copyright, 1971, Plenum Press. Used with permission.)
General Incidence
The general incidence of all types of albinism is estimated to be 1:20,000
[6]. A frequency of 1:10,000 has been reported among the Irish [34,35]. The
incidence, of course, is much higher among the partially sighted. Albinism
64
CHAPTER 1
Characteristic
Hair color
Skin color
Pink to red
Absent
++++
Gray to blue
No visible pigment
Red reflex
Present
Fundal pigment
Nystagmus
Photophobia
Visual acuity
0
++++
++++
Most legally blind;
constant or worse
with age. 20/200 to
20/400+
Normal
Normal
Stage I and II only
Source: Quevedo
No pigmentation
we Jr et al: Albinism,
White-yellow-red;
darkens with age
Pink-white to cream
May be present and
numerous
+++
Transillumination of
iris
Ty-pos
Ym
White at birth; yellowred by 6 months
White at birth; cream.
slight tan on exposed
skin
Present
Unknown
Cartwheel effect in
adults
o to
o to
+ in adults
++to+++
+ + to + + +
Children. severe defect;
adults. same or
beUer. 20/90 to 20/
400
Low to normal
Normal
To early Stage III,
polyphagosomes
Pigmentation
3HOH test suggests
heterogeneity in typos albinos
Blue in infancy;
darkens with age
Marked retinal
hypopigmentation
+ + in adults
+ to +++
+ to ++
Same as ty-neg; may
improve with age.
20/90 to 20/400
Normal
Unknown
To Stage III
polyphagosomes
None to questionable
increase
Hair bulb test
increased red or
yellow with tyrosinecysteine incubation
in The Metabolic Basis of Inherited Disease, 4th ed. Edited by JB Stanbury et al.
CHS
CMBS
Dominant albinoidism
White-red-dark redbrown
Cream-gray to light
normal
Pink to pink-white
Pink to pink-white
Present
Present
Present
Unknown
+++
++
Unknown
Unknown
Blue-gray to brown;
age and race
dependent
None to cartwheel
effect
Gray-blue
Blue
Cartwheel to normal
Unknown; cataracts
Punctate pigmentation
Present in light
Caucasians; not in
dark races
o to + + + in adults
+to+++
+to++++
Moderate decrease to
normal
Unknown; cataracts
Present
+to+++
++
++
Normal to moderate
decrease
Unknown; cataracts
+++to++++
Unknown
Blind
Punctate pigmentation
No
No
Normal to mild. 20/30 to
Normal
Unknown
To Stage III
polyphagosomes
Pigmentation
Normal
Unknown
Giant to normal Stage
IV
Pigmentation
Normal
Unknown
Scanty; Stage III;
some Stage IV
Pigmentation
Susceptibility to
infection; giant
lysosomal-like
granules;
lymphoreticular-like
malignancy
Oligophrenia;
microphthalmia;
gingival
fibromatosis;
athetosis
o to
o to
20/40
Unknown
Unknown
Probably
Pigmentation
65
GENETIC AND
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DISORDERS
66
CHAPTER 1
Albinism frequency
Population
Ty-neg
Ty-pos
Combined
Caucasian
Negro
Total U.S.
1:39,999
1:28,000
1:37,000
1:40,000
1:15,000
1:33,000
1:20,000
1:10,000
1:18,000
Corrected for 88% Caucasian and 12% black, disregarding other racial
components.
b Source: Quevedo WC Jr et al: Albinism, in The Metabolic Basis of
Inherited Disease, 4th ed. Edited by JB Stanbury et al. New York,
McGraw-Hill, 1976. Used with permission.
a
Clinical Characteristics
Regardless of racial background, ty-neg albinos have similar phenotypic
characteristics which include snow-white hair, pink-white skin, and various
eye findings. Instead of the usual brown pigmented nevi on the skin, accumulations of nevus cells appear as small reddish or purplish-red cutaneous
spots (Fig. 21). That the tips of hairs may turn yellow after prolonged sunlight
exposure has been attributed to a change in the keratin configuration. The
ophthalmologic features include gray to blue-gray irides with tangential illumination, a prominent red reflex as a result of a completely unmelanized fundus
which has a "pink eye" appearance, very diaphanous irides with no cartwheel
effect on transillumination, severe nystagmus, photophobia (Fig. 22), and markedly decreased visual acuity [15,44]. Of the ty-neg albinos examined to date,
about 90% have had moderate to moderately severe strabismus, 80% an esotropia, and 20% an exotropia. Both the nystagmus and the strabismus are more
apparent when the patient is exposed to bright sunlight. In most ty-neg albinos,
the visual acuity is 20/200 or worse and remains stable or deteriorates with age
[15].
67
GENETIC AND
CONGENITAL
DISORDERS
FIGURE 21. In albinos, accumulations of nevus cells appear as small reddish or purplish-red
spots on the skin.
68
CHAPTER 1
decreased melanosome
melanization
Biochemical Abnormalities
In ty-neg albinos, serum levels of L-tyrosine, copper, and J3-melanocytestimulating hormone (J3-MSH) are within normal limits. There is no evidence
of a circulating inhibitor of pigment formation [9,14,47] . If hair bulbs from
normal red-haired individuals and from ty-pos albinos are incubated in ty-neg
albino serum, pigment forms readily.
The ty-neg mutation appears to involve the tyrosinase locus so that no
active tyrosinase is synthesized; the defect may involve the operator portion
of the genetic control mechanism [9,21].
Pathophysiology
Witkop and his associates concluded that ty-neg oculocutaneous albinism
results from a tyrosinase defect [9,13,21]. Depilated hair bulb melanocytes
incubated in a buffered solution of tyrosine do not deposit melanin. That there
is no melanin deposition in Stage I or Stage II melanosomes supports an absence
of tyrosinase activity, although the precise nature of the defect is unknown.
69
GENETIC AND
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DISORDERS
70
CHAPTER 1
Ty-pos is the second most common type of albinism in the United States
and is much more common among blacks than among Caucasians (1 :15,000 vs.
1:40,000) [9]. Isolated populations have a particularly high incidence of ty-pos
albinism; all involved American Indians and Chinese tested by Witkop [10]
have been ty-pos.
Clinical Characteristics
The major clinical difference between ty-pos and ty-neg albinism is that
in the former some melanin pigment is formed and is clinically detectable in
skin, hair, and eyes. Since the onset of visible pigment formation is delayed,
ty-pos infants, regardless of their racial background, may phenotypically resemble and be identical with ty-neg albino infants. As the ty-pos albino ages,
however, he accumulates small amounts of pigment, the intensity of which is
a function of the pigmentary (racial) background of the patient (Figs. 24, 25).
Irrespective of the age of the patient, however, incubation of tissues such
as hair in L-tyrosine or L-dopa [9,13,37,59] usually shows evidence of tyrosinase
activity. Hair bulbs from these patients frequently have a few pigment granules
observable under the light microscope, and lightly pigmented Stage III melanosomes can be identified in thin-section electron photomicrographs. Unlike
ty-neg hair, incubation of ty-pos hair bulbs by the method of Kugelman and
Van Scott [37] forms increased amounts of pigment discernible by light microscopy, and increased melanosomal melanization identifiable by electron
microscopy.
Phenotypically, the clinical characteristics of the ty-pos albino overlap
those of the ty-neg albino on one hand, and normal lightly pigmented individuals on the other hand. In fact, some ty-pos adult black albinos have been
observed to have darker skin color than that of some normal blond Caucasians .
Oculocutaneous albinism in two black patients. The color of the skin is milk-white
and some tanning of sun-exposed areas is apparent (a, b).
71
GENETIC AND
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DISORDERS
FIGURE 25.
Most ty-pos albino infants of all racial backgrounds have white hair, but with
age they frequently gradually accumulate pigment so that the hair color turns
to cream, yellow, light brown, or even red.
There is often also a history of change in eye color from light gray to blue,
yellow, hazel, or even brown. A red reflex is usually easily elicited in most
infants and adult Caucasians with ty-pos albinism. However, it may be absent
or diminished in American Indian and American black ty-pos albino children
and adults. Adult Caucasian albinos usually have a light retina compared to
adult black and Indian albinos, but some darkening may be noted with age.
The macular reflex is usually markedly diminished or absent. Of 52 ty-pos
albinos from the Brandywine isolate, only 10% had a normal macular reflex;
25% had mesodermal remnants on the anterior surface of the iris and on the
posterior surface of the cornea on slit-lamp examination, and 20% had strabismus, usually esotropia. On transillumination, the irides are diaphanous, less
so in ty-pos albinism than in the ty-neg type [15,61]; there is a prominent
"cartwheel effect" with pigment accumulation particularly at the pupillary
border of the iris and the limbus [9]. All albinos examined had horizontal or
rotatory nystagmus and photophobia which appear to be less severe in the typos than in the ty-neg type of albinism. In some subjects, it has been observed
that photophobia and nystagmus decrease with age [6].
In general, visual acuity is more variable but, like nystagmus, less severe
among ty-pos than ty-neg albinos. Ty-pos adults may have better visual acuity
72
CHAPTER 1
and less severe nystagmus than they had as children [15] in contradistinction
to ty-neg albinos who tend to have the same or more severe defects as adults
than they had as children.
Pigmentation of the locus caeruleus and substantia nigra of ty-pos albinos
is normal; clearly neuromelanin is present in these structures [62,63].
Biochemical Abnormalities
Serum copper levels and ~-melanocyte-stimulating hormone (~-MSH) levels are normal in ty-pos albinos.
Tyrosine levels have been variably reported to be low normal or normal.
Ty-pos albinos have approximately half of the normal concentration of salivary
tyrosine. This suggests a tyrosine transport defect [64]. If hair bulb incubation
studies are performed with a dilution gradient of substrate concentration, there
is no evidence for a defect in substrate transport in ty-pos albinism [9].
King [55] assayed tyrosinase activity of hair bulbs from a number of albinos
whose hair bulbs formed increased pigment when tested by the method of
Kugelman and Van Scott [37]. His studies suggest that there are two types of
ty-pos albinos. He found Type I ty-pos albinos to have a two- to fourfold increase
in tyrosinase activity compared to hair bulb assays of normal blond, brown,
and black hair, whereas Type II tyrosinase activity was no different from that
of normally pigmented subjects. The ty-pos albinos thus must be biochemically
and genetically somewhat heterogenous.
If the skin of ty-pos albinos is stripped with cellulose tape to the point of
punctate bleeding, is packed for one week with wet gauze packs containing a
solution of L-tyrosine and L-dopa, and is then irradiated by ultraviolet radiation
[11], pigmentation will result. However, oral L-dopa alone does not overwhelm
the metabolic block. One ty-pos albino subject ingested L-dopa, 5.5 g daily for
100 days, with no resultant increase in pigmentation of skin, hair, or eyes;
addition of 500 mg of pyridoxine to the above regimen for two weeks had no
effect on pigmentation [17].
Pathophysiology
The basic defect in ty-pos albinism remains unknown. Serum tyrosine and
phenylalanine levels are generally normal [17]. Since hair bulbs from ty-pos
albinos as well as from normal blonds will pigment in vitro in their own serum
without the addition of substrate, no serum inhibitory factor can be present
[9]. The minimum substrate concentration needed to induce visible or microscopic hair pigment formation over a given time is no different for ty-pos albinos
than for normals [9,14]. The tyrosinase activity of hair bulbs in vitro ranges
from normal to four times normal [55]. Pigmentation is not increased in vivo
by prolonged oral administration of L-dopa or by ultraviolet radiation.
In mice, a recessive allele at the p locus reduces the melanin content of
eyes and hair while the absolute amount of pigment is a function of another
gene locus. The overall features of the pink-eyed dilution mutant strongly
resemble ty-pos oculocutaneous albinism in humans. Limitations in the amount
of tyrosine available for melanin synthesis and not an impaired tyrosinase
(enzyme) system are primarily responsible for the restricted melanin deposition
within pip melanosomes. The pip melanosomes in retinal melanocytes exhibit
a defective alignment and cross-linkage of many compound fibers [65,66]. Melanosomes of the pip follicular melanocytes, unlike the pip retinal melanocytes
[65], appear to have essentially normal matrices [67]. A normal structure of the
melanosomal matrix in pigmented tissues of the eyes of pip mice also has been
reported [68].
The plucked hair bulbs of ty-pos oculocutaneous albinos have tyrosinase
activity and will darken if incubated in buffered tyrosine solution. This darkening of hair bulbs forms the basis for two classes of ty-pos oculocutaneous
albinism. Type I has a two- to fourfold increase in tyrosinase activity compared
to normal blond-, brown-, and black-haired people, whereas Type II activity is
within the normal range. It was once thought it was limited availability of
tyrosine within melanosomes which resulted in failure of melanogenesis. This
was thought to result from reduced or absent "permease," a substance required
for tyrosine to penetrate into melanosomes. More recent evidence, however,
does not support this view.
Other possible mechanisms to explain the pigmentary changes in ty-pos
oculocutaneous albinism are a defect in cAMP, phosphokinase activation of
tyrosinase, presence of an intracellular inhibitor, or a defect in the feedback
control mechanism. The presence of inhibitors andlor reduced amounts of
tyrosinase cannot be excluded. Abnormal matrices in some melanosomes in
oculocutaneous albinism have been described [69] but it is not known to which
type of oculocutaneous albinism this applies.
No reliable clinical or biochemical tests are available to identify ty-pos
albino heterozygotes. Iris translucency in ty-pos obligate heterozygotes is ob-
73
GENETIC AND
CONGENITAL
DISORDERS
74
CHAPTER 1
served not to differ significantly from the range of values of normally pigmented
subjects [15,61]. Neither is there any difference in tyrosinase activity as measured by the conversion of 3H-tyrosine to L-dopa and 3(H)OH in ty-pos obligate
heterozygotes.
HERMANSKY-PUDLAK SYNDROME
The Hermansky-Pudlak syndrome (HPS) [72] or albinism with hemorrhagic diathesis [73] is an autosomal recessive disorder consisting of a triad of
ty-pos oculocutaneous albinism, hemorrhagic diathesis due to storage-pooldeficient platelets, and an accumulation of a ceroid-like material in the reticuloendothelial system, oral mucosa, and urine [72-79] (Fig. 26).
The essential features of this syndrome were first described by Hermansky
and Pudlack in two 33-year-old albino patients who had repeated episodes of
epistaxis, bruising, or prolonged bleeding following tooth extraction. Approximately 50 patients with HPS have been reported.
HPS is particularly common among Puerto Ricans. It is also said to be
particularly common among the natives of South Holland and those of the
Madras State of India.
A genetically determined enzyme defect is presumed to account for the
diverse alterations in pigment formation, a defect in the platelet storage-pool,
and a storage defect of an abnormal lipid-like material. That all three defects
are segregated as a unit trait within kindreds indicates that the three defects
can be attributed to a pleiotropic effect of a single autosomal recessive gene
FIGURE 26.
Jr .. M.D.)
J. Witkop
75
GENETIC AND
CONGENITAL
DISORDERS
76
CHAPTER 1
mutation or to the effect of two or more closely linked mutations [80]. Since
current genetic theory dictates that recessive traits primarily involve enzymatic
protein defects whereas dominant traits primarily represent mutations of structural proteins [81], the basic defect in HPS probably involves an enzyme alteration.
Clinical Characteristics
The phenotypic expression of the pigment disorder in HPS is a function
of the age and the racial ancestry of the patient. While pigmentation of patients
of Northern European ancestry may closely resemble that of the ty-neg phenotype, patients from India and Puerto Rico resemble normal Northern Europeans. The essential pigmentary dilution of the HPS patient may be apparent
only when patients with nystagmus and photophobia are compared to their
deeply pigmented unaffected family members.
The patients of Hermansky and Pudlak [72] had some obvious yellowgreen iris pigment and were of intermediate phenotypic expression. Several
extremely blond Irish and Dutch patients [82,83] have been noted to resemble
closely ty-neg albinos. These patients had no visually detectable pigment in
their hair or skin, had marked nystagmus, a prominent red reflex, completely
depigmented irides, and light gray-blue eyes with little evidence of a cartwheel
effect of transillumination. However, other Dutch patients [84] of relatively
darkly pigmented parents were observed to have reddish-brown hair. In the
absence of nystagmus, photophobia, and bleeding defect in these families, the
isolated finding of altered pigmentation was insufficient evidence to arouse
clinical suspicion that these patients were obviously unusual.
HPS among Puerto Ricans frequently appears to present with considerable
pigmentation in skin, eyes, and hair, the latter often being red or red-brown.
One such patient [85] had reddish-brown hair, mottled brown irides, pigmented
nevi, freckles, and deposits of pigment in the normally sun-exposed skin. The
patient, who had been a sugarcane cutter exposed to intense sunlight, showed
granular deposits of melanin in the dermis not unlike those observed in patients
with xeroderma pigmentosum. Deposits of brown pigment were prominent,
especially at the lumbus and at the pupillary borders of the irides. Although
a red reflex could be elicited, it was not a prominent feature of his disorder
[17]. Pigmentary features of patients of East Indian (Madras) extraction [17]
resemble those of normal U.S. Caucasians; that is, they have cream-colored
skin which can show some tanning effect, light brown hair, green to hazel eyes,
frank or latent nystagmus, photophobia, depigmented fundi, and the biochemical features of HPS.
Hemorrhagic episodes are a cardinal feature of the syndrome. Most patients
give a history of mild bleeding events including easy bruisability, epistaxis,
gingival bleeding, prolonged bleeding following tooth extraction, and hemoptysis. In a few cases massive fatal bleeding has occurred. Women with HPS
have had massive bleeding following childbirth and have required blood transfusions with each delivery [17,82,84]. In one kindred, an affected sister of the
propositus married an unaffected cousin and died of massive hemorrhage at
the time of the birth of an affected daughter. At age 26 this daughter developed
Pathophysiology
The underlying pathologic defect in HPS remains unknown. It is attractive
to think that an enzymatic alteration may be responsible for the platelet storagepool defect, the lipid storage disorder, and the pigment defect. A defect in
glutathione peroxidase as proposed by Witkop et al. [79] seems unlikely, as no
abnormality of this enzyme has been found in platelets. A prostaglandin defect
that has been found in storage-pool disease without albinism may explain HPS.
More recent studies have shown the selective immunologic defect in CHS
to be a markedly decreased natural killer activity of peripheral lymphocytes
[86a,86b].
77
GENETIC AND
CONGENITAL
DISORDERS
78
CHAPTER 1
histiocytes [17,100,101].
No abnormal lipids nor abnormal levels of normal lipids have been reported
in the plasma (serum) of HPS patients [17,79].
CHEDIAK-HIGASHI SYNDROME
Chediak-Higashi syndrome (CHS) is a rare autosomal recessive disease
characterized by oculocutaneous albinism, hematologic and neurologic abnormalities, and usually death before the age of 10.
Historical Background
In 1943, Beguez-Cesar [104] reported the first three cases of CHS among
three children of consanguinous marriage. Death resulted at an early age. In
1948 Steinbrinck [105] and in 1954 Higashi [106] each reported a case; the
latter had been diagnosed as xeroderma pigmentosum. In 1952 in a review of
this syndrome, a Cuban hematologist, Chediak [107], emphasized the hematologic findings. Sato [108] in 1955 applied the Chediak-Higashi eponym, and
outlined the clinical features of albinism, photophobia, characteristic blood
morphology, and early death from lymphoma. He concluded that early death
is related to a leukocyte abnormality transmitted by each or either of healthy
consanguinous parents. Kritzler et al. [109] reported defects in various tissues.
Clinical Characteristics
CHS is a truly rare disease; by 1972 only 59 cases had been reported [110].
Cases have been reported from North and South America, Europe, and Asia,
but no cases are reported among blacks [111]. Moran and Estevez [112] reported
an incidence of three per 15,500 hospital admissions.
Of 56 reported patients [110], 26 were males and 30 were females. Fortyeight percent were born of consanguinous marriages. The mean age reported
was 5.8 years, with only 13 over 10 years and two ages 21 and 25. Of the 56
patients, 37 had died at an average age of 3.1 years; the 19 living had an average
age of 9.2 years. Several patients surviving to over 30 years of age have been
reported.
Pigmentation Abnormalities
CHS patients have a pigmentary dilution that involves skin, hair, and eyes.
Of 55 patients with CHS, 53 were found to have pigmentary dilution in at least
one of skin, hair, or eyes. All three were involved in 38 patients and two of
the three in seven patients [110]. The cutaneous pigmentary defect is partial
to complete albinism and may be overlooked in patients of fair-skinned ancestry. The color of the skin varies from light cream to slate-gray. Even moderate
sunlight exposure may cause a sunburn. Some darkening of exposed skin and
darkening of the skin with age have been reported [113]. Hypopigmentation of
nipples, areolae, genitalia, and axillae has been described [114,115]. Lentigines,
cafe-au-Iait spots, and nevi may occur in some CHS patients [116]. Hair color
79
GENETIC AND
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DISORDERS
80
CHAPTER 1
FIGURE 27. Loss of iris pigmentation in a patient with Chediak-Higashi syndrome (a,b).
varies from light blond to brunette, but may assume an unusual frosted metallicgray sheen, which is characteristic.
The eyes are usually pigmented, with a pale blue-violet to a brown color,
usually as a function of parentage (Fig. 27). Many patients have been found to
have a loss of iris pigmentation, increased red reflex, and photophobia. Cases
of iris hyperpigmentation have also been described [109,117]. There may be
moderately to markedly decreased retinal pigmentation [118-120].
Leukocyte Abnormalities
Neutrophils from CHS patients contain a few giant (up to 4 J.1) azurophilicstaining granules [121-124] (Fig. 28). In vivo neutrophils show reduced migration into inflammatory sites and in vitro chemotaxis is defective [125-127].
Following bacterial ingestion, there is delayed degranulation of leukocytes
accompanied by an absence of peroxidase activity and by reduced bactericidal
activity [125-129]. Lysosomal enzymes, alkaline phosphatase, (3-g1ucuronidase,
and myeloperoxidase are reduced [127], and the cell is believed to be unable
C.HS
CHS
81
GENETIC AND
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DISORDERS
82
CHAPTER 1
Other Manifestations
In early childhood, routine inoculations are well tolerated. There are recurrent staphylococcal and streptococcal infections. At about five years of age,
convulsions and neuropathy frequently develop. Neuropathic changes include
cranial and peripheral neuropathy, a wide-based stamping gait [109,130]' muscle weakness, foot drop, and decreased deep tendon reflexes [131].
Later, anemia (88% of patients), thrombocytopenia (50%), and absolute
neutropenia (44%) develop. In the later stages, mediastinal and hilar lymphadenopathy, jaundice [132]' marked splenomegaly, moderate hepatomegaly, a
leukemic type of gingivitis, and pseudomembranous sloughing of buccal mucosa may occur [130]. The latter may be regarded as harbingers of a lymphoreticular malignancy and are poor prognostic signs.
l
increased
melanosome
degradation
syndrome.
83
GENETIC AND
CONGENITAL
DISORDERS
FIGURE 30. The massive Chediak-Higashi granules have a bizarre pattern and reach tremendous
proportions(x 27,394). (From: Zelickson AS et al: The Chediak-Higashi syndrome: formation of
giant melanosomes and the basis of hypopigmentation. J Invest Dermato149:575-581, 1967. Copyright, 1967, The Williams & Wilkins Company. Used with permission.)
Pierini and Abulafia [136] found melanin granules to be increased in number and size. Stegmaier and Schneider [113] were unable to find fully formed
melanin granules, but they found a few tyrosinase-positive cells in the epidermis. They reported electron microscopy studies to show degeneration and
vacuolization of epithelial cells and melanocytes. In six homozygous patients,
Bedoya [117] found some to have complete absence of pigment, but others to
have large clumps of enlarged melanin granules in both the epidermis and the
dermis. In the dermis, melanin was found in histiocytes, endothelial cells,
perithelial cells, fibroblasts, and Schwann cells, but in the interstitial areas
none was found. Changes in the heterozygotes included segmental basal deposition of normal melanin, clumping of irregyJar somewhat enlarged melanin
granules, mild atrophy of the malpighian layer with scattered cell vacuolization,
and abundant melanin in the melanophages in the papillary dermis associated
with a mononuclear infiltrate. Windhorst [137] found the early melanosomes
in CHS to be extremely large. The pattern of the membrane of maturing CHS
melanosomes suggested fusion of smaller forms. Based on this, plus demonstration of adequate tyrosinase activity, Windhorst suggested that the pigmentary dilution in CHS was secondary to a primary defect in melanosome structure
84
CHAPTER 1
FIGURE 31. The pigment granules that are passed to the epidermal cells are located in lysosomelike structures, often surrounding the nucleus (x 29,410). (From: Zelickson AS et al: The Chediak-Higashi syndrome: formation of giant melanosomes and the basis of hypopigmentation. J
Invest Dermato149:575-581, 1967. Copyright, 1967, The Williams & Wilkins Company. Used with
permission.)
[120] (Figs. 31, 32). Zelickson et al. [138] showed the destruction of melanosomes within the keratinocytes may be accelerated. Lutzner and Lowrie [139]
suggested in the mutant beige (bg) mouse (an animal model of CHS) that "giant
beige melanin granules are formed through the continual deposition of melanofilaments by granule fusion and/or failure of size-control mechanisms." Whether
the giant pigment granules result from abnormal synthesis or fusion of smaller
granules is not completely established, though evidence favors the latter.
Hair incubated in tyrosinase undergoes darkening of the matrix. Examination of unstained hair mounts shows abnormally large but sparsely clustered
melanin granules. Similar granules are seen in the hair follicles [112]. Large
melanin granules have also been found in the retina and in the choroid of
mammalian models and humans, as well as in the pia-arachnoid of humans
[117,120,139a].
85
GENETIC AND
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DISORDERS
FIGURE 32. The hypopigmentation in Chediak-Higashi syndrome is most likely due to abnormal
packaging of normal melanosomes in giant epidermal celllysosomes( x 39.825). (From: Zelickson
AS et al: The Chediak-Higashi syndrome: formation of giant melanosomes and the basis of hypopigmentation. J Invest Dermatol 49:575-581, 1967. Copyright, 1967, The Williams & Wilkins
Company. Used with permission.)
Pathogenesis
Animal models of CHS are known and have facilitated understanding of
the genesis of this disease [140) (Table 17).
The giant granules found in this disease were first studied in leukocytes,
where it was shown that histochemically they stained positively for acid phosphate and peroxidase [104,121-124), both of which localize in lysosomes. These
abnormal membrane-bound lysosomal-like organelles have also been found in
cells of buccal, gastric, and duodenal mucosa, the adrenal and pituitary glands,
the pancreas, liver, spleen, and kidney, and in bone marrow, hair, skin, and
iris [123,131,141). Many of these abnormal granulations show fragility of their
limiting membranes and undergo fragmentation and degeneration within leukocytes, Schwann cells, melanocytes, and keratinocytes [131,134,141).
86
CHAPTER 1
Characteristic
Autosomal recessive mode of
inheritance
Clinical studies
1. Increased susceptibility
to infection
2. Similar distribution of
enlarged granules
3. Similar morphology of
enlarged granules
4. Similar histochemistry of
enlarged granules
5. Bleeding tendency
6. Similar inflammatory
response
7. Immunologic deficiency
8. Pigmentary dilution
9. Accelerated phase
10. Elevated muramidase
levels
Experimental studies
1. Delayed chemotaxis in
vitro
2. Decreased serotonin
levels
3. Virus-like particles
observed
4. Sequestration vacuoles
observed
5. Abnormal serum lipid
pattern
6. Autophagy
7. Abnormally fragile
enlarged granules
8. Abnormal bactericidal
capabilities of
neutrophils
9. Abnormal membrane
permeability
10. Decreased renal tubular
catabolic function
a
Humans
Cattle
Mink
Mice
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
?
No
Yes
Yes
Yes
No
Yes
No
No
No
Yes
No
No
?
Yes
No
No
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Occasional
No
Occasional
No
Occasional
No
No
No
Yes
No
No
No
Occasional
Yes
No
No
No
No
No
No
No
Occasional
No
No
Yes
Yes
Source: Windhorst DB, Padgett G: The CMdiak-Higashi syndrome and the homologous trait in animals. J.
Invest Dennatol 60:529-537, 1973. Copyright, 1973, The Williams & Wilkins Co. Used with permission.
Diagnosis
The presence of oculocutaneous albinism, recurrent infections, neurologic
abnormalities, and peculiar leukocyte inclusion in a young child suggests the
diagnosis of CHS.
Prognosis
The prognosis for longevity is poor. Although childhood infections and
inoculations are handled well and although delayed hypersensitivity and antibodies are normal, most patients succumb by age 10 because of infection or
hemorrhage.
Clinical management problems include diagnosis and treatment of infection, maintenance of hemostasis, and correction of anemia and pancytopenia.
Infiltrative lesions may regress with antimetabolite therapy. Peripheral neuropathy may improve as the infiltrative lesions regress.
Khan et al. [144] reported one patient with abnormal delayed hypersensitivity (poor lymphocyte blastogenesis, failure to respond to DNCB sensitization, and negative delayed hypersensitivity skin test) who improved clinically and in terms of delayed hypersensitivity parameters in response to transfer
factor.
87
GENETIC AND
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DISORDERS
88
CHAPTER 1
in one patient but a few were found in the other. Skin from two parents and
two siblings of one patient was normal by light and electron microscopy. These
findings together with the presence of a very limited number of dendrites
suggest a transfer defect such as the dilute (d/d) mouse.
Granulocytes were morphologically normal and bactericidal activity was
only moderately reduced. T and B cells were quantitatively normal but studies
suggested defective serum immunoglobulins and diminished antibody production secondary to defective helper function by T cells. Defective distribution
of Con A receptors of polymorphonuclear membrane was observed and could
be corrected in vitro by cyclic GMP or its activators. Unlike CHS, leukocytespecific protease activity was normal.
CROSS-McKUSICK-BREEN SYNDROME
Cross-McKusick-Breen syndrome (CMBS), also referred to as "oculocerebral-hypopigmentation syndrome" [145], "hypopigmentation and microphthalmia" [9], "gingival fibromatosis, hypopigmentation, microphthalmia,
oligophrenia, and athetosis" [146-148], is an extremely rare syndrome originally described in a girl and two boys who were products of multiple consanguinous marriages in an Amish family in Ohio [145]. CMBS is characterized
by extremely blond hair with a slight yellow-gray metallic sheen and by absolutely white skin which is present at birth and is exquisitely sensitive to
sunburn reaction. Lightly pigmented nevi may be present.
Ocular findings include microphthalmia, cloudy corneas, and coarse, jerky
nystagmus. All children by late infancy have opacified and vascular corneas.
All are below the third percentile in height and weight and suffer from severe
mental retardation. By three months of age, the typical patient has developed
writhing motions of the arms and legs, a constant sucking movement, and a
weak high-pitched cry. In general, physical development is so severely retarded
that sitting unassisted is impossible. The eruption ofthe primary teeth [146,147]
is accompanied by development of gingival fibromatosis.
No chemical abnormalities have been detected in urine, serum, or cerebrospinal fluid. Serum tyrosine and phenylalanine levels are in the high normal
range. Routinely prepared formalin-fixed tissue specimens from one child who
died at 12 years of age from inanition and respiratory failure failed to show
abnormal inclusions in the brain, liver, spleen, or bone marrow [149].
Light microscopy reveals no pigment in fresh hair bulbs [9], but L-tyrosine
or L-dopa incubation reveals a weakly positive reaction, demonstrating the
presence of a few melanocytes in the hair bulb. Electron photomicrographs
show a scanty number of melanocytes and these contain small clusters of
melanosomes of all four stages. Incubation in L-tyrosine converts most mel anosomes to fully pigmented Stage IV melanosomes [9,17].
The basic defect in CMBS is unknown. Two features of CMBS-pigmentation and microphthalmia-are seen in mice homozygous for mi/mi (microphthalmia gene). These mice have been described as mock albinos because
of a deficiency of melanocytes [5].
OCULOCUTANEOUS ALBINOIDISM
A few families with a rare form of inh.erited ocular and cutaneous hypopigmentation have been reported [22-24) (Figs. 33, 34). Unlike all forms of
oculocutaneous albinism, oculocutaneous albinoidism is inherited as an autosomal dominant trait, and only rarely do patients have associated nystagmus,
photophobia, and markedly decreased visual acuity. The color of the hair is
white to slightly yellow or reddish tinged, and the skin which is pink-white
is very sensitive to sunburn reaction. Very slight tanning has been reported
[22,24]. L-tyrosine incubation of hair bulbs results in increased pigment [22].
Tangential lighting reveals blue irides and transillumination of the irides shows
a diffuse pattern of pigment distribution which is also present on the retina
[22].
None of the above families exhibited deafness. Other reports of oculocutaneous albinos born to albino parents probably represent pseudodominance
of a recessive oculocutaneous albinism arising from inbreeding [6,9,116,150].
OCULAR ALBINISM
Ocular albinism is most commonly inherited as an X-linked trait in which
only ocular pigmentation is abnormal [25,32,151,152]. In addition to the two
known types of X-linked ocular albinism, the Vogt type [25] and the Forsius-Eriksson type [29], there is a much rarer form of ocular albinism that has
been observed in four families and which appears to be inherited as an autosomal recessive trait [31).
FIGURE 33. Transmission of dominant oculocutaneous hypomelanosisin a family. (From: Quevedo WC Jr et al: Light and skin color, in Sunlight and Man: Normal and Abnormal Photobiologic
Responses. Edited by MA Pathak et al. Copyright, 1974, University of Tokyo Press. Used with
permission. )
89
GENETIC AND
CONGENITAL
DISORDERS
90
CHAPTER
FIGURE 34. Oculocutaneous hypomelanosis in a family illustrating a clear dominant trait. The
light-skinned, light-haired, blue-eyed mother and two sons contrast strikingly with the dark-skinned,
dark-haired daughter (not shown) who has dark brown eyes and a marked ability to tan. (From:
Quevedo WC Jr et al: Light and skin color, in Sunlight and Man: Normal and Abnormal Photobiologic Responses. Edited by MA Pathak et al. Copyright. 1974. University of Tokyo Press. Used
with permission.)
Visual acuity is seldom better than 20/100 and usually 20/200 or worse.
However, close vision is barely adequate; most patients are able to read N5 or
N6 type at four to five inches. About 60% also have strabismus. Exotropia is
about four times more common than esotropia [151] in contradistinction to typos albinism in which exactly the opposite prevails [9].
The background of the fundus is pale yellow to pale yellow-orange, not
dead-white as in choroidermia [43,151]. The choroidal vessels are easily visualized. The electroretinogram is usually normal [156].
While heterozygous females generally show minor pigmentary changes in
irides and retina, hemizygous males are severely affected. Females heterozygous
for X-chromosomal ocular albinism usually show only translucent irides and
a mosaic pattern of pigment distribution in the fundus [25-28,124,135,151,
157,158]. The mosaic appearance of the fundus, which has been described as
tigroid, pigment dusting, or "splashes of mud" [26-28]' has been attributed to
a Lyonizing effect [159]. Occasionally, apparent X-linked inheritance has been
observed in a female who then may be affected as severely as a male; nystagmus,
photophobia, and severe iris and fundal hypopigmentation [33,160] are observed. This probably represents the chance selection by nearly all progenitor
optic pigment cells of the X-chromosome bearing the mutant gene as the active
X-chromosome.
Macromelanosomes have been observed in the eyes and the normal skin
of patients with X-linked albinism [160a,160b].
Measurable linkage between ocular albinism and Xg blood group from
combined kindreds estimates the recombination fraction to be 0.15 [161-163].
91
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the same authors. All of the former have normal pigmentation of skin and hair
and a normal hair bulb test. All the expected features of ocular albinismdecreased visual acuity, prominent red reflex, photophobia, nystagmus, strabismus, diaphanous irides, and light yellow fundi-are observed. Except for
diaphanous irides, the fathers have no sign of the disorder. No mosaic pigment
patterns of the fundi are present. The mothers have no history of affected male
relatives. In some cases, parents have been shown to have diaphanous irides
but this has not been detectable in other deeply pigmented families. Two of
the families were Amish and the parents were multiply consanguinous. This
syndrome did not resemble the Ym albinism [70], Cross-McKusick-Breen syndrome [145-147], or ty-neg oculocutaneous albinism which have been described among Amish families. There was no evidence of Turner syndrome in
the affected women; buccal Barr bodies were of normal female pattern and
chromosomal analysis of lymphocytes from one patient revealed a normal female karyotype. A similarly affected female without familial or chromosomal
evidence of X-linkage was described by Scialfa [168]. An autosomal recessive
form of ocular albinism has been described in rabbits [169].
Ocular albinism features a characteristic pigmentary dilution of the iris
and of the fundus. The amount of pigment is reduced but the biochemical
abnormality and the ultrastructural appearance of melanosomes is unknown.
It is possible but not established that a mechanism comparable to that in typos oculocutaneous albinism is operative. The presence of a mosaic pattern of
pigmentation in the fundus of heterozygous females presumably results from
X-inactivation during early embryonic development. Thus, some retinal pigment cells have an active X-chromosome with the recessive ocular albinism
allele, whereas the others have an active X-chromosome containing the normal
allele.
DIFFERENTIAL DIAGNOSIS
The presence of at least some pigment in skin, hair, and eyes, pigmented
nevi, freckles, and a positive tyrosine incubation test of hair bulbs will distinguish ty-pos from ty-neg albinism. Ym albinos may be more difficult to distinguish, but characteristically they have pigment in hair, skin, and eyes, exhibit
slight sun-induced melanogenesis, and have a negative or faintly positive hair
bulb test. A bleeding diathesis and multisystem abnormal inclusions suggest
HPS. CHS patients have repeated infections, giant peroxidase-positive granules,
a steel-gray sheen to their hair, and, in some cases, abnormal neurologic findings. The CMBS features severe oligophrenia, athetosis, gingival fibromatosis,
and microphthalmia.
TREATMENT OF ALBINISM
There is no treatment for the pigmentary abnormalities in any type of
albino. Psoralen therapy to induce melanogenesis is unlikely to offer significant
solar protection in ty-pos and Ym albinos.
The major problems that confront most albinos are ease of sunburn (Fig.
35), susceptibility to skin cancer, marked photophobia, and decreased visual
acuity. All albinos should be encouraged to avoid sun exposure, particularly
between 10:00 a.m. and 3:00 p.m. in the northern summers. Any sun exposure
should be preceded by application of an effective sunscreen. Albinos should
be checked yearly for skin cancers.
The use of sun glasses (NoIR) will reduce photophobia. In albinos, unlike
93
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94
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FIGURE 35. Oculocutaneous hypomelanosis in the propositus who complained of marked intolerance to sunlight with increased sunburning. There is dilution of hair, eye, and skin color.
(From Quevedo WC Jr et al: Light and skin color, in Sunlight and Man: Normal and Abnormal
Photobiologic Responses. Edited by MA Pathak et al. Copyright, 1974, University of Tokyo Press.
Used with permission.)
normal persons, early correction of strabismus does not restore binocular vision.
Although distant visual acuity is limited, close vision is good enough that
children, if properly seated in the classroom, generally do better in public
schools than in special schools for the visually handicapped [10].
Genetic counseling should be undertaken in all cases. Patients should be
aware that their children will carry the albinism gene and that marriage to an
albino of the same type will produce albino offspring. Children of an oculocutaneous albinoid have a one in two chance of being affected, even if one
parent is normal.
Caution should be exercised in the administration of aspirin or aspirincontaining medications to HPS patients. Routine platelet aggregation studies
should probably be done in those HPS patients who must use salicylates.
CHS patients will require appropriate antibiotic treatment of infections.
The lymphoma-like stage should be treated with systemic antimetabolites and
corticosteroids.
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animals [8]: rats [9-11], guinea pigs [12], rabbits [9,13]' cats [9], cattle [14],
goats [14], and sheep [15], Although the exact mechanism of depigmentation
is unknown, there is evidence that pantothenic acid may be directly involved
in copper metabolism. Pantothenic acid-deficient rats that have depigmented
skin have a cutaneous copper concentration five times normal [16], Furthermore, addition of either copper or pantothenic acid restores normal pigmentation in depigmented rats subsisting on copper-deficient diets [17], The evidence suggests that the presence of pantothenic acid is essential to the catalytic
role of copper in the skin melanogenesis. Pantothenic acid may be important
in the binding of copper to the protein moiety of tyrosinase [17].
103
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as decreased hepatic copper levels in children with kinky hair disease. Experimental studies implicated a defect in copper absorption [25] from the small
intestine secondary either to inadequate intracellular transport or to a defect
in migration across intestinal mucosa [31]. Furthermore, Danks et al. [32] found
that fibroblastic skin cultures of both hemizygote and heterozygote patients
develop metachromasia which clears on serial cultures. They considered this,
which may be related to the high copper content of the calf serum used in the
culture medium, to be characteristic of cells with the kinky hair gene [31].
O'Brien et al. [33] found lipid abnormalities in the gray matter of the brain but
were unable to relate this to the pathogenesis of Menkes kinky hair syndrome.
Similar copper concentrations in affected and unaffected brains have been
demonstrated [34]. Administration of oral or parenteral copper do not appear
to reverse the syndrome [24,35].
Pigmentary Dilution in Menkes Kinky Hair Syndrome
Hypopigmentation probably results from enzymatic (tyrosinase) dysfunction secondary to copper deficiency. This functional disturbance may be related
to covalent bonding of copper by the increased sulfhydryl groups found in
Menkes kinky hair syndrome.
There is an animal model for Menkes kinky hair syndrome. Hunt [38]
described a primary defect of copper transport in mottled mouse mutants (Mobr)
105
GENETIC AND
CONGENITAL
DISORDERS
FIGURE 36. Severe pigmentary dilution in an Mobr male mouse. (From: Hunt DM: Primary defect
in copper transport underlies mottled mutants in the mouse. Nature 249:852-854, 1974. Copyright,
1974, MacMillan Journals, Ltd. Used with permission.)
(Fig. 36). Danks [39] concluded there is defective transport of copper from the
serum to the intracellular site of tyrosinase activity. A number of different
mutant alleles at the "mottled locus" are known. If the male hemizygote survives
beyond birth, there is a severe pigmentary dilution. All individual hairs are
pigmented at the ends. The hair structure is altered and the whiskers are curly.
Phenotype variation from random X inactivation in a female to an X-linked
coat color mutant depends on the cell autonomy of the mutant defect. This
varied appearance of the mottled heterozygote therefore suggests the presence
of a copper-transport defect in the follicle and pigment cells of the skin [38].
Copper-deficient cells would be expected to be at a selective disadvantage in
competition with their normal counterparts, resulting in progressive dilution
of mutant cells during development. The depigmented patches are clones of
cells in which chromosomes carrying the normal alleles are inactivated so that
only the mutant gene is active. The progressive darkening of Mobr heterozygotes
with age is consistent with the hypothesis.
Histology and Electron Microscopy
Epidermal and follicular melanocytes show decreased dopa oxidase activity. Ultrastructurally there is a decrease in the number of Stage III and IV
melanosomes, suggesting an impairment of their melanization [39a].
Other Features in Menkes Kinky Hair Syndrome
Menkes kinky hair syndrome has been associated with the abnormalities
summarized in Table 19.
Diagnosis and Treatment
The diagnosis of Menkes kinky hair syndrome must be based on clinical
findings; the pigmentary dilution is a nonspecific finding.
106
CHAPTER 1
In the light of the findings of Danks et al. [25,31,32,35,39) and of observations in animals, Menkes kinky hair syndrome appears associated with copper deficiency. However, copper supplement does not appear helpful. No effective treatment is available.
HISTIDINEMIA
Histidinemia is a rare autosomal recessive inborn error of histidine metabolism. It was first described in 1961 by Ghadimi, Partington, and Hunter
[41) in two sisters with elevated blood and urinary histidine levels. Neville et
al. [42), in 1972, found 42 reported cases in a survey of the literature. In 1962,
Auerbach et al. [43) identified a patient with imidazolepyruvic, imidazoleacetic,
and imidazolelactic acids in the urine and attributed the positive ferric chloride
test to the presence of imidazolepyruvic acid accumulated because of the absence of histidase. Histidase deficiency has been demonstrated in the skin by
Ladu et al. [44), and in the liver by Auerbach et al. [45).
One three-year-old boy described by Woody et al. [46) had a few areas of
cutaneous depigmentation over the left flank and scalp suggestive of tuberous
sclerosis.
107
GENETIC AND
CONGENITAL
DISORDERS
108
CHAPTER 1
CNS abnormalities
Mental retardation (23/42 cases)
Speech difficulties (18/42)
Convulsions (6/42)
Ataxia (3/42)
Infantile psychosis (2/42)
Tremor of the hands (1/42)
Emotional disturbance (1/42)
Signs of degenerative brain disease (1/42)
Abnormal behavior and short attention span (1/42)
Other features
Small stature (1/42 cases)
Recurrent infections (1/42)
Anemia (3/42) or congenital hypoplastic anemia (1/42)
Proteinuria (1/42)
Blond or fair hair (10/42), fair skin (5/42), and blue eyes (10142)
a
From: Neville BGR et al: Histidinemia. Study of relation between clinical and
biological findings in seven subjects. Arch Dis Child 47:190-200, 1972.
Biochemical Features
The biochemical features of histidinemia include elevated blood and urinary histidine levels, a positive urinary ferric chloride test, and defective histidase activity in the skin and liver.
Diagnosis
Some authors consider the triad of fair hair, blue eyes, and mental retardation as highly suggestive of the diagnosis of histidinemia. The diagnosis must
be confirmed by biochemical assays.
Treatment
By analogy with other inborn errors of metabolism, treatment with a low
histidine diet has been undertaken as a trial to attempt to prevent permanent
eNS damage and other changes, but at the present time the success of this
treatment is unknown.
PHENYLKETONURIA
Phenylketonuria (PKU) is an autosomal recessive disorder of phenylalanine
metabolism characterized by mental retardation and pigmentary dilution of
skin, hair, and eyes (Fig. 37). Hypomelanosis in PKU is one of the rare pigmentary diseases for which a specific biochemical defect is known-there is a
deficiency of phenylalanine hydroxylase. Since phenylalanine normally is metabolized to tyrosine, a melanin precursor, this disease is central to interest in
pigmentation.
Today in many areas, mass biochemical neonatal screening is used to
diagnose the disease so as to institute effective treatment before irreversible
mental retardation develops.
History
In 1934 F~lling [48] first described PKU in 10 patients, including several
siblings, discovered in a survey of 430 mentally retarded patients in Norway.
F~lling discovered phenylpyruvic acid in the urine of these patients and coined
the term "imbecillitas phenylpyruvica" for this disease. Various other terms
used to refer to this disease include "phenylpyruvic amentia" and "phenylpyruvic oligophrenia." In 1937, Penrose and Quastel [49] introduced the now
universally accepted name "phenylketonuria. " In 1939, Jervis [50] recognized
PKU to be an autosomal recessive trait.
109
GENETIC AND
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DISORDERS
110
CHAPTER 1
Clinical Features
Incidence
There have been various estimates of the frequency of PKU. Jervis [51]
estimated the general incidence in the United States to be 4/100,000. Nearly
the same frequency (1/24,000) was reported by Knox [52]. An incidence of
2/100,000 has beenreportedin England [53], whereas 3.5/100,000 is the reported
incidence in Sweden [54]. Other estimates vary from 5.3/100,000 in Israel to
22.2/100,000 in Ireland [55]. Considered together, the average frequency calculated from 12,412,716 individuals is 8.5/100,000.
Among institutionalized mentally retarded individuals, the incidence of
PKU is estimated to be 0.64% [51].
Race
Although PKU seems most common in Northern Europeans or Scandinavians [51], the disease is not restricted to anyone ethnic group. PKU has been
reported in Mongoloids [56-58] as well as in blacks [59,60]. However, the
incidence of PKU in American blacks and Indians is much lower than one
would expect [55]. In Israel, PKU is rare among Ashkenazi Jews, but it occurs
in Oriental (Yemenite) Jews [61].
Sex
Males and females are equally affected. Among 465 cases of PKU, 51%
were females and 49% were males [50].
Heredity
Familial cases were present (three sibling pairs) in the initial description
of the disease by F~lling [48]. Jervis [51] later recognized the disease to be
autosomal recessive. Parental consanguinity is frequently observed.
111
GENETIC AND
CONGENITAL
DISORDERS
Although the hair color in PKU spans the spectrum from light blond to
dark brown [49], blond hair predominates in most series (Figs. 39, 40). All the
23 cases of Fleisher and Zeligman [63] had blond hair. Jervis [60] found blond
hair in 86% of his patients. Paine [64] observed 60% of patients with PKU to
have blond hair and the remainder light brown or brown hair. Cowie [65]
observed that 14 of his patients had either red or fair hair, the darkest hair
being medium brown in color. Only eight of the 17 cases reported by Hassel
and Brunsting [66] had blond hair. Hair darkening with age does occur.
There are several striking examples of this hair pigmentary dilution. Jervis
[60] described "an idiot baby with blond hair and blue eyes who belonged to
a family of Sicilian extraction, all members of which, for at least three generations, were dark-haired." Turpin et al. [67] reported a strikingly blond patient
in a family of darkly pigmented Spaniards. In the Japanese, PKU is associated
with dark brown hair color which is distinguished from the normal black color
of Japanese hair [68] (Fig. 40). Stadler et al. [69] also observed a PKU mulatto
with sandy blond hair.
Objective evidence of hair pigmentary dilution has been obtained. Penrose
et al. [70] and Cowie and Penrose [71], by reflectance spectrophotometry, consistently demonstrated a pigment dilution of hair in PKU patients compared
with unaffected relatives.
Light skin or fair skin is associated with pigmentary dilution of hair. Jervis
[60] noted that most of his patients had fair skin. Gibson [72] reported a pallid
complexion in six of his seven cases. Fourteen of the 15 patients of Cowie's
series [65] were fair-skinned, as were the 23 cases reported by Fleisher and
Zeligman [63].
Photosensitivity was observed in a 22-year-old New Zealand female with
PKU [73]. Epstein [74] classified PKU as a disease with photosensitivity because
112
CHAPTER 1
FIGURE 39. Difference in color between the hair of an affected child (a) and that of a normal
control (b). (Courtesy of M. Seiji, M,D.)
113
GENETIC AND
CONGENITAL
DISORDERS
FIGURE 40. Lighter hair color in children with PKU compared to that of normal mother.
114
CHAPTER 1
he had dark brown hair, olive skin, almost black irides, average intelligence,
and none of the other features characteristic of PKU. The metabolic disturbance
was mild and the plasma level of phenylalanine was 15 mg per 100 ml. Coates
et al. [78] also reported a case with medium brown hair and high I.Q. In this
patient, the excretion of phenylpyruvic acid was about 25% less than in other
patients with PKU. These two cases suggest that the correlation of normal hair
color with normal intelligence is not happenstance; there is either a lower
concentration of some inhibiting substance or a greater resistance to inhibition
of the chemical reactions needed for melanin formation and for the transmission
of neural impulses. However, Paine [64] and Schanenberg et al. [79] could not
correlate hair and eye color and intelligence levels [64,79]' although in neither
of two studies reported was the color dilution established by a comparison of
the hair and eye color to that of siblings. Neither were Berg and Stern [76] able
to relate the I.Q. of phenylketonuric patients to the iris pigmentary dilution.
In general, it has not been possible to correlate pigmentary dilution and mentation.
Lack of pigmentation in the normally pigmented areas of the brain, such
as the substantia nigra and locus ceruleus, has also been reported in phenylketonuric patients [80,81].
Mental retardation
Agitation
Seizures and EEG abnormalities
Muscular hypertonicity
Microcephaly
Hyperactive reflexes
Inability to talk
Hyperkinesis
Inability to walk
Incontinence
Tremors
The brain is critically affected in PKU. Brain weight is reduced and there
is defective myelinization. The biochemical basis for this is not clearly understood, but it is possible that a combination of biochemical events rather than
a single one is responsible for the brain damage. A low phenylalanine diet, if
instituted within the first few years of life, can prevent intellectual impairment
or may reverse recently established impairment [83-87]. This suggests that the
phenylketonuric infant is normal at birth. The retardation begins in the first
months of life and become progressively more severe. Later, the retardation
becomes irreversible.
Growth retardation, decreased birth weight, and reduced life expectancy
are characteristic of untreated PKU.
Skin Lesions
Dermatographism [62,72,88] and acrocyanosis or poor peripheral circulation [60] have been frequently mentioned. Scleroderma-like changes have
been observed in patients with PKU [89].
Multiple nerve tumors [90], pigmented nevi, melanotic macules [66], and
cafe-au-lait spots are also seen though not necessarily with significant frequency
[63].
F~lling [48] and Jervis [60] stressed the description of skin disorders "consisting of more or less diffuse eczema." Jervis observed diffuse patches of eczema
in over half of his cases reported in 1937. Examination of patients with PKU
by F~lling [62] failed to establish any connection between the "skin affections"
and the metabolic disorder. Fleisher and Zeligman [63] found atopic dermatitis
in three of 23 patients with PKU and in none of 21 controls. However, these
authors could not draw any definite conclusions from their small population.
Diagnosis
Knox and Hsia [91] said, "few human diseases are so uniformly and precisely identifiable as PKU." The clinical picture of untreated PKU is characteristic. However, awaiting the typical clinical picture often means irreversible
mental retardation.
Several methods have been used for early diagnosis and mass screening
for PKU. Addition of ferric chloride to urine containing phenylpyruvic acid
115
GENETIC AND
CONGENITAL
DISORDERS
116
CHAPTER 1
PROTE IN
NORMAL
DIETARY
PROTEIN
PHENYLKETONURI A
Pheny l aceric ac i d
p- OH ' Phe nylacltic acid
levels in the serum and the urine. Jervis [93] demonstrated that there is a lack
of transient rise of the serum tyrosine levels in phenylketonuric patients after
phenylalanine loading; he concluded that phenylalanine is the primary metabolite that accumulates. With in vitro liver studies he further demonstrated
that there is a lack of phenylalanine hydroxylation. Phenylalanine to tyrosine
conversion was often found to be less than 10% of that expected. Mitoma et
al. [94], Wallace et al. [95], and Kaufman [96] showed that the deficiency
involved the labile hepatic enzyme, phenylalanine hydroxylase, and not the
cofactor system. This was confirmed by Justice et al. [97] and Friedman et al.
[98]. There is now no question that the inactivity of phenylalanine hydroxylase,
which normally catalyzes the oxidation of L-phenylalanine to L-tyrosine, is the
primary phenotypic defect in PKU.
The chemical consequences of such a metabolic block are extensive. Phenylalanine accumulates in body fluids so long as constant dietary intake continues. In PKU, the plasma phenylalanine concentration typically exceeds 16.5
mg per 100 ml and may reach as high as 90 mg per 100 ml [75]. There is a
relative deficiency of tyrosine, which becomes an essential dietary amino acid.
Also, numerous aromatic compounds accumulate and are found in abnormally
high amounts in the blood and the urine [75]. These include various derivatives
of phenylalanine, namely, phenylpyruvic acid, phenyllactic acid, phenylacetic
acid, and acetylglutamine. Aromatic compounds accumulate in much smaller
amounts than do phenylalanine, and their degradation products include derivatives of tyrosine: p-hydroxyphenylpyruvic acid, p-hydroxyphenyllactic acid,
p-hydroxyphenylacetic acid, a-tyrosine, a-hydroxyphenylpyruvic acid, 0hydroxyphenylacetic acid, and tryptophan breakdown products, indoleacetic
acid and indolelactic acid.
117
GENETIC AND
CONGENITAL
DISORDERS
118
CHAPTER 1
of a repressor and a competitive inhibitor effect. However, this has not yet been
possible to establish in vivo.
Treatment
The only practical mode of therapy of PKU is restriction of dietary phenylalanine. Pigment darkening occurs with treatment in most of the patients and
is best observed at the zone of new growth at the hair roots. With the exception
of structural defects and severe brain damage, most of the signs of PKU are
ameliorated by treatment. Mental retardation, once apparent, is largely irreversible, but is perfectly preventable by physician awareness, mass PKU screening programs, and early dietary restriction.
Homocystinuria
Homocystinuria, first described in 1962 by Field et al. [111], is an autosomal
recessive inborn error of metabolism of methionine which is an essential sulfurcontaining amino acid. The frequency of homo cystinuria ranges between
1 : 100,000 and 1 : 200,000 births [112]. Homocystinuria may be inapparent at
birth but may in time involve hair and skin changes, ocular changes, central
nervous system abnormalities, Marfan-like features, thromboembolic events,
and skeletal abnormalities.
Anyone of three metabolic defects may cause homocystinuria. Of these,
cystathionine synthetase deficiency is the most common, but deficiencies of 5methyltetrahydrofolate methyltransferase [113,114] and of 5,10-methylene tetrahydrofolate reductase [115] also occur.
Cystathionine synthetase deficiency was first recognized and described by
a Belfast-London group [116] and presents a rather distinct clinical picture
[117]. This deficiency alone among the biochemical forms of homo cystinuria
is associated with hair and skin pigmentary abnormalities.
Pigmentary Dilution in Cystathionine Synthetase Deficiency (Table 21)
In general, patients with cystathionine synthetase deficiency have fine
blond hair, blue eyes, and fair skin [116-130]. Blond hair was found in 34%
of 91 cases [118]. In another series [117], 10 patients had blond hair, whereas
in another [127], only two cases with blond hair were found among 38 patients.
Patients with black or dark brown hair have been documented [122,131]. The
blond hair is otherwise normal on routine microscopic examination but acridine orange stain gives an orange-red fluorescence, not the green fluorescence
expected of normal hair.
Compared to the hair color of unaffected siblings, the light hair color in
homocystinuria is most impressive, particularly in those of Mediterranean extraction [132]. That the metabolic defect is important to hair color is emphasized
119
GENETIC AND
CONGENITAL
DISORDERS
120
CHAPTER 1
Birth, childhood
Areas affected
Hair
Eyes
Skin
Mechanism
Associated dermatologic
or systemic findings
by the darkening of hair that occurs both with restricted methionine intake
[132] and with pyridoxine supplement [133,134].
Barber and Spaeth [133] observed striking repigmentation of the hair in
one of their patients treated with pyridoxine. A picture of the hair showed a
central band of blond hair which represents a 30-day period during which
treatment was interrupted (Fig. 42). Analysis of the dark hair revealed considerably more cysteine than in the light hair that formed prior to treatment. The
authors noted this difference in one of four controls. They suggest that increased
pigmentation after pyridoxine treatment may result from derepression of melanin formation. Tyrosinase may be inhibited by homocysteine in tissues.
Pyridoxine-deficient hair depigmentation was found in a 16-year-old white
girl with homo cystinuria and yellow-blond hair [134]. The initial trial of pyr-
FIGURE 42. Effect of pyridoxine treatment on hair pigmentation in a patient with homocystinuria. There is dark hair near
the scalp and a dark band further
out. The intermediate light zone
represents a 30-day period during which treatment was interrupted. (From: Barber JW, Spaeth
JH: The successful treatment of
homo cystinuria with pyridoxine. J Pediatr 75:463-478, 1969.
Copyright, 1969, The C. V. Mosby
Company. Used with permission.)
Diagnosis
121
GENETIC AND
CONGENITAL
DISORDERS
122
CHAPTER 1
Ectopia lentis
Iridodonesis
Retinal degeneration or detachment
Uveitis
Glaucoma
Skeletal abnormalities
Osteoporosis
Dolichostenomelia
Genu valgum (35.1%1"
Pes cavus or planus (19.8%)
Pectus carinetum or excavatum
Kyphoscoliosis
Long extremities and digits
Marfan-like appearance (30.7%t
Mental retardation (74.7%t
Seizures (major or minor motor type) or EEG
abnormalities (25.2%)
(32.9%)
Cardiac abnormalities
Anemia
Cutaneous abnormalities
Malar flush
Livedo reticularis (extensor surface of the limbs)
Decreased subcutaneous fat
Blue eyes (13.2%) and blond, fine, fair hair (34%)
Biochemical abnormalities
Treatment
Tietz Syndrome
In 1963, Tietz [146] reported a six-generation pedigree with a syndrome
of deaf-mutism, hypoplasia of the eyebrows, blue eyes, and a cutaneous depigmentation, which was referred to by the author as albinism. This syndrome,
which was observed in 14 (eight females, six males) of the 68 individuals in
this family, showed autosomal dominant inheritance and complete penetrance.
The cutaneous depigmentation in this disease is described as generalized.
The hair is light blond. The eyes are blue, but there is no photophobia, no
nystagmus, and the fundi are normal. There is no dystopia canthorum. The
deafness is of the perceptive type. Skin biopsies in one of the patients revealed
complete lack of melanin.
However, no other reports mention this syndrome and Witkop [147] regards
it as a questionable entity. Reed et al. [148] were able to reexamine two siblings
of this family and pointed out that the patients had freckling, that one had a
black patch in the nuchal area, and that one female of this kindred was light
blond but not deaf. The mother and her four sisters noted darkening of their
hair, and tanning was observed in the mother and her sons. It was suggested
that perhaps these individuals were very blond normal individuals with autosomal dominant deafness. Furthermore, since one of the female siblings was
blond and her brothers were not deaf, there are serious doubts as to the existence
of this disorder.
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GENETIC AND
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65. Cowie V: Phenylpyruvic oligophrenia. J Ment Sci 97:505-531, 1951
66. Hassel CW, Brunsting LA: Phenylpyruvic oligophrenia: an evaluation of the light sensitive
and pigmentary characteristics of seventeen patients. Arch Dermatol 79:458-465, 1959
67. Turpin R et al: Presentation clinique d'un malade atteint d'oligophrenie phenylpyruvique.
Ann Med Psychol [Paris) 105:65-67, 1947
68. Shizume K, Naruse H: Dilution of hair colour in Japanese children with phenylketonuria. J
Ment Defic Res 2:53-54, 1958
69. Stadler HE et al: Phenylpyruvic oligophrenia in a mulatto: probably manifestation of the
pleiotropic effect. J Nerv Ment Dis 124:205-207, 1956
70. Penrose LS et al: Mesure de l'hypopigmentation chez l'oligophrene phenylpyruvique. C R
Soc BioI [Paris) 144:244-245, 1950
71. Cowie VA, Penrose LS: The dilution of hair color in phenylketonuria. Ann Eugenics 15:297-301,
1951
72. Gibson R: Phenylketonuria: survey of cases of Manitoba school. Can Med Assoc J 74:897-900,
1956
73. Medlicott RW: Some rarer forms of mental deficiency: phenylpyruvic oligophrenia. New
Zealand Medical Journal 43:191-194, 1944
74. Epstein JH: Phototoxicity and photoallergy: clinical syndromes, in Sunlight and Man: Normal
and Abnormal Photobiologic Responses. Edited by MA Pathak et al. Tokyo, Univ of Tokyo
Press, 1974, pp 459-477
75. Fitzpatrick TB, Mihm MC Jr: Abnormalities of the melanin pigmentary system, in Dermatology
in General Medicine. Edited by TB Fitzpatrick et al. New York, McGraw-Hill, 1971, pp
1591-1637
76. Berg JM, Stern J: Iris color in phenylketonuria. Ann Hum Genet 22:370-372, 1958
77. Cowie VA, Brandon MWG: Follow-up note on an atypical case of phenylketonuria. J Ment
Defic Res 2:55-58, 1958
78. Coates S et al: Phenylketonuria with normal intelligence and Gower's muscular dystrophy.
Arch Dis Child 32:313-317, 1957
79. Schanenberg H et al: Der phenylbrenztraubensaure Schwachsinn. Z Kinderheilk 77:363-383,
1955
80. Weinhouse S, Millington RH: Ketone body formation from tyrosine (letter). J BioI Chern
175:995-996, 1948
81. Weinhouse S, Millington RH: Ketone body formation from tyrosine. J BioI Chern 181:645-653,
1949
82. Bechelli LM et al: Dyschromie et etude quantitative ultrastructurale de la couche basale de
l'epiderme dans 3 cas de phenylcetonurie. Presented at the XVth Congres de l'Association
des Dermatologistes et Syphiligraphes de Langue Francaise, Ajaccio, 1976
83. Armstrong MD et al: Studies on phenylketonuria, IX. Further observations on the effect of
phenylalanine restricted diet on patients with phenylketonuria. Am J Clin Nutr 5:543-551,
1957
84. Blainey ]D, Gulliford R: Phenylalanine restricted diets in the treatment of phenylketonuria.
Arch Dis Child 31:452-466, 1956
85. Horner FA et al: Effect of phenylalanine-restricted diet in phenylketonuria. J Dis Child
93:615-618, 1957
86. Hsia DYY et al: A one year controlled study of the effect of low-phenylalanine diet on
phenylketonuria. Pediatrics 21:178-202, 1958
87. Woolf LI et al: Dietary treatment of phenylketonuria. Arch Dis Child 33:31-45, 1958
88. Bates RM: Three cases of phenylpyruvic oligophrenia. J Ment Sci 85:273-275, 1938
89. ]ablonska S et al: Skin and muscle induration in phenylketonuria. Arch Dermatol 95:443-450,
1967
90. Penrose LS: Phenylketonuria, a problem in eugenics. Lancet 1:949-953, 1946
91. Knox WE, Hsia DYY: Pathogenetic problems in phenylketonuria. Am JMed 22:687-707,1957
92. Medical Research Council: Working party on phenylketonuria. Present status of different
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93. Jervis GA: Phenylpyruvic oligophrenia: deficiency of phenylalanine oxidizing system. Proc
Soc Exp Biol Med 82:514-515, 1953
94. Mitoma C et al: On the nature of enzymic defect in phenylpyruvic oligophrenia. Proc Soc
Exp Biol Med 94:634-635, 1957
95. Wallace HW et al: Studies on conversion of phenylalanine to tyrosine in phenylpyruvic
oligophrenia. Proc Soc Exp Biol Med 94:632-633, 1957
96. Kaufman S: Enzymatic conversion of phenylalanine to tyrosine. J Biol Chern 226:511-524,
1957
97. Justice P et al: Clinical and biochemical observations of patients with atypical phenylketonuria. Pediatrics 45:83-92, 1970
98. Friedman PA et al: Detection of hepatic phenylalanine 4-hydroxylase in classical phenylketonuria. Proc Natl Acad Sci USA 70:552-556, 1973
99. Dalgiesh CE: Metabolism of the aromatic amino acids. Adv Protein Chern 10:31-150, 1955
100. Armstrong MD, Tyler FH: Studies on phenylketonuria, I. Restricted phenylalanine intake in
phenylketonuria. J Clin Invest 34:565-580, 1955
101. Bickel H: Effects of phenylalanine-free and phenylalanine-poor diet in phenylpyruvic oligophrenia. Exp Med Surg 12:114-118,1954
102. Bickel H et al: The influence of phenylalanine intake on the chemistry and behaviour of a
phenylketonuric child. Acta Paediatr Scand 43:64-77, 1954
103. Braude H: Phenylketonuria: a case report in an European child treated with a diet low in
phenylalanine. S Afr Med J 30:83-85, 1955
104. Woolf LI et al: Treatment of phenylketonuria with a diet low in phenylalanine. Br J Med
1:57-64, 1955
105. Snydermann SE et al: Effect of tyrosine administration in phenylketonuria. Fed Proc 14:450-451,
1955
106. Dancis J, Balis ME: A possible mechanism for disturbance in tyrosine metabolism in phenylpyruvic oligophrenia. Pediatrics 15:63-66, 1955
107. Miyamoto M, Fitzpatrick TB: Competitive inhibition of mammalian tyrosinase by phenylalanine and its relationship to hair pigmentation in phenylketonuria. Nature 179:199-200,
1957
108. Boylen JB, Quastel JH: Effects of L-phenylalanine and sodium phenyl pyruvate on the formation of melanin from L tyrosine in melanoma. Nature 193:376-377, 1962
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127
GENETIC AND
CONGENITAL
DISORDERS
128
CHAPTER 1
Tietz Syndrome
146. Tietz W: A syndrome of deaf-mutism associated with albinism showing dominant autosomal
inheritance. Am J Hum Genet 15:259-264, 1963
147. Witkop CJ Jr: Albinism, in Advances in Human Genetics. Edited by H lJarris, K Hirschhorn.
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148. Reed WB et al: Pigmentary disorders in association with congenital deafness. Arch Dermatol
95:176-186, 1967
Definition
Vitiligo is the prototype of hypomelanotic disorders. It is an idiopathic,
acquired, circumscribed leukoderma which often is associated with a positive
family history and is characterized by discrete, pale white macules, few or
many in number, that tend to enlarge centrifugally over time. Vitiligo is one
of the most common leukodermas known, and whether it is associated with
other disorders or is a cosmetic problem that does not affect the general health
of the patient, the physical disfigurement perceived by those afflicted and those
they confront often leads to social embarrassment and psychologic turmoil.
Historical Background
Early Confusion of Leprosy and Vitiligo
The stigma associated with vitiligo must date from ancient times when
vitiligo was confused with contagious or severely disfiguring disease entities.
The earliest reference to vitiligo would seem to be the Ebers Papyrus which
attempted to distinguish two types of pigmentary dilution. One type had tumors
and mutations "thou shalt not do anything about it" and in the other "thou
findast only change of colour." The former probably represented leprosy and
the latter vitiligo, which, according to the Ebers Papyrus, was treatable.
In a sacred Indian book, Atharva Veda, dating to 1400 B.C., the condition
"shwetakustha" likely referred to vitiligo.
White spots were also described in the Greek literature; Herodotus (484-425
B.C.) wrote in Clio 1:138 in 449 B.C.:
If a Persian has leprosy or white sickness he is not allowed to enter into a city or to
have dealings with other Persians, he must, they say, have sinned against the sun.
Foreigners attacked by this disorder are forced to leave the country, even white pigeons
are often driven away as guilty of the same offense. [1]
129
GENETIC AND
CONGENITAL
DISORDERS
130
CHAPTER 1
Aristotle also observed that gray hair was a feature of leprosy and reasoned
that those who do not get gray hair cannot have leprosy.
Although skin disorders with anesthesia and paresthesia were described
in 7th Century China, as were various skin disorders in India as far back as
7000 years, and alopecia with sensory changes and skin disturbance in the
Berlin Papyrus and the Ebers Papyrus, no evidence for leprosy has been found
among ancient Egyptian mummies or in the pre-Columbian Americas (although
ceramics of pre-Columbian Middle Andean civilizations display evidence of
many other disease entities). Leprosy then must not have been so common and
many leukodermas must have been other than leprosy.
Against a clear description of leukoderma among the ancients, the first
clear account of leprosy, according to Kaposi [2], was given by Danielssen and
Boeck [3] in 1842. Since throughout early literature it is not possible to find
definite evidence for leprosy, qua leprosy, until the nineteenth century, much
historical "leprosy" may be vitiligo. The old Hebrew "zora'at" may not even
apply to leukodermas or epidermal proliferative disorders.
Yet from the historical associations with leprosy-pandemics in the Middle
Ages and uncleanliness of biblical times-the stigma of leprosy, bolstered by
old edicts and cruel laws, remains. Following the urging of Pope Pius XII in
1943 and with the official American Catholic translation in 1952 with reference
to Leviticus XIII, the Church added the following footnote:
Various kinds of skin blemishes are treated here which were not contagious but simply
disqualified their subjects from associations with others, especially in public worship,
until they were declared ritually clean. The Hebrew term used does not refer to
Hansen's disease, currently called leprosy.
Still, in the 1963 New English translation of the New Testament, "lepra"
is still translated "leprosy." Hence, literal confusion is perpetuated.
Vitiligo in Ancient Times
The term "vitiligo" was first used in the 2nd Century A.D. by Celsus, who
observed the appearance of the patches of vitiligo resembled the white patches
of a spotted calf. "Vitiligo" has often been said to have been derived from the
Latin vitellus, meaning "calf." Professor Herbert Block* has suggested "vitiligo"
is derived from "vituim" (defect or blemish) plus the suffix "igo" (condition
or disease of) with the "I" introduced for euphony.
Many earlier terms have been applied to what we now call "vitiligo."
Ancient Indian culture [4] is replete with references to vitiligo. The sacred
Indian book Atharva Veda (1500-1000 B.C.) mentions the words "kilas" meaning white spot or patch on the skin and "palita" which applies to the yellow
tinge of these spots. That "palita" is derived from "pal," meaning "old" or
"aged," suggests this term applies to the canities or leukotrichia associated with
aging.
"Shvetkushtha" is derived from "shvet" (white) and "kushtha" (referring
to skin diseases in general) and according to the Sanskrit dictionary means
"that which makes the body ugly or spoils the blood." Villagers applied the
term "charak," meaning "that which is secret" or "that which spreads"; both
interpretations seem appropriate for a progressive condition with marked social
stigma.
From the Far East in Makatominoharai, a collection of Shinto prayers
dating from 1200 B.C., "shira-bito" or white man is mentioned. This also could
have been vitiligo [5].
In the Buddhist sacred book Vinay Pitah (624-544 B.C.), "kilas" is mentioned; those afflicted with leukoderma could not be ordained.
Manusmriti (200 B.C.) shows the lack of respect accorded one with "svitra,"
a term applied to vitiligo. One who had stolen clothing in his former life might
be reincarnated with "svitra."
In Amarkosha (600 A.D.) the term "svitra" was used synonymously with
"padasphota" (flower of legs), "twakpuspi" (flower of skin), and "sidhmali"
(spreading whiteness).
"Bohak," "bahah," and "baras" are the Arabic names for vitiligo [6]. In the
Koran (3:48, 5:109), "In accord with God's will Jesus was able to cure patients
with Baras."
Later Descriptions of Vitiligo
Casual use of the terms "vitiligo" and "leukoderma" has introduced considerable confusion into the scientific literature over the last century and to
this day. Beigel [7], in his memoir of 1864, reserved the term vitiligo for those
cases with observable change of structure as well as loss of pigment in the skin.
* Professor of Classics, Harvard University.
131
GENETIC AND
CONGENITAL
DISORDERS
132
CHAPTER 1
This clearly does not apply to vitiligo as we diagnose it today. Pearson et al.
[8], just after the end of the 19th century, used the term "leukoderma" to
designate a disease which seems to be vitiligo.
The geographically scattered early reports of vitiligo emphasized the global
incidence of the condition and often dramatized the social seriousness of it.
Fifteen cases of vitiligo in blacks were recorded between 1698 and 1910. The
first case, that of Byrd [9], was of a black boy who had been "dappleI'd" with
white spots in several places. "The spots are wonderfully white at least equal
to the skin of the fairest lady and have advantage in this, that they are not able
to be tanned." Early cases were also reported in Europeans, North American
Indians, Egyptians, and Bengalese [8].
It is clear, from the clinical description of the disease by Pearson et al. [8]
in 1911 that early clinicians appreciated many of the features of this condition.
While in the twentieth century there has been general agreement about the
broad nature of vitiligo, significant controversy remains. Many leukodermas of
various origin-chemical depigmentation, tuberous sclerosis, melanoma, halo
nevus, etc.-have been and still are described under the title "vitiligo."
Modern Nomenclature and Definition
Vitiligo is a circumscribed, acquired, idiopathic, progressive hypomelanosis of skin and hair which is often familial and which is characterized microscopically by a total absence of melanocytes. Melanocytes of the skin and
of the hair are the commonly recognized end organs of this disorder in which
melanocytes of the leptomeninges, retinal pigment epithelium, uveal tract, and
inner ear may also possibly be involved. The cutaneous patches are chalkwhite, separate and discrete, often progressively confluent, and on occasion
universal. The presence of disease associations and autoantibodies in too many
patients to be coincidental suggests that vitiligo must be a systemic and not
just a purely cutaneous disease. The definition, by stressing an "absence of
etiology," carefully excludes chemically induced depigmentation, depigmentation associated with melanoma, depigmentation secondary to various other
dermatoses, and other entities for which the precipitating factor seems clear.
Since no specific biochemical features of vitiligo have been identified and
since the most characteristic histologic feature is a total absence of melanocytes,
rigid laboratory criteria for a diagnosis of vitiligo are lacking. It is uncertain
whether vitiligo is one disease entity with a specific pathogenesis or a final
common pathway of several different processes.
Clinical Features
Incidence
among all peoples of the world. Review of the various studies on vitiligo in
different countries reveals a generally higher incidence in India and Mexico
than in Japan and a relatively lower incidence in all of Europe. The incidence
figures reported for the United States vary from 0.14% to 8%, but the overall
incidence is thought to be 1% of the entire population [29].
Country
AFRICA
Egypt
ASIA
India
Calcutta
Vellore
Calcutta
Aramavati
Delhi
Rural South Gujanat
Urban South Gujanat
Goa
Japan
Sendai
Malaysia (Singapore)
EUROPE
Denmark
Denmark
England
England
France
France
Italy
Russia
Switzerland
NORTH AMERICA
Mexico
Mexico
United States
Michigan University
Pendleton (Oregon)
Nevada (Missouri)
Indiana University
Massachusetts General
Hospital
Sample
population'
(%)
D.O.
6
4
4.3
8
8.8
2.9
1.64
1.3
0.7
D.O.
D.O.
D.O.
G.O.P.
D.O.
P.L.
P.L.
D.O.
G.O.P.
D.O.
D.O.
0.38
1.44
0.15
0.42
3
0.6
0.3
0.14
0.39
P.L.
G.I.P.
0.1.
D.O.
Children
D.O.
Children
D.O.
D.O.
4
2.6
D.O.
D.O.
0.66
0.14
0.19
3.2
8
G.I.P.
P.L.
P.L.
P.L.
D.O.
~::~ }1.79
133
GENETIC AND
CONGENITAL
DISORDERS
134
CHAPTER 1
These differences among various global populations are likely more apparent than real because the reported incidence is often directly related to the
depth of constitutive pigmentation. Vitiligo seems most common in populations
in which the contrast in skin color is readily apparent. In India, it is the
association with social stigma that compels a greater percentage of afflicted
individuals in this population to seek medical care as opposed to populations
in which vitiligo is socially insignificant; surveys from India may show a falsely
increased incidence for this reason. It is, however, possible that such highly
active melanogenic pathways are somehow predisposed to vitiligo.
Basic differences among the sample populations are also partially responsible for the wide scattering of reported incidence figures. Dermatologic outpatients or general inpatients are not necessarily representative of the population at large. For example, the 8% incidence reported from the Dermatology
Department at Massachusetts General Hospital, Boston, Massachusetts [32] reflects the long-standing interest of this department in pigmentary abnormalities.
The low incidence reported from the University of Michigan [28] is based on
a retrospective study of hospitalized patients; since patients are not hospitalized
for the treatment of vitiligo and since vitiligo is probably overlooked in the
inpatient record of medical diagnoses, an artificially low incidence figure is
not unexpected. The studies from Pendleton, Nevada [29] were based entirely
on the observations of patients; those with only a few macules or very fair skin
would not all be expected to be aware of their disease. The only studies of
populations at large are from the United States [29,30], India [16], and Denmark
[21], and these incidence figures vary from 0.14% to 3.2%. Probably the worldwide incidence is at least 1% or more and all geographic areas of the globe are
equally affected.
Race
Vitiligo affects all races [8]. Most reported series are of Caucasians but there
are several among Orientals [19,20] and a few among blacks [33]. A statistical
tabulation [34] of 3860 consecutive black dermatologic outpatients revealed a
1.6% incidence of vitiligo, no different from the 0.7% to 1.6% reported from
Orientals.
Sex Prevalence
In 13 of 18 series (Table 24), there are more women than men. Among all
series, 41 % to 73% are women, and 27% to 59% are men. The generally reported
prevalence in women is considered not to represent a real difference. Rather
it is likely that women are more sensitive to cosmetic disfigurement and more
likely than men to present themselves for treatment. Probably neither sex is
predisposed to vitiligo.
Heredity
Even the early writings on vitiligo included many cases of familial vitiligo.
In 1911, Pearson et al [8], noting a patient with a rather heterogeneous genetic
background, suggested a hereditary factor and stated, "There is some evidence
Males
(%)
34.7
59
32.5
57
28
45.9
53.25
34.7
27
48
48.9
42
26.7
41
48
48
51
Females
(%)
135
Total no.
of patients
65.3
41
67.5
43
72
54.1
46.75
65.3
73
52
51.1
58
73.3
59
52
52
49
70
405
200
340
60
545
650
70
380
400
129
200
116
100
202
179
430
for supporting that leukoderma ... may occur as a result of pigmentation upset
following hybridisation."
The prevalence of a positive family history of vitiligo varies from 6.25%
to 38% (Table 25). Lerner [29] stated that the prevalence figure of 38% is
probably minimal. Artificially low incidence figures may result from lack of
communication among relatives and from unawareness or nonchalance because
of late onset of the condition. The highest prevalence, 78.27%, has been reported
from India [16] but the small size (46 patients) of this series diminishes the
Incidence
(%)
Total no.
of patients
6.5
22
11
38
35
35.25
17.75
6.25
33
78.25
18.75
6.9
700
219
244
200
430
545
650
400
340
46
96
202
GENETIC AND
CONGENITAL
DISORDERS
136
CHAPTER 1
FIGURE 43. Familial vitiligo. a: Vitiligo in identical twins: distribution of leukoderma is similar.
b: Vitiligo affecting father and son (forearms and hands of father and trunk of son are shown).
Dark brown is the most common scalp hair color in vitiligo populations.
In a population of 100 French patients [39], 76% were found to have dark
brown hair, 13% light brown, 7% black, and 4% blond hair. Of 100 Massachu-
137
GENETIC AND
CONGENITAL
DISORDERS
138
Type I
CHAPTER 1
Type II
Type III
Type IV
Type V
Type VI
70
l!l
60
50
....
o
...
40
<:
8!.
<:
'"
~
'"
c..
30
20
10
0----~V~C~--~~~---LV~7CL---~V~~CL---~~~--~~~
FIGURE 44. Skin Types in 100 vitiligo and 100 control patients. V = vitiligo patients; C = control
patients.
setts General Hospital vitiligo patients, 36% were found to have dark brown
hair, 11% medium brown hair, and 30% light brown hair. Black, blond, and
red hair occurred in 11%, 10%, and 2% of patients, respectively.
Eye Color
Most vitiligo patients have brown eyes. Ortonne [39] found 77% of his
vitiligo patients to have brown eyes, 13% blue, 5% blue-green, and 5% dark
brown to black. Of 100 Massachusetts General Hospital general dermatology
patients without vitiligo, 48% had brown eyes, 25% blue eyes, 14% green eyes,
and 13% hazel eyes. Lerner [39], who found four patients with vitiligo in one
family, observed that only those with brown eyes were affected and suggested
a genetic linkage between brown eyes and vitiligo. No definite linkage, however,
has been established. We have one patient who has observed a change of her
iris color from brown to blue and another case has been reported [61].
Age of Onset
Vitiligo may first appear from birth to senescence (Table 26), though onset
between 10 and 30 years of age is most common.
Although vitiligo is generally considered an acquired condition, several
cases of "congenital vitiligo" have been described. Depigmentation in a threeday-old child was surely congenital vitiligo [62]. Panja [11] found seven of his
260 cases to be congenital. In one of the two "congenital" cases reported by El
Mofty [6], the depigmentation appeared as a linear streak down the inner left
leg. In the other there were depigmented macules on one side of the abdomen.
Although further information is not available on each case, these most likely
represent nevus depigmentosus and not vitiligo. In another case of what probably is congenital vitiligo [63], there was evidence of spontaneous repigmentation and marked improvement with oral psoralens and ultraviolet irradiation.
Another, who was born with a large patch of amelanosis on the right hand,
was 14 years of age before any other new macules appeared. Several months
of 8-methoxypsoralen treatment resulted in islands of repigmentation in the
Author
Levai (1958) [12]
Lerner (1959) [29]
Dutta and Mandai (1969) [13]
Fitzpatrick and Mihm (1971) [32]
Behl and Bathia (1972) [15]
Ortonne (1974) [39]
Howitz et al. (1977) [21J
139
6 months
8 months
6 months
1 year
8 months
4 years
Birth
to
to
to
to
to
to
to
70
70
72
69
75
81
85
years
years
years
years
years
years
years
new lesion, but not in the congenital one; unfortunately electron microscopy
was not available to confirm the diagnosis of the congenital lesion which could
have been nevus depigmentosus.
Nearly all vitiligo is acquired relatively early in life. The average age of
onset is around 20. The peak onset has been reported to be between five and
10 [11], six and 15 [16], seven and 12 [40], 10 and 19 [17], 11 and 30 [15], 22
and 30 [6], 25 and 45 [35], and 50 and 59 [21]. Lerner [29] observed 50% of
his patients had incurred the disease by the age of 20, 45% between 20 and
40, and only 5% developed it after the age of 40. Of 129 patients, Mehta et al.
[16] found one to be less than five years of age and 15 older than 55. Seghal
[17] noted 8.6% of males and 9.6% of females in the age group of birth to four
years, and 0% and 1.1%, respectively, greater than 70 years of age. There is
one epidemiologic survey, that of Howitz et al. [21], which is atypical in that
over half of the patients reported onset after the age of 40. Onset as late as 75
and even 81 years has been reported [15,39]. Vitiligo most commonly begins
between 10 and 30 years of age and rarely in infancy or senescence (Fig. 45).
All surveys but that of Howitz et al., however, are flawed by being extracted
from average vitiligo populations which tend to be young; those who develop
vitiligo in older age may not see their physician about it.
Many reports suggest that the mean age of onset is younger in females than
in males. Levai [12] from India found the average age of onset to be 18 for
females and 26 for males, while Howitz et al. [21] found virtually no difference-3 6.7 and 38.7 years , respectively-among the Danes. Seghal [17] reported
that 62.7% of females and 55.5% of males surveyed had developed their diseases
by the age of 19. He found the majority of patients between 10 and 19 and
again in old age to be females, whereas male onset predominated among those
in the third and fourth decades. This is similar to the observation of Ortonne
[39] who found a slightly earlier onset among females with clustering among
the second and third decades. It seems unlikely that the age of onset should
vary between the sexes. That women may have a heightened concern about the
appearance of their skin may contribute to an early awareness of the condition.
Duration and Age of Presentation for Evaluation
In general, females present for treatment for their vitiligo earlier than do
males. Seghal [17] found that 50.5% of females and 38.2% of males eventually
seen with vitiligo had presented for evaluation by the age of 19. Levai [12]
GENETIC AND
CONGENITAL
DISORDERS
30
140
CHAPTER 1
25
...c:'"
20
r-
Ql
.;:;
'"a.
15
r-
'0
r-
10
5
0
~ill
9 19 29 39 49 59 69 79
Age (years)
~Total
Males
Females
FIGURE 45. Age of onset of vitiligo. ( From: Ortonne J-P: Le Vitiligo: Maladie ou Syndrome. These
Medicine, Lyon, 1974.1
found the average age of presentation to be 21 for females and 29 for males.
Mehta et al. [16] noted in the evaluation of 66 cases that the duration of the
condition was less than one year in 12, from one to five years in 33, from five
to 10 years in 70, and more than 10 years in 14. Seghal [17] found 18.1% of
females and 22.7% of males had had the condition less than three months and
23.8% of females and 20.6% of males longer than five years. Levai [12] found
the duration of the condition to be two weeks to 30 years, with an average of
three years. It may be that patients delay being seen because of the notion
among general practitioners and the population at large that no treatment is
available.
Precipitating Factors
There is no single factor known to cause vitiligo. However, some patients
and physicians have observed that one or more events seem to precipitate or
at least to antedate the initial awareness of vitiligo. From 10% to 76% [13,15]
of vitiligo patients are able to implicate a precipitating cause such as physical
injury, sunburn, emotional trauma, illness, etc. Many can cite an emotionally
traumatic event such as a quarrel, death of a parent or spouse, bad accident,
or other event after which they first became aware of their vitiligo [64-69].
Huriez et al. [70] found significant psychologic factors in 58.3% of his 72 cases.
Lerner [29] found among his patients that 30% claimed an antecedent emotional
upset, that 39% could cite an antecedent accident, illness, operation, or parturition, and that only 31 % were unable to associate their condition with any
type of stress event. In another series [13], 40.75% implicated local trauma,
17.5% gastrointestinal complaints, 8.25% emotional upset and insomnia, 2.5%
pregnancy and delivery, 1.5% operations and accidents, and 5.5% miscellaneous illnesses; 25% could identify no single precipitating event.
Certainly many patients link the onset or progression of their disease to
specific physically or emotionally traumatic events. However, such events may
heighten individual awareness of oneself and permit discovery of a previously
established but unnoticed pigment defect.
Psychologic Factors
Reporting on a patient whose leukoderma began after the Jamaican earthquake of 1907, Pearson et al. [8] comment skeptically, "We do not wholly
dismiss shock as a possible initial source but only wish to indicate that neither
shock nor sudden illness seems essential."
The literature is replete with cases of "acute vitiligo" attributed to various
emotionally traumatic events. In a young girl with vitiligo, the depigmentation
became generalized after an explosion [71]. Another young girl thought she
had developed vitiligo overnight; the morning after she had been nearly hit by
gunfire, she awakened to note the presence of macules of vitiligo [72]. After a
woman was found to have a malignancy, her father and daughter developed
vitiligo [39]. Abrupt onset was observed by the wife and the son of a man
revealed to be homosexual. The authors [73] suggested that vitiligo represents
an equivalent or consequence of traumatic anxiety or the equivalent of object
loss.
Gajwani and Seghal [74] have reported a woman in whom hypnotherapy
led to repigmentation of perioral vitiligo.
A significant increase in the incidence of psychologic trauma has been
reported among vitiligo patients as opposed to controls [75]. This raises the
question of the premorbid psychologic constitution of the afflicted individual
or a "vitiligo personality." The psychiatric profile of 16 other patients with
vitiligo was found to include de~nite premorbid abnormalities including neurotic behavior, psychomotor agitation, insomnia, and emotional immaturity
[76]. Only four of the cases displayed significant psychologic reaction to the
disease. However, 12 had been able to associate their vitiligo with a specific
emotional event, and in several there was particular symbolic meaning to the
localization of the macules (genital involvement in a man whose wife was
unfaithful, vitiligo of the feet in a prisoner, and vitiligo of the abdomen in a
pregnant female).
It has been suggested that emotional factors are of greatest significance in
acrofacial vitiligo and of least significance in the zosteriform type.
While it is possible that these observations may be explained by a neuropsychiatric factor responsible for vitiligo-a mediator acting at the terminal
end plate or at a more central level such as the hypothalamus to inhibit the
melanogenic pathway-all of these anecdotes-must be interpreted with caution.
In most people, emotionally significant events occur, yet vitiligo is uncommonly the result. Furthermore, there is always, in the phase of development
of the condition, a tendency to feel compelled to affix "blame," and here emotional trauma may be found causally guilty but be, in fact, only casually present.
Cause and effect is not established. Since the presence of the leukoderma must
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Well, I have had vitiligo almost half my life and to be honest I feel as though life
stopped somewhere around age 23 or so for me. This is when it started getting bad.
Since then I have been in a sort of limbo waiting for a miracle cure to take place. I
am not enjoying life the way it was meant to be. I am simply existing, waiting for my
cure so I can catch up with and join the rest of the beautiful people. I may sound
bitter about this and maybe I am. I don't recall doing anything bad enough to deserve
this, and why has it been decided for me to have it instead of you, anyway? Why did
I get it now instead of when I got real old and wouldn't care? People expect me to
just accept it and continue on. I wonder if, in my shoes, they could, and if they had
two beautiful children who have a good chance of getting it, would they just sit and
say "This is fine, we don't mind if we're covered with crud, if we're stared at, snubbed,
laughed at." Would they really just take it as easily as they expect me to? They can't
possibly answer as they really haven't any way of knowing how it actually is till they
have been there.
Before I joined the ugly group, I used to work next to a woman covered with vitiligo.
I, like all the rest of the human race, couldn't talk to her. All I could do was look the
other way and think "My god, is she ever messed up!" Well if I were she I would
rather be dead than go through life like that. I wish I could have spoken to her as if
she were normal. So I do realize how people feel about us ugly ones. People can't
accept anything that is less than perfect and that is why I can't accept it.
Friends try to tell me not to let it bother me, to get into a bathing suit and go to the
beach. The fun I may have isn't worth the snubs, pointed fingers, and gossip. I get
these disgusted looks, as if "Here she comes, the walking talking horror show." I feel
I should join the circus as one of their freak acts. They have the snake man, albino
lady, fat lady, now what they need is the bleach lady. I feel like "Casper the friendly
ghost." All I want is to be friends, but the sight of me makes people feel ill at ease,
very uncomfortable with me.
When the doctor asked me what vitiligo means to me, my first answer was that I feel
like a mistake. If it isn't a mistake then all you one-colored-persons are the mistake.
I don't see all you one-colored-persons trying to get bleached out till you're two colors.
So this shows that it is just that: I am a mistake!
I believe if there were no hope for me I would crack up, but if I were lucky I would
end it all first. They say where there is life there is hope. The doctors say they will
treat me only as long as I am repigmenting. At least fully dressed, with long pants
and long sleeved shirts, I look almost like one of you humans. To be rid of vitiligo
would be like being reborn for me, to be normal and happy,
Perhaps this patient is a bit more overtly angry and hostile about her
affliction than most, but some of her expressed feelings exist to a lesser or
greater degree in many vitiligo patients we see. However, whether or not there
is a preexistent vitiligo personality is uncertain.
One study has attempted to catalogue the psychologic ramifications of
vitiligo. These were found to include inferiority complexes, variable aggressiveness, shame, seclusion, and resentfulness [79]. The following factors were
found to be important to the adjustment of the patient to the condition: the
premorbid psychologic makeup, the anatomic area of the body involved and
the social, economic, and physiognomic importance thereof (most difficult for
adolescents and very young adults), the insidious or acute nature of the condition (patients adjust better to slow evolution than to abrupt changes), and
the duration of the condition and course (rate of progression). A certain emotional adaptation seems to occur over time; patients "learn to live" with their
condition and after a time no longer actively seek treatment.
Many of the patients who present for treatment of their vitiligo are aggressive and often angry individuals. It may be that this behavior pattern results
from the condition, but more aggressive patients are those more likely to seek
treatment. Since dermatologists generally see only those patients who seek
treatment, it may not be correct to assume that the personality profile of vitiligo
patients who seek help is representative of the vitiligo population at large.
Physical Trauma
Some patients have attributed their vitiligo to actual physical injury [29].
Vitiligo has been observed to begin at the site of a recent injury. Onset of vitiligo
of the neck was observed after contusion of the occiput [80] in one patient and
a direct blow with a bowling ball to the right temple area seemed to result in
segmental vitiligo of the right side of the face in another. In one case, whitening
of the scalp and pubic hair was first observed six months after a contusion.
There are many other cases of vitiligo appearing after head injury [32]. An
occasional patient may report hislher vitiligo initially began on a site of trauma
or at a surgical site and later spread centrifugally or new macules developed
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elsewhere. Curiously, there are several reports of vitiligo appearing at sites of,
and corresponding to, the array of injuries incurred four to five years earlier
[81].
reaction has also been reported [35]. A role of sunlight is further suggested by
the fact that in about 70% of cases, vitiligo seems to appear first on sun-exposed
areas of the skin-80% [29], 70.9% [6], 66% [39], 53% [32], according to various
series. However, vitiligo is a well-known Koebnerizing disease and onset or
spread following a burn is an example of this phenomenon. Among lightskinned people and on normally unexposed cutaneous areas of any Caucasian,
newly acquired vitiligo macules may not be noticed until the normal skin
becomes tanned enough to provide contrast. This may explain why most of the
vitiligo patients date the onset of vitiligo to spring [39].
Vitiliginous skin is more sensitive to sunburn than is normally pigmented
skin [88]. A decreased minimal erythema dose in macules of vitiligo [89] and)
increased tendency to sunburn in macules of vitiligo compared to normally
pigmented skin of the same patient [90] is well established. Patients who normally tan well and who rarely if ever burn their normal skin may develop a
severe acute sunburn reaction in their vitiligo macules but not on their normally
pigmented skin. Some patients do observe hardening, that is, their vitiligo
macules are less likely to burn after several sun exposures than with the initial
exposure of the season. This has been attributed to ultraviolet radiation-induced
thickening of the stratum corneum of vitiligo macules; this thickening, in turn,
is somewhat photo protective to the vitiligo macules [91]. This phenomenon is
probably of minor clinical significance however.
Clinical Findings
Typical Lesions
The typical lesion of vitiligo is a discrete, well-circumscribed, chalk-white
macule, a few centimeters in size, with sharp, convex margins (Fig. 46). Although the margins of the lesion are sharp, they are not so sharp or punchedout as are lesions of idiopathic guttate hypomelanosis. Often the vitiligo macules appear to be invading the normally pigmented skin (Fig. 47). There are
usually no other epidermal changes and the skin appears otherwise normal.
Color of Macules
The most common form of vitiligo is a totally amelanotic macule surrounded by normal skin. The color of the macule is usually uniformly pure
white or chalk-white. In very fair-skinned people, the lesions are not very
apparent but are easily distinguishable with Wood's light examination or after
delayed tanning of uninvolved skin. In dark-skinned people, the contrast between vitiliginous skin and normally pigmented skin is striking, even in habitually unexposed areas of Skin Types V and VI.
While vitiligo macules are characteristically uniformly chalk-white in color,
two other pigmentary changes are observed in many cases. In addition to totally
depigmented white macules, there may be pigmentation that takes on an intermediate tan (trichrome) color, and hyperpigmented dark brown islands either
within or at the periphery of these vitiliginous patches. All these color reaction
patterns may occur in a single patient, or either trichrome or hyperpigmented
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FIGURE 47.
macules may accompany the depigmented macules. The presence of all these
color patterns together-normal, achromic, trichrome, and hyperpigmentedwe refer to as "quadrichrome."
The third color, or trichrome (tan), on rare occasions, is the only feature
of vitiligo; usually there is a tan zone of varying width between the normal
and the totally depigmented skin and this exhibits the intermediate hue. The
term "trichrome vitiligo" was suggested in 1964 by Fitzpatrick [41] who observed this gradual change of color from milk-white in the center through light
tan to normal brown at the periphery of the lesions in both Caucasian and darkskinned individuals (Fig. 48). Siemens [92] called this "vitiligo gradata." The
German term "Stufen-Vitiligo" (vitiligo by steps) also denotes this phenomenon.
Lerner [29] also noted around depigmented macules a "lightly colored broad
band, one to three centimeters in width," but observed the intermediate hue
to be surrounded peripherally by a hyperpigmented border, an observation not
commonly made by others (and named quadrichrome by us). This intermediate
hue is particularly accentuated in those who tan deeply. Trichrome is not a
gradation of color from white to normal, but rather a fairly uniform intermediate
hue; the color is generally uniform from macule to macule in a given patient.
Sometimes the entire vitiligo macule is only hypopigmented and not totally
depigmented. These lesions have an intermediate, uniform tan color identical
to the light brown color of trichrome. All of these types of hypomelanosis may
coexist in a single patient.
Several reports show trichrome to be part of a dynamic process. Dupre et
al. [93,94] reported "cockade vitiligo" in a fair-skinned French boy and in a
North African who had usually two but sometimes more trichrome concentric
rings or lines surrounding an achromic line corresponding to former scratches.
This was the first description of trichrome as an isomorphic phenomenon. Small
achromic macules in the intermediate hypochromic area and numerous brown
speckles were also observed. A gradually spreading "symmetrical primary leukomelanoderma" described by Basset [95] and Sarrat and Nouhouayi [96] in
black patients is also probably trichrome vitiligo.
The significance of trichrome is unknown, but clearly it is a metastable or
transitional pigmentary state, though it may persist for months to years with
little change. Fitzpatrick [41] and Pincus [97] interpreted trichrome as suggestive of a gradual centrifugal spread of hypomelanosis or stepwise depigmentation. But Dupre et al. [93,94] pointed out that the sharp demarcation between
the three areas in their cases, as well as the lack of gradual changes of color
and the stability of the lesions, is inconsistent with the interpretation of trichrome vitiligo as an active centrifugally spreading lesion. Evidence for the
lack of stability, however, includes the observation that when a trichrome area
repigments, the trichrome is lost as the perifollicular dots appear (unpublished
observation).
Other color changes are also described. Sidi et al. [35] mention "vitiligo
ponctue," small depigmented macules occurring on a hyperpigmented macule.
These confetti or tiny discrete hypomelanotic macules may also occur on otherwise normally pigmented skin (Fig. 49). "Speckled vitiligo" or "vitiligo
mouchete," as described by Sezary and Dupuy [98], denotes pigmentary islands
scattered throughout the vitiliginous macules. These macular islands are perifollicular and represent repigmentation arising from the hair follicles. Occa-
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GENETIC AND
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150
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Generally, vitiligo macules have fairly discrete margins and are rounded,
oval, or linear in shape (Fig. 50). The borders of these lesions are usually convex,
as if the depigmenting process were "invading" the normally pigmented skin
[32]. The concave borders of the normally pigmented skin in a vitiligo patient
may help to distinguish a remaining pigmented macule in a patient with generalized vitiligo from an isolated area of hyperpigmentation in a very fairskinned individual (Fig. 51). In the former, remaining pigmented skin has
concave borders and in the latter "abnormally" pigmented skin shows convex
borders. Vitiligo macules enlarge centrifugally over time but the rate of change
may be slow to rapid.
In trichrome vitiligo, the presence of a tan band of varied width between
the normally pigmented skin and the depigmented macule of vitiligo may give
151
FIGURE 51. a and b: Irregular margins of macules of normal pigmentation surrounded by vitiligo.
The concave borders portray the invasive nature of vitiligo.
a feathered appearance to the margin of the vitiligo macule, but close inspection
reveals a distinct margin between normal skin color and the intermediate hue
and also between the latter and the white central area.
Generally, the macules of an area of involved skin have no uniformity of
size. Vitiligo macules may be millimeters to centimeters in size (Fig. 52) and
increase centrifugally in size over time. Several sizes often prevail in a single
patient. The macules become confluent and develop serpiginous margins as
they enlarge and coalesce.
Lichenification, inflammation, and raised borders have, on a few occasions,
FIGURE 52. Macules may be variable in size. a: Small macules on knees; confetti spots are also
present. b: Large macules with a few small macules on knees; trichrome is also apparent.
GENETIC AND
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152
CHAPTER 1
FIGURE 53. a and b: Inflammatory vitiligo with raised borders which usually are somewhat erythematous. The raised
border represents an advancing
front of depigmentation.
of the margin. Certainly the raised margins are a rare macroscopic presentation
of what must be characteristic of active vitiligo macules-some degree of inflammation at the margins of the macules of progressive lesions. Vitiligo macules with raised margins otherwise resemble those with flat margins.
Number of Depigmented Macules
The number of lesions varies considerably from one patient to another.
Levai [12) noted that 118 of her 410 patients had single lesions. whereas the
remaining 292 averaged lesions in three different locations. While some individuals have only one macule which remains little changed for a long period
of time. others have up to several hundred macules and seem to develop new
lesions periodically. The vitiligo may be so extensive that depigmentation of
the entire skin occurs. The number of macules present in a patient usually
increases with age but may remain the same or rarely decrease spontaneously.
Distribution of Depigmented Macules (Fig. 54)
Vitiligo has distinguishable patterns. Vitiligo lesions may be localized or
generalized. the latter being more common. Localized vitiligo involves vitiligo
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macules restricted to one general area including a segmental or quasidermatomal distribution. Segmental vitiligo is vitiligo roughly corresponding to areas
of innervation of one or more of the cutaneous nerves, is strictly unilateral,
and does not extend beyond the midline. Generalized vitiligo implies more
than one general area of involvement; the macules are usually found on both
sides of the trunk either symmetrically or asymmetrically arrayed (Fig. 55).
Segmental involvement may coexist with generalized vitiligo (mixed type).
Dutta and MandaI [13] found bilateral lesions in 74.5% of their 650 cases. Seghal
[17] observed unilateral lesions in 11 of his 65 patients with upper limb in-
FIGURE 55. a-c: Examples of symmetrical generalized vitiligo; similar areas are involved on each side,
although one side is not the mirror image of the other.
volvement and in 16 of 107 patients with leg involvement. Dutta and MandaI
[13] found unilateral focal or segmental lesions in 25.5% of patients.
Although vitiligo may occur anywhere on the skin, there are characteristic
patterns of involvement. One of the most fascinating features of the localization
of vitiligo is its frequent localization to the sites that are normally hyperpigmented, such as the face and dorsal hands (facultative tanning reaction), axillae,
umbilicus, nipples, sacrum, and inguinal and pudendal regions (constitutive
color) (Fig. 56).
Typically, vitiligo occurs around the eyes and mouth (periorificial), the
anterior neck, extensor elbows and digits, perineum, palmar wrists and dorsal
ankles, anterior tibial regions, and low back (Figs. 57, 58). Dutta and MandaI
[13] found the most commonly involved sites to be the lower extremities,
particularly the pretibial areas (27.5%), the upper extremities with maximum
involvement of the hands (22%), the face (20.5%), the hair (8.7%), the chest
(5.8%), the neck (4%), the back (3.7%), and the abdomen (3.6%). In 365 Indian
patients, 72% had involvement of the legs, 57% the feet, 55% the arms, 51%
the back, 50% the face, 47% the chest, 47% the hands, and 31% the neck
(personal observations). Seghal [17) noted that women are more likely to have
involvement of the face, arms, and legs, while the chest and back are more
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GENETIC AND
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FIGURE 57. Typical case of generalized vitiligo involving dorsal hands, including periungual areas (a), extensor forearms (b), axillae and
low back (c).
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GENETIC AND
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FIGURE 58. More extensive involvement with vitiligo; large macules of trichrome are present
and trichrome borders many of the amelanotic macules.
Involvement of palms and soles has heretofore not been well appreciated
(Fig. 60). Costa [50] observed palm and sole vitiligo in two Brazilian patients
in 1928; Ferraz-Alvim and Guerner [111] reported one case of palm and sole
involvement in a vitiligo patient with goiter and mental confusion. Ochi and
De Groot [112] reported palm and sole involvement in three of their six patients
who also had Graves disease; they suggested that this distribution of vitiligo
marked the presence of thyroid disease. Seghal [17] makes no mention of palm
and sole involvement but Dutta and MandaI [13] noted that palms, and particularly the soles, are quite often affected. Of our 365 Indian patients, 117 have
palm and/or sole involvement (unpublished observation). Probably palm and
sole involvement in whites is underreported because the normal light skin
color of Caucasoid palms makes vitiligo difficult to visualize without Wood's
light examination.
Mucous membrane involvement (Figs. 61, 62) in vitiligo seems historically
to be uncommon, if not rare. However, the early cases reported by Bate [113]
in 1760, by Jefferson [114] in 1787, and by Brown [115] in 1824 probably had
involvement of the mouth and lips. In 1917, Pusey [116] reported a dark-skinned
patient with vitiligo of the lips. Other isolated cases of mucosal involvement
have been observed on the vaginal mucosae [82] and on the lower lip [117].
Brunnauer [118] stated that vitiligo of the lips occurs only in blacks, but Montgomery [119] described involvement of the upper lip in a Japanese farmer. In
1944, Arguelles-Casals [120] also reported two cases with mucosal involvement,
one in a black and the other in a Cuban. Costa [50] in Brazil observed several
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FIGURE 59. Typical examples of vitiligo. a: Patchy periorificial involvement; macules of repigmentation on the neck are a result of psoralen therapy. b: Vitiligo of periorbital skin. lips. and
dorsal hands. c: Vitiligo of extensor surfaces, particularly over metacarpal-phalangeal joints and
proximal interphalangeal joints. d: Periungual depigmentation is not uncommon.
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FIGURE 59 (Continued). e: Vitiligo of upper and mid-lower central back, medial arms , and extensor surfaces of elbows. f: More extensive vitiligo of the anterior lower legs and extensor surface
of the knees . g: Flexor wrists are commonly involved; as in this case, the leukoderma may extend
onto the palms.
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FIGURE 60. Vitiligo of the palms. In this patient some sparing of folds has occurred. Wood's
lamp examination may be required to appreciate palm and sole involvement in a light-skinned
Caucasian.
FIGURE 61.
of the lips.
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GENETIC AND
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cases with involvement of the lip. Dummet [121] described an American black
with complete clinical depigmentation of the oral mucosa.
In our study of 365 East Indians we have found lip involvement in 189
(unpublished observation). Of 202 vitiligo patients, Seghal [17] found isolated
mucous membrane involvement in 10.3% of males and 3.8% of females; 28.9%
of males and 26.7% of females had some mucosal involvement (total of 27.8%).
The age of onset of "vitiligo mucosae" was 24.4 16.1 years (20.9 in all types)
and the mean age of reporting was 28 15.1 years , no different from other
types of vitiligo. Lip involvement was equally distributed among men and
women. Genital involvement alone occurred in seven cases, five of whom were
men. Of 100 cases of leukoderma of the lips observed by Coondoo et al. [122],
52% had evidence of vitiligo in other areas; of those with lip leukoderma alone,
many had antecedent lip rashes , suggesting postinflammatory hypomelanosis
or a Koebner reaction.
In many series, mucosal involvement is not mentioned or is said to be rare.
One presumes that the apparent low incidence in Caucasians is a reflection of
the normally light color of the mucosa.
Involvement of Body Hair and Scalp Hair
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FIGURE 63. This patient had extensive vitiligo of his chest yet few hairs were depigmented.
hair, but total depigmentation of all scalp hair may occur. This may occur with
or without vitiligo of associated scalp macules. Vitiligo may involve only the
skin of the scalp though less commonly than the face or neck (Fig. 64). Dutta
and MandaI [13] noted scalp involvement in only 2.5% of their cases. Khoo
Oon Teik [20] observed that forehead involvement often extends to include the
scalp skin and hair. Nearly one-third of our cases had white scalp hair (unpublished observation). Scalp involvement without leukotrichia is probably
much more common than with leukotrichia.
Presence of leukotrichia has been accorded special significance. According
to Lerner and Nordlund [123], people with much gray hair before 30, that is,
those who "are mostly gray by age 25 or 30," but still do not have white spots
on the skin, have vitiligo; this is a broader use of the term vitiligo than we
accept. Dutta and MandaI [13] noted that variable repigmentation, either spontaneous or posttherapeutic, occurs in 59% of cases without achromotrichia,
while it occurs in only 24% of those with white hair. They concluded that
absence of hair depigmentation is a favorable prognostic sign. Our studies do
not support this conclusion (unpublished observations).
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GENETIC AND
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b
FIGURE 64. Macules of vitiligo extending onto the scalp line. a: Scattered hairs are amelanotic.
Some macules of psoralen-induced repigmentation are apparent. b: Extensive depigmentation of
hair in woman with vitiligo of the face, scalp, and neck.
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FIGURE 65. The Koebner or isomorphic phenomenon is leukoderma developing in sites of trauma.
The macules are usually remarkably linear or correspond to the shape of the offending agent. a:
Scratch macules. several with trichrome. b: Vitiligo from pressure of a Canadian crutch. c: Site of
a laceration; note leukoderma along laceration and with suture lines. d: Trichrome vitiligo or an
isomorphic phenomenon. (From: Dupre A et al: Une variante du vitiligo trichrome de Fitzpatrick:
vitiligo en concorde et vitiligo lineaire sur cicatrice. Bull Soc Fr Dermotol Syphiligr 81:530-532,
1974. Copyright, 1974, Masson et Cie. Used with permission.)
There have been many attempts to classify types of vitiligo, often with
confusing results. The classification of vitiligo is usually based on the distribution or localization of hypopigmented macules. A common classification
provides four general types of vitiligo as follows:
Focal: One or several macules in one area (Fig. 66).
Segmental: One or more macules more or less along one or more dermatomes, always unilateral (Fig. 67).
Generalized: Macules distributed over several or more areas of the skin,
mayor may not be unilateral (Fig. 68).
Universal: Extensive vitiligo with only a few or no areas of normal pigmented skin remaining (Fig. 69).
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Of 365 vitiligo patients in our series from India, 17 were classified as focal,
nine as segmental, 339 as generalized, and none as universal (unpublished
observations) .
The classification system is important because of special significance assigned by some to each type of vitiligo. For example, vitiligo vulgaris is reportedly more common in women and vitiligo zosteriformis and mucosal vitiligo in men. Vitiligo acrofacialis has been reported to be slightly more common
among females than males, although this seems unlikely. Zosteriform vitiligo
may have the earliest age of onset and acrofacial and mucosal later onset. In
response to psoralen therapy, vitiligo areata (focal) does better than vitiligo
acrofacialis; mucosal types do poorly. Zosteriform or segmental types are not
necessarily poor responders (unpublished observations).
Many classification systems have been proposed. Robert [18] distinguished
localized, bilaterally symmetrical, asymmetrical generalized; and lateral, asymmetrical, and symmetrical exanthematous forms.
Another classification system [20] distinguished three groups: peripheral,
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GENETIC AND
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FIGURE 68. Generalized vitiligo in two patients. a: All areas are not uniformly involved. The
arms still have large areas of normal pigmentation but on the abdomen most of the skin is vitiliginous. b: Koebner phenomenon across abdomen at the site of a surgical scar.
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central, and mixed vitiligo, the latter combining the first two types. Each of
these groups is further divided into the blotchy (massive) and punctate (discrete) types.
Lerner [29] suggested three groups: (1) segmental, localized, partial or iocal
vitiligo, corresponding to a dermatome or adjacent dermatomes; (2) generalized
vitiligo or vitiligo vulgaris involving hands, face, axillae, and occasionally also
macules in a segmental array; and (3) complete, total or universal vitiligo of
all or nearly all the skin. Among 25 vitiligo patients, Lerner noted 21 with
generalized, three with segmental, and one with total vitiligo.
Dutta and MandaI [13] found 74% of their 650 cases to have one of two
types of multifocal vitiligo. Both types-vulgaris and acrofacialis-are nearly
bilaterally symmetrical. Vulgaris, occurring in 51 %, was often symmetrical but
scattered over different parts of the body, whereas acrofacial, affecting 23%,
primarily involved the distal arms and legs, principally fingers and toes, palms
and soles. Perioral and forehead skin, and occasionally other areas, were sooner
or later involved.
Dutta and MandaI found zosteriformis or pseudosegmental vitiligo in 21%.
The areata (focal) form, characterized by one or two isolated lesions remaining
stationary for months to years, was found in only 4%; this was considered to
be a transitional or early phase of vitiligo vulgaris.
A periorificial distribution which often accompanies generalized vitiligo
is well recognized and involves the perioral, periorbital, and perianal skin.
Macules may also occur elsewhere (Fig. 70).
Koga [129] suggested Type A (nondermatomal) and Type B (dermatomal).
Based on sweat stimulation studies, Type A was considered an autoimmune
disease, had normal sympathetic function, and responded to steroids. Type B,
FIGURE 70.
169
GENETIC AND
CONGENITAL
DISORDERS
170
CHAPTER 1
with sympathetic dysfunction, was treatable with oral nalimide. This distinction remains to be confirmed.
Goudie et al. [130] suggest the variants of generalized vitiligo are a function
of underlying associated disease. They noted eight cases of vitiligo on the
eyelids and skin overlying the thyroid gland; two of these were thyrotoxic.
Other variants included the following: an ankylosing spondylitis variant, affecting skin over the sacrum, vertebral column, shoulder girdle, tibial tuberosities, and anterior chest wall; an ulcerative colitis variant affecting the groin
and abdominal wall; and a rheumatoid arthritis variant with depigmentation
overlying affected joints. A reciprocal pattern sparing normally involved areas
was also suggested.
Seghal [17] observed vitiligo mucosae in which only mucous membranes
are involved.
The following classification recognizes the most common patterns described:
A. Localized
Focal: One or more macules in one area, but not clearly in a segmental
or zosteriform distribution (Fig. 71).
171
GENETIC AND
CONGENITAL
DISORDERS
172
CHAPTER 1
Universal types may be more likely to have associated diseases. Mixed types,
particularly acrofacial or vulgaris with a segmental pattern, are an enigma. The
more generalized areas in these patients may be progressive, whereas the segmental pattern may be relatively stationary.
Course of the Disease
Mode of Onset
The onset of vitiligo is insidious. Most patients become aware of depigmented patches on their skin, often in the anogenital area and particularly on
sun-exposed areas during spring or summer when repeated sun exposures
increase the contrast between involved and uninvolved skin.
Curiously, the exact evolutionary appearance of early lesions is unknown,
but probably the early macules gradually uniformly lose pigment until a discrete
173
GENETIC AND
CONGENITAL
DISORDERS
KOEBNER PHENOMENON
IN SITE OF TRAUMA
174
CHAPTER 1
\ j
In mapping primary lesions, Mehta et al. [16] found 53% to be on the lower
extremities, 11% on the head, face, neck, and scalp, 7% on the upper extremities, and 5% on the thorax.
Progression and Repigmentation
The course of vitiligo on a case by case basis is unpredictable. Vitiligo
becomes more extensive either by appearance of new depigmented macules,
TABLE 27.
Multicentric
Author
(%)
(%)
74
75
73
26
25
27
Unexposed
skin
Author
(%)
(%)
80
70.9
53
66
20
29.1
47
34
175
GENETIC AND
CONGENITAL
DISORDERS
176
Spontaneous
repigmentationa
CHAPTER 1
Author
Lerner (1959) [29)
Dutta and MandaI (1969) [13)
(%)
44
6
(1 leukotrichia)
(5 without leukotrichia)
30
10
22
(20 sun-exposed skin)
(2 unexposed skin)
0
Total no.
of patients
179
650
430
84
100
26
Ocular Changes
The uveal tract (iris, ciliary body, and choroid) and retinal pigment epithelium have been traditionally considered unaffected in vitiligo. However,
ocular abnormalities in vitiligo patients have been observed. Chronic uveitis,
Auditory Changes
Auditory abnormalities are not characteristic of patients with vitiligo. However, we have seen two patients with a family history of vitiligo and otosclerosis.
Interestingly, there is a report of autosomal recessive congenital deafness and
vitiligo occurring in an inbred family in a remote small village where multiple,
repeatedly consanguinous marriages are common [145d]. In this kindred, seven
had profound, severe, bilateral, nonprogressive, sensorineural hearing loss and
five had vitiligo. Of these, three had both vitiligo and hearing loss; their parents
were unaffected but two brothers were deaf. The vitiligo in all those affected
appeared initially at the waist beginning at six to eight years of age and pro-
177
GENETIC AND
CONGENITAL
DISORDERS
178
CHAPTER 1
gressed slowly. Audiometric studies of apparently unaffected individuals suggested heterozygotes may be predisposed to noise-induced hearing loss.
Nail Involvement
There is no specific nail abnormality in vitiligo. Costa [50] did report two
cases of vitiligo and discoloration of the nails, a condition he called "ungual
vitiligo." Aleixo [146] reported that melanonychia and hyperchromia of the
nail matrix may result from vitiligo. He also suggested that leukonychia may
occur and ascribed to this the same significance as the discoloration of hair in
achromic vitiligo macules. We have observed one vitiligo patient with nail
plate hypochromia. Leukonychia is a rare feature of vitiligo. Linear hypochromic bands may also occur, particularly in patients with periungual vitiligo.
A 34-year-old woman with vitiligo and periodic seasonal detachment of
all fingernails has been reported [147].
Lerner [148] described three cases with a syndrome of total alopecia, total
vitiligo, and nail changes (fine pitting, friability, and horizontal splitting). Two
similar cases were reported by Demis and Weiner [149]. In these patients,
however, the nail changes were characteristic of alopecia areata, which has
been associated with vitiligo.
Vitiligo and Blood Groups
44.6
25.53
16.4
37.54
39.7
48.55 0
19.3
26.020
8.80
6.58
9.9
8.20
23 0
33.26
27
24.74
29
8.67
8.88
17.64 0
36.24
27.46
23.94
15.68
7.83
9.43
10.98
100
35.08
35
36.69
39.940
AB group
(%)
24.34
23.27
19.17
B group
(%)
25
Author
A group
(%)
TABLE 30.
33.20
16.76
30
39.210
30
29.89
(%)
30.35
31.1
33.80
30.94
32.75
30.58
o group
250
173
100
102
80
535
No. of
patients
tIl"">
:::o>Z
cnrt:l
Oel...,
:::0 tIl ......
t:l~C")
c;::ZtIl
C")el
t:lO~
=
"I
...
TABLE 31.
180
CHAPTER 1
Secretors
Nonsecretors
(%)
(%)
Vitiligo
Controls
Vitiligo
Controls
86.7
68.8
18.1
75.6
70
73.3
70
70
13.3
31.2
18.9
24.4
30
26.7
30
30
troIs, and concluded, that the presence of this dominant factor is associated
with increased susceptibility to vitiligo. Other authors have been able to substantiate a statistically significant increase in the number of secretors among
vitiligo patients as opposed to controls.
Seghal and Dube [157,158] claimed a statistically better therapeutic response among the nonsecretors than among the secretors. In a study from India,
nonsecretors were found to be more responsive to psoralen therapy than secretors [158a]. However, Heid et al. [159] found the presence or absence of
secretory factor of no prognostic value. Further study is required to determine
any meaningful relationship between vitiligo and secretory state.
HLA Typing
Although there has been considerable interest in identifying an HLA marker
for vitiligo, convincing evidence is lacking. In a study of 48 unrelated blacks,
the incidences of HLA-Al, -A2, and -Aw31 were higher and HLA-Al0 lower
than in 107 normally pigmented black controls; the presence or absence of
associated diseases in these patients was not reported [160]. Another study
showed four of five children with vitiligo and juvenile diabetes mellitus to
have HLA-B8 or HLA-Bio 15, both found in insulin-dependent diabetes. Three
of eight with vitiligo but not diabetes also had HLA-B8 [161]. Another study
[162] showed no HLA pattern among 35 vitiliginous blacks. HLA typing of 90
other vitiligo patients revealed no HLA pattern characteristic of vitiligo [163,164]
or any subpattern characteristic of any clinical feature (sex, age of onset, extent,
precipitating factor, follicular involvement). Furthermore, HLA typing did not
distinguish familial from nonfamilial vitiligo, nor did it distinguish those affected from those unaffected in a family in which vitiligo was present (Fig. 76).
There was, however, an increased incidence of HLA-13 in those vitiligo patients
who had antithyroid antibodies. This result is curious because HLA-13 is not
normally related to the presence of antithyroid antibodies in normally pigmented patients with or without thyroid diseases. No particular HLA pattern
was found to characterize patients having both vitiligo and thyroid disease.
Furthermore, in this study the incidence of antithyroid antibodies in the control
group is unknown. Despite the two reports of specific (but different) HLA
antigens in vitiligo patients, it appears that a specific HLA marker for vitiligo,
if there is one, has yet to be identified.
181
GENETIC AND
CONGENITAL
DISORDERS
II
III
W30-HL-A13
HL-A3-HL-A12
0+
Do
W30-HL-A13
HL-A3-HL-A12
0+
W28-W16
HL-A9-W18
O~
vitiligo
o~
FIGURE 76. HLA typing in a family with vitiligo. Only two HLA antigens are found in patient
1-1. Patients 11-2 and 11-5 have the same HLA phenotype. Patient III-2 has a different phenotype,
but has haplotype 3-12 like patients 11-2 and 11-5. His brother, with the same HLA phenotype, is
normal. (From: Retornaz G: Les groupes HLA en dermatologie. Revue bibliographique. Etude personelle de 90 vitiligos et 14 sclerodermies. These Medecine, Lyon, 1975.)
whorls and an increased incidence of radial loops. Radial loops and arches
were found in increased frequency on the second and third digits, respectively.
On the fifth digit, the ulnar loops were increased and the whorls decreased.
182
CHAPTER 1
In females with vitiligo, arches were present in increased frequency, whereas ulnar loops were present in decreased frequency on the third digit, and
thenarlII patterns were significantly reduced. On the right hand, ulnar loops
were significantly reduced.
Sahasrabudhe et a1. concluded that vitiligo is characterized by certain
significant dermatoglyphic features and that this supports the importance of
heredity in vitiligo.
Associated Disorders
While most vitiligo patients are generally healthy, several disorders have
been found in many patients. Though the frequency is still disputed, clearly
the established associations must be excluded in all patients.
Established Associations
Vitiligo appears to be a marker for certain diseases. Thyroid disease, diabetes mellitus, pernicious anemia, and Addison disease are reported frequently
enough to be considered definite associations. Other established associations
include three cutaneous markers, namely, halo nevi, prematurely gray hair,
and alopecia areata.
Vitiligo and Thyroid Disease
Trousseau [168], in 1877, was probably the first to report an association
between vitiligo and thyroid disease. Thibierge [169], in his 1895 textbook,
mentioned the existence of vitiligo in patients with exophthalmic goiter. In
1899, Caracoussi [170] noted the appearance of vitiligo during an exacerbation
of Basedow disease (thyrotoxicosis with exophthalmic goiter). Darier [80], in
1904, stated that vitiligo was relatively common in patients with exophthalmic
goiter. It was later suggested that vitiligo occurs in 10% of patients with Graves
disease [104,171].
At the turn of the century, the association of thyroid disease and vitiligo
was reported several times and, in 1929, in a review of the European literature,
Parhon and Derevici [172] collected 25 reports of vitiligo associated with Graves
disease. In 1923, Ayers [173] reported in the North American literature a case
of vitiligo associated with severe hyperthyroidism and alopecia areata. Other
cases of vitiligo and hyperthyroidism were described in 1927 by Pierini and
Herrera [174] in Argentina, and in 1928 by Ferraz-Alvim and Guerner in Brazil
[111].
In 1926, Peynet [175] noted the course of vitiligo to parallel that of exophthalmic goiter, and in one of the cases mentioned by Sainton et a1. [176]
in 1928, vitiligo disappeared after treatment of Graves disease.
While most of the reported cases relate vitiligo to exophthalmic goiter and
hyperthyroidism, myxedema has also been mentioned [177,178]. Faber [179],
in 1934, noted vitiligo in a patient with myxedema and facial hemiatrophy.
Author
Miklaszewska et al. (1972) [180]
Perrot et al. (1973) [25]
Allison and Curtis (1955) [28]
7
41
28
183
GENETIC AND
CONGENITAL
DISORDERS
Total no.
of patients
56
4627
475
12.5
0.9
0.6
Number
Percent of total
Total no.
of patients
Hyperthyroidism
0.5
1289
Hyperthyroidism
5.7
140
Graves disease
6.6
90
Hyperthyroidism
154
5
4
27
21
0
6
27.7
36
1.4
1.7
0
1.7
18
11
1994
2297
450
347
2.3
85
Diagnosis
Hyperthyroidism
Graves disease
Hyperthyroidism
Graves disease
Toxic adenoma
Diffuse goiter with
secondary
Basedow disease
Hyperthyroidism
184
CHAPTER 1
Number
Percent of total
25
Total no.
of patients
Hashimoto thyroiditis.
b Type of thyroiditis not specified.
recording a higher incidence was based on only 18 patients with hyperthyroidism. Two cases of vitiligo were found among 85 hyperthyroid patients over
the age of 65 [183] but this represents the incidence expected in the population
at large.
According to the literature, the incidence of vitiligo in Graves disease
would seem to be between 1.7% and 6.6%. A series reporting an incidence of
36% is based on a sample size of 11 [180]. One endocrinologist has found
leukoderma to be common in Graves disease patients over the age of 50 (L.
Wood, personal communication); the definitive study has yet to be done.
Vitiligo may also be associated with toxic adenomas, but in the series of
Perrot et al. [25] 1.7% of 347 patients with toxic goiter had vitiligo. No case of
vitiligo was found among 450 cases of toxic adenomas [25]. In another series,
one case of vitiligo was found among seven patients with toxic adenomas [180].
Reported cases of vitiligo with thyroiditis are too few to be conclusive.
None of 130 patients with thyroiditis (Table 34) were found to have vitiligo
[25], but Miklaszewska et al. [180] found two cases of vitiligo among eight
patients with thyroiditis.
Vitiligo does not appear to be more frequent among those with myxedema
or thyroid carcinoma than expected in control populations. The incidence of
vitiligo among myxedema patients (Table 35) has been reported to be 0.88%
to 1.43% and that of vitiligo in nontoxic goiter to be from 0% of 18 patients to
0.6% of 2122 (Table 36). Perrot et al. [25] found vitiligo in 0.3% of 268 patients
with carcinoma of the thyroid (Table 37).
It is notable that the series of Miklaszewska et al. [180] consistently reports
high incidence figures for vitiligo in hyperthyroidism, Graves disease, and toxic
goiter. Perhaps vitiligo is underreported in most other thyroid series.
TABLE 35. Incidence of Vitiligo in Myxedema
Patients with vitiligo
and myxedema
Author
Allison and Curtis (1955) [28]
Sandrasekar et al. (1973) [184]
Perrot et al. (1973) [25]
Number
Percent of total
5
1
1
1.1
Total no.
of patients
1.4
470
70
0.9
113
Number
Author
Total no.
of patients
185
12
18
2122
0.06
Number
Percent of total
Total no.
of patients
0.37
268
GENETIC AND
CONGENITAL
DISORDERS
186
CHAPTER 1
Number
% of Total
Total no.
of patients
12
7
17
7
1
4
6
2
4
7
41
7
3
7
4
2.2
3.8
30.4
1.3
1.6
5.7
5.9
6.6
12.5
17.1
20.5
7.0
2.6
14.5
13.3
531
183
56
545
62
70
102
30
32
41
200
100
116
48
30
Diagnosis
Number
% of Total
Total no.
of patients
Hyperthyroidism
1.3
531
Hyperthyroidism
Hyperthyroidism
Graves disease
Toxic adenoma
Hyperthyroidism
Hyperthyroidism
5
5
3
2
5
2
3.3
8.9
5.3
3.5
0.9
6.6
183
56
56
56
545
30
Graves disease
2.9
102
Graves disease
Hyperthyroidism
Graves disease
Toxic adenoma
Hyperthyroidism
Graves disease
4
5
4
1
3
2
12.5
12.2
9.8
2.4
3.0
1.7
32
41
41
41
100
116
Graves disease
10.0
30
Number
Percent of total
7
2
2
12.5
187
Total no.
of patients
56
102
1.9
4.9
41
however, that if older patients are examined, vitiligo will be found in many
patients with thyroiditis or myxedema.
However, among vitiligo patients, the incidence of Graves disease, hyperthyroidism, toxic adenoma, thyroiditis, and myxedema clearly is increased.
Nontoxic goiter has not been shown to be associated.
The issue of association of thyroid disease with vitiligo is an important
one. Underreporting has resulted from the relatively young average age of patients in most series-often around 20 years. For example, among 212 of our
patients surveyed, with an average age of 25, the incidence of known thyroid
disease was 10%. Another group of 40 patients, surveyed at an average age of
40, was found to have a 24% incidence of thyroid disease by history alone.
Furthermore, among 20 vitiligo patients over 50 years of age contacted for
thyroid studies, 18 of whom were studied, only two had clinical symptoms of,
or were aware they had, thyroid disease. Two other patients were under treatment for thyroid disease and refused to be studied. The total incidence of known
thyroid disease in this small group, then, was 20%; five others also had borderline or abnormal TSH, the significance of which was confirmed with abnormal TRH stimulation tests. The latter five patients (25%) were thus found
to be hypothyroid. The prevalence of clinical and subclinical thyroid disease
in this group was 45%. Two conclusions are appropriate from all these observations. First, thyroid disease is more likely to be observed as vitiligo patients
become older and, second, vitiligo must be considered an important marker
for present or impending thyroid disease, particularly thyroid failure in older
age groups [1911.
Clinical Features of Vitiligo Associated with Thyroid Disease
There appear to be no distinguishing features of vitiligo associated with
thyroid disease. Although Ochi and De Groot [112] suggested that vitiligo associated with thyroid disease has a characteristic pattern-involvement of the
TABLE 41. Incidence of Nontoxic Goiter in Vitiligo
Associated goiter
Author
Cunliffe et al. (1968) [185]
Grupper et al. (1970) [37]
Ortonne and Alario (1978) [165]
Number
Percent of total
Total no.
of patients
8.9
5.7
3.0
56
70
100
GENETIC AND
CONGENITAL
DISORDERS
188
Associated myxedema
CHAPTER 1
Author
Number
Percent of total
Total no.
of patients
5
1
2
2
3
1
1
1
0.9
0.5
0.4
1.6
2.9
1.0
0.9
3.3
531
183
545
62
102
100
116
30
palms and soles and minor involvement elsewhere-there seems to be no clinical picture of vitiligo predictive of the presence or absence of associated or
impending thyroid disease.
Ochi and De Groot stated that in their cases the onset of thyroid disease
always preceded the appearance of vitiligo; but in an examination of 17 patients,
Perrot et al. [25] found only seven whose thyroid disease preceded the vitiligo,
as opposed to five in whom the vitiligo preceded the thyroid disease, and
another five in whom the two conditions were observed to occur simultaneously. In a survey of 10 of 40 vitiligo patients with thyroid disease, we have
also found vitiligo to precede or follow vitiligo with equal frequency (unpublished observations). Perrot et al. [25] also observed that treatment of thyroid
disease did not appear to alter the course of vitiligo. Of our five patients with
elevated TSH values, one observed her vitiligo to improve for six months on
thyroid replacement. This, however, gradually reversed despite continued thyroid therapy. The other patients observed no pigmentary changes as a result
of thyroid replacement.
Thyroid Studies in Vitiligo Patients
Thyroid function has generally been considered normal in vitiligo patients,
but this may be misleading. Increased basal metabolic rate (BMR) has been
reported in 10 out of 20 vitiligo patients [18] and functional thyroid abnormalities (generally increased) in 57 out of 100 patients [194]. However, proteinbound iodine in vitiligo patients has been reported to be normal [29,180].
Normal radioactive iodine uptake was found in 22 patients, and increased
uptake in two [29]. In 30 vitiligo patients, Jacyk et al [195] noted abnormal
radioactive iodine uptake in seven, three of whom had both thyroid disease
and diabetes mellitus. Recent studies of Wood et al [191] have demonstrated
abnormal TSH values in 39% of 18 patients over the age of 50, all but one of
whom had normal T4 determinations and had been considered euthyroid. The
overall incidence of thyroid diseases in the vitiligo clinic at the Massachusetts
General Hospital has been 8% to 10%, representing a population with an average
age of 25; results of the preliminary study of Wood et al suggest this may be a
minimal incidence figure and that the incidence of clinical and subclinical
thyroid disease among vitiligo patients may increase dramatically with age.
189
GENETIC AND
CONGENITAL
DISORDERS
Antithyroid antibodies
Vitiligo
Controls
Author
(%)
(%)
Total no.
of patients
32.6
30
20
53.3
28
14.9
51.7
3.8
6
5
20
9
0
9.2
52
80
70
30
93
107
59
(%)
24.5
8.7
43.3
50.0
5.3
44.4
12.1
7.1
Controls
(%)
4.0
16.6
Total no.
of patients
52
80
30
10
93
27
58
42
190
CHAPTER 1
Controls
Author
(%)
(%)
11.6
27.5
23.3
25.8
37.0
43.1
11.9
0
7.5
3.3
Total no.
of patients
52
80
30
93
27
58
42
4.7
Type of antibodies
Thyroid microsome
+ thyroglobulin
Thyroid microsome
Thyroglobulin
Percent of
patients
affected
No. of
patients
affected
Vitiligo without
thyroid diseases (65)b
Percent of
patients
affected
No. of
patients
affected
46
13
20
13
46
14.2
13
4
18.4
1.6
12
1
'From: Perrot H et al: Vitiligo, thyreopathies et autoimmunisation. Lyon Med 230:325-331, 1973.
b Total number of patients.
normal tyrosine levels. Regardless, such a hypothesis could explain only the
association of hyperthyroidism and not hypothyroidism with vitiligo.
Additional occurrences observed in some factory workers adds considerable credence to the common pathogenesis theory [200,201]. Three men working in a factory producing paratertiary butylphenol developed, over one to two
years, vitiligo-like skin changes, hepatosplenomegaly, and diffuse goiter with
increased TSH secretion.
Morgans [181] suggested that vitiligo could be one manifestation of a genetic link which, under certain circumstances, could present as thyroid disease.
The observation that there is an increased incidence of thyroid disease among
the relatives of patients with vitiligo supports a genetic basis for the link between these two conditions.
Vitiligo and Addison Disease
Thomas Addison [202] in 1855 in his book, On the Constitutional and
Local Effects of the Disease of the Suprarenal Capsules, noted in one instance
that "there were in the midst of this dark mottling certain insular portions of
integument presenting a blanched or morbidly white appearance ... from an
actual defect of coloring matter in this part." It appears that one of the first
patients with Addison disease was suffering from vitiligo. In 1891, Mathieu
[203] reported a case of vitiligo which he suggested was a sign of Addison
disease.
Many cases and diverse theories surround the association between vitiligo
and Addison disease. Levi [204] found 12 cases of Addison disease with albinotic decoloration. In his 1920 textbook of internal pathology, Dieulafoy [205]
related the two diseases. In 1922, Pieri [206] based his thesis on 16 cases of
Addison disease and vitiligo. Artom [207], in 1926, reported an Addisonian
woman who developed vitiligo during pregnancy; he attempted to relate the
hormonal alterations of pregnancy to the pigmentary disorder. In 1939 there
were two case reports of vitiligo, melancholy, and adrenal cortical insufficiency,
with a parallel evolution of these three conditions [208]. The same year also
saw a report of a case of vitiligo and Addison disease in a 12-year-old girl with
increased creatinuria [209]. Many cases of Addison disease associated with
vitiligo have been reported [210-224].
191
GENETIC AND
CONGENITAL
DISORDERS
192
Associated vitiligo
CHAPTER 1
Author
Number
Percent of total
6
20
6
15
4
3.1
7.5
5.7
4
2
17
19
Total no.
of patients
50
100
63
224
329
Not specified.
Author
Pousset et a1. (1970) [229]
Irvine and Barnes (1972) [231]
Irvine and Barnes (1975) [232]
a
Tuberculous
Addison disease
Associated
vitiligo
174
261
(%)
No. of
patients
3
9.1
7.8
46
1
Associated
vitiligo
Others
(%)
No. of
patients
1
2.1
1.6
4
4
Author
(%)
0
0
0
1.0
1.0
0
Total no.
of patients
56
70
102
200
100
116
Vitiligo
Controls
(%)
(%)
4.0
4.1
0
7.1
0
0
5
(%)
0
0
Not specified.
Associated Addison
disease
Associated
vitiligo
Total no.
of patients
80
24
53
14
42
193
Not associated
with vitiligo
Associated
with vitiligo
Not associated
with vitiligo
Number Percent of total Number Percent of total Number Percent of total Number Percent of total
38
95
5.0
205
92.7
16
7.3
GENETIC AND
CONGENITAL
DISORDERS
194
CHAPTER 1
53)
Number
Percent of total
22
1.6
10.6
8.8
11
Total no.
of patients
with
pernicious anemia
1398
84
125
TABLE 53.
195
Associated pernicious
anemia
Author
Allison and Curtis (1955) [28]
Cunliffe et al. (1968) [185]
El Mofty (1968) [6]
Bor et al. (1969) [186]
Bleifeld and Gehrmann (1969) [247]
Grunnet et al. (1970) [22]
Howitz and Schwartz (1971) [187]
Pottgen et al. (1971) [248]
Perrot et al. (1973) [25]
No. of
patients
Percent of total
Total no.
of patients
22
3
0
2
5
5
8
3
2
4.1
5.3
0
3.2
9.2
3.7
7.8
8.1
1
531
56
545
62
54
135
102
37
200
that only three out of 28 patients with vitiligo had normal gastric acid secretion.
Huriez et al. [70] also found an increased frequency of gastric hypochlorhydria
in vitiligo patients, and Ishida [251] reported achlorhydria in patients with
vitiligo.
Abnormal histamine stimulation tests have also been reported. Lerner [29]
found achlorhydria after subcutaneous histamine injection in one out of five
males and in two of 15 females and concluded that the average female patient
with vitiligo secretes abnormally small amounts of free hydrochloric acid in
response to histamine stimulation. Howitz and Schwartz [187] performed augmented histamine tests in 102 vitiligo patients. Twenty of the patients (nearly
20%) were found to have achlorhydria; eight of these had frank pernicious
anemia and one had latent pernicious anemia. Of another 26 vitiligo patients
subjected to augmented histamine or histamine infusion testing, five were
achlorhydric by the former technique, a finding confirmed by the latter technique in two; three were hypochlorhydric. The five had significantly elevated
GENETIC AND
CONGENITAL
DISORDERS
196
CHAPTER 1
average gastrin levels and one had frank pernicious anemia [252]. Among 540
vitiligo patients, Shukla and Mukerji [36] found 40 had gastric achlorhydria
after alcohol stimulation but a normal response to histamine stimulation.
Shukla [253], in 1961, found reduced gastric pepsin levels in 30 vitiligo
patients; he proposed [254] treatment with a mixture of psoralen, isopsoralen,
and proteolytic enzymes.
Decreased vitamin B1z absorption has been observed in vitiligo patients.
Bleifeld and Gehrmann [247,255], in 1967, performed Schilling tests on 54
patients and found defective vitamin B12 absorption in roughly one-third, five
of whom were said to have pernicious anemia. Watzig [256] also reported
decreased B12 absorption in a patient with vitiligo and alopecia areata. Howitz
and Schwartz [187] observed significantly lower serum B12 levels in vitiligo
patients with pernicious anemia, but found the serum B12 level not to vary
significantly between the groups of vitiligo patients with hypo- or achlorhydria
and those with normal acid secretion. Repigmentation in two patients was
reported after oral administration of dilute hydrochloric acid and vitamin B
complex [257]. Of the next 14 vitiligo patients so treated, seven repigmented,
but two of them only partially.
Decreased intrinsic factor production was found in 15 vitiligo patients with
gastric achlorhydria or hypochlorhydria [187].
Howitz and Rehfeld [38] found raised serum gastrin concentrations in 25
of 29 patients with hypo- or achlorhydria; 87 patients with normal acid secretion had normal gastrin concentrations. Okosdinossian et al. [252] found elevated gastrin levels in five of 26 vitiligo patients; two were achlorhydric and
three hypochlorhydric on histamine infusion tests. One was found to have
frank pernicious anemia.
A difference between the turnover of transcobalamin I in a control group
and in patients with vitiligo or pernicious anemia has been reported [258].
However, another study, using purified trans cobalamin I labeled with radioactive iodine and cobalamin for turnover studies showed no differences between healthy controls, patients with vitiligo, and those with vitiligo and hypoor achlorhydria or pernicious anemia [259].
Pottgen et al. [248], in 1971, found normal gastric mucosal histology in
only five of 26 vitiligo patients biopsled. Chronic superficial gastritis and chromatrophic gastritis were observed in 11 and 10 patients, respectively. Of the
one-third of the 26 patients over 50 years of age, none had histologically normal
gastric mucosa. The gastric mucosal changes resulting in chronic atrophic gastritis were considered to occur earlier, more frequently, and to a greater extent
in patients with vitiligo. Hypertrophic gastritis has also been described [260].
Pathogenic Relationship between Vitiligo and Pernicious Anemia
Observations of an association between vitiligo and pernicious anemia have
led to several theories and therapeutic trials. Hathaway [257] found two patients
treated with B complex for pellagrous dermatitis who reported complete clearing of long-standing vitiligo. Shukla and Mukerji [36] presumed that pyridoxine
deficiency is the common etiologic factor in vitiligo and gastric hypochlorhydria. Shukla [254] suggested that gastric hypochlorhydria and reduced pepsin
levels result in decreased protein hydrolysis at the more centrally located peptide linkage of the alpha-carboxyl group of decarboxylic amino acid and the
alpha-amino radical of aromatic amino acid; as this type of peptide linkage is
present in L-tyrosine and L-phenylalanine residues, less of the latter is available
for melanin synthesis. Paradda [261] suggested that deficient conversion of
pepsinogen to pepsin in the presence of achlorhydria interferes with the release
of L-tyrosine from proteins. But these hypotheses are untenable because serum
tyrosine levels are usually normal in vitiligo patients.
The possibility of a common etiologic mechanism for both gastric mucosa
changes or pernicious anemia and vitiligo was raised when Bor et al. [186], in
1969, found a significantly increased incidence of gastric parietal cell antibodies
(PCA) in 62 vitiligo patients compared with an age- and sex-matched control
group of hospitalized patients; 22.5% of the patients had PCA compared to 8%
of the controls. None of the vitiligo patients had been reported to have pernicious anemia. Nine other series (Table 54) mention an increased incidence
of PCA in vitiligo, but not all of these series include controls. Only Woolfson
et al. [198] have observed a higher incidence of PCA in controls (19%) than in
vitiligo patients (14.2%). In vitiligo patients with gastric achlorhydria, the incidence of PCA has been reported to be 80%, as opposed to 7% among normal
acid secretors [38,187]; both elevated serum gastrin concentrations and PCA
were found in 72% of vitiligo patients with hypochlorhydria or achlorhydria.
Anti-intrinsic factor antibodies have been reported in those patients with both
vitiligo and pernicious anemia [38,187,248] but not in those with vitiligo alone.
According to Howitz and Schwartz [187] vitiligo patients with gastric
achlorhydria have an increased incidence of insulin-dependent diabetes and
thyrotoxicosis or Hashimoto struma. They suggested that females with vitiligo
and achlorhydria are subject to immunologic disorders marked by increased
autoantibody formation and an increased incidence of organ-specific
autoimmune disease. They suggested two types of vitiligo seem to exist. First,
there is "hereditary vitiligo" which is closely associated with achlorhydria and
organ-specific autoimmune disease, and, second, a vitiligo in which the patients
TABLE 54. Incidence of Gastric Parietal Cell Antibodies in Vitiligo
Gastric parietal cell
antibodies
Vitiligo
Controls
Author
(%)
(%)
22.5
21.2
45.4
20.0
32.4
20.0
25.0
11.8
14.0
40.0
14.2
8
1.2
35
6.0
6
1.8
19
No. of
vitiligo
patients
62
80
70
102
37
10
116
59
107
25
42
197
GENETIC AND
CONGENITAL
DISORDERS
198
CHAPTER 1
hydria and two had pernicious anemia). Non-insulin-dependent diabetes mellitus was found in one male with normal gastric acid production. Blood glucose
levels are usually normal in patients with vitiligo [37,70], although Chojnacki
et al. found hyperglycemia in glucose tolerance tests of six of 17 nondiabetic
vitiligo patients with a positive family history of vitiligo and in seven of 26
nondiabetic vitiligo patients with a negative family history of vitiligo; two in
the former and one in the latter group were frankly diabetic [267]. Grupper et
al. [37] were unable to find anti pancreas antibodies in 20 vitiligo patients.
Diabetes is often present in close relatives of patients with vitiligo [37,185,186,268].
Incidence of Vitiligo in Diabetes Mellitus [Table 56)
The incidence of vitiligo among 520 diabetic patients has been reported
to be 4.8% as opposed to 0.7% among 433 nondiabetic controls [23]. The female
and male prevalence figures were 6.1% and 2.9%, respectively, against 0.7%
and 0.6% in controls. Dawber observed that in his 25 cases, only six had
(%)
No. of
vitiligo patients
1
1.6
7.1
1.6
2.8
5
3.3
3.1
7.0
1.7
2.9
5.0
6.2
6.6
5.5
182
545
56
62
70
102
30
32
200
116
202
100
48
30
54
acquired their vitiligo before the age of 40 [23]. He suggested, therefore, that
diabetes mellitus should be excluded in cases of late-onset vitiligo.
Macaron et al. found vitiligo among 1.66% of 300 juvenile insulin-dependent diabetics [161]; it is likely that a follow-up survey in a decade would
show an increased incidence.
Vitiligo seems to be associated with both adult-onset and juvenile-onset
diabetes. Some of the adult patients are insulin-dependent and others are not.
The incidence figures of 1% to 7.1% strongly support the existence of a link
between vitiligo and diabetes mellitus. Diabetes has been suggested to be of
autoimmune or viral origin in a susceptible individual. Two-thirds of patients
with insulin-dependent diabetes have HLA-B8 and/or HLA-Bw15 antigens. Although an autoimmune mechanism for diabetes mellitus has not been proved,
anti-islet cell antibodies have been found in juvenile-onset diabetes [269]. Other
observations that support the concept of autoimmunity include the presence
of a lymphocytic infiltrate in the pancreas of a newly diagnosed case of insulindependent diabetes, islet-cell antibodies, cell-mediated immunity to human
pancreas, and the increased frequency of gastric, adrenal, and thyroid antibodies [161]. Whittingham et al. [270] noted an increased level of various
TABLE 56. Incidence of Vitiligo in Diabetes
Diabetic patients
with
vitiligo
Author
(%)
No. of
diabetic patients
4.8
1.7
520
3000
Juvenile diabetes.
199
GENETIC AND
CONGENITAL
DISORDERS
45
58
52
60
De Mowbray (1965)
[275]
40
33
28
Age
Catanzaro Mannino
(1919) [271]
Reference
Case
Sex
Disease
Vitiligo
Pernicious anemia
Hypothyroidism
Addison disease
Vitiligo
Pernicious anemia
Vitiligo
Addison disease
Pernicious anemia
Hypothyroidism
Insulin-dependent
diabetes mellitus
Vitiligo
Adrenal insufficiency
Myxedema
Hypogonadism
Ovarian insufficiency
Hyperthyroidism
Addison disease
Insulin-dependent
diabetes mellitus
Vitiligo
Addison disease
Vitiligo
Graves disease
30
52
32
14
45
45
45
29
31
31
38
27
Age of
onset
Anti-intrinsic factor
Antithyroid
Antigastric parietal
cell
Anti-intrinsic factor
Antithyroid
Antiadrenal
Autoantibodies
Vitiligo
Pernicious anemia
Hypothyroidism
TABLE 57.
Family history of
pernicious anemia
and of antithyroid and
antigastric antibodies
Family history of
vitiligo (maternal. son.
uncle) and Graves
disease (son)
Additional
history
63
81
50
10
11
12
13
14
58
51
73
57
15
43
56
16
46
50
Vitiligo
Pernicious anemia
Hypothyroidism
Vitiligo
Diabetes mellitus
Pernicious anemia
47
50
57
17
48
49
40
75
76
33
41
63
30
61
68
Hypothyroidism
Vitiligo
Pernicious anemia
Vitiligo
Pernicious anemia
Hypothyroidism
Vitiligo
Pernicious anemia
Diabetes mellitus
Vitiligo
Hypothyroidism
Addison disease
Pernicious anemia
Vitiligo
Pernicious anemia
Thyroiditis
Antithyroglobulin
Antithyroglobulin
Antigastric parietal
cell
ANA
Antithyroglobulin
Antigastric parietal
cell
ANA
Antithyroglobulin
Antigastric parietal
cell
ANA
Antigastric parietal
cell
ANA
Antigastric parietal
cell
Anti-intrinsic factor
Antiadrenal
Antithyroglobulin
Antigastric parietal
cell
Anti-intrinsic factor
(Continued)
Family history of
pernicious anemia
and hypothyroidism
Alopecia areata
Family history of
vitiligo (both parents),
hypothyroidism
and diabetes mellitus
(mother), pernicious
anemia (father,
paternal
grandmother, uncle)
Chronic ulcerative
colitis and alopecia
areata
Antithyroid
28
28
14
25
25
34
29
55
Vitiligo
Thyroiditis
Addison disease
Pernicious anemia
36
65
19
20
Vitiligo
Insulin-dependent
diabetes mellitus
Thyroiditis
Family history of
vitiligo and possibly
thyroiditis
Antithyroid
Antigastric parietal
cell
Antiadrenal
18
22
23
Vitiligo
Graves disease
Insulin-dependent
diabetes mellitus
Addison disease
Pernicious anemia
28
18
57
58
28
35
Addison disease
Thyrotoxicosis
Vitiligo
29
17
Antithyroid
Antigastric parietal
cell
Anti-intrinsic factor
Antiadrenal
Antithyroid
Antiadrenal
Antigastric parietal
cell
Family history of
vitiligo, diabetes
mellitus, pernicious
anemia (brother)
44
50
54
Vitiligo
Hypothyroidism
Pernicious anemia
54
16
Antithyroglobulin
ANA
19
74
78
Vitiligo
Diabetes mellitus
Hypothyroidism
79
Additional
history
15
Autoantibodies
Sex
Case
Age
Age of
onset
(continued)
Reference
Disease
TABLE 57.
TTnc;:.np.r+fip.cL
Antimel anocyte
3
3
3
6
9
16
Candidi asis
Alopeci a totalis
Vitiligo
Hypopa rathyroi dism
Addison disease
Primary ovarian failure
18
26
Antimel anocyte
6
6
9
13
15
28
34
Alopeci a areata
Candidi asis
Hypopa rathyroi dism
Pernicio us anemia
Primary ovarian failure
Vitiligo
Addison disease
34
25
Adolesc ence
45
75
Vitiligo
Pernicio us anemia
Hypothy roidism
75
24
Family history of
diabetes mellitus and
Graves disease
Antithy roid
Antiadr enal
20
46
55
Vitiligo
Graves disease
Addison disease
Insulin- depende nt
diabetes mellitus
64
23
Family history of
diabetes mellitus and
Graves disease
Pretibia l myxede ma
Antithy roid
Antiadr enal
23
27
31
Vitiligo
Addison disease
Graves disease
66
22
36
41
Vitiligo
Graves disease
Diabetes mellitus
51
21
204
CHAPTER 1
autoantibodies in 400 diabetics, particularly in those patients with insulindependent diabetes. The mechanistic relationship between diabetes mellitus
and vitiligo is unclear. Expanded studies are required to isolate vitiligo patients
who are most predisposed to diabetes mellitus at any age.
Vitiligo and Multiglandular Insufficiency Syndromes (Table 57)
Vitiligo has been reported among many patients with multiglandular insufficiencies [247,271-278,280-283,285,286,288]. Of 26 such vitiligo patients,
20 had thyroid disease (11 hypothyroidism, six hyperthyroidism or Graves
disease, and three thyroiditis), 16 pernicious anemia, 12 Addison disease, nine
diabetes mellitus, and four gonadal dysfunction. These observations generally
support the autoimmune hypothesis for the pathogenesis of vitiligo. A hereditary factor among this cluster of patients has also been suggested [285].
Vitiligo and Hypoparathyroidism, Addison Disease, and Chronic
Mucocutaneous Candidiasis Syndrome (Fig. 77)
In 1937, Martinez-Jaureguy and Mendez-Schiaffino [289] published two
cases in which vitiligo improved after surgical removal of the parathyroids.
One patient had scleroderma, hypercalcemia, and possible hyperthyroidism.
The second patient also had hypercalcemia as well as chronic arthritis. Fisher
and Fitzpatrick [290] described a 20-year-old female with a syndrome of vitiligo,
Addison disease, hypoparathyroidism, and chronic mucocutaneous candidiasis. Other similar cases include a patient with this syndrome and vitiligo
universalis [32] and a 15-year-old Caucasoid with hypoparathyroidism, mucocutaneous candidiasis, diffuse nonscarring alopecia, and vitiligo [291]. Among
series of patients with hypoparathyroidism alone there is no mention of vitiligo
[292]. In two such patients with the syndrome of hypoparathyroidism, Addison
Author
Roxburgh (1929) [302]
Waisman and Kepler (1941) [303]
Anderson (1950) [304]
MacAlpine (1958) [305]
Demis and Weiner (1963) [149]
Muller and Winkelmann (1963) [306]
Main et al. (1975) [307]
Perccent of alopecia
areata
patients with vitiligo
No. of patients
with
alopecia areata
4
4.3
4.4
1.6
15.6
3.9
8.9
42
138
114
125
45
736
78
205
GENETIC AND
CONGENITAL
DISORDERS
206
No. of patients
with
vitiligo
0.4
1.6
16
1.5
4.8
2.5
4.3
9.3
1.5
2.0
3.4
3.3
253
62
56
545
62
650
70
32
200
100
202
30
CHAPTER 1
Author
Levai (1958) [12]
Chorazak and Rzempoluch (1968) [308]
Cunliffe et al. (1968) [185]
EI Mofty (1968) [6]
Bor et al. (1969) [186]
Dutta and Mandall (1969) [13]
Grupper et al. (1970) [37]
Bleehen (1972) [42]
Perrot et al. (1973) [25]
Ortonne (1974) [39]
Seghal (1974) [17]
Schnitzler et al. (1974) [189]
El Mofty [6], in eight patients, noted that hair loss preceded, accompanied, or
followed the onset of depigmentation. One of his cases had alopecia totalis and
the others alopecia areata, either localized to a single patch or in multiple
round patches of the scalp or beard area. None of these eight patients had the
nail involvement observed by Lerner [148] and Demis and Weiner [149] in
patients with total vitiligo and alopecia totalis.
The presence of alopecia areata may carry no prognostic significance with
regard to vitiligo. However, in three cases of alopecia universalis and very
extensive vitiligo vulgaris seen at Massachusetts General Hospital, both disease
entities were refractory to psoralen photo chemotherapy.
Pathogenetic Relationship between Vitiligo and Alopecia Areata
Enough parallels between vitiligo and alopecia areata exist to suggest a
common pathogenesis. Sidi et al. [35] pointed out that there are similarities in
the clinical course of both diseases. Onset of either condition may follow physical or mental trauma [302,309]. Both conditions have been said to respond to
psoralen therapy. The hair regrowth in a patch of alopecia areata is usually
white. Both vitiligo and alopecia areata have been associated with thyroid
diseases [173,310]; 8% of 736 patients with alopecia areata have been reported
to have thyroid abnormalities [306]. Alopecia areata and vitiligo are both seen
in those with multiple glandular insufficiencies [279-281,283].
A significant correlation between alopecia areata and the presence of autoantibodies to thyroglobulin, parietal cells, adrenal cells, thyroid cells, and smooth
muscle has been reported [311]. The histologic presence of lymphocytes in
alopecia areata is consistent with an autoimmune mechanism [307]. The number of T cells was found decreased in patients with alopecia areata, Down
syndrome, and vitiligo [166]. Future definition of any etiologic relationship
between alopecia areata and vitiligo, however, remains elusive.
Many conditions have been reported with enough frequency among vitiligo
patients to deserve special notice even though there is not yet adequate evidence
to consider them definitely correlated with vitiligo.
Vitiligo and Psoriasis
Neumann in 1890 [312] was probably the first to associate vitiligo and
psoriasis. de Moragas and Winkelmann, in a survey of the literature, found
more than 20 cases reported between 1898 and 1965. Vitiligo has also been
observed [313,314] with psoriatic arthritis.
Incidence
of Vitiligo in Psoriasis
207
GENETIC AND
CONGENITAL
DISORDERS
208
No. of patients
with
vitiligo
0.4
0.7
4.8
0.5
4.0
4.1
253
545
62
200
100
48
CHAPTER 1
Author
Levai (1958) [126]
El Mofty (1968) [6]
Bor et a1. (1969) [186]
Perrot et a1. (1973) [25]
Ortonne (1974) [39]
Heid et a1. (1974) [159]
No. of
cases
1
1
1
2
1
2
1
2
9
2
6
1
8
209
GENETIC AND
CONGENITAL
DISORDERS
210
CHAPTER 1
The presence of leukoderma carries an uncertain prognosis for the melanoma patient. There are reported cases of vitiligo progressing and metastatic
melanoma regressing and others of 10-year or more survival after metastatic
melanoma and vitiligo [336]. Lerner and Nordlund have cited three cases of
coexisting early vitiligo and melanoma with two to 19 years' survival [337].
Others have also suggested that the depigmentation associated with melanoma
carries a favorable prognosis but further observations revealed no correlation
between the clinical course of vitiligo and melanoma [326]. Furthermore, in
two patients repigmentation preceded death by only several months. Treatment
of the melanoma does not seem to affect the vitiligo-like depigmentation. It is
difficult to ascribe prognostic significance to any of the types of depigmentation
associated with melanoma. The suggestion of Lerner and Nordlund that lateonset vitiligo developing in patients with melanoma may be a poor prognostic
sign, suggests the immunologic system may have been overwhelmed [337].
This requires documentation.
The histology of the depigmented macules mayor may not mimic that of
vitiligo. In some cases histopathology of the depigmented skin of these patients
reveals a nearly complete loss of melanin, negative dopa reaction, and an
absence of melanocytes. Balabanov et al. [323] used zinc osmium iodide staining to show a lack of high-level epidermal dendritic cells, a finding that was
not confirmed by Frenk [325] who found the same dendritic cell population
in vitiliginous skin and in the depigmented skin from melanoma patients.
Recent studies of depigmented macules in three melanoma patients have shown
a reduced number of dopa-positive melanocytes; these giant melanocytes are
three times normal size [338].
Several hypotheses are extant to explain the phenomenon of cutaneous
depigmentation. Melanoma therapy has been implicated. It has been suggested
that x-ray therapy [321,324] initiates a series of neuroendocrine changes which
may be responsible for the cutaneous depigmentation or the destruction of
melanoma cells with resultant release of antigenic substances, so that specific
antimelanocyte antibodies are formed. However, in many patients the vitiligolike depigmentation precedes treatment.
The suggestion [326] that depigmentation could result from the "stressful
situation" in these patients seems unlikely because of the considerable lag time
between the diagnosis of the melanoma, hence the stress, and the appearance
of the depigmentation. Furthermore, the stress is universal in melanoma patients and the depigmentation is uncommon.
With much evidence accumulating to show humoral and cell-mediated
immunologic reactions in patients with melanoma, an immune pathogenesis
for these phenomena seems most likely. The association of melanoma and
leukoderma is observed to occur spontaneously in swine [339] and various
strains of horses [333].
Vitiligo and Halo Nevus
See "Halo Nevus" in Chapter VIII.
211
Dermatoses
There are many scattered reports of this or that disease occurring in vitiligo
patients. Those reported multiple times merit special attention; the others are
tabulated at the end of this discussion. As time passes, these lists will undoubtedly lengthen.
Vitiligo and Lichen Planus
The early reports of Wielander [340] in 1894 of lichen planus and vitiligo
were thought by Sezary and Dupuy [98] to represent fortuitous association. As
both lichen planus and vitiligo are common diseases, it is not surprising that
they have been reported to occur in the same patients [341]. The incidence of
lichen planus in three series of vitiligo patients varies from 0.5% to 4.8% as
opposed to the incidence of 1% in the general population (Table 62). There is
no statistical evidence to substantiate a correlation between vitiligo and lichen
planus.
In the case of coexisting vitiligo and lichen planus, the lesions may be
observed on the same or different sites [342,343]. Both lichen planus and vitiligo
have been associated with scleroderma and chronic active hepatitis [344], scleroderma [345], lichen sclerosus et atrophicus and morphea [346], and ulcerative
colitis and alopecia areata in a patient with myasthenia gravis [347].
Vitiligo and Atopic Dermatitis
Although Kierland [348] asserted that vitiligo is seen more frequently in
patients with atopic dermatitis, this is unsubstantiated. One patient with eczematous lesions surrounding but not involving the vitiliginous skin has been
reported [349]. However, the "delayed blanch" phenomenon, considered as
a specific stigma in atopic dermatitis, was observed both in dermatitic and
vitiliginous skin. In most vitiligo series, atopic dermatitis is not mentioned.
Vitiligo and Scleroderma [Fig. 78)
Pautrier and Lepinay [350], in 1932, observed morphea and vitiligo in a
37-year-old man. Three other cases of morphea and vitiligo have been reported
TABLE 62. Incidence of Lichen Planus in Vitiligo
Author
Bor et al. (1969) [186]
Perrot et al. (1973) [25]
Ortonne (1974) [39]
No. of patients
with
vitiligo
62
200
100
GENETIC AND
CONGENITAL
DISORDERS
212
CHAPTER 1
by Lerner and Nordlund [123]. In 1935, Grenet and Isaac-Georges [351] observed
linear scleroderma in an eight-and-one-half-year-old girl with vitiligo. Progressive systemic sclerosis together with vitiligo was reported in 1939 by Deglos
and st. Girons [352] . Many other cases have been reported [344-346,353-359].
In a review of four cases of coexistent morphea and vitiligo, Saihan and Peachey
[360] cite 31 other cases reported in the literature. In most cases the disorders
did not involve the same anatomic areas of skin. In 47% of 22 cases of circumscribed scleroderma and vitiligo, foci of scleroderma developed before the
occurrence of vitiligo, in 26.5% they appeared simultaneously, and in 26.5%
vitiligo preceded scleroderma [361,362]. Since we also have observed four cases
of morphea in 300 cases of vitiligo, the relationship is probably more than
fortuitous (personal observation).
Vitiligo and Lichen Sclerosus et Atrophicus
There are only a few reports of lichen sclerosus et atrophicus and vitiligo.
One of the 52 vitiligo patients of Chorazak and Rzempoluch [308] had lichen
sclerosus et atrophicus. Wallace [363] found several cases of vitiligo in a series
of patients with lichen sclerosus et atrophicus. The number of reports is inadequate to conclude these reports reflect other than chance associations.
Vitiligo and Porphyria
One case of vitiligo has been reported among four patients with congenital
porphyria. Four of 52 cases of porphyria cutanea tarda [364] also had vitiligo.
Guseinov thought this association to be significant and hypothesized that in
these patients free porphyrins might be inhibiting melanin synthesis. Many
patients with porphyria cutanea tarda and erythropoietic protoporphyria show
hyperpigmented macules on the exposed skin but no evidence of vitiligo. The
association of vitiligo with porphyria, not reported in most series, is more likely
to represent a chance occurrence.
Vitiligo and Lupus Erythematosus (Table 63)
In 1921, Barber [365] reported a patient with alopecia areata who, some
years later, developed vitiligo and lupus erythematosus. Both systemic and
discoid lupus erythrematosus have been reported in patients with vitiligo
[70,366-369]. In a few cases, lesions of discoid lupus erythematosus were
located almost exclusively on the hypopigmented skin [369a]. However, the
occurrence of only two cases of lupus in 253 vitiligo patients in one series and
only one case of systemic lupus erythematosus in another series of 200 vitiligo
patients is weak evidence for any association [25,126]. Most series do not
mention discoid or systemic lupus erythematosus.
TABLE 63. Incidence of Lupus Erythematosus (DLE - SLE) in
Vitiligo
Author
Cunliffe et al. (1968) [185)
Perrot et al. (1973) [25)
Associated
lupus erythematosus
(%)
0
0
0.5
(SLE)
(OLE)
(SLE)
Total no.
of patients
56
200
213
GENETIC AND
CONGENITAL
DISORDERS
214
CHAPTER 1
Antinuclear antibodies
Controls
(%)
(%)
No. of vitiligo
patients
3.7
15.4
7.1
2.5
80
26
28
58
107
42
Vitiligo
Author
Brostoff et al. (1969) [196]
Grupper et al. (1970) [37]
Pottgen et al. (1971) [248]
Ortonne (1974) [39]
Heid et al. (1974) [159]
Woolfson et al. (1975) [198]
1.7
3.7
14.2
2.1
16.6
Author
Cunliffe et al. (1968) [185]
Bor et al. (1969) [186]
Ortonne (1974) [39]
215
56
62
100
3.5
6.4
3.0
Method
Waaler-Rose
Latex
Waaler-Rose
Rheumaton
Vitiligo
2.7
0
28.2
19.0
Controls
No. of
vitiligo
patients
7.1
36
36
46
42
GENETIC AND
CONGENITAL
DISORDERS
216
CHAPTER 1
In 1908 Gandy and Paillard [384] reported two patients in whom vitiligo
occurred in the course of jaundice or cirrhosis of the liver and suggested a
biliary origin of some cases of vitiligo. Banerjee and Pal [385], who in 1956
found amebiasis in 85% of 125 cases of vitiligo, suggested that liver damage
may be an important etiologic factor. However, Levai [12] found only 1.5% of
her vitiligo patients to have Entamoeba histolytica, 10% a history of jaundice,
and only 1% liver or gallbladder disease. The incidence of these in the normal
Indian population is not reported. But only isolated cases of vitiligo associated
with chronic active hepatitis [344], hemochromatosis [386], primary biliary
cirrhosis [387], hepatoma [388], and cirrhosis [389] have been reported. Clinically, there seems to be no connection between vitiligo and liver disease.
Most series report normal liver functions in vitiligo patients [12,29,308].
There have been some scattered exceptions. In one series from India [390],
increased transaminase was noted in 43%, increased alkaline phosphatase in
42%, and decreased paraphenylene diamine oxidase in 8%. A Polish study
[391], however, reported decreased alkaline phosphatase. Leucine amino peptidase is normal in vitiligo [392].
Antimitochondrial antibodies, which are associated with chronic active
hepatitis and primary biliary cirrhosis, are not present in vitiligo (Table 67).
Danzig [389] reported a case of vitiligo and cirrhosis of the liver with
jaundice; there were no signs of icterus in the depigmented vitiliginous macules
although the surrounding skin was jaundiced. Bilirubin was absent from the
depigmented skin. Lerner [29] suggested that the involved skin does not become
icteric because the blood vessels are constricted in macules of vitiligo. Another
patient was reported to show jaundice in both normal and in vitiliginous skin
[393]. A patient with vitiligo treated by mepacrine did not appear yellow in
the vitiliginous skin; however, the fluorescent dye was found in the vitiliginous
skin and the depigmented skin appeared yellow when seen against a white
background (M. A. Pathak, F. Dall'Acqua, G. Rodighiero, unpublished observations).
Vitiligo and Dysglobulinemia
Vitiligo
Controls
(%)
(%)
No. of vitiligo
patients
0
0
0
1.4
4.7
107
42
72
Not done.
217
GENETIC AND
CONGENITAL
DISORDERS
218
CHAPTER 1
219
GENETIC AND
CONGENITAL
DISORDERS
tection. Certainly one would expect to observe some late actinic changes in
those who developed facial vitiligo before their teens.
Gastroenteropathies
Vitiligo and Protein-Losing Gastropathy
Two cases have been reported. One was noted to have multiple gastric
polyps and a protein clearance rate of 15 times normal from the gastrointestinal
tract. Gastric histology showed hypertrophic mucosal glands and cystic dilation
deep to the mucosal layer [260]. The authors point out that occasionally such
changes were observed in atrophic gastritis, known to be associated with vitiligo.
Vitiligo and Celiac Disease
One case of vitiligo has been reported among 57 patients with biopsyproved celiac disease [412]. This patient, a 62-year-old female, had developed
both progressive vitiligo and celiac disease at the age of 40. Smooth muscle
antibodies were present but antireticulin antibodies were not. Among patients
with celiac disease, 19% had an associated autoimmune disease and 30% had
antireticulin antibodies. The authors could not use this case to support an
autoimmune pathogenesis of vitiligo, as they concluded that there may exist
an association between celiac and autoimmune disease but not between celiac
disease and vitiligo.
220
CHAPTER 1
McCallum and Kinmont [413] found three cases of vitiligo among 138
patients with Crahn disease. An additional case of almost simultaneous occurrence of vitiligo and regional enteritis has been described [414]. In another
series of 101 cases, none had vitiligo. All reported incidence figures are within
expected limits.
Vitiligo and Ulcerative Colitis
Among 56 patients with vitiligo, one case of ulcerative colitis was noted
and another was found among their relatives [185]. One patient with ulcerative
colitis, vitiligo, atypical lichen planus, alopecia areata, and myasthenia gravis
[347], and another with alopecia areata, vitiligo, and scleroderma [415] are
described in the literature. Although three patients with vitiligo are among 40
cases of ulcerative colitis in one series [416], other large series of patients with
the gastrointestinal diseases contain no mention of vitiligo. There is no statistically significant correlation between vitiligo and ulcerative colitis.
Vitiligo and Intestinal Parasitism
Especially in India, intestinal infection (parasitic or helminthic) has very
often been incriminated in the pathogenesis of vitiligo. One study associated
enteric helminths, especially ascariasis, with vitiligo; treatment was said to
result in repigmentation [417]. But, in 650 patients, Dutta and MandaI [13]
found no more intestinal parasitism than in controls. Levai [12] found the same
incidence of intestinal parasitism in 206 vitiligo patients and in 488 controls.
Vitiligo and Myasthenia Gravis
Four cases of myasthenia gravis and vitiligo have been reported in the
literature. In two of these patients, vitiligo became apparent two months after
thymectomy [418]. In the two other patients, vitiligo preceded [380] or followed
[347] the onset of myasthenia gravis. However, Cunliffe et al. [185] did not
observe myasthenia gravis in any of their 56 vitiligo patients and it is not
described in most series. We have seen myasthenia gravis also in the father of
a girl with vitiligo.
The incidence of striated muscle antibodies seen in myasthenia gravis has
been reported to be higher in vitiligo patients than in controls [37] (Table 68).
The incidence of smooth muscle antibodies is not increased in vitiligo (Table
69).
Author
(%)
(%)
No. of vitiligo
patients
38.4
25.0
18
Vitiligo
a Not done.
Controls
Author
(%)
(%)
0
4.1
0
9.5
aNot done.
No. of vitiligo
patients
80
72
0.7
9.5
107
42
221
GENETIC AND
CONGENITAL
DISORDERS
222
CHAPTER 1
(%)
Author
Grupper et al. (1970) [37]
Ortonne (1974) [39]
a
b
BM
ICS
BM
ICS
Controls
(%)
24.4
No. of
vitiligo
patients
40
o
o
o
o
72
72
Not specified.
Not done.
Pathologic Findings
The characteristic histologic picture of vitiligo is the total absence of melanin and identifiable melanocytes. In general, the epidermis and dermis are
otherwise normal.
Controls
Author
(%)
(%)
No. of
vitiligo
patients
0
2.3
0
2.3
80
42
223
GENETIC AND
CONGENITAL
DISORDERS
224
CHAPTER 1
Apart from the absence of melanin and of identifiable melanocytes, vitiliginous epidermis appears to be normal. However, sporadic reports of abnormalities do appear in the literature. Recently, vacuolated keratinocytes have
been observed in normally pigmented and perilesional skin in vitiligo patients
[451a].
Various parameters of epidermal function have been studied. Gopinathan
[128] found no difference in epidermal thickness between vitiliginous and
adjacent or contralateral normally pigmented epidermis. Tsvetkova et al. [452]
found reduced protein and keratin synthesis in the epidermis of achromic
macules. Mori [446] described karyolysis of the epidermal cell nuclei in all his
cases of vitiligo over three years' duration, but not in younger lesions. These
changes are those observed in the epidermis of denervated skin on the seventh
day post sympathectomy. Decreased acid phosphatase levels have been reported in vitiliginous epidermis [440].
Abdullakhodzhaeva and Abidov [453] found low RNA and tyrosine levels
and high sulfhydryl levels in the depigmented epidermis. Chaudhuri et al.
[454] also found RNA and tyrosine in vitiliginous epidermis and noted larger
than normal nuclei of basal cells and prickle cells. Nucleoli were more fragmented and there was a weak DNA reaction. However, hyaluronic acid, mucopolysaccharides, and alkaline phosphatase activities were stronger in nuclei.
Garner and Everett [455] found staining in vitiliginous epidermis negative for
tyrosine but positive for epinephrine. Califano [456] reported nuclear abnormalities of the basal germinal elements. Using acridine orange fluorescent staining, he described in the vitiliginous epidermis zones of germinal cells characterized by nuclear abnormalities and quantiative alterations of DNA content.
The basement membrane also stained poorly.
Other Histologic Disturbances
Inflammatory Changes
Although the dermis is usually normal in standard hematoxylin and eosin
preparations of vitiliginous skin, lymphocytes may occasionally be seen, particularly in inflammatory vitiligo. Inflammatory cells, mainly lymphocytes,
have been observed in the upper dermis and a focal collection of mononuclear
cells occasionally at the dermal-epidermal junction of the epidermis of the
border of early vitiligo [128]. A perivascular infiltrate may sometimes be observed [35]. Breathnach et al. [457] found in the de pigmented and marginal
areas an increased number of mast cells around nerves and small vessels and
in the upper dermis. Lymphocytes and fibroblasts were numerically increased.
Vesicular structures with internal reticular material were also commonly seen.
In one study of "leukomelanodermie," which is probably trichrome, a dense
inflammatory infiltrate was found in the dermis. The uncommon cases characterized by raised borders generally have a mononuclear dermal infiltrate.
Perrot et al. [458] described many abnormalities. Numerous histiocytes
were found in achromic skin. Macrophages with melanophagosomes were more
numerous at the periphery of the lesions. In one case, at the periphery of a
225
GENETIC AND
CONGENITAL
DISORDERS
ZZ6
CHAPTER 1
macule there was a cell in the dermis in close proximity to the dermal-epidermal junction, facing a melanocyte and in direct contact with a weakly
active melanocyte. The identity of this cell could, however, not be established.
Beneath the basement membrane were cellular fragments rich in ribosomes or
glycogen. The authors noted frequent hyaline bodies, not all of which had
crossed the basement membrane and which may represent necrotic keratinocytes or dendritic cells.
Pigmentary Incontinence
Numerous oval, stellate, and branched pigment cells around blood vessels,
hair follicles, and sebaceous glands in macules of vitiligo have been observed
[298]. These could represent melanophages. Pigmentary incontinence may be
seen at the border of a macule of vitiligo.
Dermal Connective Tissue
Califano [456] described degenerative changes in the dermal connective
tissue architecture, particularly vacuolization of the superficial papillary dermis. Investigation with polarizing light revealed a sharp line of demarcation
between the papillary dermis of the vitiliginous area and the adjacent papillary
dermis, the former being doubly refractive and the latter practically not at all.
Sweat and Sebaceous Glands
Yokota [440] noted in some cases that the Nadi reagent activity (indophenol
oxidase) in the sweat and sebaceous glands was lower in vitiliginous skin than
in normal skin. The degree of difference seemed to be related to the duration
of the disease. To assess sweat gland function, Gokhale et al. [458a] studied
resistance to direct electric current. In some patients they observed increased
resistance which they correlated with inflammation and fatty alveolar degeneration of sweat glands.
Neural Structures
Although no consistent neural abnormalities are present in vitiligo, there
have been reports of alterations of peripheral nerves in vitiliginous skin. Shao
Chan Gen [459] noted peculiar dystrophic changes that were more apparent in
older lesions. In four-year-old lesions, a silver stain revealed thickening and
irregularity of contours of the neutrophils, influx of axoplasm, and varicose
dilatations along the thin axial cylinder. In 14-year-old lesions, there was a
dramatic decrease in the number of cutaneous nerve elements, a nearly total
absence of nerve endings, as well as other dystrophic changes. Iijima [460],
with the use of Gomori's modification of cholinesterase staining and Falck's
fluorescent technique for catecholamines, found the adrenergic nerve fibers of
the blood vessels and the arrector pili muscle to appear unchanged. However,
in depigmented skin, an occasional fibrillar structure was seen in the papillary
dermis, whereas no such structures were seen in the normal skin. Yokota [440]
a
a
a
Melanosomes in melanocytes
Number
Size
Shape
Melanization
Secretion
a
a
a
a
a
Melanosomes in keratinocytes
Number
Distribution
Degradation
a
a
a
227
GENETIC AND
CONGENITAL
DISORDERS
228
CHAPTER 1
Fitzpatrick [462] have shown the clinical color of the macule reflects the number
of melanocytes. Where the color is intermediate between the normally dark
brown skin and the white vitiliginous skin, there is a marked reduction in the
number of melanocytes and the individual melanocytes are hardly recognizable
because of profound changes in morphology, namely, loss of dendrites and
disappearance of melanosomes. In the completely amelanotic zones, there are
very, very few, if any, melanocytes present. Bleehen et al. [441] found marginal
melanocytes to have small, incompletely melanized melanosomes, some damaged and degenerating.
Electron microscopy of vitiliginous skin (Figs. 80,81,82) reveals two dendritic cell populations, one being Langerhans cells (LCs) with typical organelles
and the other indeterminate cells (ICs) or alpha-dendritic cells which lack any
identifiable organelles. The IC is probably of the melanocyte-macrophage line
and the LC of the monocyte-macrophage line.
The first ultrastructural study of vitiligo was reported by Birbeck et al. in
1961 [451]. Cells identical to LCs were observed apparently to have replaced
basal melanocytes and to be present in increased numbers in the suprabasal
layers of the epidermis. Breathnach [463], attempting to explain this observation, suggested that at intervals individual melanocytes divide into two daughter cells that resemble LCs. One of these daughter cells, representing an immediate postdivision stage of a mature, previously active melanocyte, immediately
ascends to the suprabasallevel, is never active in melanogenesis, and is eventually sloughed off with the stratum corneum. The other daughter cell was
thought to remain in the basal layer to become an active melanocyte and later
to divide to repeat the cycle. Vitiligo then would result from a failure of the
second type of daughter cell to mature. This hypothesis explained the disappearance of melanocytes from the basal layer, their replacement by LCs, and
the increased number of LCs in the suprabasallayers. However, Breathnach et
al. [464], in 1968, disproved this hypothesis by demonstrating LCs in the skin
of neural crest-free mice, in which melanocytes were absent. The authors concluded that the Les do not arise from the neural crest and, therefore, they
cannot belong to the melanocyte cell line which is of neural crest origin.
More recent studies have shown Les to be dynamic rather than static cells.
Zelickson and Mottaz [465], in 1970, found increased numbers of Les in vitiliginous skin exposed either to sun or to ultraviolet radiation. Perrot et al.
[458,466] found older lesions to have only Langerhans-type dendritic cells with
a normal or decreased number of typical granules. LCs were frequently present
in the upper epidermis. In one case, LCs with melanophagosomes were observed. Migration of dendritic cells thought to be LCs was observed to occur
from the dermis. In occasional specimens, ICs were also observed, usually at
the basal layer, but occasionally at the upper levels. Perrot et al. suggested that
an increased number of LCs in the depigmented skin marked the onset of the
disease, and attributed their presence to migration of Les from the dermis and
not to a redistribution of cells within the epidermis. This suggested the LC
could be a macrophage or a lymphocyte that migrates from the dermis. But
although LCs may have phagocytic function and take up ferritin and thorotrast,
keratinocytes are much better phagocytes. It would seem that Les must be
present for other reasons. Les have been found in epidermis, dermis, lymph
229
GENETIC AND
CONGENITAL
DISORDERS
FIGURE 80. Vitiliginous skin. a: Indeterminate cell in suprabasal layer (x 18,000). b: Indeterminate cell in contact with disrupted basement membrane (x 2000). c: Macrophages in vitiliginous
epidermis (x 6500). d: Melanosomes and various inclusions within macrophages (x 40,600). Mb.
basement membrane; K. keratinocyte; Ma, macrophage. (From: Perrot H et al: Etude ultrastructurale
du vitiligo. Lyon Med 232:439-446, 1974. Copyright, 1974, Lyon-Medical. Used with permission.)
nodes [467], and thymus tissue; in addition, cells resembling LCs have been
observed in histiocytosis X, monocytic leukemia. and reticulum cell sarcoma.
This and other observations have shown the LC to be an immunologically active
cell. In guinea pig epidermis, the LC is the only cell that forms rosettes with
IgG to antibody-coated bovine red blood cells. Ia antigens are expressed and
there are Fc and C3 receptor sites on LCs of guinea pig epidermis. Like other
230
CHAPTER 1
FIGURE 81. Border of vitiliginous macules. a: Layering of basement membrane and adjacent
melanocyte (x 25,000). b: Melanocyte containing vacuoles and round melanosomes (x 32,000).
c: Melanocyte of basal layer (x 8,800). d: Necrotic melanocyte (x 16,200). Me, melanocyte; m,
melanosome; K, keratinocyte; Mh, basement membrane; v, vacuole. (From: Perrot H et al: Etude
ultrastructurale du vitiligo. Lyon Med 232:439-446, 1974. Copyright, 1974, Lyon-Medical. Used
with permission.)
231
GENETIC AND
CONGENITAL
DISORDERS
FIGURE 82. Border of vitiliginous macule. a: Indeterminate cell containing granular cell and
altered mitochondria (x 16,000). b: Hyaline material near basement membrane (x 16,000). c :
Contact between melanocyte and dermal histiocyte with disruption of basement membrane (x
8000). Me, melanocyte; K, keratinocyte; Mb, basement membrane; Ve, vesicle; H, histiocyte. (From:
Perrot H et al: Etude ultrastructurale du vitiligo. Lyon Med 232:439-446, 1974. Copyright, 1974,
Lyon-Medical. Used with permission.)
immune cells, LCs have high metabolic activity and certain hydrolytic enzymes
in common [468]. Also, mononuclear cell-LC apposition has been found in
delayed contact sensitivity. LCs may be visualized as an epidermal contact
antigen trap [469]. Damaged LCs have been observed at sites of specific challenge to a variety of contact allergens in actively sensitized patients and guinea
pigs and in passively sensitized guinea pigs in which LCs are found in dermal
blood vessels resembling lymphatics. The number of dermal LCs is increased
after a challenge with contact allergens [470]. Some LCs in vitiligo lesions have
shown marked vacuolar fonnation, suggesting degenerative changes [252]. While
the number of LCs appears to be increased in vitiliginous macules and although
mononuclear leukocytes have been observed in the epidermis, actual contact
between these cell types is not well documented [471]. The presence of such
cells, probably in increased numbers at least in the basal layer [472] of vitiligo
Z3Z
CHAPTER 1
Epidermal keratinocytes are morphologically normal in vitiliginous epidermis [451]. They, of course, contain few or no melanin granules. Keratinocytes contain more melanin per cell in the hyperpigmented ring than in the
surrounding normal skin [442]. Breathnach et al. [457] reported in one case the
presence of vesicles in the perinuclear region of the keratinocytes of the depigmented epidermis. Also vacuolated keratinocytes have been found on l-lJ.m
sections in normal and perilesional skin of vitiligo patients [451a]. Mast cells
have also been observed in the vitiliginous epidermis [457,458].
Basement Membrane Abnormalities and Immunofluorescence
233
GENETIC AND
CONGENITAL
DISORDERS
234
CHAPTER 1
negative split-dopa preparations. Voulot and Ortonne [480] did an electrophoretic gel study of vitiliginous skin extract and then used the dopa histochemical
reaction to identify melanotic bands. Such bands, which are present in normal
skin, are different in their electrophoretic mobility from the other dopa melanin
bands observed in human melanoma and nevus and from those described by
Burnett and Seiler [481] as soluble tyrosinases. While the study of Voulot and
Ortonne suggests tyrosinase is present in vitiliginous skin extracts, the dopa
reaction is not specific for tyrosinase. A dopa melanin band is observed on the
gels with hemoglobin [482] or with ceruloplasmin [480]. Tyrosinase may be
inhibited in vivo but not in extract preparation and electrophoretic separation
processes. More recently, tyrosinase activity has been demonstrated in vitiligo
epidermal homogenates by a highly sensitive fluorometric method, as well as
by 14C(U)-L-tyrosine incorporation into melanin [482a].
Copper
Since tyrosinase is a copper-requiring enzyme, it has been suggested that
vitiligo results from a disturbance of copper metabolism. The occurrence of
hypomelanosis in Menkes kinky hair further suggests a defect in copper metabolism can affect pigmentation. Furthermore, copper therapy has been reported to result in repigmentation [483,484]. But the very diverse results of the
many works done on this subject make it impossible to identify any definite
copper-related defect.
Low serum copper levels have been reported [70,309,314,485,486] in up
to 60% of cases of vitiligo. It has been reported that decreased serum copper
levels are more marked in children or in those with vitiligo of less than one
year's duration [487]. The serum copper levels have been observed to rise during
treatment with oral meladinine (8-methoxypsoralen and 8-isoamylinoxypsoralen) [488]. This rise, which was not significant at the 5% level, was attributed
to the 8-methoxypsoralen fraction of the meladinine [489]. EI Mofty et al.
[490,491] postulated that psoralens work through mobilization of hepatic copper stores. El Hefnawi et al. [394] suggested that the psoralens influence the
incorporation of copper into the protein to form ceruloplasmin. This would
explain the authors' observation that most rapid psoralen repigmentation occurs
in vitiligo patients with normal serum globulins and normal serum copper.
Increased serum copper levels have also been reported. The finding of
Genov et al. [492] of 30% higher serum copper levels in vitiligo patients than
in normal healthy controls suggested a functional impairment of serum copper
in vitiligo. A few cases of vitiligo with elevated copper levels were said to have
other diseases that may explain the biochemical abnormality [70]. In others,
the levels were only slightly elevated [493] or were not elevated to a statistically
significant degree [494].
Among 28 vitiligo patients, Ito [495] observed that 10 had elevated serum
copper levels, three decreased levels, and 15 were normal. Most agree serum
copper levels are normal [496,497].
Although decreased copper levels have been reported [497,498] in vitiliginous skin, in a study of the skin of 12 vitiligo patients, no difference was
observed in the copper levels in vitiliginous compared to normal skin. Molokhia
235
GENETIC AND
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DISORDERS
236
CHAPTER 1
237
GENETIC AND
CONGENITAL
DISORDERS
238
Melanin Metabolites
CHAPTER 1
Sensory Function
There are no gross abnormalities of sensation in vitiligo macules. Studies
of cutaneous sensation in vitiligo macules have given somewhat contradictory
results. No changes were reported by Habermann [104] and Rothman et al.
[522], although two of the 10 patients with vitiligo volunteered that during
galvonic testing they felt less burning in the vitiliginous macules than in the
surrounding area. This latter observation seemed to support the statement of
Konigstein [523] of decreased perception of pain in vitiligo skin.
Ono [524] measured sensory thresholds in 30 cases of vitiligo and found
normal tactile sensation in skin that had depigmented within the previous year,
markedly decreased sensation in macules a year older, and moderately decreased sensation in those macules of more than two years'duration. Pain per-
ception in vitiligo skin was abnormal in macules within one year of onset, was
more marked in two or three years, and became relatively mild thereafter. These
disturbances of tactile and pain senses were not considered significant enough
to suggest a sensory neuropathy. The author presumed that such sensory disturbance in vitiligo macules could be a secondary phenomenon.
Maiti et al. [525] studied the tactile gnosis of the involved skin and of the
contralateral normally pigmented areas in 23 patients with segmental vitiligo.
That there was no significant difference between the sides excluded any disturbance of somesthesis in vitiliginous skin. There is no difference in the distribution of sensory receptors for pain, touch, heat, and cold in the vitiliginous
skin compared to normal skin of vitiligo patients or to normal skin or normal
controls.
Cutaneous Blood Flow
Various techniques and observations have been used in an attempt to
demonstrate aberrations of cutaneous blood flow in vitiliginous skin. Lerner
[29] has quoted reports that vitiligo skin does not yellow from ingestion of
quinacrine or become jaundiced and noted that blood constriction has been
reported in vitiligo macules. With the use of reflection photoelectric phlethysmography, Ono [524] simultaneously observed the cutaneous blood flow in
the depigmented skin and in the contralateral normally pigmented skin. In 10
of 56 cases, differences in vasomotor reflexes and blood flow pattern were
observed. Marked differences of the pulse wave amplitudes were seen in 13
cases, particularly in the relatively new cases of vitiligo. Grana and Marchiolo
[526] used radioisotopic studies to demonstrate abnormal blood flow in vitiligo
macules.
Altered vascular responses of cooled or warmed vitiligo skin have also
been reported. Maiti et al. [525] concluded that cold exposure gave relatively
more numbness in fingers affected with vitiligo than unaffected normal fingers
in control subjects. Dutta et al. [527] observed a slow rate of warming in vitiliginous skin exposed to cold. This was considered indirect evidence of hypertonic vasomotor reflex and supportive of the hypothesis of peripheral adrenergic hyperactivity in vitiliginous skin.
The average blister resorption time has been reported to be increased nearly
60% in vitiliginous skin compared with normally pigmented skin [528].
Skin Temperature
Skin temperature measurements were compared before and after sweating
in 22 vitiligo patients [529]. Nine of these registered higher temperatures in
vitiliginous skin, both before and after sweating, although the latter was less
markedly increased. Studies of vitiliginous skin with the bolometer and the
thermovisual camera revealed six cases in which there were minimal differences, the depigmented skin being warmer by O.lC to 0.3C by direct measurement. One patient with both malignant melanoma and vitiligo-like depigmentation showed depigmented skin to be 0.8C warmer than normally pigmented
skin. Lowered temperature in vitiligo skin, even during psoralen therapy, has
239
GENETIC AND
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DISORDERS
240
CHAPTER 1
in the segmental vitiligo macules. Vitiliginous macules in patients with nonsegmental vitiligo had normal sweat responses. The investigators [129] suggest
segmental vitiligo is different pathogenetically from vitiligo vulgaris, which
has a normal stimulation response. Segmental vitiligo was found to repigment
with nialamide, a monoamine oxidase inhibitor.
Bleeding Times
Abnormal bleeding times have been noted. Chanco-Turner and Lerner [529]
compared the bleeding time in vitiliginous and normal skin in 10 patients with
vitiligo and found it to be consistently increased in six patients, decreased in
one, and unchanged in two. (In one subject it was slightly decreased in one
area and increased in another.) The mean bleeding time in vitiliginous skin
was 30 seconds longer than in normal skin. The authors concluded that this
increased bleeding time in vitiliginous skin may reflect increased blood flow.
Dutta and Dermat [533] found a nearly 29% increase of bleeding times in the
vitiligo skin. Zebracka et al. [531] made similar observations. However, bleeding
time determinations tend to be somewhat imprecise and there is no evidence
to suggest that clinically significant prolonged bleeding times prevail in vitiligo.
241
GENETIC AND
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242
CHAPTER 1
FIGURE 83. Sinclair swine provide an animal model for depigmentation; these animals have
many pigmentary tumors resembling the human melanocytic nevus and superficial spreading
melanoma. Hair depigmentation of lesions often is an early sign of regression.
the melanomas do not resolve, the horses seem to tolerate them well. Their
longevity is not compromised unless the metastases implant themselves in a
vital area, such as the surface of the small intestine or the heart.
Several investigators have used immunologic techniques to induce depigmentation in animals. Hornung and Krementz [534] injected antihuman melanoma cells into adult normal chimpanzees. Depigmentation occurred remote
to the sites of injection.
Boissy et al. [535] have developed a mutant line of chickens which begins
to develop amelanosis at five weeks. They also develop degeneration of choroidal melanocytes. A very few chickens develop some small degree of repigmentation. Electron microscopy has shown absence of melanotic melanocytes
except in cases of repigmentation where smaller cell bodies without normal
dendritic processes were observed. The White Leghorn chicken studied by
Jimbow et al. [535a] undergoes in utero autophagocytosis of melanocytes. A
family of elephants which develops progressive whitening of their ears and
other areas has been observed in the zoo in Sri Lanka (Dr. Subash Chaula,
personal communication).
Antiskin and antierythrocyte antibodies have been observed in rabbits,
depigmented by paratertiary butyphenols [536].
Kahan et al. [537] sensitized rabbits with human uveal pigments and induced depigmentation.
Pathogenesis
243
Over the years, the concept of the pathogenesis of vitiligo has survived
notions of infections, paraneoplasia, evil vapors, and more. Today, there are
three prevailing theories of the pathogenesis of vitiligo: the immune hypothesis,
the neural hypothesis, and the self-destruct hypothesis. All have their champions and supporting evidence. None is without some conceptual problems.
When the answer is known, it is likely each theory will be shown to be relevant.
Although they are discussed separately, in the end they must be considered
together (the composite hypothesis).
Immune Hypothesis of Vitiligo
One of the most attractive theories to explain vitiligo is that there is induced
an antigen antibody reaction which results in melanocyte dysfunction, destruction, or both (Fig. 84).
Two immunologic mechanisms could explain the pathogenesis of vitiligo
(Fig. 85).
A primary disturbance in the immunologic system may result in autoimmunization with the formation of autoantibodies against an antigen of the
melanogenic system. This results in inhibition of melanin formation or in
melanocytotoxicity. An alternative mechanism is that there is some injury to
the melanocytes which results in release of an antigenic substance so that
antibody formation occurs and melanogenesis is inhibited. The first mechanism
implies only one defect, autoimmunization, whereas the second mechanism
implies a primary inducing factor and a secondary autoimmunization.
This concept of an immunologic basis for depigmentation is not new; in
fact. Rohdenburg [538] suggested. in 1927. that halo nevus results from an
GENETIC AND
CONGENITAL
DISORDERS
First Hypothesis
244
CHAPTER 1
Primary disturbance
in the
immune system
Antibody against
component of the
melanogenesis sytem
Antiorgan antibodies
Destruction and
disappearance of
melanocytes
Second Hypothesis
immune mechanism. Lorincz [512], noting that Wheeler had been able to induce
antityrosinase antibodies, first speculated that vitiligo might result from specific
inactivation of the protein component of tyrosinase. Since that time, considerable clinical and histopathologic evidence has accumulated to support an
immunologic basis of depigmentation in vitiligo.
Halo nevi
2.
Vogt-Koyanagi-Harada syndrome
3.
Malignant melanoma
a. Halos around primary or metastatic cutaneous malignant melanoma
-at sites of partial regression and within the primary lesion of
malignant melanoma
-at site of total spontaneous regression of primary malignant melanoma
b. Distinct from the primary melanoma or its metastases
-vitiligo-like depigmentation
-nonspecific hypopigmentary phenomenon
c. Appearance of halo nevi in the course of an evolving malignant
melanoma prior to or after treatment but without hypopigmentation
around the primary
d. Vogt-Koyanagi-Harada-like syndrome in melanoma patients
-spontaneous
-after immunotherapy
245
GENETIC AND
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CHAPTER 1
that keratinocytes are much more effective in this role also suggests LCs must
have a function other than plragocytosis.
Immunologic Studies
A considerable number of laboratory observations also support an immunologic basis for depigmentation (Table 75). Three of five patients with
active vitiligo and one of six with inactive vitiligo were found to have (like
patients with active halo nevi) urinary protein that can inhibit cytoplasmic
staining of melanoma cells by specific rabbit antihuman melanoma antiserum
[546]. It is not clear whether it is humoral or cell-mediated immunity that is
implicated, or both.
Humoral Immunity
247
GENETIC AND
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248
CHAPTER 1
T- and B-cells seem normal [165] but one study has shown decreased Tcell levels [166]. Extracts of autologous tumor cells [561-563] have been used
to demonstrate melanoma antigen-specific delayed hypersensitivity in malignant melanoma patients. In a study of five patients with halo nevi and malignant
melanoma, Epstein et al. [539] found strong cellular immunity against melanoma antigens (lymphocyte stimulation, migratory inhibitory factor production, and rosette-forming lymphocytes).
Friedenwald [564] and MacPherson and Woods [565] respectively demonstrated delayed-type hypersensitivity to ultracutaneous uveal pigment in
sympathetic ophthalmia and Vogt-Koyanagi-Harada syndrome. Kahan et al.
[537] correlated the results of skin tests (sterile bovine uveal pigment) with
disease activity. Specific lymphocyte transformation with bovine uveal pigment
in patients with Vogt-Koyanagi-Harada syndrome and sympathetic ophthalmia has been reported. This suggests that these diseases are of pigment autoaggressive and delayed hypersensitivity nature [566].
Cytotoxic peripheral lymphocytes have been reported against cultured homologous and autologous melanoma cells in patients with malignant melanoma
[319,567-569] and against homologous cultured melanoma cells in patients
with halo nevi and malignant melanoma-associated halo nevi, vitiligo, and
nonspecific depigmentary phenomena [332,539,545,570]. Lymphocytes of pa-
tients with halo nevi without melanoma are cytotoxic to melanoma cell lines
(W. H. Clark Jr., K. L. Leung, M. J. Mastrangelo, unpublished data), but those
of individuals with vitiligo alone are not [570a].
Mishima [472] showed abnormally high blastoid formation against premelanosome antigens in a number of cases of vitiligo vulgaris but not in the
segmental or localized type. Mishima suggests generalized vitiligo is an immunologic disorder and segmental is not.
Where the Immune Hypothesis Fails
The immune hypothesis of vitiligo, although increasingly attractive, is by
no means universally accepted.
Absence of eye involvement has been regarded against the immune hypothesis. Recent reports of pigmentary abnormalities in the retinae of some
vitiligo patients suggests this objection is no longer completely valid.
The usual absence of a mononuclear infiltrate in the macules of vitiligo
seems inconsistent with an immune mechanism. However, it is possible that,
as in resolved halo nevus, the white macules represent the end stage of an
auto immunologic process in which the immunologic marker has disappeared.
In chimpanzees hyperimmunized with human melanoma cells, the mononuclear infiltrate occurs only at the site of injection which does not depigment,
and not at the remote sites of pigment loss [534]. If activated lymphocytes
stimulate Langerhans cells to migrate into the epidermis to alter melanocytes,
the paucity of lymphocytes would be of little conceptual consequence.
No circulating melanocyte antibodies (antigens from normally pigmented
skin or malignant melanoma) [197], antitumor antibodies (antigens from malignant melanoma, lentigo simplex, and benign blue nevus) [198,460]' or malignant melanoma cytoplasmic antibodies [554] have been observed in patients
with vitiligo alone.
Furthermore, the work of Langhof et al. in identifying antimelanin antibodies in vitiligo sera [556] has never been confirmed. Sera from their patients,
containing antimelanin antibodies, were not cytotoxic against melanoma cells.
Since, as pointed out by Wasserman and Van der Waalt [571], the melanin
preparations used by Langhof et al. [556] contained many cellular elements, it
is possible that the antibody reported by Langhof et al. was directed towards
an antigen other than melanin. It has even been suggested that melanin may
not be antigenic. Blois [572], using synthetic melanin, and Wasserman and Van
der Waalt [571], using melanoprotein of baboon eyes, were unable to produce
specific antimelanin antibodies. But Mason et al. [558] and Vial and Callahan
[559] did produce antimelanin antibodies in rabbits. It is possible that Langhof
et al. [556] produced antibodies against a protein moiety of incompletely melanized melanosomes.
Other immunologic markers are lacking. No consistent abnormalities of
skin testing [39], lymphocyte transformation with antigens extracted from lymph
node metastases of malignant melanoma or human hair melanin [573], or lymphocyte typing [574] have been demonstrated.
Serum immunoglobulins are usually normal in vitiligo [308,394,395,575].
Gatti [396] did report IgA deficiency in five patients with vitiligo, and Bader
249
GENETIC AND
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250
CHAPTER 1
et a1. [397] also reported an eight-year-old female with vitiligo and a dysglobulinemia characterized by absent 19A, very low IgG, and normal IgM with an
intact T-cell system. However, Ruiz-Maldonado et al. [398] found normal 19A
levels in 45 Mexican children with vitiligo. Furthermore, Pottgen et al. [248]
and Ortonne [39] found normal IgA, IgM, and IgG in their patients with vitiligo.
Complement levels (C, C3, C3Pa, C4) are normal [159,574]. Attempts to identify
immunoglobulins and complement deposition in vitiliginous skin have also
been unsuccessful [39,159,197,198,441].
Immunologic inactivation of tyrosinase could also cause vitiligo. Although
antityrosinase antisera with T1 and T2 specificity have been produced in rabbits
using extracts of Harding-Passey melanoma, active sites of tyrosinases were
not improved by immunochemical reaction [576-578]. Owen and Market [579]
prepared antisera from rabbits by injecting them with tyrosinase extract of plant
(Glomerella cirgulata) cultures. Subsequent addition of the antisera produced
a marked, rapid inhibition of in vitro tyrosinase activity and a slower specific
precipitation of tyrosinase.
The balance of evidence seems to support the immune theory of vitiligo
yet there is no compelling argument available to substantiate this theory. Probably at whatever level the immunologic mechanism interacts, melanocytes are
destroyed (or tyrosinase inhibited or tyrosinase synthesis blocked) via action
of the Langerhans cells serving as antibody receptors and as effector cells.
Neural Hypothesis of Vitiligo
The neural hypothesis of vitiligo suggests that vitiligo results from the
accumulation of some neurochemical mediator which causes decreased melanin production [29]. Both melanocytes and nerve cells are of neuroectodermal
origin and both utilize tyrosine to produce an end product, melanin or catecholamines. The similarity of the structures of dopa and catechols suggests that
a translation error of receptor sites controlling melanogenesis may be the aberration in vitiligo. Abundant and conflicting observations have been advanced
to support this hypothesis.
Clinical Evidence
Segmental vitiligo, a localized leukoderma that appears to follow one or
more dermatomes, is a well-recognized entity [580-583a]. A patient with hypopigmentation confined to the distribution of the trigeminal nerve [584] and
another with small macules of hypopigmentation along the distribution of the
sacral nerves [11] have been described. One recent study has demonstrated
decreased physostigmine-induced sweating in segmental vitiligo macules [129].
Numerous clinical observations have been reported in which vitiligo patients became white in cutaneous areas corresponding to areas of neurologic
damage or in whom pigment loss was spared in a neurologically compromised
part of the body. A patient with transverse myelitis and paralysis from the
waist down developed vitiligo of the face and upper portion of the body but
not below the level of cord damage [29]. The patient underwent a hysterectomy
and no depigmentation occurred in or near the surgical scar. Another patient
[29] developed vitiligo several years after contracting poliomyelitis which had
left a unilateral neuropathy. Less depigmentation occurred over the leg with
nerve damage. A patient with extensive vitiligo and diabetes repigmented macules where she developed a severe diabetic neuropathy [584]. In a child with
viral encephalitis, unilateral vitiligo and poliosis appeared over areas innervated by both the trigeminal and upper cervical nerves [585]. Although these
are all striking observations, there are no studies that purport to show the
incidence of leukoderma in patients having cerebrovascular accidents or other
neurologic disorders.
A woman, after right cervical sympathectomy, noted more gray hair on the
left than on the right side [586]. Gray hair has been observed on the skin over
the distribution of a nerve affected with peripheral neuritis [587].
Onset of vitiligo after anesthesia and nerve injury has been reported. Tremittera [588], in 1927, reported vitiligo developed in one patient after spinal
anesthesia. Costea et al. [589] observed a 31-year-old patient who, upon developing traumatic paralysis of the right brachial plexus, exhibited ipsilateral
macules of vitiligo at the level of the upper arm, chest, buttock, sacrum, and
scrotum. The authors suggested the phenomenon of "sympathetic repercussion" resulted in widespread leukoderma; irritation of the sympathetic nerve
endings of the Cs and Dl roots induced a series of reflexes which resulted in
depigmentation exceeding the area innervated by the brachial plexus. However,
this explanation seems doubtful as their patient had insular canities prior to
the accident and showed a predisposition to dyschromia.
Vitiligo has been reported in patients with syringomyelia [590], von Recklinghausen disease [426], medullar tumor [591], multiple sclerosis with Horner
syndrome [592], poliomyelitis [29], neuritis [584,587], encephalitis [159,585]'
myelitis [29], or following peripheral nerve injury [589,593]. A patient with
encephalitis was observed to develop rapid graying of hair and total vitiligo
[594].
Vitiligo is sometimes observed to begin after severe emotional trauma such
as death of a parent or spouse, loss of a job, financial reversal, or severe fright.
A young girl, nearly struck by gunfire in the war, became suddenly aware of
having vitiligo [72]. An hysterical woman who complained of low back and
right thigh pain developed urticaria and vitiligo after electromyographic needle
insertions [595]. It was suggested that these cutaneous responses resulted from
neurohormonal changes induced by some psychic stimulus of the examination
procedure. Some reports mention an increased incidence of vitiligo in psychiatric patients [78,596-598]. History is replete with tales of sudden whitening
of hair following significant events. All such reports suggest a role of the CNS
in the pathogenesis of vitiligo.
Leukoderma occurring in a hypesthetic leprous macule has also been interpreted to favor the neurogenic hypothesis of leukoderma. But since there is
some evidence to suggest direct action of Mycobacterium Jeprae on melanocytes, the nervous system need not be implicated.
Several early authors have noted cerebrospinal fluid (CSF) abnormalities
in several vitiligo patients. CSF lymphocytosis and CSF cytologic abnormalities
have been described [599,600]. Increased CSF glucose in one patient has been
reported [601]. However, many of these patients had concomitant lues; in fact,
251
GENETIC AND
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252
CHAPTER 1
253
GENETIC AND
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254
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the sites of the disease process in vitiligo. He observed that in all cases where
the normal skin transplanted to the middle of a vitiliginous lesion underwent
depigmentation, a slight spread of depigmentation was seen on the previously
normal skin around the homologous pathologic grafts, and in those cases where
the vitiliginous grafts had become repigmented, a spread of pigmentation was
seen to extend onto the surrounding vitiliginous skin from the corresponding
normal skin grafts. In the latter group, the author noted signs of spontaneous
partial or complete repigmentation of many lesions on the body. He concluded
that if the vitiligo is in a progressive state, depigmentation will be the predominant change in the grafts, and if the disease is undergoing remission, then the
pathologic graft will also repigment. He found no difference in the behavior of
thick or thin grafts.
Where the Neural Hypothesis Fails
The most compelling arguments for the neural hypothesis are the dramatic
presence of segmental vitiligo and the evidence for neural control mechanisms
in fish. Recent studies demonstrating an anatomic linkage between melanocytes
and nerve cells are also fascinating. Yet there remains no direct evidence for
a primary neural defect in humans and there are several problems with this
hypothesis.
The weight of clinical observations among neurologic disorders is against
the neural hypothesis. Vitiligo is not a classical feature of denervation syndromes or of such diseases as peripheral neuritis or herpes zoster. Neural
dysfunction, is seems, is not usually associated wtih hypopigmentation. Depigmentation is not observed after sympathectomy and, conversely, sympathectomy in one vitiligo patient had no effect on the course of the disease [584].
The depigmented macules of vitiligo do not usually assume the true dermatomal pattern of known lesions of the peripheral nervous system. This quasidermatomal distribution of vitiligo also occurs in piebaldism or in nevus depigmentosus, in which neural factors are not usually implicated.
It is difficult, especially in vitiligo universalis, to explain on the basis of
inhibitory neurochemical mediators the absence of pigment inhibition in the
uveal pigmentary cells, since the iris is richly endowed with melanin, unless
one hypothesizes that the iris is somehow protected. Iris pigmentary lightening
has been reported in vitiligo but its occurrence must be rare [61]. No definite
reproducible pathophysiologic or biochemical abnormality has been demonstrated in vitiliginous skin.
Szcepanski [628] found no changes in the cerebrospinal system in 18 cases
of vitiligo. Furthermore, chronaximetry revealed no autonomic dysfunction.
Exchange transplant studies are beset with many technical difficulties [128];
several factors may influence the skin grafts (circulatory changes, pigment spread
phenomenon, scar formation) and explain the diverse results.
Serri and Cerimele [629] observed an anatomic association of cholinesterase-positive nerve endings and dendritic cells in the human fetal skin, and
Mori [446] obtained findings that might suggest a connection between the vegetative nerves and melanocytes mediated by the taste cells in the papillary
dermis. A recent report [456] has shown an anatomic relationship between
255
GENETIC AND
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DISORDERS
256
CHAPTER 1
nerve cells and melanocytes. Yet more observations must be made before it can
be concluded that there is functional control of melanocytes by the nervous
system.
The role of the nervous system in the pathogenesis of vitiligo is ill defined,
and although some observations suggest that loss of sympathetic innervation
precipitates changes in pigmentation, this must not be regarded as firmly established. The problems with the hypothesis, simply distilled, are that most of
the observations on fish, etc., may not apply to mammals, particularly humans,
that the clinical evidence is circumspect, and that no functional association
has yet been made between melanocytes and neural cells.
Self-Destruct Hypothesis of Vitiligo
disease is consistent with this observation. The increased output of MSH increases the levels of cyclic AMP in the melanocytes; increased cyclic AMP
increases tyrosinase synthesis, melanogenesis, and thereby accumulation of a
melanocytotoxic product. Lerner's theory [263] implies that vitiligo would be
more frequent in people with dark skin and dark hair; but an increased incidence of vitiligo in blacks or those with black hair cannot be considered established.
Ultrastructural and Experimental Evidence
Catechols or phenolic derivatives, which selectively destroy melanocytes,
may induce vitiligo-like cutaneous depigmentation in humans or in animals.
Frenk [634] reported the ultrastructure of chemically induced depigmentation
to be similar to that of vitiligo. Some of these depigmenting agents show a
striking structural similarity to tyrosine or dopa. Brun [633] observed two tyrosine derivatives, p-hydroxycinnamic acid and p-hydroxyphenylpyruvic acid,
to be strong inhibitors of melanogenesis. Tyrosine, dopa, and tryptophan show
a selective toxicity towards melanotic cells. Treatment of cells with phenylthiourea, a selective inhibitor of tyrosinase activity, completely protects the
cells from the toxicity of the melanin precursors [350].
For most of these depigmenting agents, the precise mechanism of melanocytotoxicity is unknown. Riley [632] suggested that hydroxyanisol depigmentation is brought about by the synthesis of semiquinone free radicals. These
compounds diffuse out of the melanosomes to initiate the chain of lipid peroxidation. This causes damage to cellular organelles and ultimately the selective destruction of melanocytes. However, neither such semiquinone-free radicals, nor increased levels of the two tyrosinase inhibitors described by Brun
[633] have been found in vitiliginous skin.
Where the Self-Destruct Hypothesis Fails
The major failing of the self-destruct hypothesis is that it does not embrace
the immunologic or neurologic theories. As an inhibiting or precipitating factor,
it is attractive but, alone, it leaves too many observations unexplained.
The Composite Hypothesis
257
GENETIC AND
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258
CHAPTER 1
sunburn, etc., may upset this homeostasis in favor of melanin destruction, again
with incontinence of antigenic material and resultant immunologic melanocyte
destruction or inhibition.
Finally, it cannot be excluded that the primary event is a deficit in feedback
control from keratinocytes to melanocytes such that whatever mechanism genetically limits the number and packaging of melanosomes in keratinocytes
becomes defective and dominant so as to "turn off" melanocytes completely.
This too could implicate neural, immunologic, and self-destruct factors.
Diagnosis
Establishing a diagnosis of most types of vitiligo is usually not difficult.
History of an acquired progressive depigmentation excludes piebaldism, Woolf
syndrome, Waardenburg syndrome, Ziprkowski-Margolis syndrome, and nevus depigmentosus. The hypopigmented macules of tuberous sclerosis and of
tinea versicolor are not amelanotic and the latter usually are raised, scaling,
and sometimes have hyperpigmented margins. Postinflammatory hypomelanoses are likewise not amelanotic and require a history of an antecedent cutaneous eruption. Chemically induced depigmentation may be indistinguishable from vitiligo clinically and histologically; a history of industrial chemical
exposure (especially phenols) can usually be elicited and confetti white macules are usually present clinically.
When the clinical diagnosis is unclear, Thiersch biopsies for split dopa
and electron microscopy should be done. Absence of melanocytes in a biopsy
from a fully depigmented macule is required for diagnosis. A biopsy should
also be taken from clinically normal skin for comparison.
The observation of Harsoules et a1. [268] that 19 of 85 vitiligo patients (ages
4 to 78) had thyroid disease or diabetes mellitus and our observation that nearly
half of a small sample of vitiligo patients over the age of 50 have a thyroid
disease diathesis [191] make it imperative that vitiligo-associated conditions
be excluded. When the diagnosis is established, every patient should be screened
for diabetes mellitus, thyroid disease, and pernicious anemia. Addison disease
seems to be infrequent enough that laboratory screening can be reserved for
the patient who is symptomatic or has other evidence for autoimmune disease.
Probably in older patients with vitiligo, laboratory tests should be repeated
every few years indefinitely.
For those patients who wish some form of treatment, photographs prior to
therapy will later prove useful for comparison.
Treatment
There are several options for the approach to treatment of vitiligo. Simple
reassurance that the condition is not infectious or cancerous may be all the
patient requires. But for many patients the goal is to be again one color, preferably their normal constitutive skin color.
Cosmetic coverup may be adequate to satisfy the patient's needs. Vita dye
(Elder), Dy-O-Derm (Owen), dihydroxyacetone-containing quick-tanning agents,
and opaque cosmetics are satisfactory for some (Fig. 86). These must be applied
carefully to produce good camouflage but there are limitations. They gradually
wash off and must be reapplied to the vitiligo macules every few days. Unfor-
FIGURE 86. a: Patient with bilaterally symmetrical vitiligo of the dorsal hands obtains excellent
coverup match with Dy-O-Derm. b: This patient uses Vitadye to camouflage vitiligo of the chin.
259
GENETIC AND
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260
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The ancients had some success with herbal therapy of vitiligo. In an 1880
compilation of ancient Indian medicine (Ashfangahridaya, Bombay, Krishna
Sarma, 1880), Vaghbhata summarized the nineteenth century status of therapeutic success: "The lesions where hairs have not turned white, which are not
associated with swellings, which have not become confluent, are of recent
origin, and do not follow burns are curable. The lesions which show characteristics contrary to this should be discarded (not treated). The lesions that
occur on the genitalia, hands and feet and lips, even if of recent origin should
be discarded." One hundred years later, this is not so far afield; there are still
some limits to our expected success. That so many different treatment modalities have been attempted attests to the lack of complete and ready success of
any of the methods. The list includes surgical procedures (Thiersch grafts [636],
dermabrasion, vibropuncture [637], and tattooing), vitamin therapy, hormonotherapy (MSH) [374], copper therapy [70], tyrosinase [638], p-aminobenzoic
acid [639], mepacrine [640], and chloroquine [641]. Recently L-dopa, Lamprene,
quinacrine, corticosteroids (topical, intralesional, and oral), and ACTH have
been reported to induce repigmentation. The most successful current therapy,
however, involves the use of oral (trioxsalen, methoxsalen) or topical (methoxsalen) psoralens and subsequent exposure to long-wave ultraviolet radiation
(320-400 nm) from sunlight or from high-intensity artificial sources. This is at
present the only treatment modality with a reasonable hope of achieving repigmentation of vitiliginous macules.
Psoralens and Ultraviolet Radiation
History of Psoralen Therapy
The Hindus of India in the ancient Ayurvedic system of medicine used
psoralen, the active ingredient of the seeds of Psoralea corylifolia L., for repigmentation of vitiligo. The treatment of leukoderma (vitiligo) with the plant
OCH3
r('o~0'f0
(a)
Ll~
(b)
CH3
rW
I
"""
I.&".&"
CH3
(c)
FIGURE 87. Structure of psora len (a). 8-methoxypsoralen (b), and 4,5' ,8-trimethylpsoralen (c)
(x 27).
261
GENETIC AND
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1.0
262
CHAPTER 1
....>-
iii
c::
~ 0.5
,"
iij
i
o
200
300
Wavelength mp
400
FIGURE 88. Absorption spectra of var= Psoraious psoralen compounds. len; - - - = 5-methoxypsoralen; - - - = 8methoxypsoralen; ..... = 5,8-dimethoxypsoralen.
sorption (Le., below 320 nm). Experimental studies show that action spectra
lie between 320 and 380 nm (UVA) and that peak of the action spectra for
8-MOP and TMP is at about 340 to 360 nm.
Pharmacology of Psoralens
Recently, considerable experimental evidence about psoralen pharmacology has accumulated. Pathak et al. [645] studied the rate of absorption, excretion, and the time at which maximum photosensitivity is elicited after oral
administration of psoralen, 8-MOP, and TMP. In humans, mice, and guinea
pigs, the maximum concentration of the photosensitizing drug in blood is found
two to three hours after oral ingestion of a single dose; this usually correlates
with the time course of maximal cutaneous phototoxicity. In not all cases does
the minimal phototoxic dose correlate with 8-MOP levels, skin type being a
factor [646]. Since the limiting factor is usually phototoxicity of amelanotic
vitiliginous skin, blood levels not skin type are the critical difference in these
patients. Blood levels may be affected by the mode of ingestion. Studies of
Ehrsson et al. [647] have shown higher blood levels when 8-MOP was ingested
with food, but absorption rate and half-life were unaffected. Cutaneous sensitivity is low or minimal in the first hour after psoralen ingestion and peak
levels occur in one-and-one-half to three hours. Likewise, four hours after
ingestion, skin has begun to lose its sensitivity to UVA. Comparative studies
have shown not all capsule forms are similar, one type (Hoffmann-La Roche,
Inc., Nutley, New Jersey) giving consistently higher blood levels than the other
(Elder Co., Bryan, Ohio). A tablet form with one-hour postingestion maximal
bioavailability was described by Thune [648] (pills supplied by Nyegaard &
Co., A/S, Oslo). Some patients have been shown to absorb 8-MOP poorly; this
occurs with either formulation.
FIGURE 89. Psoralens form thymine dimers in DNA (covalent bonds) (x 30).
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GENETIC AND
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264
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(10-3 seconds) and plays a major role in the transfer of energy and the initiation
of biologic photosensitization.
In vitro studies of the photoreactivity of psoralens with pyrimidines and
the photoreactivity of psoralens with the purines (adenine and guanine) are of
fundamental importance to an understanding of the process of psoralen-induced cutaneous photosensitivity. From spectroscopic data, Pathak et a1. [650]
concluded that psoralen and thymine or psoralen and uridine form a nonfluores cent C4 -cycloaddition product; the 3,4 double bond of the pyrone ring of
psoralen attaches to the 5,6 double bond of the pyrimidine (e.g., thymine).
Bonding may also be induced at the 4' ,5' double bond of the furan ring to
produce another type of C4 cycloadduct of psoralen and pyrimidine. The photoreaction of TMP with DNA has also been documented in vitro.
Methyl-substituted psoralens at the 4 or 4' position (e.g., 4,5',8-trimethylpsoralen) have a very low capacity to form cross-links with DNA. It has been
suggested that the formation of bifunctional ad ducts is probably more important
than monofunctional adducts in photosensitization and in lethality of cells
[655]. There is a very effective DNA repair process operating in normal mammalian skin [656]. In yeast cells it appears that the damage due to monofunctional ad ducts is more easily repaired than that due to bifunctional adducts
which form interstrand cross-linking [657].
To elucidate the nature of in vivo cutaneous photosensitivity, Pathak et
a1. [650] applied 3H-labeled TMP to sensitized guinea pig skin which was then
exposed to 365-nm ultraviolet radiation. TMP formed photoadducts primarily
with DNA and to a lesser extent with RNA. The changes in DNA preceded
other biochemical cellular or vascular changes. The formation of a C4 -cycloaddition product of TMP with DNA during irradiation appeared to be primarily
responsible for epidermal cell damage and cutaneous photosensitivity. Impaired duplication, transcription, and translation have been found to be the
main mechanisms of psoralen photosensitization [658].
Increased Melanogenesis. Topical or oral psoralens and subsequent exposure to ultraviolet radiation (320-400 nm) cause increased melanogenesis in
normal skin [659-663]. During psoralen-induced pigmentation, the following
events take place in normal skin [650] (Figs. 90, 91):
The number of functional melanocytes increases three- to fivefold as the
result of proliferation and/or activation of melanocytes. Melanocytic hypertrophy and increased arborization of melanocytic dendrites may accompany this
increase.
Tyrosinase activity increases as tyrosinase is synthesized in proliferating
melanocytes.
The number of melanosomes (Stages I to IV) in melanocytes increases as
a result of increased synthesis.
The number of melanosomes in keratinocytes increases because of increased transfer.
The melanosome packaging in Caucasoid skin changes, possibly secondary
to increased melanosome size. Whereas in normal unexposed skin of a lightskinned Caucasian the melanosomes are packaged as aggregates of smaller
melanosomes (1 IJ.), topical psoralen and UVA results in the formation of larger
melanosomes (1-2 IJ.) packaged as singles (nonaggregated), as in the normal
265
GENETIC AND
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DISORDERS
1l7345
19301-104
130855
190345
FIGURE 90. Increase in melanocyte population in normal human skin after exposure to longwave ultraviolet radiation in the presence of 8-methoxypsoralen. a, b: Unirradiated skin. expressed in melanocytes per mm 2 S.E. c. d: Five days after a single exposure to solar radiation,
expressed in melanocytes per mm 2 S.E. Split-dopa preparation (x 28).
skin of blacks and Australian aborigines. The persistent hypermelanosis observed with the psoralen reaction appears to be correlated with the presence
of large single or nonaggregated melanosomes.
The mechanism of psoralen photoactivation melanogenesis is unclear. Ultrastructural studies [664] of human skin suggest that the keratinocyte may be
the reactive site of photoaddition products of TMP and DNA. But how this
translates into activation of melanogenesis is unclear.
Microscopic Appearance of Repigmentation of Vitiliginous Macules. Repigmentation of vitiliginous macules following oral or topical psoralen therapy
usually begins with the appearance of discrete macules of pigment within the
macule or at the periphery (Fig. 92). Studies of Pegum [665] suggest that follicular melanocytes colonize vitiliginous skin; the epidermis of vitiliginous
skin containing pigmented hairs was demonstrated to show follicular repigmentation in some patients. Migration of melanocytes from follicular reservoirs
has been demonstrated with scanning electron microscopy [666] (Fig. 93). Autoradiographic techniques with 3H-thymidine labeling has shown concentrated
activity at margins of vitiligo macules and in perifollicular array [667,668]. It
appears that follicular repigmentation is not the only mechanism. Some macules repigment not from around hair follicles but from lesional margins which
mayor may not be hyperpigmented; some of these may be from marginal
follicular reservoirs, however. Also, macules of repigmentation resembling those
observed around hair follicles may develop in the amelanotic skin of the palm,
sole, and mucosal surfaces, where the absence of hair follicles precludes the
possibility of a follicular cell-mediated process [669].
266
CHAPTER 1
FIGURE 91. Electron microscopy before and after topical TMP and long-wave UV A exposure.
1a: Melanocyte before exposure. 1b: Increase in melanosomes after TMP administration and UV A
exposure. 2a: Melanosomes in keratinocytes before exposure. Aggregates are noted. 2b: Increase
in melanosomes. now singles. after TMP and UVA exposure.
267
GENETIC AND
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DISORDERS
FIGURE 92. PUVA-induced repigmentation of vitiligo of the forearm; after 20 treatments, myriads
of perifollicular macules of repigmentation occurred. Such macules gradually coalesce to repigment
fully a vitiligo macule.
were no mitoses. The melanosomes were slightly increased in size but keratinocyte packaging was unaltered. This suggests a repigmenting follicular reservoir [670] but does not demonstrate the mechanism. In another study, it was
concluded that the early stage of repigmentation occurs in the outer root sheath
between the infundibulum and the hair bulb [670a] and that both activation
of inactive melanocytes and their subsequent proliferation are involved in the
process of repigmentation. Evidence that mitotic activity of melanocytes must
be capable of inducing macroscopic changes arises from the observation that
Thiersch biopsy sites generally repigment fully even though the melanocytes
of the dermal-epidermal junction have been shaved away. In normal patients
many laceration scars repigment. Melanin synthesis must be arising in these
areas from melanocytes in hair bulbs, eccrine sweat glands, or in sebaceous
glands. Miyazaki et al. [474] reported evidence suggesting activation of indeterminate cells; in hairless mice indeterminate dendritic cells represent two
cell populations, one of which belongs to the melanocyte line and is thereby
an amelanogenic melanocyte. No enzyme inhibitors or melanocyte structural
aberrations have been identified. The question of the mechanism of photopharmacology of PUV A-induced melanogenesis remains.
Clinical Use of Psoralens (Table 76)
Patient Selection, Instructions, and Precautions. The well-motivated patient may wish to repigment with psoralens and UV radiation. Patient selection
dictates certain exclusions at the outset, namely:
(a) History of photosensitivity or photomediated disorders
(b) History of Grenz-ray or x-ray therapy
268
CHAPTER 1
269
GENETIC AND
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DISORDERS
c
FIGURE 93 (Continued)
270
CHAPTER 1
TABLE 76.
Distribution
Areas that respond well: face, neck, trunk, proximal arms and legs
Areas that respond poorly: mucosa, dorsal hands and feet, fingers and toes, palms and soles
Clinical Pattern
Presence of multiple perifollicular macules is a favorable prognostic sign
Presence of marked leukotrichia in a macule may be a poor prognostic sign for that macule
Variables of Treatment
Drug
TMP preferable to 8-MOP for treatment not under direct physician
supervision. Relative effectiveness of 8-MOP, TMP, and psoralen not well
established. Relative responsiveness individually variable.
At least 0.3 mg/kg 8-MOP or 0.6 mg/kg TMP (increasing increments of dosage
Dose
cannot necessarily be expected to give proportionately better results).
Sunlight or high-intensity long-wave UV radiation (UVA) equally effective.
UV radiation
UVB (290-310 nm, sunburn spectrum) ineffective.
source
Optimal signal dose exposure not established. Persistent erythema of vitiligo
Dosimetry of
patches not necessarily required. Severe sunburn reactions may cause more
UV
depigmentation (Koebner phenomenon) in the normal skin and should be
radiation
avoided.
At least twice weekly, but not two days in a row. Probability of sunburn
Frequency of
increases with treatment frequency, particularly with 8-MOP.
treatment
Twelve months or more for best results, as continuously as possible.
Duration
Fully repigmented macules stay filled in; subtotal repigmentation may
Permanence
undergo reversal if treatments are discontinued.
Since the period for successful repigmentation is very long, only those patients
who are highly motivated should undertake therapy. During the course of the
treatment, the normally pigmented areas become markedly tanned, so that the
cosmetic disfigurement is enhanced while the vitiligo macules are repigmenting
(Fig. 94). Showing the patient the contrast of his skin under the Wood's light
is an effective means of demonstrating the potential contrast that will occur
with psoralen therapy. The importance of patient compliance cannot be overemphasized to the patient.
Patients must be instructed in which psoralen to use, when to take it, how
to expose to light, and how frequently to treat.
The treatment regimen for repigmentation consists of the oral administration of 0.6 to 1.2 mg/kg of 4,5' ,8-trimethylpsoralen (TMP), 0.3 to 0.6 mg/kg of
8-methoxypsoralen (8-MOP), or a combination of these. 8-MOP is manufactured
as 10-mg capsules (Elder Co., Bryan, Ohio); TMP is available in 5-mg tablets
(Elder Co., Bryan, Ohio). Neither unsubstituted psoralen nor 5-methoxypsoralen is commercially available in the United States. The tablets/capsules should
be ingested in a single dose two hours before anticipated exposure. Artificial
long-wave ultraviolet radiation (UVA) or midday sun can be used. Treatments
are given two or three times weekly, preferably not two days in a row. A careful
record should be kept of each treatment exposure.
Selection of psoralen derivative for use is not completely arbitrary. We
usually select TMP for outdoor therapy because it is in most cases much less
erythemogenic on normal skin [6711 and is less likely to cause severe phototoxic
271
GENETIC AND
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DISORDERS
272
CHAPTER 1
273
GENETIC AND
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DISORDERS
FIGURE 95. Psoralen-induced repigmentation of the low back of a young Caucasian male. Areas
of repigmentation are not so intensely melanized as previously uninvolved skin. a: Before treatment.
b: After treatment.
274
CHAPTER 1
ally occurs as perifollicular dots which enlarge progressively, though there may
also be gradual concentric spread of the pigment from the peripheral border.
This repigmentation usually begins to appear one to four months after the
beginning of treatment, and a very definite cosmetic improvement takes 12 to
24 months of two or more treatments per week (100 to 300 treatments). An
occasional accelerated responder will have hundreds to thousands of tiny perifollicular dots within 10 treatments.
Fortunately, the face and neck, which are the most important from a psychosocial viewpoint, respond best; 60% to 70% of patients who persist will fill
these areas in completely. The arms, legs, and trunk do nearly as well. Vitiligo
on the digits, volar wrists, palms, dorsal feet, soles, and glans penis respond
so poorly that treatment of these areas alone is rarely indicated. The lips may
or may not respond. Hair depigmentation may be associated with poor prognosis, but we have seen patients who have white hair in macules obtain good
results. Lesions of recent onset have been claimed to do better with psoralen
and ultraviolet radiation than older lesions, but this cannot be considered
established. Dramatic results have been observed in vitiligo present over 10
years. The extent of vitiligo has little bearing on the response rate.
Many workers have reported experience with psoralen photo chemotherapy
of vitiligo. Psoralens result in acceptable repigmentation in about 70% of those
treated [3,645]. Using 8-MOP, Sidi et a1. [35] observed partial or complete
repigmentation in 73% of their patients, and El Mofty [6] in nearly 90% of his
75 patients. Similar results were reported by Elliott [672] and Kenney [673].
Fitzpatrick et a1. [31] reported that more than 70% of 84 patients treated with
TMP showed marked repigmentation in vitiliginous areas. The best results were
obtained with 30 to 50 mg TMP in persons treated for more than two years.
Bleehen [42] also reported a significant cosmetic improvement in 15 of 22
patients with vitiligo, although he used smaller doses of TMP (15 to 20 mg).
FIGURE 96. Caucasian male with vitiligo of the chest and neck. a: Before therapy. b: After 40
treatments with 40 mg TMP plus artificial UV A. Many macules of repigmentation are apparent. c:
After 100 treatments, almost complete repigmentation is apparent. Small macules of vitiligo remain
at the base of the neck.
275
GENETIC AND
CONGENITAL
DISORDERS
FIGURE 96 (Continued)
276
CHAPTER 1
Many others have reported good results with psoralen therapy of vitiligo [674-679]
(Table 77). Those who repigment one area will usually do well elsewhere;
dramatic differences in repigmentation rate of the face and trunk should raise
the question of inadequate exposure of the nonresponding site or of chronic
phototoxicity.
Annamalai et al. [680] treated 200 patients with 10 mg TMP but found
topical TMP was required for satisfactory results. They found the 60 diabetics
and 40 myxedema patients to be responders; those without thyroid disease or
diabetes were poor responders as were those with amebiasis. We have not been
able to separate responders from nonresponders by the presence or absence of
any of the associated diseases.
Seghal [681] compared responses of 89 patients treated with TMP, psoralen,
or 8-MOP (10 mg of each-37, 29, and 23 patients, respectively). Although more
patients on 8-MOP repigmented completely (13%) on treatment for 26 weeks
or less, overall results were better with psoralen or TMP. One of the patients
on psoralen developed granulocytosis which reversed when the psoralen was
discontinued [681]. This study involved use of very low dosages of psoralens
used.
In a long study of 365 East Indian vitiligo patients, of those treated over
26 months with psoralens and sunlight nearly half of the patients repigmented
over 50% of their vitiligo when treated with 60 mg TMP, 20 mg 8-MOP, or 20
mg 8-MOP plus 40 mg TMP; between 38% and 45% fully repigmented the face.
In limited follow-up, increasing the TMP severalfold did not appear to increase
overall responsiveness. The relative responsiveness as measured by facial repigmentation is shown in Table 78. This suggests, although the numbers are
limited, that 0.3 mg/kg 8-MOP, 8-MOP plus TMP (0.3 mglkg plus 0.6 mglkg),
and high-dose TMP (1.8 mg/kg) may be equally effective. The concerns about
acute and chronic phototoxicity make it advisable to use the lowest-dosage
psoralens effective-0.3 mg 8-MOP or 0.8 mg TMP. Poor responders to 8-MOP
may respond to TMP and vice versa.
In a study using an artificial UVA source [135], among 26 patients treated
TABLE 77.
Author
Sidi et al. (1957) [35]
El Mofty (1968) [6]
Fulton et al. (1969) [688]
Africk and Fulton (1971)
[668]
Bleehen (1972) [42]
Fitzpatrick et al. (1974) [31]
Parrish et al. (1976) [135]
a
Topical.
Induced
repigmentation
(%)
Total no.
of patients
73
61
93
219
75
15
91
20
47
70
70
32
84
26
277
GENETIC AND
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DISORDERS
278
CHAPTER 1
Overall
repigmentation
(%)
No. of
patients
18
15
66.7
26.6
36
24
47.2
29.2
60 mg
125 mga
250 mga
16
28
24
37.6
35.7
58.3
23
57
42
47.8
19.3
35.7
Psoralen
40 mg
80 mg
13
5
23.1
40.0
30
7
16.7
28.6
8-MOP
20 mg
25
64.0
47
53.2
Drug
8-MOP
TMP
TMP
a
Dosage170 kg
individual
No. of
patients
20 mg
40 mg
40 mg
(%)
279
GENETIC AND
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DISORDERS
280
CHAPTER 1
been found to develop in mice that receive large doses of 8-MOP and intense
ultraviolet radiation [689,690], particularly if the drug was administered intraperitoneally [691]. It is the question of probability of tumors in humans that
troubles many. Certainly in experimental situations PUVA is capable of causing
inhibition of DNA synthesis, mutations, chromosomal aberrations, and cell
transformations [692,693]. Some patients with xeroderma pigmentosum developed skin tumors within a month of initiation of therapy and one patient
developed a lymphatic leukemia. Stern et al. [694] reported an increased formation of squamous cell carcinomas in psoriatics treated over two years with
PUVA, a finding not confirmed by Roenigk et al. [695] who found no increased
incidence. No increase in the number of melanomas or basal cell carcinomas
was reported by either group. Whether PUVA may act as an inducer or a
promoter in animals or humans is unsettled. However, in one study in which
ultraviolet-induced tumors were transplanted to syngeneic mice, tumors grew
in those treated with PUVA but not in the untreated mice [696]. This suggests
that immunosuppression may be important and that, as suggested by Bridges
and Strauss [697], the immune surveillance concept may be viable for skin.
Nevertheless, the paucity of reports of tumors in PUVA-treated vitiligo
patients is curious in light of the long history of its use. It may be that PUVA
is a promotor and that in the absence of use of therapeutic modalities common
to psoriatics (tar plus UVB) or of x-ray therapy, the risk is minimal. Nevertheless, we recently have seen two Type III patients with actinic keratoses. Both
patients had lesions on the legs; one had developed a squamous cell carcinoma
in one of these lesions. Both patients had also received large amounts of UVB
in their early lives.
In a 54-month follow-up study of 230 East Indian patients treated with
sunlight and 8-MOP (0.3-0.6 mg/kg), TMP (0.8-3.6 mg/kg), or psoralen (10.6-1.2
mg/kg), 13% developed discrete lesions in remaining vitiligo areas, particularly
on the lower legs. Seven percent had actinic keratoses but there were no squamous cell carcinomas, basal cell carcinomas, or melanomas [698]. None of these
lesions had been present at two-and-one-half-year follow-up. The occurrence
of these lesions cannot be clearly attributed to PUVA, UVB, or both, but it does
make it imperative that all patients be examined routinely during and after
therapy. Furthermore, there should be a UVA cumulative dosage limit such as
3,000 to 5,000 J/cm2/lifetime/person.
2. Ocular Toxicity. Because of the optical properties of the anterior segment
of the eye, UVA is absorbed by the lens. There is experimental evidence linking
psoralens and UVA to effects of ocular photosensitization. Guinea pigs fed 88
mg/kg 8-MOP were found to have photosensitization injury, particularly in the
320 to 340 nm range. Animal model system differences were demonstrated in
that the injury threshold was 25 mg/kg for guinea pigs, but 200 mg/kg for rabbits
[699].
Although cataract formation has been reported in albino mice [700], albino
guinea pigs, and rabbits [699] following administration of very high doses of
8-MOP and exposure to ultraviolet radiation, the doses of 8-MOP and ultraviolet
radiation used in these ocular experiments were more than 100-fold greater
than those currently in therapeutic use in humans. Intraperitoneal injection of
8-MOP in rats is followed by phosphorescence of the lens, indicating presence
of 8-MOP in the lens as early as two hours but not beyond 24 hours after
injection. That the phosphorescence emission is decreased by ultraviolet exposure suggests 8-MOP is metabolized in the lens [701]. Furthermore, the visible/ultraviolet radiation-induced increased fluorescence at 440 nm is enhanced
by prior intraperitoneal injection of 8-MOP.
Pigmented rats fed oral 3H-8-MOP were found to have high levels of radioactivity in the retina, ciliary body, and iris within an hour of ingestion.
Levels were detected in the cornea but little was found in the lens [702].
Incubation of whole lens in 8-MOP-containing medium followed by UVA
exposure is followed by diffuse nuclear labeling of lens epithelial cells [703].
Such unscheduled DNA repair synthesis may result in abnormal macromolecular and membrane synthesis, abnormal cell differentiation, and crystalline
production, all potentially with a resultant decrease in visible light transmission [704]. Other agents, such as ionizing radiation and alkylating agents, which
similarly damage DNA in lens epithelium, cause cataracts, but there is evidence
such effects may be reversible by repair mechanisms [705,706]. Because of
anatomic considerations and lens epithelial cell kinetics, there may be considerable delay in development of lens opacities following the ultraviolet insult.
Methoxsalen also interacts with lens protein in another fashion. The triplet
psoralen state may be quenched by various amino acids, namely tryptophan
[707]. 8-MOP also forms stable cyclobutane photo ad ducts with lens protein in
vitro; such extracellular binding may be relatively long-lasting [708].
Dosimetry clearly is an important consideration. Doses of UV A and 8-MOP
that do not result in acute or chronic phototoxic reactions to the skin do not
appear to change the lens. Guinea pigs administered 0.5 mg/kg 8-MOP intraperitoneally and exposed to 10 hours of F40 BLB (UVA) at 10 inches had no
ocular abnormalities (based on gross ophthalmologic examination, slit-lamp
examination, and histology) [709].
In another study, four groups of female Dutch belted rabbits were fed 12
mg/kg 8-MOP or placebo and exposed to two or eight hours of UV A five times
weekly for 18 months. All animals showed signs of acute and chronic phototoxicity. No cataracts were observed on repeated examinations of these animals
[710].
In a study of 1000 psoriatics treated with PUV A for two years, there was
no increased incidence of cataracts (R.S. Stern, personal communication). One
report of cataracts in a 42-year-old woman treated with oral 8-MOP is seriously
marred by the absence of baseline ophthalmologic examination; since the lens
opacities were not causing visual symptoms and the patient had no prior examination, it is impossible to exclude antecedent presence [711]. There are no
other reports of cataract formation in patients with vitiligo who have been
treated with large doses of psoralens [650]. One study from Scandinavia has
shown no cataracts among 13 vitiligo patients treated with 8-MOP for up to 12
years [712]. Another study [713] also showed no abnormalities in 15 patients
aged 20 to 40 treated five to 23 years. No eye protection had been used by either
group.
3. Lymphocyte Function. Studies of Morison and Parrish [714] have shown
PUVA caused localized and systemic suppression of delayed hypersensitivity
in guinea pigs; both induction and elicitation were affected.
281
GENETIC AND
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DISORDERS
282
CHAPTER 1
Increased vascular permeability with albumin leakage has also been demonstrated after short-term PUVA therapy [715].
Laboratory Abnormalities. Extensive clinical studies over the past 25
years have found orally administered 8-MOP and TMP to be virtually nontoxic
in humans [716]. Extensive clinical use of these substances has produced no
evidence of hepatotoxicity [717,718]. In over 365 patients followed up to 40
months, no liver function test abnormalities were observed (personal observations).
Increase of Tolerance to Sunlight. A curious observation is that after
several PUVA treatments many patients observe that their vitiliginous macules
have developed an increased tolerance to UVB. This increased tolerance has
been observed with 8-MOP and TMP and occurs before or independent of
repigmentation of the vitiligo areas [31,684,719]. The same phenomenon has
also been observed by normal individuals [593,684,720] and by albinos [721],
but has not been scientifically studied in double-blind trials.
Electron microscopy observations [664] suggest that the combination of
ultraviolet irradiation and psoralen accelerated keratinization. It is possible,
therefore, that the protection against severe sunburn reaction and the increased
ultraviolet tolerance is due to an increased thickness of the stratum corneum
in the vitiliginous macules [6].
Topical and Intralesional Corticosteroids
The use of topical and intradermal corticosteroids has been received with
mixed enthusiasm.
Kandil [722] treated 63 vitiligo patients with 0.2% betamethasone-17-valerate in flexible collodion. Twice-daily applications resulted in complete repigmentation of some or all macules in 28 patients. Kandil [723] also used
0.1% betamethasone-17-valerate in isopropyl alcohol. Koopmans-Van Dorp et
al. [724] employed 0.2% betamethasone-17-valerate in DMSO (43%) in a cream
base in 21 patients. Both diffuse and perifollicular repigmentation was observed
in 18, none of whom repigmented 90% or more. Bleehen [725] treated 20 vitiligo
patients with either betamethasone-17-valerate (0.1%) or with clobetasol propionate (0.05%). After three months of treatment, he observed partial repigmentation in only four patients. Light and electron microscopic study of the
repigmented areas showed dopa-positive melanocytes containing many melanosomes of normal size, shape, and melanization. El Mofty and Nada [726],
using betamethasone-17-valerate in collodion, found that none of their patients
treated with topical steroids alone had any response to this therapy. Clayton
found excellent results with two of 23 patients and limited results with another
10 treated with topical clobetasol propionate for four months; all developed
dermal atrophy [727]. However, in a double-blind multicenter study Seiji et al.
[7281 found 0.05% fluocinonide cream more effective than placebo in eight of
12 weeks of therapy. But there was no difference after four months. Atrophy
occurred in three of 108 cases. According to these authors no better response
was observed in those using PUVA than in those not using it, although the
latter group was small. Prolonged use of topical steroids may result in undesirable steroid atrophy, striae, and disfiguring telangiectasia. This makes steroid
283
GENETIC AND
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DISORDERS
284
Thiambutosine BP
CHAPTER 1
If more than 50% of the skin is depigmented and the patient has failed
with, cannot, or does not wish ever to undergo psoralen photochemotherapy
to repigment, a uniform color may be attained by deliberate, permanent chemical depigmentation of the normally pigmented areas; this may be done by
twice daily applications of 20% monobenzylether of hydroquinone (MBEH) in
an ointment base (Benoquin). The patient must understand that the depigmentation is irreversible. The depigmentation usually takes several months to
appear, a year to complete [742], and is effective in almost every patient. Depigmentation of eyes and hair does not occur, and the patients are usually very
satisfied with the cosmetic results. The newly depigmented skin must be protected against UVB burn by application of an effective sunscreen preparation.
The use of MBEH cream (Benoquin) has been reported in a retrospective
study of 18 patients with extensive vitiligo [742] (Figs. 98, 99). Of these 18
patients (16 Caucasian and two blacks), eight experienced complete depigmentation. Of those who depigmented fully, some hypopigmentation was first
noted within one to six months (average, under three months) of institution of
therapy, and full depigmentation was achieved in four to 12 months. All those
who depigmented fully were very pleased with their results. However, the
incidence of side effects of this therapy (subjective burning and itching, erythema or rash, dryness, contact dermatitis, and edema) was high. Only seven
patients reported no such complaints. The authors concluded that MBEH is a
useful agent for those vitiligo patients who wish to be one color and who can
accept the emotional and physical limitations of such a decision. The following
guidelines for the use of MBEH are suggested:
desire of permanent depigmentation in a patient with vitiligo;
(2) age over 40;
(3) more than 50% of the skin depigmented;
(4) willingness to accept the fact the repigmentation will no longer be
possible.
(1)
285
GENETIC AND
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DISORDERS
FIGURE 98. a: This woman with very extensive vitiligo is an ideal candidate for Benoquin therapy.
Once undertaken, Benoquin therapy should be considered irreversible. b: Benoquin may give
satellite depigmentation as occurred in this patient. This is usually irreversible depigmentation
and not responsive to psoralen photo chemotherapy.
FIGURE 99. Benoquin depigmentation. a: Legs of woman with extensive vitiligo prior to institution of Benoquin therapy. b: After six months of Benoquin usage, the skin is fully amelanotic.
No obvious evidence of vitiligo remains and the skin has an alabaster color.
286
CHAPTER 1
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683. Van Dijk E: The treatment of vitiligo using a local application of 8-methoxypsoralen followed
by long-term irradiation with longwave u.v.light. Ned Tijdschr Geneeskd 111:805-807, 1967
684. Kanof NB: Melanin formation in vitiliginous skin under the influence of external applications
of 8-methoxypsoralen. J Invest Dermotol 24:5-10, 1955
685. Kelly EW Jr, Pinkus H: Local application of 8-methoxypsoralen in vitiligo. J Invest Dermotol
25:453-456, 1955
686. Arora SK et al: Factors influencing methoxsalen phototoxicity in vitiliginous skin. Arch
Dermotol112:327-332, 1976
687. Petrozzi, JW et al: Topical methoxsalen and blacklight in the treatment of psoriasis. Arch
Dermotol113:292-296, 1977
688. Fulton JE Jr et al: Treatment of vitiligo with topical methoxsalen and blacklite. Arch Dermotol
100:224-229, 1969
689. Griffin AC et al: The wavelength effect upon erythemal and carcinogenic response in psoralen
treated mice. J Invest Dermotol 31:289-295, 1958
690. O'Neal MA, Griffin AC: The effect of oxypsoralen upon ultraviolet carcinogenesis in albino
mice. Cancer Res 17:911-916, 1957
691. Urbach FJ: Modification of ultraviolet carcinogenesis by photoactive agents. JInvest Dermotol
32:373-378, 1959
692. Bridges B et al: Possible long-term hazards of photochemotherapy with psoralens and near
ultraviolet light. Clin Exp Dermotol 3:349-355. 1978
693. Vella Briffa D, Warin AP: Photochemotherapy in psoriasis: a review. JR Soc Med 72:440-445,
1979
694. Stern RS et al: Risk of cutaneous carcinomas in patients treated with oral methoxsalen for
psoriasis. N Engl J Med 300:809-813, 1979
695. Roenigk HH Jr et al: Skin cancer in PUVA-48 cooperative study of psoriasis (abstract). JInvest
Dermotol 74:250, 1980
696. Spellman CW: Skin cancer after PUVA treatment for psoriasis. N Engl J Med 301:554-555,
1979
697. Bridges B, Strauss G: Possible hazards of photochemotherapy for psoriasis. Nature 283:523-524,
1980
698. Mosher DB et al: Development of cutaneous lesions in vitiligo during long-term PUVA therapy
(abstract). J Invest Dermotol 74:259, 1980
699. Freeman RG, Troll D: Photosensitization of the eye by 8-methoxypsoralen. J Invest Dermotol
53:449-453, 1969
700. Cloud TM et al: Photosensitization of the eye with methoxsalen. Arch Ophtholmol 66:689-694,
1961
701. Lerman S et al: The photoreactions of 8-methoxypsoralen with tryptophan and lens proteins.
Photochem Photobiol 31:235-242, 1980
702. Wulf HC, Hart J: Distribution of tritium labelled 8-methoxypsoralen in the rat studied by
whole body autoradiography. Acta Derm Venereol (StockhJ 59:97-103, 1979
703. Jose JG, Yielding KL: Photosensitive charactogens, chlorpromazine and methoxypsoralen
cause DNA repair synthesis in lens epithelial cells. Invest Ophtholmol Vis Sci 17:687-691,
1978
704. Jose JG: The role of DNA damage, its repair and its misrepair in the etiology of cataract: a
review. Ophthol Res 10:52-62, 1978
705. Evans TC et al: Histologic studies of neutron and x-irradiated mouse lenses. Rodiot Res
13:737-750, 1960
706. Worgul BV, Rothstein H: Radiation cataract and mitosis. Ophthol Res 7:21-32, 1975
707. Bensasson RV et al: Triplet excited state of furocoumarins: reaction with nucleic acid bases
and amino acids. Photochem Photobiol 27:273-280, 1978
708. Veronese FM et al: Drug protein interaction. The binding of 8-methoxypsoralen by human
serum albumin. Framoco [Sci] 33:667-675, 1978
709. Freeman RG, Troll D: Photosensitization of the eye by 8-methoxypsoralen. I Invest Dermotol
53:449-53, 1969
710. Parrish JA et al: Dermatological and ocular examinations in rabbits chronically photosensitized with methoxalen. I Invest Dermotol 73:250-255, 1979
711. Pedvis L et al: Cataracts in a patient with vitiligo who received photochemotherapy. Arch
DermotoI115:1253-1254, 1979
712. Bach 0 et al: Absence of cataract ten years after treatment with 8-methoxypsoralen. Acto
Derm Venereal (Stockh) 60:79-80, 1980
713. El Mofty AM, El Mofty A: Retrospective ocular study of patients receiving oral 8-methoxypsoralen and solar irradiation for the treatment of vitiligo. Ann Ophtholmol 11:946-948,
1979
714. Morison WL et al: Influence of PUVA and UVB radiation on delayed hypersensitivity in the
guinea pig. I Invest Dermotol 76:484-488, 1981
715. Worm A-M: Microvascular leakage of plasma proteins after short term PUVA treatment. I
Invest Derm 74:158-160, 1980
716. Fitzpatrick TB et al: Hydroquinone and psoralens in the therapy of hypermelanosis and
vitiligo. Arch Dermotol 93:589-600, 1966
717. Fitzpatrick TB et al: Effect of methoxsalen on liver function. lAMA 167:1586-1589,
1958
718. Tucker HA: Clinical and laboratory studies in volunteers given oral methoxsalen. I Invest
Dermotol 32:277-280, 1959
719. Lerner AB et al: Clinical experimental studies with 8-methoxypsoralen in vitiligo. I Invest
Dermotol 20:299-314, 1953
720. Imbrie JD et al: Follow-up study of effect of oral methoxsalen (8-methoxypsoralen) on sunburn
and suntan. Arch Dermotol 82:617-620, 1960
721. Hu F et al: Studies on albinism: demonstration of dopa positive melanocytes in albino skin.
Arch Dermotol 83:723-729, 1961
722. Kandil E: Vitiligo-response to 0.2% betamethasone 17-valerate in flexible collodion. Dermotologico 141:277-281, 1970
723. Kandil E: Treatment of vitiligo with 0.1% betamethasone 17-valerate in isopropyl alcohol. A
double blind trial. Br I Dermotol 91:457-460, 1974
724. Koopmans-Van Dorp B et al: Treatment of vitiligo by local application of betamethazone 17
valerate in a dimethyl sulfoxide cream base. Dermotologico 146:310-314, 1973
725. Bleehen SS: The treatment of vitiligo with topical corticosteroids. Light and electron microscopic studies. Br I Dermotol 94(suppl 12):43-50, 1976
726. El Mofty AM, Nada MM: Vitiligo and its treatment. Aust I Dermotol15:15-22, 1974
727. Clayton R: A double blind trial of 0.05% clobetasol propionate in the treatment of vitiligo.
Br I Dermotol 96:71-73, 1977
728. Seiji M et al: Furocoumarin treatment of vitiligo vulgaris--multiinstitutional double blind
study. Ipn I Clin Dermotol 30:735-746, 1976
729. Kandil E: Treatment of localized vitiligo with intradermal injection of triamcinolone acetonide. Dermotologico 140:195-206, 1970
730. Bedi BMS: Reported at the Fourth Annual Conference of the Indian Association of Dermatologists, Venerologists, and Leprologists, New Delhi, India, 1976
731. Farah FS et al: The treatment of vitiligo with psoralens and triamcinolone by mouth. Br I
Dermotol 79:89-91, 1967
732. Imamura S, Tagami H: Treatment of vitiligo with oral corticosteroids. Dermotologico 153:179-185,
1976
733. Brostoff H, Brostoff J: Vitiligo and steroids (letter). Loncet 2:688, 1978
734. Woolfson H, Finn OA: Topicallevodopa in vitiligo. Loncet 1:598, 1972
309
GENETIC AND
CONGENITAL
DISORDERS
310
CHAPTER 1
735. Mishima Y, Tanay A: The effect of a-methyldopa and ultraviolet irradiation on melanogenesis.
Dermatologica 136:105-114, 1968
736. Goolamali SK: Levodopa in vitiligo. Lancet 1:675-676, 1973
737. Iparraguire CE: Parkinsonism, vitiligo, and L-dopa. Contribution to the study of the embryological and functional correlation between nervous system and skin. Rev Neuropsiquiatr
34:274-281, 1971
738. Gonin J: Traitment du vitiligo par la L-Dopa. Nouv Press Med 3:151, 1974
739. Gokhale BB: Vitiligo and anti-malarials (letter). Int J Dermatol17:843, 1978
740. Verbov J: Use of CIBA 1906 (Thiambutasine BP) in vitiligo. Br J Dermatol 87:81-82, 1972
741. Bor S et al: Vitiligo and its aetiological relationship to organ specific autoimmune disease.
Br J Dermatol 81:83-88, 1969
742. Mosher DB et al: Monobenzylether of hydroquinone: a retrospective study of 18 severely
affected vitiligo patients. Br J Dermatol 97:669-679, 1977
743. Kligman AM, Willis I: A new formula for depigmenting human skin. Arch Dermatolll1:40-48,
1975
PIEBALDISM
There is a painting in the Paris Museum by Le Masurier of a mulatto aged two years
with the white forelock and white spotting of partial albinism (1).
Nomenclature
Piebaldism has historically been described under many different names.
binism," "albinoidism," "congenital achromia," "congenital vitiligo," "poikilochromia alba," "white spotting," and "piebaldism" [2-9]. It is now well established that this condition is not related to generalized albinism, and that the
commonly used term "partial albinism" is inappropriate. Since there is in
animals a similar inherited white spotting called "piebaldism," this term seems
most appropriate to designate this syndrome in humans.
History
Piebaldism dates from the classical Greek and Roman literature [7]. Lucian
mentioned a man from Egypt "one-half absolutely coal black and the other half
unusually snow white, the two colors evenly distributed." Philostratus, in Life
of Apponius, described an Indian woman "black from head to chest, white
from chest to feet." These two descriptions may represent the earliest reported
cases of piebaldism. Probably many persons with piebaldism were chosen as
slaves, coliseum curiosities, and gladiators during the Roman period as a direct
result of their striking pigmentary abnormality.
TABLE 79. Isolated Piebald Black Cases of the 18th and 19th CenturiesO
Case
no.
1
2
3
4
5
6
7
8
9
a
Name of case
Sex
Gumilla's case
La Mathe's case
Bluemenbach's case
"Jean-Pierre"
"Adelaide"
Da Rocha's pied girl
Richardson's spotted boy
Darwin's case
Wilson's case
F
M
M
M
F
F
M
M
F
Date
reported (R)
or
born (B)
(R)
(R)
(B)
(B)
(B)
(R)
1743
1752
1774
1782
1783
1785
1808-1813
1872-1878
(R) 1878
Investigator
Pearson (1913)
Pearson (1913)
Granger (1804)
Morgan (1786)
Morgan (1786)
Arthaud (1789)
Pearson (1913)
Wilson (1878)
Wilson (1878)
Source: Froggatt P: An outline, with bibliography, of human piebaldism and white forelock. Ir J Med Sci
398:86-94, 1959. Used with permission.
311
GENETIC AND
CONGENITAL
DISORDERS
312
CHAPTER 1
Another family, the Anderson family, probably carries one of the most famous
pigment anomalies in existence. The original mutant, a black woman born in
Louisiana in 1848, married a normally pigmented black and bore 15 children,
eight piebald and seven normal. Three of the eight piebald children married
and had nine piebalds and two normal offspring. Several of the Anderson
children were exhibited in Barnum and Bailey's circus throughout America
and Europe and have been described in the medical literature of various countries. In 1896, Maass [17] was the first to attempt to establish the pedigree of
this family. Gould and Pyle [18], in 1897, illustrated three of the Anderson
children as "The Leopard Family" but labeled their condition "vitiligo." In
1901, Neveu-Lemaire [19] published a photograph of a piebald black woman
who probably is also a member of this family. Baudouin [20], in 1905, and Levi
[21], in 1909, extended and published this pedigree. Pearson et al. [7] also
mentioned this family in their monograph. A photograph of the "Three Striped
Graces" (Anderson children) was reproduced in 1910 in the British Medical
313
GENETIC AND
CONGENITAL
DISORDERS
FIGURE 101. Wax model of the piebald black girl from St. Lucia (Warren Anatomical Museum
at the Harvard Medical School, Boston, Massachusetts). (From: Pearson K et al: A Monograph on
Albinism in Man: Drapers' Company Research Memoirs. Biometric Series VI, Atlas, Part I. London,
Dulau, 1911.)
Journal by Hutchinson [22] (Fig. 102). Frassetto [23] and Simpson and Castle
[24] published further reports and photographs. The most recent pedigree of
this family was collected in 1934 by Keeler [25].
Some other papers from the 20th century mentioned classical piebalds but
the family data are minimal or absent (Table 81). Table 82 summarizes the
cases reported since 1960.
314
CHAPTER 1
TABLE 80. Classical Piebald Families Reported since 1871 and in Which Pedigrees
Have Been Publisheda
Case
no.
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
Q
Family designation
Berger's family
Rizzoli's family
Baader's family
Harman's family
Florence Bay family
Cane's family
Jones' family
Cockayne's 1st Suffolk
Miller's family
Barton's family
Zsako's family
Mazzini's 2nd family
Meirowsky's family
Pardo-Costello's family
Meirowsky and
Spickernagel's family
Gunther's family
Cockayne's 3rd family
Sanders' 1st family
Anderson family
Sanders' 2nd family
Sanders' 3rd family
Cockayne's 2nd Suffolk
Frant's family
Fitch's family
Nussey's family
Sundfor's family
Cromwell's family
Cooke's 1st family
Cooke's 2nd family
Jahr's family
Smith and Schultz's family
Nationality
or race
German
Italian
Swiss
English
Negro
English
English
English
English-American
English
Hungarian
Italian
German
Spanish-Cuban
German
German
English
Dutch
Negro
Dutch
Dutch
English
Dutch
American
English
Norwegian
Mulatto
American
American
Negro
American
Investigator
Berger (1871)
Rizzoli (1878)
Baader (1883)
Harman (1909)
Stannus (1913)
Cane (1912)
Jones (1913)
Cockayne (1914)
Miller (1915)
Pearson (1920)
Zsako (1923)
Mazzini (1923)
Meirowsky (1925)
Pardo-Costello (1926)
Meirowsky and Spickernagel
(1926)
Gunther (1932)
Cockayne (1933)
Sanders (1934)
Keeler (1934)
Sanders (1935)
Sanders (1935)
Cockayne (1935)
Frant (1937)
Fitch (1937)
Nussey (1938)
Sundfor (1939)
Cromwell (1940)
Cooke (1952)
Cooke (1952)
Jahr and McIntire (1954)
Smith and Schultz (1955)
Source: Froggatt P: An outline, with bibliography, of human piebaldism and white forelock. Ir J Med Sci
398:86-94,1959. Used with permission.
Race
Piebaldism has been found in various races and in widely separated parts
of the world. No race appears to be spared, and black, Caucasian, and Mongoloid
piebalds have been reported.
Sex
Both sexes are equally affected [3]. As would be expected from an autosomal dominant inheritance pattern, among the 108 patients collectively reported by Cooke [3], Smith and Schultz [1], Comings and Odland [29], and Van
Velde [9], the overall female to male ratio was 54 to 54.
TABLE 81. Classical Piebald Families with Minimal Pedigree Information and
Individual Piebalds of the 20th Centurya
Case
no.
1
2
3
4
5
6
7
8
9
10
11
a
Designation
La Vallois' Martinique
family (19th century)
Emslies' negro family
(19th century)
The Cape Verte family
The Loyalty Islands case
The Papuan piebald
The Honduras piebald
Maynard's negro piebald
Dengler's two cases
European family
Sorsby's cases
Germeraard's family
Nationality
or race
Investigator
Mulatto
Cockayne (1933)
Negro
Cockayne (1933)
Negro
Negro
Papuan
Negro
Negro
American
European
English
Dutch
Neveu-Lemaire (1901)
Fram;ois (1901)
Seligmann (1902)
Blanchard (1910)
Maynard (1914)
Dengler (1925)
Hollander and Schmitt (1933)
Sorsby (1953)
Sorsby (1953)
Source: Froggatt P: An outline, with bibliography, of human piebaldism and white forelock . Ir ] Med Sci
398:86-94, 1959. Used with permission.
The Three Striped Graces. (From Sir J. Hutchinson, Pro Neisser, reproduced by
Pearson K et al: A Monograph on Albinism in Man: Drapers' Company Research Memoirs. Biometric
Series VI, Atlas, Part I. London, Dulau, 1911.)
FIGURE 102.
315
GENETIC AND
CONGENITAL
DISORDERS
316
CHAPTER 1
Number of cases
Number of
families
Generations
Total
Female
Male
1
1
4
5
6
19
3
7
3
12
24
12
12
Reference
Ansari (1960) [26]
Kugelman and Lerner
(1961) [27]
Campbell and Swift
(1962) [28]
Comings and Odland
(1966) [29]
Grupper et a1. (1970) [30]
Telfer et a1. (1971) [31]
Van Velde (1972) [9]
Funderburk and Crandall
(1974) [32]
Bonerandi et a1. (1976)
[33]
Marchand (1976) [34]
1
2 {Family A
Family B
2 {Family A
Family B
1
11
2
32
6
1
16
1
4
1
2
3
2
16
5
3
1
10
Rare
Autosomal dominant
Birth
Bilateral-symmetrical
Chalk white with hyperpigmented
macules in white areas
Trunk (anterior and lateral with
middorsal sparing)
White forelock; body hair or other
scalp hair may be involved
Rarely involved
Variable
Irregular, well-delineated
None
None
None
Hyperpigmented macules on areas of
normally pigmented skin
None
Age
317
Heredity
Piebaldism is inherited as an autosomal dominant trait. Cooke [3] summarized 23 families in the literature and noted that when a parent had the trait,
it was transmitted to more than half of the 796 children (53.2%), while of the
more than 474 children of unaffected parents, only 15 (3.4%) were piebald.
Cooke concluded that among piebald pedigrees, unaffected parents generally
do not transmit piebaldism to their children. Thus, a child of an unaffected
member in a piebald family is unlikely to be affected.
Families with affected members in four [1,15,36-42]' five [8,9,14,16,31]'
or six or seven [28,29,43] generations are not uncommon (Figs. 103, 104). It is
clear that the trait is transmitted as an autosomal dominant pattern with a very
high degree of penetrance and that those descendants who are free of the
affection do not carry or transmit the trait to their offspring.
Chromosomal studies in two patients with piebaldism have been reported.
Funderburk and Crandall [32] reported a three-year-old child with piebaldism
and marked growth and mental retardation. His parents had no pigmentary
abnormalities. The authors attributed these features to a reciprocal translocation
between chromosomes 4 and 15, with a single band deletion from chromosome
4, just proximal to the site of the translocation. Although the dominant piebald
trait may be a coincidental mutational change, it may result from translocation,
o
1I!r
I!II-Gr
I
=.::=.~~~
....,........
UNltfH'tO
~ BrCil"" ft
iIW - Gr.,
...........
FIGURE 103. The pedigree of a piebald family. (From: Comings DE, Odland GF: Partial albinism.
JAMA 195:519-523,1966. Copyright, 1966, American Medical Association. Used with permission.)
GENETIC AND
CONGENITAL
DISORDERS
318
CHAPTER 1
FIGURE 104. A piebald family. The mother (left) and three affected daughters. Only the middle
subject is unaffected. (From: Telfer MA et al: Dominant piebald trait (white forelock and leukoderma) with neurological impairment. Am J Hum Genet 23:383-389.1971. Copyright. 1971. The
University of Chicago Press.)
deletion, or both. However, Telfer et al. [31] described a patient with normal
chromosomal studies.
Clinical Description
The White Forelock
The white forelock, present in 80% to 90% of the patients [3] (Fig. 105),
is the most familiar feature of piebaldism. It is present at birth and is usually
first observed at birth or soon thereafter. All the hairs of the forelock are hypopigmented as is the skin of the scalp. The hair color is reported to be white
or white-silver [30]. Therefore, in fair-haired patients, the poliosis may not be
apparent. According to Cooke [3], lack of hair pigment in scalp areas other than
midfrontal seems not to occur, but Pearson et al. [7] mentioned that a piebald
girl described by Usher had two tufts of white hair on the left side of the scalp
(parietal and occipital regions) and Telfer et al. [31] reported in one case a
small parietal tuft of white hair which, because of its small size, could possibly
have been overlooked. But in most instances where there is a white forelock,
the rest of the scalp hair is normal.
The hypopigmented area of the skin of the white forelock is well circumscribed and hyperpigmented borders have been observed [31] (Fig. 106). The
patch of skin from which the forelock arises is usually located in the midline
and is triangular, elongated, or diamond-shaped, and often symmetrical. The
319
GENETIC AND
CONGENITAL
DISORDERS
White forelock in
three patients with piebaldism.
(From: Telfer MA et al: Dominant
piebald trait (white forelock and
leukoderma) with neurological
impairment. Am J Hum Genet
23:383-389. 1971. Copyright,
1971, The University of Chicago
Press.)
FIGURE 105.
320
CHAPTER 1
apex usually points posteriorly, and it can reach the bregma and the vertex. It
may extend forward to the root of the nose but the nose itself is rarely involved;
Grupper et al. [30], in their two cases, found the apex to be anterior and to
extend to the nose. The medial third of the eyebrows may be unilaterally or
bilaterally involved [29,31]. Involvement of eyelashes has also been reported
[29,31] .
Many authors have described patients with a white forelock under the
titles "white blaze," "poliosis circumscriptum," or "white forelock." But in
many of these cases, the clinical observations were limited to the localized
canities and the rest of the skin was not examined. Some well-known families,
for example, the Rohan family in France, were known to have a white forelock.
Some family names, like Whitlock, Horlock, Horlick, Silverlock, and Blaylock,
attest to the occurrence of this inherited white forelock. Is the white forelock
alone synonymous with piebaldism or can a classical white forelock occur
alone, as a separate genotype? Froggatt [4] quoted cases of isolated white fore-
321
GENETIC AND
CONGENITAL
DISORDERS
322
CHAPTER 1
FIGURE 107. Scattered lack of pigmentation on the chest. abdomen. and arms with hyperpigmented macules. (From: Telfer MA et al: Dominant piebald trait (white forelock and leukoderma)
with neurological impairment. Am J Hum Genet 23:383-389. 1971 . Copyright. 1971. The University
of Chicago Press .)
323
GENETIC AND
CONGENITAL
DISORDERS
HYPERPIGMENTED
MACUlES
The face may show depigmentation in areas other than the white lock.
Occasionally, there is a white patch on the center of the chin [4,29,46]. The
white area over the anterior neck may extend upward to the lower part of the
chin [3].
Mucous membrane involvement has been reported. Ansari [26] described
depigmentation of the lips. Intraoral depigmentation of the anterior gingiva
may occur; these depigmented macules may be as randomly scattered as in the
hypopigmented skin [3].
Hyperpigmented Macules
324
CHAPTER 1
pects of the legs in one of their patients. They mentioned the occurrence of
these hyperpigmented macules in normally pigmented skin as well as in the
hypopigmented areas (Fig. 112). Grupper et al. [30] described a patient with
many hyperpigmented cafe-au-Iait macules, oval in shape, located on the dorsal
trunk; some of these hyperpigmented macules were quite large (2 by 4 em and
7 by 11 cm). Ansari [26] observed numerous darkly pigmented patches of
various size all over the body. Some of these were several centimeters in diameter. The pigmented patches were darkest on the legs, feet, neck, and dorsa
of the hands. These macules are thought to result from exposure to sunlight.
Associated Systemic Findings
Although there have been several isolated reports of associated neurologic
and ectodermal abnormalities, most patients with piebaldism are otherwise
well.
Several cases of piebaldism and heterochromia irides have been described.
325
GENETIC AND
CONGENITAL
DISORDERS
326
CHAPTER 1
327
GENETIC AND
CONGENITAL
DISORDERS
FIGURE 112. Hyperpigmented macules overlaying normal skin and in piebald macules.
The cases of Urbantschitsch [54] and Van Gilse [55], in which skin and
hair depigmentation was associated with heterochromia irides and deafness,
most likely represent instances of Waardenburg syndrome in which dystopia
canthorum was not expressed.
Piebaldism has also been reported in association with multiple systemic
abnormalities, particularly neurologic impairment. Franceschetti et al. [56] reported deafness and mental retardation with white forelock, depigmentation
of the forehead, trunk, and distal limbs. Funderburk and Crandall [32] reported
a four-year-old boy with mental retardation, short stature, and typical piebaldism associated with chromosomal abnormalities. Neurosensory hearing loss,
cerebellar ataxia, impaired motor coordination, and mental retardation of variable severity were described in two Pennsylvania families [31] with white
forelock in the typically affected individuals, a minute parietal white tuft in
one individual, and leukoderma of the dorsal as well as of the ventral trunk.
Unaffected individuals of these kindreds did not display hearing loss. Nonpiebald family members had neither ataxia nor impaired motor coordination.
The presence of these manifestations in only two piebalds in the family could
328
CHAPTER 1
be fortuitous. None of these patients showed dystopia canthorum, heterochromia irides, or fundus abnormalities.
In these patients, one possible explanation of the concomitant occurrence
of neurologic and cutaneous pigmentary disorders is a mutation at the neural
crest level. Such mutants are known to occur in mice, and it has been shown
that several mechanisms can lead to piebald spotting [57]. Perhaps, in these
rare patients, the mechanism of cutaneous spotting is different from that of
piebaldism without associated neurologic impairment because the mutant gene
in the latter might act at a different developmental anatomic level than the
neural crest.
Piebaldism has been reported in association with Hirschsprung disease
[57a]. This can perhaps be explained on embryologic grounds. Neural crest
cells give rise to melanocytes and intravisceral ganglia. Defective embryonic
migration of the neural crest cells could explain absence of cutaneous melanocytes, on one hand, and of ganglion cells on the other. This association could
be homologous with that noted in piebald mice with megacolon [57b].
329
GENETIC AND
CONGENITAL
DISORDERS
FIGURE 113. A melanocyte (MC) found in the hypomelanotic skin of a patient with piebaldism.
a: Abnormal indentation of the nucleus (N). No melanosomes were transferred into the keratinocytes. (x 4900). b: A high-power view of a melanocyte showing abnormal spherical melanosomes
(SM) and normal ellipsoidal melanosomes (EM). Both types of melanosomes are in unmelanized
stages (x 67,000). (From: Jimbow K et al: Congenital circumscribed hypomelanosis: a characterization based on electron microscopic study of tuberous sclerosis, nevus depigmentosus and piebaldism. J Invest Dermoto1 64:50-62, 1975. Copyright, 1975, The Williams & Wilkins Company.
Used with permission.)
Electron Microscopy
330
CHAPTER 1
defined internal structure. With several sections, Jimbow et al. [58] found only
one melanocyte. This melanocyte contained a remarkably indented nucleus, a
large perikaryon, and a few unmelanized ellipsoidal and spherical melanosomes; the spherical melanosomes contained unmelanized grains.
Langerhans cells are reported increased in number. Crupper et al. [30]
observed many Langerhans cells and other Langerhans-like cells without typical Langerhans granules in the basal layer and at the suprabasallevel in the
epidermis of the white macule. Comings and Odland [29] reported an increased
number of Langerhans cells in either the basal layer or in the suprabasallayer.
Breathnach et al. [61] noted very rare but normal Langerhans cells and other
abnormal Langerhans cells that showed a tendency toward nuclear-cytoplasmic separation. One of the Langerhans cells contained a granule similar to
those seen in the abnormal melanocytes of the basal layer. The number of
indeterminate cells appears increased [60]. Mast cells have been described in
the depigmented epidermis [59,62].
In studies of the progressive transition zone between depigmented and
normal skin, Crupper et al. [30] found a normal number of melanocytes containing normal premelanosomes. However, some melanocytes had abnormal
features; they were characterized by reduced size, indented nuclei, and
shrunken, vacuolar, and granular cytoplasm. Most of the melanosomes were
abnormal in one of three ways, namely, irregularity of size and shape of mature
melanosomes, presence of ill-defined material in small round melanosomes, or
degenerative changes within melanosomes containing a granular material surrounded by a clear halo. They also observed typical Langerhans cells in the
basal layer and at a high level in the epidermis as well as cells with a Langerhans
cell appearance but without Langerhans granules (indeterminate cells).
In the hyperpigmented borders of hypomelanotic macules, Comings and
Odland [29] observed melanocytes, Langerhans cells, and an increased number
of melanin granules.
A large number of hyaline bodies in the dermis and epidermis have been
discussed [59].
White Forelock
There are no melanocytes in the follicles of the white forelock [58,61], and
no melanosomes in the surrounding keratinocytes [58]. There is an abnormally
large number of typical Langerhans cells in the basal layer and in the suprabasal
layer. Cells resembling Langerhans cells but without Langerhans granules (indeterminate cells) have also been observed [61].
Hyperpigmented Macules in the Center of the Depigmented Macules
An abundance of melanosomes in the melanocytes and keratinocytes characterizes the hyperpigmented macules [59] (Fig. 114). These melanosomes are
either normal (ellipsoidal) or abnormal (spherical) in shape, the latter (about
0.5 to 0.7 f..Lm in diameter) being more prominent. The normal ellipsoidal melanosomes, whose inner matrices are composed of lamellae, show normal mel-
331
GENETIC AND
CONGENITAL
DISORDERS
FIGURE 114. The melanocyte and melanosomes in the hypermelanotic lesion in the center of a
hypomelanotic area of skin of a patient with piebaldism. a: An abundance of spherical melanosomes
(SM) with various stages of melanization. (x 28,500). b: Abnormal degradation of the melanosomes
in the keratinocytes (arrows). Spherical, granular melanosomes (SM) are present in the dendritic
process of the melanocyte (x 27,000). (From: Jimbow K et al: Congenital circumscribed hypomelanosis: a characterization based on electron microscopic study of tuberous sclerosis, nevus
depigmentosus and piebaldism. J Invest Dermato1 64:50-62, 1975. Copyright, 1975, The Williams
& Wilkins Company. Used with permission.)
anization, transfer, and degradation. On the other hand, the spherical melanosomes, whose inner matrices are also composed of lamellae, show abnormal
melanization and degradation. In the spherical granular melanosomes, melanization often seems to start from the central part of the melanosomes. When
transferred into the keratinocytes, the melanosomes undergo marked degradation and often are fused with each other in the lower epidermis [58]. Jimbow
et al. [58] consider the presence of spherical granular melanosomes to be characteristic of piebaldism.
Normal Skin of Piebalds (Distant from the Hypomelanotic Areas)
According to Comings and Odland [29], a normal complement of melanin
granules, Langerhans cells, and melanocytes is found in normal skin. But
Breathnach et al. [61] pointed out that the melanocytes in normal skin of
piebalds differ in several respects from those found in the epidermis of normal
subjects. These melanocytes show a greater degree of nuclear indentation, ir-
332
CHAPTER 1
Amelanotic
skin
Melanocytes
Number
Dopa reaction
Dendrites
Melanosomes
Size
Shape
Inner structure
Melanization
Number in melanocytes
Secretion
Number in keratinocytes
Keratinocytes
Distribution pattern of
melanosomes
Degradation of melanosomes
White
hair
Hypermelanotic islands
within hypomelanotic
lesions
Normal
Increased
Well-developed
Normal
Abnormal (Le .
ellipsoidal and
spherical)
Abnormal (Le . lamellar
and granular)
Increased markedly
Increased
Normal
Increased
Normal
Abnormal or increased
Source: Jimbow K et al: Congenital circumscribed hypomelanosis: a characterization based on electron microscopic study of tuberous sclerosis. nevus depigmentosus and piebaldism. ] Invest Dermatol 64:50---62, 1975.
Copyright, 1975, The Williams & Wilkins Company. Used with permission.
b None detectable.
a
Pathogenesis
There are animal models for piebaldism. Gnus show a white forelock [35].
Various mechanisms have been identified to explain a white-spotting pattern
in mice. A clonal distribution of melanocytes has been observed in piebaldspotted and variegated mice [63]. In the case of the belted (bt) mutant, the skin
in the spotted areas selectively prevents the survival or differentiation of melanoblasts [64]. More specifically, the hair follicles seem to be the affected tissue,
for there are melanocytes in the skin between the pigment-free hair follicles.
In the WV mutation, the defect appears to be at the neural crest level. The
skin of the mutant genotype does not influence normal melanoblasts in any
adverse way [65]. WV/Wv melanoblasts either never enter the skin or they do
not survive because of some intrinsic factor operative immediately after colonization of the skin [66].
In the SLISL mice, the melanoblast component of the neural crest appears
to be normal [65], but the skin seems to playa determining role in the pigment
block. The skin of steel mice either prevents the differentiation of the normal
melanoblasts or inhibits their migration [66].
In the case of piebald mice (SIS), according to Mayer [57], the development
of white spotting occurs because the neural crest-derived cells seem to have a
reduced capacity to differentiate into melanocytes [57,64]. There is also evidence that the spotting pattern results from the differential resistance of certain
areas of the skin to the differentiation of melanoblasts [67].
These animal models suggest that the absence of melanocytes in hypomelanotic areas results from a failure of melanoblasts either to migrate into the
skin or to differentiate into melanocytes. The major target of involvement may
be the melanoblast in the neural crest, melanoblast migration or survival in the
skin, or both (Fig. 115). Since a very few melanocytes may overcome this hostile
embryonic environment [58], a few melanocytes may be found in hypomelanotic lesions. Abnormality of melanosomes within the melanocytes of hyperpigmented spots would also be a consequence of such hostile environmental
influences. The occurrence in some patients of concomitant neural disturbances
further supports a defect at the level from which these structures (skin and
neural tissues) both originate, i.e., the neural crest. That there are, in humans,
several pathogenic pathways resulting in the piebald phenotype is certainly
also possible.
Diagnosis
Vitiligo, which may also involve both skin and hair, is the major hypomelanosis that must be distinguished from piebaldism (Table 85). The following
features distinguish piebaldism from vitiligo: the white areas in piebaldism are
to migrate
or
failure of melanoblasts
to sUf"vive
or differentiate
333
GENETIC AND
CONGENITAL
DISORDERS
334
Vitiligo
Piebaldism
CHAPTER 1
Mode of inheritance
Autosomal dominant
Age of onset
Birth
Variable
Distribution pattern
Characteristic
White forelock
Anterior trunk
Arms and legs
Characteristic
Extensor surfaces
Sites of repeated trauma
Course
Stable
No extension
No spontaneous
repigmentation
Progressive
Extension or spontaneous
repigmentation
present from birth, usually remain constant throughout life, and show a characteristic distribution pattern with islands of normally pigmented or hyperpigmented skin.
In Waardenburg syndrome, the skin and hair depigmentation is similar to
piebaldism. However, the associated eye and ear findings differentiate Waardenburg syndrome from piebaldism. Ziprkowski-Margolis syndrome and Woolf
syndrome can be excluded by the absence of these characteristic features (see
appropriate sections in this chapter).
Treatment
The natural course of piebaldism is to remain unchanged throughout life.
Darkening of normal skin and of melanotic macules may follow sun exposure,
but the size and shape of the depigmented macules is usually fixed from birth.
Witkop (personal communication) has observed that piebald macules may vary
in size, and Davis and Verdol [68] have observed a piebald patient whose
hypopigmented macules expanded and contracted.
Several types of treatment have been attempted. Trisoralen has been used
in one patient who did not improve [28]. Bleaching normally melanized skin
of another patient with 20% mono benzyl ether of hydroquinone has been successful (unpublished observation). Cosmetic embarrassment may be diminished by cover-up, make-up, and clothing. Protection against UVB sunburn is
necessary.
Full-thickness autografts of normal skin into amelanotic areas have been
reported to result in peripheral spread of repigmentation from grafted sites
[69,70]; epidermal grafts are stable but lead to no peripheral spread [70].
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15. Mazzini G: Long heredity of partial albinism (abstr). Gass Osp Milano 45:403, 1923
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21. Levi E: Hereditary familial partial albinism in a Louisiana Negro family. Arch Anthropol
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22. Hutchinson J: On palaeogenic face-pattern in acroteric piebalds. Br Med J 1:1479-1481, 1910
23. Frassetto G: Casi di albinismo parziale ereditario nella famiglia Anderson della Louisiana (S.U.
d'A.). Considerazioni sulla genesi delle acromia ed i percromia congenite. Atti della Societa
Romana de Antropologia 15:115-171, 1910
24. Simpson QI, Castle WE: A family of spotted Negroes. American Naturalist 47:50-56, 1913
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26. Ansari MY: Partial albinism. J Indian Med Assoc 34:49-51, 1960
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28. Campbell B, Swift S: Partial albinism, nine cases in six generations. JAMA 181:1103-1106,
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29. Comings DE, Odland GF: Partial albinism. JAMA 195:519-523, 1966
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Syphiligr (Paris) 97:267-286, 1970
31. Telfer MA et al: Dominant piebald trait (white forelock and leukoderma) with neurological
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intercalary translocation. Am J Hum Genet 26:715-722, 1974
33. Bonerandi JJ et al: Piebaldism: etude ultrastructurale de 3 cas. XV Congres de l'Association
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34. Marchand JP: Piebaldism humaine (forme "variegata"). Bull Soc Med Afr Noire Lang Fr 21:185-189,
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35. Witkop CJ Jr: Albinism, in Human Genetics. Edited by H Harris, K Hirschhorn. New York,
Plenum, 1917, vol II, pp 61-142
36. Cockayne EA: A piebald family. Biometrika 10:197-200, 1914
37. Cromwell AM: Inheritance of white forelock in mulatto family. J Hered 31:94-96, 1940
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GENETIC AND
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38. Fitch L: Inheritance of white forelock through five successive generations. JHered 28:413-414,
1937
39. Frant R: A family with albinismus circumscriptus. Ned Tijdschr Geneeskd 31:120-121, 1937
40. Mierowsky, Spickernagel: Uber Vererbung und Lokalisation der Scheckenbildung sowie ihre
Bedeutung fUr die Naevusatiologik. Arch Dermatol Syphilol (Berlin) 150:384-392, 1926
41. Nussey AM: A piebald family. Biometrika 13:65-67, 1938
42. Zsako I: Pigment loss in five generations. Z Gesamte Neurol Psychiatr 34:208-212, 1923
43. Pierard GE et al: Six generations of piebaldism. Dermatologica 158:184, 1979
44. Jahr HM, Mcintire MS: Piebaldness or familial white spotting (partial albinism). Am J Dis
Child 88:481-484, 1954
45. Sundfor H: A pedigree of skin-spotting in man. J Hered 30:67-77, 1939
46. Woolf CM et al: Congenital deafness associated with piebaldness. Arch Otolaryngol 82:244-250,
1965
47. Stannius H: In discussion on Ellis RWB: Heterochromia of irides and hair. Proc R Soc Med
24:1057-1058, 1931
48. Ahuja YR: A human mosaic involving eye and hair color differences. Acta Genet Med Gemeilol
(Rom a) 9:427-431, 1960
49. Duke-Elder WS: Textbook of Ophthalmology, vol II. London, Henry Kimpton, 1938
50. Di George AM et al: Waardenburg's syndrome. J Pediatr 57:649-669,1960
51. Busti-Rosner L: Deux cas d'albinisme universel incomplet (albinoidisme) d'un biotype particulier dans une sauche valaisanne. J Genet Hum 5:197-215, 1956
52. Campbell B et al: Waardenburg's syndrome. A variation of the first arch syndrome. Arch
Dermatol 86:718-724, 1962
53. Reed WB et al: Pigmentary disorders in association with congenital deafness. Arch Dermatol
95:176-186,1965
54. Urbantschitsch E: Zur Aetiologie der Taubstdummheit. Verh Dtsch Otol Ges (fena) 19:153-159,
1910
55. Van Gilse PHG: Gival van pigmentonomalie en doofheid. Ned Tijdschr Geneesk 70:479-480,
1926
56. Franceschetti A et al: Albinisme partiel, surdits, arrisration mentale. Dermatologica 106:279,
1953
57. Mayer TC: The development of piebald spotting in mice. Dev BioI 11:319-334, 1965
57a. Mahakrishnan A, Srinivasan MS: Piebaldness with Hirschprung's disease. Arch Dermatol
116:1102, 1980
57b. Bielschowsky M, Schofield GC: Studies on megacolon in piebald mice. Aust J Exp Med Sci
40:395-404, 1962
58. Jimbow K et al: Congenital circumscribed hypomelanosis: a characterization based on electron
microscopic study of tuberous sclerosis, nevus depigmentosus and piebaldism. J Invest Dermatol 64:50-62, 1975
59. Barneon G, Baldet P: Piebaldism: ultrastructural study and pathogenic interpretation. Ann
Anat Pathol (Paris) 23:143-152, 1978
60. Bonerandi JJ et al: Piebaldism. Clinical. pathological and ultrastructural study of three cases.
Ann Dermatol Venereo1105:67-72, 1978
61. Breathnach AS et al: Electron microscopy of melanocytes in human piebaldism. J Invest Dermatol 45:28-37, 1965
62. Nagao S et al: Mast cells in the epidermis of piebaldism. Arch Dermatol Forsch 251:221-226,
1975
63. Schaible RH: Clonal distribution of melanocyte in piebald-spotted and variegated mice. J Exp
Zoo1172:181-199, 1969
64. Mayer TC, Maltby EL: An experimental investigation of pattern development in lethal spotting
and belted mouse embryos. Dev BioI 9:269-286, 1964
65. Mayer TC, Green MC: An experimental analysis of the pigment defect caused by mutations at
the W" and SL loci in mice. Dev BioI 18:62-75, 1968
66. Mayer TC: A comparison of pigment cell development in albino steel and dominant spotting
mutant mouse embryos. Dev BioI 23:297-309, 1970
67. Mayer TC: Temporal skin factors influencing the development of melanoblasts in piebald mice.
J Exp ZooI166:397-404, 1967
68. Davis BK, Verdol LD: Expansion and contraction of hypomelanotic areas in human piebaldism.
Hum Genet 34:163-170,1976
69. Selmanowitz VJ: Pigmentary correction of piebaldism by autografts. II. Pathomechanism and
pigment spread in piebaldism. Cutis 24:66-71, 1979
70. Selmanowitz VJ et al: Pigmentary correction of piebaldism by autografts. I. Procedures and
clinical findings. J Dermatol Surg Oneol 3:615-622, 1977
WAARDENBURG SYNDROME
The mother has heterochromia ... the family name is Whitlock (white-lock),
and ... records dating back to the middle of the 18th century (show) an inherited
white forelock from which the family name originated [1).
History
Although Waardenburg's name has been appended to this syndrome, review of the medical literature reveals many cases that may represent earlier
examples of this disease.
In 1905, Hammerschlag [4] reported a ten-year-old boy with deaf-mutism
associated with clear blue eyes, albinoid fundus, white forelock, craniofacial
dysostosis (narrow forehead, prominent jaw, high-arched palate), ataxia, mental
retardation, and unilateral undescended testicle. In 1910, Urbantschitsch [5]
and later Van Gilse [6] observed the association of partial albinism, heterochromia irides, and deaf-mutism. van der Hoeve [7], in 1961, described monozygotic twin girls with blue eyes, deaf-mutism, ankyloblepharon, lateral displacement of the inferior lacrimal puncta, and blepharophimosis. Mende [8],
in 1926, published a pedigree with affected individuals in four generations
with white forelock, discoloration of eyebrows and eyelashes, patchy whiteness
of the trunk and limbs, deaf-mutism, persistent lanugo hair of the neck, and a
mongoloid facial appearance probably due to lateral displacement of the inner
canthi. The combination of heterochromia irides with lateral displacement of
the inner canthi was observed in 1931 by Leonardi [9] and in 1934 by John
[10]. In 1947, Goedbloet [11] presented a case at the Netherlands Ophthalmological Society with the association of deaf-mutism and lateral displacement
of the medial canthi. Walsh [12] in 1947, in his textbook of clinical neurophthalmology, showed the picture of a brother and sister with deaf-mutism,
white forelock, and lateral displacement of the medial corner of the eyelids
and of the inferior lacrimal points. In the same year, Klein [13] presented to
the Genetics Society of Switzerland a ten-year-old girl with the following features: partial albinism of the skin and hair, bilateral slate blue irides, blepharo-
337
GENETIC AND
CONGENITAL
DISORDERS
338
CHAPTER 1
FIGURE 116. Klein's patient with hypomelanosis of skin and hair and multiple associated abnormalities. (From: Klein D: Albinisme partiel (leucisme) avec surdimutite, blepharophimosis et
dysplasie myo-osteo-articulaire. Helv Paediatr Acta 5:38-58, 1950. Copyright, 1950, Schwabe and
Co, Basel. Used with permission.)
339
HETEROCHROMIA IRIDES
DYSTOPIA CANTHORUM AND
BROAD ROOT OF THE NOSE
CUTANEOUS DEPIGMENTATION
FIGURE 117.
syndrome.
Waardenburg
Animal Models
Some animals appear to have Waardenburg syndrome. Wolff [19], in 1942,
noted that there had been many earlier reports describing this syndrome, particularly in Persian cats, and reported deafness in three generations of white
cats. Deaf white cats with blue irides have been observed [20). Wilson and
GENETIC AND
CONGENITAL
DISORDERS
340
CHAPTER 1
Kane [21] described heterochromia irides in a totally deaf white cat. Hereditary
deafness in association with white hair color is also known to occur in bull
terriers, Sealyhams, dalmations [22], dachshunds, and collies [18]. A horse
with white coat, deafness, and heterochromia irides has also been reported
[23].
Clinical Features
Incidence
Any race may be affected. For a long time this disease was thought to
involve only the Dutch; in fact, in 1961 an article was subtitled "Report of a
Case in a Non-Dutch Family" [27]. And while the original cases concerned
only Caucasoids, Waardenburg syndrome has also been observed among most
European nationalities, Americans, Mongoloids, Japanese [28-30], Chinese [31],
North American blacks [23,32], and African blacks [18,33]. The syndrome shows
no particular geographic distribution.
Sex
Males and females are equally affected.
Heredity
Not all cases are familial. Isolated cases do occur, and as Waardenburg
suggested, spontaneous mutations must occur [16,25,36]. The mutation could
occur in the generation of the proband's parents and escape detection because
of variable expression or penetration. One case has been attributed to 40 x-ray
examinations performed on the father of the patient [37].
Any theory of inheritance for Waardenburg syndrome must also explain
the occasional presence of musculoskeletal defects [13,38,39]' cleft lip, and
cleft palate [8,16,24,26,40-43]. A disturbance of gene reparation, deletion, or
some other gene disturbance may be responsible [13]. Or perhaps these cases
are new mutations or represent homozygous presence of an autosomal recessive
gene (related to consanguinity or incidental occurrences).
Arias [2] suggested possible genetic heterogenicity in Waardenburg syndrome, and this was demonstrated in a review of 1319 such patients. One family
has been reported in which none of its members has dystopia of the inner
canthi or lower puncta, while four siblings have the combination of hyperopia-estropia-amblyopia and foveal hypoplasia; iris translucency dramatizes
this heterogeneity [44]. Two distinct autosomal dominant entities have been
described as follows: Type I with dystopia canthorum, and Type II without
dystopia canthorum. Type II also has a greater incidence of bilateral deafness
[3]. Among 30 patients from Kenya, 18 were Type I and 12 Type II [45].
There have been no other reported markers for Waardenburg syndrome.
No chromosomal abnormalities have been found [13,25,39,46,47] in those with
Waardenburg syndrome. Although six patients of blood group A have been
reported as a series [48], there is no evidence that Waardenburg syndrome and
ABO blood groupings are correlated [47]. HLA typing performed on six patients
has been reported to be inconclusive [48]. Dermatoglyphics are usually normal;
however, one case with a transverse palmar fold has been reported [49].
Characteristic feature
Dystopia canthorum
Partial albinism (white forelock, other white
spots, and early graying)
Heterochromia irides
Bilateral isohypochromic irides
Congenital deafness
Hyperplasia of nose root
Hyperplasia of eyebrows
Waardenburg
Later
publications
Reed et a\.
(161)b
(181)b
(24)b
99%
17%
(159)
(27)
77.9%
43.6%
(141)
(79)
69%
60%
25%
(41)
20%
78%
45%
(32)
21.5%
14.9%
37.5%
(39)
(27)
(68)
28%
28%
100%
69%
Source: Reed WB et al: Pigmentary disorders in association with congenital deafness. Arch Dermato195:176-186,
1967. Copyright. 1967. American Medical Association. Used with permission.
b Numbers in parentheses indicate number of patients.
a
341
GENETIC AND
CONGENITAL
DISORDERS
342
CHAPTER 1
Hair
White forelock
Early graying of hair
Hypomelanosis of eyebrows. eyelashes. or body hair
Skin
Eyes
Heterochromia irides
Bilateral isohypochromia irides
Fundus pigmentary abnormalities
Author
White
forelock
17%
50%
58.4%
43.5%
Premature
graying
scalp
Cutaneous
hypomelanosis
No. of
cases
161
7%
50%
8.3%
24
23
343
GENETIC AND
CONGENITAL
DISORDERS
the forehead to involve both medial eyebrows [23]. A few patients have had
white hair in areas other than the frontal region. Involvement of the frontoparietal scalp [17] and of the posterior scalp has been reported [36]. The skin
beneath the white forelock mayor may not also be amelanotic [23].
The white forelock may be present at birth or may appear very soon thereafter or even later [50]. This white forelock may persist throughout life or
become less prominent and even disappear in the first months or years of life.
A typical case is that of a baby with a white forelock, 4 to 5 em wide, which
began to disappear after the first two weeks, and with depigmentation involving
two-thirds of her left eyebrow and eyelashes, both of which remained depigmented. At three years seven months of age, none of the initial white forelock
remained [51]. In another case, the congenital white forelock had disappeared
by six weeks of age except for a few white hairs and had not returned by one
year of age [52]. However, the authors are aware of one black child in whom
the white forelock had disappeared at the end of the first year of life and
reappeared at the age of 10 years.
Not all forelocks of Waardenburg syndrome are white; patches of red,
brown, and black have been observed [13,26]. One blond patient had a parietooccipital patch of red hair. Another had a bright red forelock in a field of
auburn hair, red hair at one side of the neck, auburn on the other, and eyelashes
that were bright red medially and dark brown laterally. In another, a sharply
demarcated patch of black hair on the right side of the scalp contrasted with
the fair hair of the left scalp [53]. It is reasonable to ask whether the fair color
of most of the scalp hair represents a hypomelanotic variant of the white forelock or whether the dark patch is in fact abnormal, that is, hyperpigmented
[18].
344
CHAPTER 1
FIGURE 119. Premature graying of hair. (From: Amer M, El Shazly M: The association of familial
hyperbetalipoproteinemia with Waardenburg's syndrome. Br J Dermatol 90:255-262, 1974. Copyright, 1974, Blackwell Scientific Publications. Used with permission.)
345
GENETIC AND
CONGENITAL
DISORDERS
by the age of 46. None of these three individuals had other evidence of Waardenburg syndrome.
Skin Depigmentation
346
CHAPTER 1
Year
Mazzini [57J
Mende [8J
Klein [13J
Waardenburg [16J
Fisch [37J
Partington [25J
Di George et al. [23 J
Borbolla et al. [58J
Grimaud et al. [59]
Partsch [60J
Campbell et al. [lJ
Calinkos [56J
Houghton [61J
Wilbrandt and Amman [62J
Hansen et al. [50]
McDonald and Harrison [55J
Goldberg [41 J
de Haas and Tan [46J
Boniface and Fontaine [63J
Reed et al. [26]
Fregonese et al. [64 J
Amer and El-Shazly [65J
Soussi Tsafir [18J
Ortonne et al. [47J
Parry et al. [66J
Amon and Abdurrahman [67J
1924
1926
1950
1951
1959
1959
1960
1961
1961
1962
1962
1963
1964
1964
1965
1965
1966
1966
1966
1967
1969
1974
1974
1976
1978
1979
baldism, are present at birth or are noted soon thereafter. The white macules
are usually circumscribed with sharply defined but irregular borders. The color
is dull white, and Wood's light examination shows a complete absence of
pigment (3 + hypomelanosis). Hyperpigmented macules are scattered randomly
within the larger hypomelanotic macules. The extent of the hypopigmentation
varies; it may be localized or scattered all over. Symmetry occurs in some cases
(Fig. 122). The hypomelanosis is usually found on the face and the forehead
next to the white forelock, but also may be on the neck, anterior chest and
abdomen, and the limbs, particularly on the anterior knees and arms. Both the
anterior and posterior arms may be involved and in many cases the dorsal
hands are amelanotic. Lip involvement has been observed [18]. The macules
usually do not increase in size and do not repigment. Body hair within the
white patches is usually white (Fig. 123). The hypopigmentation is asymptomatic.
Pedigrees with white spotting and familial patterns have also been described. A four-generation pedigree, all with hypopigmentation of the trunk
and limbs, has been reported [8]. The grandmother and the mother of one patient
with extensive involvement [23] had white spots on the dorsal wrists. In a five-
347
GENETIC AND
CONGENITAL
DISORDERS
348
CHAPTER 1
FIGURE 123. Depigmentation of body hair on the hypomelanotic macules. (From: Ortonne J-p
et al: Le syndrome de Waardenburg-Klein assode a une maladie de Hodgkin. Ann Dermatol
Syphiligr (Paris) 103:245-256, 1976. Copyright, Masson et Cie, Paris. Used with permission.)
349
GENETIC AND
CONGENITAL
DISORDERS
FIGURE 124. Skin from the edge of a hypomelanotic macule: melanocyte (M); colloid bodies
(CB); basement membrane (MB); vacuole (V); melanosomes (ME); mitochondria (MI); tonofibrils
(TF) (x 13,700). (From: Perrot H et al: Ultrastructural study of leucodermic skin in Waardenburg-Klein syndrome. Acta Derm Venereol (Stockh) 57:195-200, 1977. Copyright, 1977, Society
for the Publication of Acta Dermatoveneriologica. Used with permission.)
350
CHAPTER 1
FIGURE 125. Skin from the edge of hypomelanotic macule. Indeterminate cell in the basal part
of the epidermis: keratinocyte (K) ; indeterminate cell (IC) (x 18.000). (From: Perrot H et al: Ultrastructural study of leucodermic skin in Waardenburg-Klein syndrome. Acta Derm Venereol
(Stockh) 57:195-200. 1977. Copyright. 1977. Society for the Publication of Acta Dermatoveneriologica. Used with permission.)
somes were diminished in number and were sometimes found inside vacuoles
surrounded by a clear halo. Some had normal structure, but others were granular. Numerous melanosomes were found in keratinocytes.
In normal skin. distant from the lesions, many melanocytes appeared normal, many others had poorly formed dendrites and contained abnormal melanosomes characterized by an irregular outline, rounded shape, small size, and
granular inner structure (Fig. 126). Thus, in Waardenburg syndrome there are
few or no melanocytes in achromic skin and there is a disturbance in melanosome synthesis in clinically normal skin distant from the achromic patches.
This suggests biopsy of normal skin may help distinguish piebaldism from
Waardenburg syndrome.
Ocular Pigmentary Abnormalities
Isohypochromic Eyes
Goldberg [41] found bilateral iris hypochromia in 42% of his 14 patients;
in other series, an incidence of 14.9% to 28% is reported [26].
In 1961, Waardenburg [70] stated that bilateral pale blue eyes should be
regarded as a sign of his syndrome. Originally, Waardenburg [16] did not include pale blue eyes (isohypochromia) in Waardenburg syndrome because he
thought that blue-eyed individuals simply had blue eyes which somehow were
351
GENETIC AND
CONGENITAL
DISORDERS
(ME); vacuole (V); keratinFIGURE 126. Normal skin: melanocyte with abnormal melanosomes
mic skin in Waarleucoder
of
study
ocyte (K) (x 30,000). (From: Perrot H et al: Ultrastructural
ht, 1977, Society
Copyrig
.
00,1977
57:195-2
(Stockh)
l
Venereo
Derm
denburg-Klein syndrome. Acta
on.)
permissi
with
Used
ogica.
veneriol
Dermato
Acta
of
ion
Publicat
for the
became a
a genetic marker for inability to express heterochromia. Blue eyes
had
part of the clinical findings in Waardenburg syndrome once Waardenburg
eyes
blue
d
assume
he
me;
syndro
enburg
observed blue-eyed blacks with Waard
[18]
not to be a normal genetic trait of blacks (Fig. 127). But Soussi Tsafir
several
found
she
when
ct
showed Waardenburg's assum ption to be incorre
since the
cases of blue-eyed blacks withou t Waardenburg syndrome. However,
ual
individ
"an
low,
incidence of bilateral blue eyes in blacks is exceptionally
owes
eyes
blue
showing at least one other sign of Waardenburg syndrome with
noted that
his blue eyes to the Waardenburg genotype" [18]. Thorkilgaard [71]
George et
Di
and
hypoplasia of the iris may result in blue eyes. Both he [71]
enburg
Waard
of
a1. [23], who considered bilateral blue eyes to be a feature
Thorkme.
syndro
syndrome, includ ed iris hypopl asia as part of Waardenburg
since
ion,
definit
ilgaard [71] suggested the latter replace heterochromia in the
is
asia
hypopl
iris
unilateral hypopl asia of the iris gives a blue eye. When
te
comple
in
result
bilateral, both eyes are blue, but unilateral hypoplasia can
heterochromia irides with eyes of different colors.
Heterochromia Irides
hyIn total or complete heterochromia irides, the presence of unilateral
ghypopi
The
colors.
nt
differe
of
popigmentation (Fig. 128) gives rise to irides
heteroPartial
color.
blue
h
mented iris has a characteristic intense whitis
352
CHAPTER 1
chromic irides refers to the condition in which one or both irides have a sector
that is differently colored from the rest of the iris. Heterochromia, partial or
complete, was found in 21% to 28% [16,18,26,41] of cases from the literature.
Hypopigmentation of the iris in one form or another was reported [18] in 87.5%
of 24 black patients and in 87% of 24 blacks collected from the literature.
Among 96 Caucasoid patients with Waardenburg syndrome, 81.3% of the cases
showed one or another form of iris hypopigmentation [18] . Thus, Negroids and
Caucasoids seem equally affected and iris hypopigmentation is a common feature of Waardenburg syndrome. Unilateral hypoplasia of the iris stroma may
be observed by slit-lamp examination.
The possibility that heterochromia irides results from unilateral hyperpigmentation is very remote [70].
Fundus Pigmentary Abnormalities
Abnormalities of fundus pigmentation have been noted in several cases of
Waardenburg syndrome. Although their exact incidence is unknown, retinal
353
GENETIC AND
CONGENITAL
DISORDERS
354
CHAPTER 1
FIGURE 129. Lateral displacement of the inner canthi and heterochromic irides.
355
GENETIC AND
CONGENITAL
DISORDERS
FIGURE 130. Demonstration of the interocular distances used to determine the presence of lateral
displacement of the inner canthi. (From Adams RD, Reed WB: Neurocutaneous disorders, in
Dermatology in General Medicine. Edited by TB Fitzpatrick et al. McGraw-Hill, New York, 1971,
p 1409. Copyright, 1971, McGraw-Hill Book Company. Used with permission.)
et al. [26] suggested that the correct incidence of dystopia canthorum in Waardenburg syndrome is lower than that reported by Waardenburg [16] and is
probably between 70% and 80%. A range of incidences of 41.2% to 77.9% has
been reported [18,26,74]. Numerous cases of Waardenburg syndrome without
dystopia canthorum have been described [1,16,23,37,49,60,61,75]. Soussi Tsafir
[18] established that dystopia canthorum is not as regular a feature of the disease
in families of black or deeply pigmented origin as it is in Caucasoids but was
unable to provide an explanation for this. She noted also that the incidence of
this feature in black and deeply pigmented individuals is nearly the same in
males (47.4%) and in females (52.6%).
Hageman and Delleman [3] separated Waardenburg syndrome into two
genetically distinct types: Type I has dystopia canthorum, and Type II does
not. A quarter of Type I and a half of Type II also experience eventual deafness.
Broadened Nasal Root
The hyperplasia of the root of the nose was thought by Waardenburg [16]
to be one of the characteristic features of the disease. He suggested that the
medial frontal process and portions of the two medial and lateral processes
have grown hyperplastic during embryonic development. In 1959, Fisch [37]
said that the dystopia canthorum may create the illusion of a wide nasal bridge
and that the nasal bridge, which is frequently depressed, is not necessarily
abnormally wide. As emphasized by Amini-Elihou [17], it is difficult to separate
these two hypotheses. Regardless, the impression of a broadened nasal root is
part of Waardenburg syndrome.
The incidence of broad nasal root is reported by Waardenburg [16] to be
78%. The reported incidence ranges from 17.6% to 54.5% [18,74]. In black or
356
CHAPTER 1
other deeply colored patients, the incidence is nearly the same in males (46.7%)
and females (53.3%) [18].
Soussi Tsafir [18] concluded, as there are no precise quantitative data on
normal widths of nasal roots and as this feature is difficult to assess in very
young individuals or in blacks, that the value of this feature in the diagnosis
of Waardenburg syndrome,particularly in blacks, is doubtful.
Medial Eyebrow Hyperplasia
Hypertrichosis of the medial eyebrows is characteristic of Waardenburg
syndrome. In some individuals the eyebrows are confluent (synophrys) and
these confluent hairs are usually of normal color. The incidence of hyperplasia
of the eyebrows is 17.6% to 69% [16,18,26,74]. Males and females are equally
involved.
Soussi Tsafir [18] concluded that the abnormal gene penetrates only in the
presence of at least moderate hairiness, as is more likely to be found in persons
with some Caucasoid ancestry.
Congenital Deafness
Fisch [37] observed the following two distinctive patterns of audiographs
in Waardenburg syndrome:
Type I: Almost total deafness with little residual hearing at the lower
frequencies.
Type II: Moderate degree of deafness with uniform hearing loss in the
lower and middle frequencies with a remarkable improvement in the higher
frequencies.
Fisch stated that Type I is rare and usually unilateral and that he never
observed Type II to be bilateral. These types are not correlated with those of
Hageman and Delleman [3].
Almost any combination of types of hearing loss may occur in the same
family and a combination of both types may be present in the same individual.
Partsch [60] stated that, as all possible combinations of types-bilateral or
unilateral, severe or moderate--may occur, there is no audiogram characteristic
of Waardenburg syndrome.
The incidence of deafness in Waardenburg syndrome is variably reported.
Waardenburg [16] found 20% to have hearing defects but a range of 9% to 37.5%
has been reported (Fig. 131). The latter figure arises from a study conducted
in a school for the congenitally deaf. Audiograms were not performed in all
patients, so it is possible in the initial reports that some cases of mild deafness
have been overlooked. Fram;ois et al. [74] observed in the cases with unilateral
deafness associated with unilateral iris depigmentation, that the involved ear
is on the same side as the blue eye.
Soussi Tsafir [18] found a comparatively high incidence of deafness, 62.5%
of her 24 black patients and 45.8% of blacks in the literature (54.6% in these
two combined series), and concluded that the relative high incidence of deafness among blacks exemplifies the difference in the expression of Waardenburg
357
GENETIC AND
CONGENITAL
DISORDERS
syndrome in different racial groups. She also noted that deafness in black
patients was much more prevalent among males than females.
Friedman and Fisch [76] reported the histopathology of the ear of a threeand-one-half-year-old girl with Waardenburg syndrome (who died of a respiratory infection). Findings included fully developed inner ears (utricle and
saccule), normal semicircular canals, absent organs of Corti, and obvious atrophy of the spiral ganglion and nerve. Pathologic examination of the cerebral
cortex in this same patient showed no involvement of the central auditory
pathway. Deafness was attributed to a defect in the organ of Corti and in the
8th cranial nerve. An absent organ of Corti and reduction of nerve fibers have
been seen in a cat with heterochromia irides.
Pathogenesis
Several theories have been advanced to explain all the features of the
Waardenburg syndrome. Any theory must be consistent with electron microscopic studies, which show an absence of melanocytes in the depigmented
skin and abnormalities of melanocytes in the clinically normal skin [69].
The "Deficient Neural Crest" Theory
In 1959, Fisch [37] suggested that a developmental abnormality of the
neural crest may give rise to Waardenburg syndrome.
358
CHAPTER 1
359
GENETIC AND
CONGENITAL
DISORDERS
360
CHAPTER 1
Waardenburg [16] in 1951, and later Pirodda et al. [42] in 1961, suggested
that Waardenburg syndrome might be related to status dysraphicus. Pirodda
et al. [42] hypothesized a mechanism to explain defective development of the
cervical region, alterations in the bone of the nasal roots, etc. Some patients
with Waardenburg syndrome have signs suggesting dysraphism, namely, patent
metopic suture [12,23,37,94]' cleft lip, or cleft palate (see Table 90). Heterochromia irides have also been described in patients with status dysraphicus
[42]. However, Passow [108] stated that uncomplicated heterochromia irides,
which is the type most encountered in patients with Waardenburg syndrome,
are not found in status dysraphicus. On an embryogenic basis, this hypothesis
is conceivable, as the mesenchymal cords forming the solid core of the frontonasal process are derived from neural crest cells [109] (closing anterior neuropore). So an abnormality in this region could explain a neural crest disturbance as well as facial developmental abnormalities; and neural crest abnormalities
induce the pigmentary abnormalities in the skin and hair. However, Pirodda
et al. [42] concluded that this mechanism should not be regarded as more than
a hypothesis. In fact, signs of dysraphism are not common in Waardenburg
syndrome.
TABLE 90.
(continued)
Soussi Tsafir [18] noted that there is a striking similarity between some
signs of Waardenburg syndrome and some of those observed in Bonnevie-Ullrich syndrome and suggested that a similar pathogenesis might be responsible for both.
Bonnevie, in 1932, described a mutant mouse (my) characterized by head
and extremity abnormalities related to aggregation (blebs) of cerebrospinal fluid
migrating about the body [110]. The affected animals showed narrowing of the
palpebral fissures and sometimes microphthalmia, facial asymmetry, and de-
361
GENETIC AND
CONGENITAL
DISORDERS
362
CHAPTER 1
formation of the ears and limbs. Some skin areas to which blebs had migrated
were deficient in pigment. In these animals, it was found that excess cerebrospinal fluid collected below the epidermis in the neck regions of 7- to 8-mm
embryos and stagnated in concave areas. These blebs disrupted formative processes at critical phases. Substrains of these mice were obtained in which only
the head defects occurred related to a concentration of modifying genes which
reduced the probability of blebs migrating to the trunk region.
Ullrich [111] suggested a similar mechanism to explain some human congenital abnormalities of the head and extremities. A patient with Bonnevie-Ullrich syndrome showed facial asymmetry, broad nose, unilateral narrowing of the palpebral fissure, one iris darker than the other, and gray hair
interspersed with normally pigmented hair in the midfrontal region. Some of
these features are often observed in Waardenburg syndrome.
Soussi Tsafir [18] discussed the mechanism by which wandering blebs can
generate the features of Waardenburg syndrome. She suggested that areas of
skin or hair depigmentation might be the site of migration of a wandering bleb
and that heterochromia irides could result from the pressure exerted by a bleb
on the sympathetic nerve supply or blood supply to one eye. Soussi Tsafir also
hypothesized that the wandering cerebrospinal fluid blebs may affect the neural
crest and induce modifications in both melanoblasts and cells responsible for
auditory vesicle reduction.
Four pathogenic hypotheses have been discussed. None explains all the
features in Waardenburg syndrome. The most logical mechanism seems to be
a neural crest deficiency, a hypothesis supported by much experimental evidence. But these hypotheses are not mutually exclusive. It seems likely that
the defect in Waardenburg syndrome involves not only the neural crest, but
also other neighboring structures closely related to it during the embryonic life.
The nature of this defect is unknown.
some cases, a faintly marked furrow in the forehead extending to the tip of the
nose. Fisch [37] also observed this in one of his patients.
In some cases, skull x-ray abnormalities have been reported. Patent metopic
suture has been observed. Occipitoparietal hyperostosis and frontal bossing
have been described [43,59].
Most of these features have been reported in only isolated cases.
Other Features
Various other abnormalities have been described in patients with Waardenburg syndrome. These are listed in Table 90.
Associated findings
Autosomal dominant
MIF
363
GENETIC AND
CONGENITAL
DISORDERS
364
CHAPTER 1
Treatment
None is available. Early diagnosis permits appropriate treatment of the
deafness.
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73. Scott FP, Van Beukering JA: Waardenburg's syndrome: report of an abortive case. S Afr Med
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74. Fram,ois Jet al: Syndrome de Waardenburg-Klein. Acta Genet Med Gemellol (Roma) 14:353-375,
1965
75. Diallinas NP: Les alterations oculaires chez les sourd-muets. J Genet Hum 8:225-262, 1959
76. Friedman I, Fisch L: Deafness as part of an herditary syndrome. J Laryngol Otol 73:355-382,
1959
77. Arey LB: Developmental Anatomy, 6th ed. Philadelphia, Saunders, 1954
78. Horstadius S: The Neural Crest. Oxford, Oxford Univ Press, 1950
79. Jacobson AG: The determination and positioning of the nose, lens, and ear. J Exp Zool
154:273-283, 285-291, 1963
80. Rawles ME: Origin of melanophores and their role in development of color patterns in vertebrates. Physiol Rev 28:383-408, 1948
81. Rawles ME: Origin of pigment cells from the neural crest in the mouse embryo. Physiol Rev
20:248-266, 1947
82. Mayer TC: The development of piebald spotting in mice. Dev BioI 11:319-334, 1965
83. Mayer TC, Green MC: An experimental analysis of the pigment defect caused by mutations
at the Wand SL loci in mice. Dev BioI 18:62-75, 1968
84. Mayer TC: A comparison of pigment cell development in albino, steel, and dominant-spotting
mutant mouse embryos. Dev BioI 23:297-309, 1970
85. Zimmerman AA, Becker SW: Precursors of epidermal melanocytes in the Negro fetus, in
Pigment Cell Biology. Edited by M Gordon. New York, Academic, 1959, pp 159-170
86. Okamoto E, Ueda T: Embryogenesis of intramural ganglia of the gut and its relation to Hirschsprung's disease. J Pediatr Surg 2:437-443, 1967
87. Yntema CL, Hammond WL: The orgin of intrinsic ganglia of trunk viscera from vagal neural
crest in the chick embryo. J Comp NeuroI101:515-541, 1954
88. Bodian M, Garter CO: A family study of Hirschsprung's disease. Ann Hum Genet 26:261-271,
1962-1963
89. Skinner R, Irvine D: Hirschsprung's disease and congenital deafness. JMed Genet 10:337-339,
1973
90. McKusick VA: Mendelian Inheritance in Man, 3rd ed. Baltimore, Johns Hopkins Press, 1970
91. Lane P: Quoted in Mayer MC: The development of piebald spotting in mice. Dev BioI 11:319-334,
1965
92. Bielchowsky M, Schofield GC: Studies on megacolon in piebald mice. Aust J Exp BioI Med
Sci 40:395-404, 1962
93. McKenzie J: The first arch syndrome. Arch Dis Child 33:477-486, 1958
94. Mouraux JM: Le syndrome de Waardenburg. These, Nancy, 1962
95. Porot M, Filiu S: Un deuxieme cas de surdi-mutite avec heterochromie irienne et epilepsie.
Rev Otoneuroophtalmol 31:481-483, 1959
96. Keizer DPR: Een niuewe vorm van congenitale doofheid (syndroom van Waardenburg). Ned
Tijdschr Geneeskd 96:2541-2543, 1952
97. CalmeUes L et al: Syndrome de Waardenburg-Klein avec fistules lacrymales borgnes. Bull
Soc Othtalmol Fr 81:144-155, 1968
98. Stoller FM: A deaf mute with two congenital syndromes. Arch Otolaryngol 76:42-46, 1962
99. Gedda L, Magistretti SB: Sulle anomalie pigmentarie dell'occhio deUe "albinismo oculare"
ed ancora sopra il caso delle gemelle monozigotiche albine descritte da Hanhart. Acta Genet
Med Gemellol (Rom a) 10:21-47, 1961
100. Bwibo NO, Mkono MD: Waardenburg's syndrome in an African child. Hum Hered 20:19-22,
1970
101. Roux C et al: Le syndrome de Waardenburg; une observation familiale sur 4 generations et
23 sujets. Ann Genet (Paris) 13:125-128, 1970
102. Robinson GC et al: Waardenburg's syndrome. The risk of recurrence of congenital deafness
in a kindred. J Pediatr 67:491-494, 1965
103. Basile R: A pedigree of binocular heterochromia iridis associated with other anomalies (Waardenburg-Klein syndrome). J Genet Hum 14:87-92, 1965
104. Omenn GS, McKusick VA: The association of Waardenburg syndrome and Hirschsprung
megacolon. Am J Med Genet 3:217-223,1979
105. Ray DK: Waardenburg's syndrome. Br J Ophthalmol 45:568-569, 1961
106. Walsh FB, Hoyt WF: Clinical Neuro-ophthalmology, 3rd ed. Baltimore, Williams & Wilkins,
1969
107. Delleman JW, Hageman MJ: Ophthalmological findings in 34 patients with Waardenburg
synclfome. J Pediatr Ophthalmol Strabismus 15:341-345, 1978
108. Passow A: Hornersyndrom, Heterochromie und Status dysraphicus, ein Symptomen komplex.
Arch Augenheilk 107:1-51, 1933
109. Wits chi E: Prenatal development, in Congenital Anomalies of the Face and Associated Structures. Edited by S Pruzansky. Springfield, Ill, Thomas, 1961, p 103
367
GENETIC AND
CONGENITAL
DISORDERS
368
110. Bonnevie K: Zur Meckanik der Papillarmusterbildung: Anomalien der menschlichen Finger-
CHAPTER 1
und Zehenbeeren, nebst Diskussion tiber die Natur der hier wirksamen Epidermispolsten.
Arch Entwicklungsmeckanik Organ 126:348-372, 1932
111. Ullrich 0: Turner's syndrome and status Bonnevie-Ullrich. Am J Hum Genet 1:179-202,
1949
112. Delmarcelle Y, Pivont A: Heterochromie familiale associee a des malformations oculaires et
FIGURE 132. a-d: Hypomelanosis involving head, arms, and chest in brother of patient in Fig.
133; both have hereditary piebaldism and congenital deafness syndrome. (From: Woolf CM et al:
Congenital deafness associated with piebaldism. Arch Otolaryngol 82:244-250, 1965. Copyright,
1965, American Medical Association. Used with permission.)
369
GENETIC AND
CONGENITAL
DISORDERS
370
CHAPTER 1
FIGURE 133. a-d: Hypomelanosis involving head, arms, and chest in brother of patient in Fig.
132; both have hereditary piebaldism and congenital deafness syndrome. (From: Woolf eM et al:
Congenital deafness associated with piebaldism. Arch Otolaryngol 82:244-250, 1965. Copyright,
1965, American Medical Association. Used with permission.)
and symmetrical white macules over the arms, legs, and abdomen. Di George
et al. [4] reported piebaldism and deafness in a young black female.
Reed et al. [3] concluded that it is unlikely that piebaldism and deafness
had occurred together in these patients as separate genetic defects, and Konigsmark [5] suggested that it is likely that this syndrome is transmitted as an
autosomal recessive trait.
371
GENETIC AND
CONGENITAL
DISORDERS
372
CHAPTER 1
REFERENCES
JHum Genet 17:23-35,
1965
Woolf CM et al: Congenital deafness associated with piebaldness. Arch OtolaryngoI82:244-250,
1965
Reed WB et al: Pigmentary disorders in association with congenital deafness. Arch Dermatol
95:176-186, 1967
Di George AM et al: Waardenburg's syndrome. J Pediatr 57:649-669,1960
Konigsmark BW: Hereditary childhood hearing loss and integumentary system disease. JPediatr
80:909-919, 1972
2.
3.
4.
5.
FIGURE 134. a, b: Three children with large macules of hyperpigmentation, particularly in inguinal and buttock areas, on a hypomelanotic background, in the Ziprkowski-Margolis syndrome
of sex-linked pigmentary abnormalities and congenital deafness. (From: Ziprkowski E et al: Partial
albinism and deaf mutism due to a recessive sex-linked gene. Arch Dermatol 86:530-539, 1962.
ZIPRKOWSKI-MARGOLIS SYNDROME
In 1962, Ziprkowski et al. [1] and Margolis [2] reported a syndrome affecting
14 males in an Egyptian Jewish family. The syndrome consisted of deaf-mutism,
heterochromia irides, cutaneous and hair depigmentation, and localized hyperpigmentation. Since all the affected individuals were male and in all cases
the transmission was through a female carrier, this syndrome was considered
to be X-linked recessive. No "forme fruste" was discovered among the healthy
family members, including the carriers. This syndrome has been referred to as
"partial albinism" with deafness.
373
GENETIC AND
CONGENITAL
DISORDERS
374
CHAPTER 1
In the affected individuals, the skin was congenitally whitish pink in appearance. Later, hyperpigmented spots appeared, mainly on the extremities,
trunk, and rarely on the scalp, in a bilateral or roughly symmetrical distribution.
The macules were either round, oval, polycyclic, or geographical in shape, from
a few millimeters to several centimeters in size, and from light yellow-brown
to brown-black in color (Fig. 134). The presence of widespread depigmentation
and localized hyperpigmentation gave a leopard appearance. In all the patients,
the gluteal and scrotal regions were congenitally light to dark gray-brown in
color.
The hair in most cases was completely white, even over the pigmented
macules of the scalp, but in one of the patients the hair was straw colored.
Eyebrows and eyelashes were achromic.
Heterochromia irides and possibly isochromia were observed in several
patients, none of whom has nystagmus, photophobia, dystopia canthorum, or
hyperplasia of the base of the nose.
All patients were congenital deaf mutes. From audiometric examination,
it was apparent that the deafness was of the perceptive type. Caloric tests
indicated vestibular dysfunction.
Histologic studies of the hyperpigmented skin showed a strong dopa-positive reaction, as opposed to the weak reaction in the hypopigmented skin.
There was no obvious difference in the number of melanocytes in the hyperpigmented and the depigmented skin. This clearly distinguishes Ziprkowski-Margolis syndrome from piebaldism, Waardenburg syndrome, and vitiligo.
Another patient, reported by Campbell et al. [3], may be an example of
this disorder. This six-year-old white male, born of normal parents, had congenitally white hair and skin, blue eyes, and bilateral nerve deafness. At the
age of two, hyperpigmented macules appeared all over his body and a large
dark macule appeared on the sacrum. Nystagmus, photophobia, dystopia canthorum, and enlargement of the nasal root were not observed. However, because
of the negative family history, and because histologic examination of the depigmented skin was not performed, this child cannot be said definitely to have
the Ziprkowski-Margolis syndrome.
Histologically, in Ziprkowski-Margolis syndrome melanocytes are present
in the hypochromic skin; further electron microscopic studies are required to
characterize the subcellular abnormalities. Ziprkowski-Margolis syndrome appears to be a distinct entity. The mode of inheritance, the clinical and histologic
picture, and the course differ from all other depigmentary syndromes associated
with congenital deafness. It has been suggested to arise from an abnormality
of the neural crest.
REFERENCES
1. Ziprkowski L et al: Partial albinism and deaf-mutism due to a recessive sex-linked gene. Arch
Dermatol 86:530-539, 1962
TUBEROUS SCLEROSIS
... if infants have the typical white macules at birth, it is probable that tuberous
sclerosis is present [1].
nasolabial fold of a black girl with tuberous sclerosis. In the same year, Critchley
and Earl [13] observed a case of segmental hypopigmentation and two cases of
"patches of abnormal whiteness," that were the same size and shape as cafeau-lait spots. Another of their patients had, on the lateral half of one eyebrow,
a localized patch of canities. Hopwood [14], in 1937, observed innumerable
small white macules or "pale" freckles, mostly from 1 to 3 mm in size, scattered
over the skin of patients with tuberous sclerosis. In 1938, Jones and Prior [15]
reported three cases of tuberous sclerosis in one family; all had macules of
leukoderma on unexposed areas of skin. Later, in 1941, Butterworth and Wilson
[16] also noted hypopigmented macules in those with tuberous sclerosis. In
1947, Combe et al. [17] reported "vitiligo patches" all over the body of a 30month-old girl with tuberous sclerosis but called it "nevus anemicus." Debre
et al. [18], in 1952, reported three cases of tuberous sclerosis with depigmented
patches. Goodgred [19], discussing two patients presented by Friedman [20] in
1948, suggested depigmentation to be part of the disease. Chao [21], in 1959,
stated that while these areas of depigmentation were more common than cafeau-Iait spots, they were not diagnostic for tuberous sclerosis and called them
vitiligo. In 1962, Nickel and Reed [22] found leukoderma or poliosis in 40 of
375
GENETIC AND
CONGENITAL
DISORDERS
376
CHAPTER 1
377
GENETIC AND
CONGENITAL
DISORDERS
POLYGONAL
---'>-III""-of--i HYPOPtGMENTED
MACULES
IUCUlES
HYPOPIGIIENTATION
IN OERIIATOIIAL
DlSTRIBUTlON
great majority of patients have one to 20 macules, with 50% having fewer than
five and 50% having six or more macules (Fig. 136). Lesions may be lanceovate, "thumbprint," confetti, or segmental. Of the 18 patients with tuberous
sclerosis examined by Hurwitz and Braverman [33], 10 had hypomelanotic
macules. Of these lesions only 18% were lance-ovate; the white macules were
usually oval, round, or polygonal, the latter being the most common (Fig. 137).
The most characteristic but not the most frequent configuration of hypopigmented macules of tuberous sclerosis is the lance-ovate or mountain ash-leaf
spot described by Fitzpatrick et al. [1] (Figs. 138, 139). In five of 64 patients,
Soter et al. [37] noted a dermatomal distribution of depigmented macules (Fig.
140); this pattern was also observed by Critchley and Earl [13] and Zeremba
[32]. A confetti pattern has also been observed in three of the 18 patients
reported by Hurwitz and Braverman [33], and in two of the 64 patients of Soter
et al. [37] (Figs. 141, 142).
378
10
CHAPTER 1
"'
'E
.S!
a..
(;j
'0
CD
::I
r-- .
"
n-t.
f--
"
t--
r2
H }11
I I I ,{
11
10 12 13 14 15 16 17 18 19 20 22 27 106
FIGURE 136. Number of hypo pigmented macules per patient in each of 52 patients.
FIGURE 137. Several types of hypomelanotic lesions in a single patient (segmental, lance-ovate,
and small thumbprint macules). Same patient as in Figure 140.
GENETIC AND
CONGENITAL
DISORDERS
Number
1 to 100
Distribution Frequency
Trunk
Posterior trunk
(including buttocks)
Anterior trunk
Lower extremities
Upper extremities
Head and neck
56.3%
35.7%
20.6%
32.5%
6.4%
4.8%
Shape
Common
Polygonal
Lance-ovate (ash leaf)
Rare
Dermatomal
Confetti
Size
Polygonal
Ash-leaf (long axis)
Confetti
o
379
0.5-2.0 cm
3.0-4.0 cm (range 1.0-12.0 cm)
Hundreds of 0.1-0.3 cm macules
FIGURE 138. Lance-ovate macules (double arrow); thumbprint macules (single arrow).
380
CHAPTER 1
FIGURE 139. The Eastern mountain ash leaf. Each leaflet is the shape of lance-ovate macules of
tuberous sclerosis.
FIGURE 140.
381
GENETIC AN[
CONGENITAl
DISORDER~
FIGURE 141. Confetti-like hypomelanosis on the legs in mother and son with tuberous sclerosis.
(From: Adams RD, Reed WB: Neurocutaneous disorders, in Dermatology in General Medicine.
Edited by TB Fitzpatrick et al. New York, McGraw-Hill, 1971, p 1391. Copyright, 1971, McGraw-Hill Book Company. Used with permission.)
382
CHAPTER 1
Hypopigmented macules usually are found on the trunk, particularly posteriorly, but may be present on any cutaneous surface except the hands, feet,
and genitalia [37] (Fig. 143). Hypopigmented macules may involve, in descending order of frequency, the lower extremities, the upper extremities, and the
head and neck [37]. On the lower extremities, hypopigmented macules are
more common above rather than below the knees and occur with equal frequency on the flexor and extensor surfaces.
The long axis of the lance-ovate (ash-leaf) macules is predominantly in the
cephalocaudal direction on the extremities and in the transverse direction on
the trunk [37] (Fig. 144).
Hurwitz and Braverman [33] found the length of the hypopigmented lesions
to be from 4 mm to 7 cm, with the average length from 1 to 3 cm (Fig. 145).
The size of the polygonal lesions ranges from 0.5 to 2.0 cm, and the lance-ovate
(ash-leaf) lesions from 1.0 to 12 cm (usually 3 to 4 cm) in length [37].
'*
'I'..-'.
:~
.'
.::.' ;:"../
."
.. .::
t (
..'....... . ...
"..
~:.
/"'
~,
""
o.
383
GENETIC AND
CONGENITAL
DISORDERS
FIGURE 145.
384
CHAPTER 1
These macules are a dull white (hypo melanotic) , not the "pure white"
(amelanotic) of vitiligo. Since the lesions are not pure white, on casual examination of fair skin they may be inapparent. Wood's light examination reveals
only partial depigmentation.
The margins of the lesions are usually smooth but may be irregular [33].
The relative size and the number of the white macules does not change
with age and spontaneous disappearance does not occur. Bundey and Evans
[9] suggested that hypomelanotic macules occur most frequently in patients
under 10 years of age. They found hypomelanotic macules to be present in
82% of patients under 10, and 37% of patients over 10 years of age. However,
Hurwitz and Braverman [33] found, with Wood's light examination, that hypomelanotic macules were present in 89% of patients under 10 and in 71% of
patients over 10 years of age. The series of Bundey and Evans [9] and Soter et
al. [37] confirm that hypomelanotic macules persist unchanged through life.
There is no support for the hypothesis of Wilson [39] that with advancing
age hypomelanotic macules of tuberous sclerosis become cafe-au-Iait spots. The
striking differences between the melanosomes of the hypomelanotic macules
of tuberous sclerosis [30] and the giant granules in cafe-au-Iait spots of neu-
FIGURE 146. Hypomelanosis of hair (poliosis) in a patient with tuberous sclerosis. (From: Jimbow
K et al: Congenital circumscribed hypomelanosis: a characterization based on electron microscopic
study of tuberous sclerosis, nevus depigmentosus and piebaldism. J Invest Dermatol 64:50-62,
1975. Copyright, 1975, The Williams & Wilkins Co. Used with permission.)
385
GENETIC AND
CONGENITAL
DISORDERS
386
CHAPTER 1
Iris pigmentation is usually normal although one patient with a depigmented iris sector has been described [45].Fundal white macules like the ashleaf spots have been described [45a].
Skin
Melanocytes
Number
Dopa reaction
Dendrites
Normal
Normal or decreased
Poorly developed
Normal
Normal or decreased
Poorly developed
Melanosomes
Size
Shape
Inner structure
Melanization
Number in melanocytes
Secretion
Number in keratinocytes
Decreased
Normal (ellipsoidal)
Normal (lamellae)
Decreased markedly
Decreased
Normal
Decreased
Decreased
Normal
Normal
Decreased markedly
Decreased
Normal
Decreased
Normal in Caucasoids;
abnormal in
Negroids (Le., in
aggregates)
Normal
Normal
Keratinocytes
Distribution pattern of melanosomes
Degradation of melanosomes
Q
Source: Jimbow K et al: Congenital circumscribed hypomelanosis: a characterization based on electron microscopic study of tuberous sclerosis, nevus depigmentosus, and piebaldism. J Invest Dermatol 64:50-62, 1975.
Copyright, 1975, The Williams & Wilkins Company. Used with permission.
387
GENETIC AND
CONGENITAL
DISORDERS
FIGURE 148. Hypomelanotic skin and normal control skin ina Caucasoid with tuberous sclerosis.
a: Normal unexposed back skin. The melanocyte (MC) contains melanizing melanosomes (arrows)
and a large perikaryon. The keratinocyte (KG) surrounding this melanocyte contains a large number
of melanosome aggregates (x 3900). b: Melanocyte containing many melanosomes (arrows) in
various stages of melanization (x 12,000). c: Hypomelanotic skin in tuberous sclerosis. Note the
reduction in the number of melanosomes in the melanocyte (MC). All the recognizable melanized
melanosomes are in the keratinocytes (KC). The number of these melanosomes is apparently decreased. The perikaryon of the melanocyte also is smaller (x 4000). d: All the melanosomes
(arrows) in the melanocytes are in unmelanized stages and appear to be smHller (x 12,000). (From:
Jimbow K et al: Congenital circumscribed hypomelanosis: a characterization based on electron
microscopic study of tuberous sclerosis, nevus depigmentosus and piebaldism. J Invest Dermatol
64:50-62, 1975. Copyright, 1975, The Williams & Wilkins Co. Used with permission.)
388
CHAPTER 1
FIGURE 149. Hypomelanotic skin and normal control skin in a Negroid with tuberous sclerosis.
a: Normal control skin. The keratinocyte (KC) contains a large number of melanosomes. The
melanocyte (MC) contains many melanized melanosomes. (x 4,400). b: A high-power view of the
melanosomes in the keratinocytes of the normal control skin. Note the single distribution of the
melanosomes. (x 8,000). c: Hypomelanotic skin. Note the reduction in the number of melanosomes
in the melanocyte (MC) and keratinocytes (KC). Compared with the normal skin, the skin has fewer
and less melanized melanosomes in the melanocytes. (x 4,100). d: A high-power view of the
melanosomes in the keratinocytes of the hypomelanotic skin. Note that all the melanosomes form
a complex. (x 7,000). (From: Jimbow K et al: Congenital circumscribed hypomelanosis: a characterization based on electron microscopic study of tuberous sclerosis, nevus depigmentosus and
piebaldism. J Invest Dermato! 64:50-62, 1975. Copyright, 1975, The Williams & Wilkins Co. Used
with permission.)
HYPOPIGMENTED
HAIR
NORMAl HAIR
. 21'.
SIZE
309..,.
..
~52!>-i
P(o.0005
DIS1RIBUTlDN
IN
KERATINOCYTE
FIGURE 150. Compared to normal skin, melanosomes are decreased in size in hypopigmented
hair and skin in tuberous sclerosis. (Courtesy of K. Jimbow and T. B. Fitzpatrick.)
389
GENETIC AND
CONGENITAL
DISORDERS
390
CHAPTER 1
Shagreen patches are found in 21% [5], 47% [32], 48% [33], and 83% [8]
of patients with tuberous sclerosis; they are present as white collagenous plaques
1 to 20 mm in size and are usually located on the lower back and less often
on the scapular region or extremities (Fig. 152). The spectrum of appearance
of the lesions ranges from white "pigskin" or "gooseflesh" with horizontal
wrinkling to flesh-colored or violaceous cauliflower-like lesions which may be
discrete or coalescent. Time of onset corresponds to that of adenoma sebaceum.
Periungual and subungual fibromas that emerge from the nail bed groove
and lie on the nail plate have been reported in 17% [5], 30% [33], and 39% [8].
They are more frequent in females than males, occur after puberty, and are
found on toes more than fingers. Nail plate grooving may result. These fibromas
may be associated with renal hamartomas.
Intraoral fibromas occur in 9% [33] to 55% [32]; they usually are located
between the upper front incisors or between the incisors and bicuspids, but
rarely also on buccal mucosa, hard palate, and tongue. Subcutaneous fibromas
occur in 10% [5] to 16% [8], and scalp tumors in 5%. Fibromas are usually first
seen at puberty.
A few other abnormalities have been mentioned. Diffuse bronzing has been
described [13]. Cafe-au-Iait macules are reported in 7% [5], 15% [32], 26% [33],
and 27% [8] (Fig. 153). Cervical skin polyps or acrochordons are reported in
39% [8].
Systemic Manifestations
Neurologic abnormalities are the most important serious manifestations of
tuberous sclerosis. These include seizures, mental retardation, and, perhaps
more commonly than once suspected, tumors.
Convulsions occur in up to 93% [5,33a] of patients with tuberous sclerosis;
these may be infantile spasms, petit mal, or grand mal seizures and usually
begin before age five. Lagos and Gomez [5] noted the seizures to be present an
average of five years before the diagnosis of tuberous sclerosis was established.
Mental retardation is reported in 61% [8],62% [5], and 75% [33a]. Lagos
and Gomez found all patients with retardation to have seizures, whereas 69%
of those with normal mentality had convulsions. The former seemed to develop
convulsions earlier in life than those with normal mentality. Ventricular dilatation on CT scanning tends to suggest mental retardation [33a] although the
degree of retardation does not necessarily correlate with ventricle size.
391
GENETIC AND
CONGENITAL
DISORDERS
392
CHAPTER 1
TABLE 94.
Sex
History
Prevalence
Number
Size
Distribution
Shape
Color
Wood's light
Margin
Spontaneous repigmentation
Hair involvement
Diagnostic value
Associated dermatologic abnormalities
Associated systemic abnormalities
F:M = 1
Present at birth
Number and size unchanged with age
50% to 98% of cases of tuberous
sclerosis
1 to 100 (circumscribed)
Average, 10
0.1 to 12 em
Usually 3.0 to 4.0 em
Trunk and upper and lower
extremities
Face and neck
Lance-ovate (ash leaf-like)
"Thumbprint"
Polygonal
Rarely dermatomal or confetti
Dull white
Partial decrease of pigment
Smooth or irregular
Moderately sharp
No
May occur (eyelashes, eyebrows, scalp)
Yes (earliest sign)
Frequent (adenoma sebaceum,
shagreen patches, and periungual
fibromas are most common)
Frequent (mental retardation and
seizures are most common)
393
GENETIC AND
CONGENITAL
DISORDERS
394
CHAPTER 1
b
FIGURE 154. a: Hypopigmented macules in an infant with tuberous sclerosis examined with
room lighting. b: Examination of the same patient with Wood's lamp reveals many hypopigmented
macules not previously noted.
395
GENETIC AND
CONGENITAL
DISORDERS
396
CHAPTER 1
REFERENCES
1. Fitzpatrick TB et al: White leaf-shaped macules. Earliest visible sign of tuberous sclerosis.
21. Chao DH-C: Congenital neurocutaneous syndromes in childhood, II: Tuberous sclerosis. J
Pediatr 55:447-459, 1959
22. Nickel WR, Reed WB: Tuberous sclerosis, special reference to the microscopic alterations in
the cutaneous hamartomas. Arch Dermatol 85:209-226, 1962
23. Becker SW Jr: Personal communication to WR Nickel and WB Reed. Arch Dermato185:209-226,
1962
24. Gold AG, Freeman JM: Depigmented nevi: the earliest sign of tuberous sclerosis. Pediatrics
35:1003-1005, 1965
25. Crichton JU: Infantile spasms and skin anomalies. Dev Med Child Neurol 8:273-278, 1966
26. Aicardi J et al: Sclerose tubereuse de Bourneville et spasmes en flexion du nourrisson. Sem
Hop Paris 42:770-777,1966
27. Harris R, Moynahan EJ: Tuberous sclerosis with vitiligo. Br J Dermatol 78:419-420, 1966
28. Moynahan EJ: Personal communication. Quoted by Fitzpatrick TB et al: White leaf-shaped
macules. Earliest visible sign of tuberous sclerosis. Arch Dermatol 98:1-6, 1968
29. Tilgen W: Zur Ultrastruktur der sogenannten White leaf-shaped macules bei der tuberosen
Hirnsklerose Bourneville-Pringle. Arch Dermatol Forsch 248:13-27, 1973
30. Jimbow K et al: Congenital circumscribed hypomelanosis: a characterization based on electron
microscopic study of tuberous sclerosis, nevus depigmentosus and piebaldism. J Invest Dermatol 64:50-62, 1975
31. Roth JC, Epstein CJ: Infantile spasms and hypopigmented macules. Early manifestation of
tuberous sclerosis. Arch Neurol 20:547-567, 1971
32. Zaremba J: Tuberous sclerosis: a clinical and genetical investigation. JMent Defic Res 12:63-80,
1968
33. Hurwitz S, Braverman 1M: White spots in tuberous sclerosis. J Pediatr 77:587-594, 1970
33a. Maki Y et al: Computed tomography in tuberous sclerosis-with special reference to relation
between clinical manifestations and CT findings. Brain Dev 1:38-48, 1979
34. Debard A et al: Sclerose tubereuse de Bourneville chez l'enfant. Sem Hop Paris 55:1065-1072,
1979
35. Fois A et al: Early signs of tuberous sclerosis in infancy and childhood. Helv Paediatr Acta
28:313-321, 1973
36. Mattyus A et al: Tuberous sclerosis-early diagnosis and its significance in juvenile epilepsy.
Psychiatr Neurol Med Psychol (Leipz) 29:77-86, 1977
37. Soter NA et al: Hypomelanotic macules in tuberous sclerosis. A study of 65 patients. (In
preparation)
38. McWilliam RC, Stephenson JB: Depigmented hair. The earliest sign of tuberous sclerosis. Arch
Dis Child 53:961-963, 1978
39. Wilson J: Quoted in Bundey S, Evans K: Tuberous sclerosis: a genetic study. JNeurol Neurosurg
Psychiatry 32:591-603, 1969
40. Benedict PH et al: Melanotic macules in Albright's syndrome and in neurofibromatosis. JAMA
205:618-626, 1968
41. Jimbow K et al: Ultrastructure of giant pigment granules (macromelanosomes) in the cutaneous
pigmented macules of neurofibromatosis. J Invest Dermatol 61:300-309, 1973
42. Konrad K et al: The giant melanosome: a model of deranged melanosome-morphogenesis. J
Ultrastruct Res 48:102-123, 1974
43. Takahashi M: Studies on cafe-au-Iait spots in neurofibromatosis and pigmented macules of
nevus spilus. Tohoku J Exp Med 118:255-273, 1976
44. Sareen CK et al: Tuberous sclerosis. Clinical, endocrine and metabolic studies. Am J Dis Child
923:34-39, 1972
45. Kranias G, Romano PE: Depigmented iris sector in tuberous sclerosis. Am J Ophthalmol
83:758-759, 1977
45a. Awan KJ: Leaf-shaped lesions of ocular fundus and white eyelashes in tuberous sclerosis.
South Med J 75:227-228, 1982
46. Degas R et al: Epiloia deceIe par l'existence de taches achramiques. Bull Soc Fr Dermatol
Syphiligr 78:651-652, 1971
46a. Ruiter DJ et al: Hypomelanotic macules in tuberous sclerosis. An ultrastuctural and enzyme
histochemical study. Arch Dermatol Res 271:171-182, 1981
47. Zolli C et al: Unusual eyelid involvement in tuberous sclerosis. JPediatr OphthalmolI3:56-58,
1976
397
GENETIC AND
CONGENITAL
DISORDERS
398
CHAPTER 1
48. Bundey S et al: Tuberous sclerosis without adenoma sebaceum. J Ment Defic Res 14:243-249,
1970
49. Hall GS: The ocular manifestations of tuberous sclerosis. Q J Med 15:209-220, 1946
50. Alema G, Pansini A: Quoted by Randazzo SD: La Malattia di Bourneville-Pringle. Barcelona,
Ed Tipografica dell-Universita di Cantania, 1958
50a. Konishi Y et al: Tuberous sclerosis: early neurologic manifestations and CT features in 18
patients. Brain Dev 1:31-37, 1979
51. Mosher DB et al: Abnormalities of pigmentation, in Dermatology in General Medicine, 2nd
ed. Edited by TB Fitzpatrick et al. New York, McGraw-Hill, 1979, p 595
52. Adams RD: Neurocutaneous diseases, in Dermatology in General Medicine, 2nd ed. Edited by
TB Fitzpatrick et al. New York, McGraw-Hill, 1979, p 1214
53. Marden PM et al: Congenital anomalies in the newborn infant including minor variations. A
study of 4412 babies by surface examination for anomalies and buccal smear for sex chromatin.
J Pediatr 64:357-371, 1964
54. Debard A, Richardet JM: Signification des taches achromiques chez Ie nourrisson (letter). Nouv
Presse Med 4:2404, 1975
55. Bundey S: The significance of a white macule on the skin of child. Dev Med Child Neurol
12:805-806, 1970
56. Maleville J et al: Taches achromiques: signe precoce et frequent de la sclerose tubereuse de
Bourneville: donnes anatomo cliniques. Bull Soc Fr Dermatol Syphiligr 76:455-458, 1969
57. Burkhart CG, El-Shaar A: Computerized axial tomography in the early diagnosis of tuberous
sclerosis. Am Acad Dermatol 4:59-63, 1981
NEVUS DEPIGMENTOSUS
Nevus depigmentosus is an uncommon, congenital, stable, localized leukoderma. The first case of nevus depigmentosus was reported by Lesser in 1884
[1] in the Handbuch der Hautkrankheiten. Gebert [2] presented a case to the
Berlin Dermatology Society in 1889. Sporadic cases have been since reported
(Table 95).
Clinical Features
Nevus depigmentosus is probably not so uncommon as has been suggested
by the paucity of cases reported in the literature. Because case reports are rare,
true male-female incidence is difficult to establish, but males and females
appear equally affected. No familial cases have been reported. All races are
affected [22,23]. Nevus depigmentosus is present at birth, but may sometimes
be discovered within the first few weeks or, particularly in fair-skinned individuals, a few months later. Cases of late onset seem doubtful and probably,
in fact, represent segmental vitiligo [24-26]. In one such case reported as nevus
depigmentosus, the lesion was first apparent at the age of two; the father and
maternal grandfather were said to have vitiligo [24].
F
M
M
F
M
M
M
M
F
F
Left face
Eight cases, details not given
Right thorax
Left back/abdomen/thigh
Left neck/arm/chest
399
GENETIC AND
CONGENITAL
DISORDERS
400
CHAPTER 1
ISOLATED PATTERN
DERMATOMAL PATTERN
WHORLED PATTERN OF
OF HYPOMELANOSIS
HYPOPIGMENTATION
OF HYPOPIGMENTATION
401
GENETIC AND
CONGENITAL
DISORDERS
402
CHAPTER 1
403
GENETIC AND
CONGENITAL
DISORDERS
404
CHAPTER 1
FIGURE 160. a-c: Nevus depigmentosus. Whorls of hypomelanosis. (From: Jimbow K et al: Congenital circumscribed hypomelanosis: a characterization based on electron microscope study of
tuberous sclerosis. nevus depigmentosus and piebaldism. J Invest Dermotol 64:50-62. 1975. Copyright. 1975. The Williams & Wilkins Co. Used with permission.)
405
GENETIC AND
CONGENITAL
DISORDERS
406
CHAPTER 1
FIGURE 161. a: Segmental hypomelanosis from right T 10 to L2 Abrupt transition zone at midline
is apparent. b: Bilateral nasofrontal mucoceles, fully inflated by blowing the nose. (From: Tay CH:
Porencephaly, nasofrontal mucocoeles, hypertelorism and segmental vitiligo. Report of a new
neurocutaneous disorder. Singapore Med J 11:253-257, 1970. Copyright, 1970, Andre Publications.
Used with permission.)
407
c&-..
of melanosomes
in kerat.nocytes
Melanocytes
Number
Dopa reaction
Dendrites
Normal or decreased
Normal or decreased
Poorly developed and stubby
Melanosomes in melanocytes
Number
Size
Shape
Structure
Melanization
Secretion
Normal or decreased
Normal
Normal
Normal
Normal or decreased
Abnormal (autophagosomes)
Melanosomes in keratinocytes
Number
Distribution
Degradation
Decreased
Normal
Normal
From: Jimbow K et al: Congenital circumscribed hypomelanosis: a characterization based on electron microscopic study of tuberous sclerosis. nevus
depigmentosus. and piebaldism. J Invest Dermalol 64:50-62. 1975. Copyright. 1975. The Williams & Wilkins Company. Used with permission.
GENETIC AND
CONGENITAL
DISORDERS
408
CHAPTER 1
Pathogenesis
Since nevus depigmentosus is congenital, nonfamilial, and unilaterally
localized, it seems likely that it represents an embryonic developmental defect [11].
Differential Diagnosis
Nevus depigmentosus may be distinguished from localized or segmental
vitiligo, usually by history of stability from birth and by presence of melanocytes
on histologic sections. Patients with tuberous sclerosis will most often have
thumbprint or lance-ovate macules and will develop other cutaneous findings
and neurologic features not seen with nevus depigmentosus. Nevus anemicus
should be included in the differential diagnosis. Wood's light examination
accentuates nevus depigmentosus, whereas nevus anemicus disappears. Nevus
anemicus blanches with dioscopy, but nevus depigmentosus does not. Melanocytes are normal in nevus anemicus .
..
FIGURE 163. Various features of the melanocyte in patients with nevus depigmentosus. a: Hypomelanotic skin from a Caucasoid. At least nine melanosomes are recognizable in the large
aggregate (two arrows) of melanosomes. There is another vacuole (one arrow) aggregated with some
membranous organelles in the cytoplasm of the melanocyte (x 22,000). b: Hypomelanotic skin
of a Negroid. The melanocyte contains a well-developed Golgi apparatus (GA) and melanosomes
in various developmental stages. This melanocyte also contains two vacuole-like structures (VS)
aggregated with some electron-dense materials. There is no change in the size of the melanosomes.
The melanosomes (arrows) in the keratinocytes are present as a single unit (x 19,000). c: Hypomelanotic skin of a Caucasoid. There is a huge aggregate of melanosomes (MA) within the
cytoplasm of the melanocyte (x 48,000). d: Hypomelanotic skin of a Caucasoid. There is a vacuolelike structure aggregated with the melanosomes and myelin granules (arrows) in the melanocyte.
MS = melanosomes in melanizing stage (x 47,500). (From: Jimbow K et al: Congenital circumscribed hypomelanosis: a characterization based on electron microscope study of tuberous sclerosis,
nevus depigmentosus and piebaldism. J Invest Dermatol 64:50-62, 1975. Copyright, 1975, The
Williams & Wilkins Co. Used with permission.)
409
GENETIC AND
CONGENITAL
DISORDERS
410
CHAPTER 1
Age of onset
Sex prevalence
Color
Shape
Border
Distribution
Course
Local symptomatology
Associated systemic findings
Birth
Unknown: both males and females reported
White
Three patterns
Isolated circular or rectangular area of
hypomelanosis
Dermatomal pattern
Whorled pattern
Regular or occasionally serrated
Lower abdomen, trunk, proximal part of
extremities; less commonly the face and
neck
Stable
None
Usually none
Since the same whorled pattern of hypopigmented macules may be observed in both nevus depigmentosus and incontinentia pigmenti achromians,
some investigators have considered these to be the same entity. However, the
autosomal dominant pattern of inheritance of incontinentia pigmenti achromians, the clinical progression over time, and the association with neuroectodermal defects differentiate incontinentia pigmenti achromians from nevus
depigmentosus.
Treatment
Nevus depigmentosus is of cosmetic importance only; rare attempts at
repigmentation are reported. Psoralens plus ultraviolet radiation failed to repigment nevus depigmentosus in one unusual case that had undergone some
spontaneous repigmentation [29; M. A. Pathak, personal communication, 1976].
REFERENCES
1. Lesser E: In von Ziemssen H: Handbuch der Hautkrankheiten, Bd 2. Leipzig, Vogel, 1884, p
183
2. Gebert E: Krankenvorstellung Berliner dermatologischen Gesellschaft, March 7, 1899. Dermatol
Z 6:367-368, 1899
3. Hutchinson
1895
4. Harmon BN: Case quoted by Pearson K et al: A Monograph on Albinism in Man: Drapers'
Company Research Memoirs, Biometric Series VI, VIII, IX. Department of Applied Mathematics, University College, University of London. London, Dulau, 1911-1913
5. Smith G: Case quoted by Pearson K et al: A Monograph on Albinism in Man: Drapers' Company
Research Memoirs, Biometric Series VI, VIII, IX. Department of Applied Mathematics, University College, University of London. London, Dulau, 1911-1913
6. Romagna-Manoia A: Un caso di albinismo parziale. Atti Soc Rom Antrop 15:387-391, 1910
7. Remenowsky F: Case presented to the Wien dermatologische Gesellschaft, February 28, 1924.
Zbl Haut Geschlkr 12:240, 1924
8. Schulmann E, Gallerand L: Un cas de naevus achromique II disposition metamerique. Bull
Soc Fr Dermatol Syphiligr 37:1304-1306, 1930
9. Gareiso A, Alvarez G: Nevus acromino unilateral en bandas en un oligofrenco. Rev Asoc Med
Argent 52:158-160, 1938
10. Bessone L: Nevo acromico lineare. G Ital Dermatol 82:118-131, 1941
11. Coupe RL: Unilateral systematized achromic naevus. Dermatologica 134:19-35, 1967
12. Siemens HW: Zur Kenntnis des systematisierten Naevus pigmentosus mit Bemerkungen uber
die formale Genese der Naevi. Dermatol Z 42:65-75, 1925
13. Pinetti P: Albinismo parziale e disposizione metamerica unilaterale (nevo acromico). G Ital
Dermatol 78:1143-1154, 1937
14. Blaschko A: Die Nervenverteilung in der Haut, in ihrer Beziehung zu den Erkrankungen der
Haut (Paper presented to the Deutsche dermatologische Gesellschaft, May 28-30,1901). Quoted
by Coupe RL: Unilateral systematized achromic nevus. Dermatologica 134:19-35, 1967
15. Jadassohn J: Case presented to Med-Pharm Bezirksver, July 21, 1910. Quoted by Coupe RL:
Unilateral systematized achromic nevus. Dermatologica 134:19-35, 1967
16. Kuhlmann et al: Case presented to the Strassburgen dermatologischen Gesellschaft June 19,
1913. Arch Dermatol Syphilol (Berlin) 117:889, 1913
17. Meirowsky E: Uber die Entstellung der sogenannten kongenitalen Missbildungen der Haut.
Arch Dermatol Syphilol (Berlin) 127:1-192, 1919
18. Meirowsky E, Leven L: Tierzeichnung, Menschenscheckung und Systematisation der MuttermaIer. Ein Beitrag zur vergleichenden Morphologie der Haut. Arch Dermatol Syphilol (Berlin)
134:1-79, 1921
19. Gougerot H: Illustration in Darier Jet al (eds): Nouvelle Pratique Dermatologique, Paris, Masson
6:454,1936
20. Sugarman GI, Reed WB: Two unusual neurocutaneous disorders with facial cutaneous signs.
Arch Neurol 21:242-247, 1969
21. Jimbow K et al: Congenital circumscribed hypomelanosis: a characterization based on electron
microscopic study of tuberous sclerosis, nevus depigmentosus, and piebaldism. J Invest Dermatol 64:50-62, 1975
22. Berg M, Tarnowski W: Nevus depigmentosus. Arch Dermatoll09:920, 1974
23. Takaiwa T, Mishima Y: Quantitation of epidermal dendritic cells by electron microscopy:
nevus depigmentosus. Jpn J Clin Elect Microsc 3:651-652, 1970
24. Caro-Paton T: Vitiligo unilateral sistomatizado 0 nevus acromico. Actas Dermosifiliogr41:717-723,
1950
25. Leri A, Lamy L: Vitiligo zoniforme du flane droit, sclerodermie en bande avec atrophie en
masse du membre inferieur gauche. Bull Soc Fr Dermatol Syphiligr 30:127-130, 1923
26. Scholz JR, Williamson C: Vitiligo in (apparent) dermatomal distribution. Arch Dermatol
64:366-369, 1951
27. Tay CH: Porencephaly, nasofrontal mucocoeles, hypertelorism and segmental vitiligo. Report
of a new neurocutaneous disorder. Singapore Med J 11:253-257,1970
28. Mishima Y: Congenital and non-congenital depigmentation, in Modern Problems in Paediatrics, vol 20, Pediatric Dermatology: Internal and External. Edited by R Ruiz-Maldonado.
Karger, Basel, 1978, pp 18-37
29. Hewitt J et al: Naevus hypochromique unilateral en jet d'eau; repigmentation instable par Ie
soleil et les rayons UV. Bull Soc Fr Dermatol Syphiligr 5:521-522, 1955
A Japanese woman with bizarre, bilateral, and irregularly shaped depigmented patches on the trunk and extremities was reported in 1952 by Minor
411
GENETIC AND
CONGENITAL
DISORDERS
412
CHAPTER 1
Clinical Findings
Race
The first six cases reported were Japanese; incontinentia pigmenti achromians occurs in all races, however.
Sex
In the analysis of the first 17 reported patients, Jelinek et al. [1] found a
female to male ratio of four to one. If the 46 patients mentioned in the literature
through 1979 are included, the ratio appears to be over two to one.
Age on Onset
Although among the reported cases the patients when first seen ranged
from two months to 23 years of age, onset is usually at birth or early childhood.
Among 40 of the 46 reported cases, the depigmented macules were first noted
at birth (26 cases), during infancy (eight cases), or in childhood (six cases). The
oldest reported age of onset is 12 [3].
Familial History
Two European families with incontinentia pigmenti achromians have been
reported; in one there were four affected females and in the other, a black infant
girl, her two brothers, her father's aunt, and her paternal uncle were affected.
The paternal great aunt of the patient reported by Jelinek et al. is thought to
have had incontinentia pigmenti achromians.
The father-to-son transmission reported by Rubin [4] excludes X-linked
inheritance; an autosomal dominant pattern seems more likely (Fig. 164). Consanguinity has been reported [5].
Hellgren [6] described a patient with incontinentia pigmenti achromians
whose mother, sister, and brother had brown hyperpigmented macules on the
left halves of their bodies.
Another family report is less straightforward. Pifiol-Aguade et al. [7] reported incontinentia pigmenti in the daughter of a woman with inc 0 ntinenti a
pigmenti achromians; this was characterized by a congenital amelanotic zosteriform macule on the left leg and no other abnormalities apart from a bullous
reaction to heat. Jelinek et al. [1] point out that this description is insufficient
for a diagnosis of incontinentia pigmenti achromians. Furthermore, the eldest
413
GENETIC AND
CONGENITAL
DISORDERS
II
III
2
Uninvolved male
II
o
e
Uninvolved female
Propositus
FIGURE 164. Pedigree of a family with incontinentia pigmenti achromians. (From: Rubin MB:
Incontinentia pigmenti achromians. multiple cases within a family. Arch Dermatol105:624....a25.
1972. Copyright. 1972. American Medical Association. Used with permission.)
daughter is said to have had erythematous and bullous lesions that became
verrucous and later became depigmented. This description is less characteristic
of incontinentia pigmenti achromians than of incontinentia pigmenti, which
can show late-onset depigmentation. The diagnosis of incontinentia pigmenti
in this family is strengthened by the fact that another daughter had typical
clinical incontinentia pigmenti and that the mother had one spontaneous abortion of a male fetus. This family probably should not be included in a review
of incontinentia pigmenti achromians.
Clinical Description
Incontinentia pigmenti achromians appears as a negative image of the
hyperpigmented swirls of incontinentia pigmenti. The hypopigmented macules
are randomly distributed and have a bizarre, whorled, or streaked "marble cake"
configuration (Fig. 165). They do not correspond to any particular dermatome
or peripheral nerve distribution. In most instances the lesions are bilaterally
distributed but an asymmetrical pattern and two unilaterally distributed cases
have been reported [3,8]. Rubin [4] noted that the depigmented lesions on the
trunk generally assumed a parallel pattern, did not cross the inidline, and
tended to follow the long axes of the extremities. Their distribution on the back
resembled an inverted Christmas tree.
Any part of the body including the face may be involved. Among 27 patients, the following areas of involvement, in order of decreasing frequency,
were noted: trunk (20 patients), extremities (15 patients), face (3 patients),
shoulders (1 patient), and hip (1 patient). Involvement of the scalp, palms,
soles, and mucous membranes has not been reported.
414
CHAPTER 1
415
GENETIC AND
CONGENITAL
DISORDERS
The lesions are, in most instances, present at birth, but may appear after
birth, during infancy, and rarely during childhood. In many instances the depigmentation appears to be progressive [1,2,4,8-14]. However, in several cases
the hypopigmentation tended to revert to normal before or after one year of
age. In three cases described by Grosshans et al. [10], the maximal contrast
between involved and normal skin was observed at three years of age. In the
four-and-one-half-year-old girl described by Grosshans et al. [10], the depigmentation had already begun to fade. Afaint irregular hypopigmentation was
also observed in her affected mother.
416
CHAPTER 1
The macules are irregular in shape and variable in size. Borders of the
lesions are serrated and blurred or sharply outlined [9] (Fig. 166). Hyperpigmented borders have been reported in one case [10] (Fig. 167).
The lesions have normal sensation (touch, temperature, pin-prick) [9] and,
in contrast to nevus anemicus, vigorous stroking does not produce any cutaneous changes [4,9].
Neither verrucous changes nor inflammation precede the depigmentation.
The daughter of the woman reported by Piftol-Aguade et al. [7] probably had
incontinentia pigmenti and not incontinentia pigmenti achromians. The patient
of Griffiths and Payne [15] showed, at birth, diffuse erythema and, later, verrucous lesions on the axillae and neck, around the mouth, in the groin, popliteal
spaces, and in the natal cleft. This case also seems most likely to represent
incontinentia pigmenti.
FIGURE 166. The hypomelanotic macules contrast dramatically with the normal skin. (Courtesy
of T. Hood and T. B. Fitzpatrick. unpublished data. Used with permission.)
417
GENETIC AND
CONGENITAL
DISORDERS
FIGURE 167. Multiple hypo pigmented areas interspersed with hyperpigmented areas. (From:
Griffiths A, Payne C: Incontinentia pigmenti achromians. Arch Dermatol111:751-752, 1975. Copyright, 1975, American Medical Association. Used with permission.)
418
CHAPTER 1
Laboratory Investigations
No consistent laboratory abnormalities have been documented. Eosinophilia has been reported in two cases [8,12]. Chromosomal analysis and dermatoglyphics are normal. No linkage is found between the disease and the ABO
blood groups or HLA antigens [10].
TABLE 98. Cutaneous Abnormalities Associated with
Incontinentia Pigmenti Achromians
Type of abnormality
Number of patients
Skin ............................................................... 9
Diminution of capillary resistance [2,8,12)
3
Decreased sweating response to pilocarpine [2,11,12)
3
1
Relative hyperhidrosis of hypopigmented area [4)
Verrucous epidermal nevi [1,3)
2
Hyperkeratotic follicular papules running in a linear
1
fashion (flexural aspect of upper and lower
extremities) [1)
Mongoloid spots [16]
1
Facial hemiatrophy [3)
1
Mucous membrane . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .. 2
Thickening of lips [5,7)
2
Hair ............................................................... 5
Diffuse alopecia [11)
Facial hypertrichosis [11)
General hirsutism [14)
Unilateral coarse and curly hair [6)
Traumatic bilateral parietal alopecia [16)
Widow's peak [14)
1
1
1
1
1
1
Teeth .............................................................. 6
Pointed crowns [5,21)
4
Irregularly spaced teeth (17)
1
Hypoplasia of primary incisors, canines [18)
1
Number of patients
419
GENETIC AND
CONGENITAL
DISORDERS
420
CHAPTER 1
Type of abnormality
Miscellaneous. . . . . . . . . . . . . . . .
Unusual facies [14]
Diabetes mellitus [19]
Hypoplasia of the breasts [2,21]
Concave breast [8]
Congenital hydronephrosis [4]
Eosinophilia [8,12]
Dacryostenosis [24]
Number of patients
. . . . . . . . . . . . . . . . . . . . . . .. . .. . .. .
3
. .... . 7 . .
1
2
1
1
2
FIGURE 168. Compared to the control portion of the epidermis there is an almost complete lack
of melanin pigment corresponding to a depigmented streak. There is only a small amount of melanin
in the upper dermis. (From: Grosshans EM et al: Incontinentia pigmenti achromians II. Dermatologica 142:65-78, 1971. Copyright, 1971, S. Karger A.G. Used with permission.)
pigmented areas than in normal skin. Numerous Langerhans cells have been
demonstrated in the epidermis [24].
Although keratinocytes are usually normal, orthokeratotic hyperkeratosis
[10], epidermal atrophy, disorganization of the basal layer with nuclear edema,
and perinuclear vacuolization in keratinocytes have been reported [2,8,10,12].
Grosshans et al. [10] described architectural modifications of the epidermis and
disturbances in keratinization; they observed large clear cells that may represent
either pathologic Langerhans cells or dyskeratotic cells. Some mitotic figures
were present.
Dermis
Pigmentary incontinence is unusual [1,9,10,28] and the number of dermal
melanophages is not increased [6,10]. There are no inflammatory changes [9,28].
Some reports have mentioned the following dermal abnormalities: dermal
edema [12], endothelial swelling with capillary congestion, and slight cicatricial reorganization of the connecting tissue [2]. Grosshans et al. [10] observed
glomerular atrophy of the eccrine sudoral adnexae and dysmorphic changes of
the pilosebaceous apparatus.
Electron Microscopy Findings
Stoebner and Grosshans [30] did extensive ultrastructural studies of the
lesions of incontinentia pigmenti achromians; their findings are summarized
in Table 100. Their studies showed a decreased number, but not total absence,
of melanocytes and a quantitative decrease in melanin production. Stage I
melanosomes were scarce. Mature melanosomes, though small and few, were
normally pigmented and normally distributed among the keratinocytes. Morohashi et al. [22] described melanocyte destruction in the basal and lower
malpighian layers; melanocytes had cytoplasmic vacuolization, melanosome
aggregations, autophagic vacuoles, fatty degeneration, and pyknosis or homogeneous axoplasmic degeneration. Nerve fibers were also found approximating
normal and degenerating melanocytes.
Stoebner and Grosshans [301 also found an apparent increase in the number
of Langerhans cells that appeared to be losing their dendritic processes. Indeterminate cells were also observed. Dyskeratosis was associated with these
quantitative and qualitative modifications of the dendritic cells. In the papillary
dermis, many small nerve fibers were in close contact with keratinocytes. Deeper
in the dermis there was a great number of mast cells containing giant mast cell
granules.
Pathogenesis
Possibly the pigmentary changes are secondary to functional abnormalities
of keratinocytes observed in incontinentia pigmenti achromians. In incontinentia pigmenti achromians, where keratinocyte damage is less evident than
421
GENETIC AND
CONGENITAL
DISORDERS
422
CHAPTER 1
Decreased
Decreased
Decreased
Melanosomes in melanocytes
Number
Size
Shape
Structure
Melanization
Secretion
Decreased
Decreased
Ellipsoid
Transversely striated
Normal
Normal
Melanosomes in keratinocytes
Number
Distribution
Degradation
Decreased
Decreased numbers in complexes
No data
Langerhans cells
Indeterminate cells
Other changes
Increased number
Present (quantitative data)
Dyskeratosis
Mastocytosis
Pilosebaceous apparatus abnormalities
Mildly decreased number of
melanophages
with incontinentia pigmenti, the hypomelanosis may result from transfer block
as in nevus depigmentosus, in which there are melanosome complexes in the
keratinocytes. But there is also a direct effect on melanocytes, as evidenced by
the presence of few mature melanosomes and evidence of melanocyte destruction.
There are still unresolved questions concerning the concept of this disease
and its relationship to other syndromes such as incontinentia pigmenti and
nevus depigmentosus. Is incontinentia pigmenti achromians in fact an entity
sui generis?
Incontinentia Pigmenti and Incontinentia Pigmenti Achromians (Table 101)
Ramos e Silva [31] and Kitamura [23] believe that incontinentia pigmenti
achromians is a clinical variant of incontinentia pigmenti. Grosshans et a1. [10]
suggest that incontinentia pigmenti achromians represents a variant of the
Bloch-Sulzberger form in which the late stage is characterized by hypomelanosis. Hamada et a1. [11] postulated an identical pathogenesis for these two
dermatoses. It is true that there are similarities between the two conditions.
Both have the same distribution of lesions, are diseases of infancy and childhood, have a tendency later to remit, and are associated with ocular, dental,
hair, musculoskeletal, neurologic, and mental abnormalities. Some histologic
features are common to both diseases. Grosshans et al. [10] found both incontinentia pigmenti achromians and incontinentia pigmenti to have disturbances
of keratinization and malformation of skin appendages.
Furthermore, depigmentation may occur late in incontinentia pigmenti. In
studying a patient considered to have incontinentia pigmenti achromians, Braverman [32] found reflectance readings of the face and the hypopigmented skin
to be identical; he concluded that the "hypopigmented" skin was in fact normal;
therefore, the actual pigmentary abnormality was hyperpigmentation. Incontinentia pigmenti achromians, therefore, is identical with incontinentia pigmenti. This notion is not generally accepted.
But the genetic, clinical, and histologic differences between the two conditions are more numerous than their similarities. Incontinentia pigmenti is
most likely transmitted as an X-linked dominant trait lethal to males, whereas
the incontinentia pigmenti achromians female to male ratio of two to one is
not compatible with this mode of inheritance. Incontinentia pigmenti achromians appears to be transmitted as an autosomal dominant trait.
TABLE 101. Comparison of Incontinentia Pigmenti and Hypomelanosis of Ito (Incontinentia
Pigmenti Achromians)O
Features
Incontinentia pigmenti
Inheritance
Sex
Age of onset
Stages preceding
pigmentary change
Pigmentation
F:M = 98:2
Birth or early infancy
Vesiculobullous. verrucous
Distribution
Prognosis
Histologic findings
Ectodermal abnormalities
Eyes
Teeth
Hair
Musculoskeletal system
Neurologic and mental
Hypomelanosis of Ito
Uncertain; possibly autosomal
dominant
F:M = 2:1
Birth, infancy, or childhood
None
"Marble cake." generalized.
hypopigmented
Asymmetrical or symmetrical
involvement but not mirror
images, any part of body
Hypopigmentation tends to
return to normal
Basal layer normal; decrease
of numbers of pigment
cells; vacuolization of
keratinocytes
Yes (43%)
Affected frequently
Affected occasionally
Affected occasionally
Affected occasionally
Affected occasionally
Source: Jelinek JE et al: Hypomelanosis of ito. incontinentia pigmenti achromians. Report of three cases and review of the
literature. Arch Dermatol107:596...u01. 1973. Copyright. 1973. American Medical Association. Used with permission.
423
GENETIC AND
CONGENITAL
DISORDERS
424
CHAPTER 1
continence and the term is self-cancelling, and they proposed the name "hypomelanosis of Ito."
Treatment
None is available.
425
GENETIC AND
CONGENITAL
DISORDERS
426
CHAPTER 1
REFERENCES
1. Jelinek JC et al: Hypomelanosis of Ito (Uincontinentia pigmenti achromians"). Report of three
cases and review of the literature. Arch Dermatoll07:596-601, 1973
2. Ito M: Studies on melanin, XI: Incontinentia pigmenti achromians, a singular case of nevus
depigmentosus systematicus bilateralis. Tohoku J Exp Med 55(suppl):57-59, 1952
3. Koga M: Incontinentia pigmenti achromians (Ito). Opn J Dermatol 79:300, 1969). Quoted by
Jelinek JC et al: Hypomelanosis of Ito (Uincontinentia pigmenti achromians"). Report of three
cases and review of the literature. Arch Dermatoll07:596-601, 1973
4. Rubin MB: Incontinentia pigmenti achromians. Multiple cases within a family. Arch Dermatol
105:424--425, 1972
5. Masumizu T: Incontinentia pigmenti achromians (Ito). OpnJ DermatoI73[B):303, 1963). Quoted
by Jelinek JC et al: Hypomelanosis of Ito (Uincontinentia pigmenti achromians"). Report of
three cases and review of the literature. Arch Dermatoll07:596-601, 1973
6. Hellgren L: Incontinentia pigmenti achromians (Ito). Acta Dermatol (Kyoto) 55:237-240,1975
7. Piiiol-Aguade Jet al: Considerations sur l'incontinentia pigmenti achromians d'lto. A propos
de deux nouveaux cas. Bull Soc Fr Dermatol Syphiligr 16:553-555, 1969
8. Nohara N, Tasaka S: Incontinentia pigmenti achromians. Acta Dermatol (Kyoto) 56:130-133,
1961
9. Aram H: Incontinentia pigmenti achromians (Ito). Cutis 6:197-201, 1970
10. Grosshans EM et al: Incontinentia pigmenti achromians (Ito). Etude clinique et histopathologique. Dermatologica 142:65-78, 1971
11. Hamada T et al: Incontinentia pigmenti achromians (Ito). Arch Dermatol 96:673-676, 1967
12. Kato T et al: Incontinentia pigmenti achromians. Jpn J Dermatol Ural 8:214-217, 1954
13. Okuwa H, Kitamura S: Incontinentia pigmenti achromians. Jpn J Dermatol 76[A):606-618,
1966
14. Schwartz MF et al: Hypomelanosis of Ito (incontinentia pigmenti achromians): a neurocutaneous syndrome. J Pediatr 90:236-240,1977
15. Griffiths A, Payne C: Incontinentia pigmenti achromians. Arch Dermatolll1:751-752, 1975
16. Cordero AA, Woscoff A: Incontinentia pigmenti achromians (Ito). Med Cutan Iber Lat Am
4:497--499, 1970
17. Maize JC et al: Systematized hypochromic nevus. Incontinentia pigmenti achromians of Ito.
Arch Dermatoll06:884-885, 1972
18. Browne RM, Byrne JPH: Dental dysplasia in incontinentia pigmenti achromians (Ito); an unusual form. Br Dent J 140:211-214,1976
19. Cohen SR et al: Case report. New England Dermatological Society, New Haven, April, 1976
20. Hood A et al: Case presentation. New England Dermatological Society, Boston, Massachusetts,
1975
21. Lambert WC: Case report. New England Dermatological Society, New Haven, April, 1976
22. Morohashi M et al: Ultrastructural studies of vitiligo, Vogt-Koyanagi syndrome, and incontinentia pigmenti achromians. Arch DermatoI113:755-766, 1977
23. Kitamura K: Dber Incontinentia pigmenti. Mit Erinnerungen an A. Franceschetti. Hautarzt
20:492--494, 1969
24. Peiia L et al: Incontinentia pigmenti achromians (Ito's hypomelanosis). Int J DermatolI6:194-202,
1977
25. Ortonne J-p et al: Hypomelanosis of Ito: report of one case. Ann Dermatol Venereoll06:47-50,
1979
26. Stewart RE et al: A malformation complex of ectrodactyly, clefting and hypomelanosis of Ito
(incontinentia pigmenti achromians). Cleft Palate J 16:358-362, 1979
27. Happle R et al: Das Ito Syndrom (Incontinentia pigmenti achromians). Hautarzt 27:286-290,
1976
28. Piiiol-Aguade Jet al: Incontinentia pigmenti achromians (Ito). Med Cutan Iber Lat Am 3:287-290,
1968
29. Nordlund JJ et al: Hypomelanosis of Ito. Acta Derm Venereol (Stockh) 57:261-264, 1977
30. Stoebner P, Grosshans EM: Incontinentia pigmenti achromians (Ito). Etude ultrastructurale.
Arch Klin Exp Dermatol 239:227-244, 1970
INCONTINENTIA PIGMENTI
Incontinentia pigmenti or Bloch-Sulzberger syndrome is an uncommon,
sex-linked, dominant genodermatosis that usually affects female infants. Characteristically, at or shortly after birth there is an erythematous eruption with
linear vesiculation. The children afflicted, despite profound leukocytosis and
eosinophilia, do not appear toxic or generally unwell. Verrucous growths follow
after weeks to months but then resolve spontaneously to leave atrophy, hypomelanosis, or both. The final stage involves irregular macules, streaks, whorls,
or splotches of brown to slate-gray pigmentation asymmetrically distributed
over the trunk but also occasionally over the extremities. This gradually fades
as adulthood is approached. Although hyperpigmentation is the most common
residue of incontinentia pigmenti, hypomelanosis was found by Carney [1] in
13%. Other possible features include alopecia, partial anodontia, nail dystrophy, pegged teeth, ocular abnormalities (blindness, cataracts, retinitis proliferans, retrolental fibroplasia, metastatic ophthalmia, chorioretinitis, uveitis,
pseudoglioma, retinal detachment, optic nerve atrophy), and central nervous
system abnormalities (spastic or paralytic disorders, cerebellar ataxia, congenital hearing loss, hemiplegia, diplegia, psychomotor retardation, mental retardation, microcephaly, hydrocephalus, cerebral cortical atrophy, seizures, abnormal EEG).
Male cases are rare; only 16 of the 653 cases reviewed by Carney were
males. Pregnancies with affected male fetuses usually end in spontaneous abortions.
Pigmenti
Erythema
Verrucae
Pigmentation
Depigmentation
Atrophy
o
Torso
only
Extremities
only
Torso and
extremities
6
0
73
2
1
80
120
21
20
28
157
10
176
2
9
Total
243
130
270
24
38
Source: Carney RG: Incontinentia pigmenti: a world statistical analysis. Arch Dermatol11:535-542. 1976. Copyright. 1976. American Medical Association. Used with
permission.
427
GENETIC AND
CONGENITAL
DISORDERS
428
CHAPTER 1
and Frias [3] observed streaked hypopigmented macules on the posterior lower
legs of the mother of their patient (Fig. 169). "Incontinentia pigmenti et achromians" was the name Mittal et a1. [4] gave to the condition affecting a twoyear-eight-month-old girl with typical hyperpigmented lesions of incontinentia
pigmenti and with a hypopigmented, linear, irregular, "splash" pattern of lesions occurring at sites apparently separate from the hyperpigmented patches
(Fig. 170). Hypopigmentation involved mainly the back, but was also noted on
the abdomen and the proximal upper and lower limbs (Fig. 171). Apart from
nail dystrophy, no other congenital anomaly was detected in this patient. Since
the histologic appearance of the hyperpigmented macules of this patient was
consistent with incontinentia pigmenti, this case certainly represents incontinentia pigmenti with hypo pigmented macules and not incontinentia pigmenti
achromians.
From his survey of the world literature, Carney [5] could himself satisfactorily identify 24 cases with such hypopigmented lesions. Hypomelanosis has
been observed in children [1,6,7] and in adults [6,8,9] with other features of
FIGURE 169. Depigmented lesions in incontinentia pigmenti. (From: Wiley HE, Frias JL: A useful
diagnostic sign. Am J Dis Child 128:546-547, 1974. Copyright, 1974, American Medical Association. Used with permission.)
429
GENETIC AND
CONGENITAL
DISORDERS
FIGURE 170. Hyperpigmented lesions on axillae, cubital fossae, wrists, groin, and abdomen, and
hypopigmented lesions on abdomen. (From: Mittal R et al: Incontinentia pigmenti et achromians.
Dermatologica 150:355-359, 1975. Copyright, 1975, S. Karger A.G. Used with permission.)
430
CHAPTER 1
FIGURE 171. Hypopigmented lesions on back and adjoining parts of limbs. and hyperpigmented
lesions over buttocks and wrists. (From: Mittal R et al: Incontinentia pigmenti et achromians.
Dermatologica 150:355-359. 1975. Copyright. 1975. S . Karger A.G. Used with permission.)
Associated Features
Incontinentia pigmenti is most often characterized by an erythematous
eruption with linear vesiculation that is first observed at birth or shortly thereafter. Later verrucous growths usually resolve with hyperpigmentation, whichgradually fades so that it is most often inapparent by adulthood.
The cutaneous syndrome is usually associated with various abnormalities
of hair (alopecia), teeth (partial or complete anodontia, pegged teeth), eyes,
central nervous system, and development. These have been recently reviewed
by Carney [5] (Tables 105, 106, 107).
Diagnosis
The course of the disease, the family history, and the clinical picture are
usually helpful. Under certain circumstances, and even in the absence of other
dermatologic findings, the presence of typical hypopigmented lesions may confirm the diagnosis of incontinentia pigmenti. A search for such lesions, with
the help of Wood's light examination, is potentially useful in the genetic counseling of involved families [3].
Type of abnormality
Spastic paralysis
Motor retardation
Mental retardation
Microcephalus
Cerebral cortical atrophy
Hydrocephalus
Convulsive disorders
Cerebellar ataxia
Congenital hearing loss
Unspecified disorder
Abnormal EEG
Q
No. of
patients
affected b
Percent
of
patients
affected
53
35
57
22
7
6
62
2
3
7
30
11.4
7.5
12.3
4.7
1.5
1.3
13.3
0.4
0.7
1.5
6.5
Percent of general
population
affected
0.403
0.1
0.293
0.3
Source: Carney RG: Incontinentia pigmenti: a world statistical analysis. Arch Dennatol
112:535-542, 1976. Copyright, 1976, American Medical Association. Used with permis-
sion.
b Quite
Type of anomaly
Strabismus
Blindness
Cataracts
Retinal detachment
Microphthalmus
Optic nerve atrophy
Pseudoglioma
Retrolental fibrosis
Retinitis proliferans
Chorioretinitis
Metastatic ophthalmia
Uveitis
Optic nerve glioma
Retinal telangiectasia and ectasia
Vitreous hemorrhage
Avascular retina
Retinal pigmentation
Glial strands
Retinal depigmentation
Unspecified abnormalities
Glaucoma"
Blue sclerae"
Retinitis pigmentosa"
No. of
patients
affected b
Percent
of
patients
affected
83
34
18
13
13
18
16
7
2
4
2
6
1
10
4
6
18
5
2
14
4
7
1
18.2
7.5
4.0
2.9
2.9
4.0
3.5
1.5
0.4
0.9
0.4
1.3
0.2
2.2
0.7
1.3
4.0
1.1
0.4
3.1
0.9
1.5
0.2
Percent of general
population
affected
3.07
0.2
0.0004
0.025
0.9
Source: Carney RG: Incontinentia pigmenti: a world statistical analysis. Arch Dermatol 112:535-542, 1976.
Copyright, 1976, American Medical Association. Used with permission.
b Quite often individual patients had more than one type of anomaly.
"Considered to be unrelated to incontinentia pigmenti and, therefore, not included in the group of 160 cases.
Q
431
GENETIC AND
CONGENITAL
DISORDERS
432
CHAPTER 1
Type of anomaly
Skull deformities
Dwarfism, small stature
Clubfoot
Spina bifida
Cleft palate or cleft lip, or both
Ear anomalies
Hemiatrophy
Congenital dislocated hip
Chondrodystrophy
No. of
patients
affected b
9
7
6
6
5
5
4
3
2
Percent
of
patients
affected
2.1
1.6
1.4
1.4
1.1
1.1
0.9
0.7
0.5
Percent of general
population
affected
0.57
0.43
0.28
0.71
0.025
Source: Carney RG: Incontinentia pigmenti: a world statistical analysis. Arch DennatoI112:535-542,
1976. Copyright, 1976, American Medical Association. Used with permission.
b Quite often individual patients had more than one type of anomaly.
a
Differential Diagnosis
Depigmented macules in incontinentia pigmenti are similar to the cutaneous lesions of incontinentia pigmenti achromians. We believe that incontinentia pigmenti and incontinentia pigmenti achromians are distinct and separate entities (see Table 101). Unlike incontinentia pigmenti achromians, the
torso is relatively free of hypomelanosis in incontinentia pigmenti. The other
differences between the two entities have been summarized by Jelinek et al.
[11] (see section on "Incontinentia Pigmenti Achromians" in this chapter).
Treatment
The primary defect in incontinentia pigmenti is unknown and no treatment
is available.
REFERENCES
1. Carney RG: Incontinentia pigmenti: a report of five cases and review of the literature. Arch
Dermatol 64:126-135, 1951
2. Kleinhans D: Incontinentia pigmenti mit multiplex Fehlbildungssymptomatik bei einer Erwachsenen. Hautarzt 21:133-136, 1970
3. Wiley HE III, Frias JL: Depigmented lesions in incontinentia pigmenti-a useful diagnosis sign.
Am J Dis Child 128:546-547, 1974
4. Mittal R et al: Incontinentia pigmenti et achromians. Dermatologica 150:355-359, 1975
5. Carney RG: Incontinentia pigmenti. A world statistical analysis. Arch Dermatol112:535-542,
1976
6. Cramer JA, Schmidt WJ: Incontinentia pigmenti: report of six cases. Arch Dermato171:699-702,
1955
7. Gordon H, Gordon W: Incontinentia pigmenti: clinical and genetical studies of two familial
cases. Dermatologica 140:150-168, 1970
ATAXIA-TELANGIECTASIA
Ataxia-telangiectasia is an autosomal recessive neurocutaneous disease
characterized by cerebellar ataxia, chorioathetosis, ocular and cutaneous telangiectasia, and recurrent pulmonary infections with bronchiectasis, presumably related to hypogammaglobulinemia (usually IgA) resulting from hypoplasia of the thymus.
Hypomelanosis in Ataxia-Telangiectasia
In patients with ataxia-telangiectasia, two types of hypomelanosis have
been described, namely, premature graying of hair and hypomelanotic macules.
Utian and Plit in 1964 [1] reported depigmented areas scattered over the
trunk and back of a nine-year-old girl with ataxia-telangiectasia. Karpati et al.
[2] later observed a one-year-old boy with ataxia-telangiectasia, depigmented
macules on the sacral area, and premature graying of the scalp hair. Reed et
al. [3] noted hypomelanosis in eight of 22 patients. The depigmented macules
were larger than 1.5 cm in diameter. In one of these patients the depigmentation
involving the back and extremities was very extensive. The hypomelanotic
macules were present at birth and did not enlarge with age. Diffuse premature
graying of scalp hair was noted in young patients, none of whom had the typical
white forelock of piebaldism [3]. McFarlin et al. [4] found premature graying
of scalp hair in 14 of 17 patients with ataxia-telangiectasia. Most of their patients
were under 12 years of age. Hypomelanosis, described as vitiligo-like, was also
observed in several of their cases. Macules may rarely assume a dermatomal
distribution [5].
There are few reports on the histology of the pigmentary changes in ataxiatelangiectasia, but Karpati et al. [2] reported pigmentary incontinence in two
of their patients. Whether it was the hyperpigmented or hypopigmented macules that were biopsied is not specified. No electron microscopic study of the
white macules of ataxia-telangiectasia is available.
Other Cutaneous Features
Telangiectases or dilated venules are present over sun-exposed areas and
areas subjected to frequent friction. Cafe-au-Iait spots, pigmented nevi, and
sclerodermoid changes are not infrequent. Eczema, seborrhea, impetigo, and
433
GENETIC AND
CONGENITAL
DISORDERS
434
CHAPTER 1
Growth retardation
Pulmonary
Ocular
Telangiectasia (conjunctival)
Strabismus
Nystagmus
Oculomotor dyspraxia
Neurologic
Mental retardation
Cerebellar dysfunction
Choreoathetoses
Myoclonus
Decreased deep tendon reflexes
Distal weakness
Babinski's sign
Decreased sensation (vibration, position, and touch)
Gastrointestinal
Nausea
Jaundice
Diarrhea
Steatorrhea
Melena
Food intolerance
Malignancies
Lymphomas
Lymphosarcoma
Leukemia
Hodgkin disease
Astrocytoma
Medulloblastoma
Ovarian dysgerminoma
Gastric carcinoma
Endocrinopathies
Immunologic
Clinical Course
The diagnosis usually is first apparent when the neurologic abnormalities
appear in early life. The typical course is marked with frequent infections, and
death from respiratory tract infection is not uncommon. The more severe the
immunologic abnormality, the more serious and frequent are the infectious
episodes. Many patients succomb to malignancies.
REFERENCES
1. Uti an HL, Plit J: Ataxia telangiectasia. J Neural Neurasurg Psychiatry 27:38-40, 1964
2. Karpati G et al: Ataxia telangiectasia: further observations and report of 8 cases. Am JDis Child
110:51-63, 1965
3. Reed WB et al: Cutaneous manifestations of ataxia telangiectasia. JAMA 195:746-753, 1966
4. McFarlin DE et al. Ataxia telangiectasia. Medicine (Baltimore) 51:281-314, 1972
5. Berg M, Tarnowski W: Nevus depigmentosus. Arch Dermatoll09:920, 1974
XERODERMA PIGMENTOSUM
Xeroderma pigmentosum is a recessive hereditary disorder clinically characterized early in life by photophobia and persistent erythema, and later by
hyper- and hypopigmentation, scarring, premature aging of the skin, and development of epithelial tumors and, less frequently, melanomas. In xeroderma
pigmentosum, there is a defect in excision repair of ultraviolet damage to DNA
[1,2].
FIGURE 172. Comparison between skin exposed to sunlight (left forearm) and the unexposed buttock. Freckling is
apparent on the forearm but absent on the buttock where,
on the contrary, the multiple white macules are clearly
visible. (From: Cesarini JP et al: Hypopigmented macules
of sun-unexposed skin in xeroderma pigmentosum. An
electron microscopic study. J Cutan Pathol 2:128-139, 1975.
Copyright, 1975, Munksgaard International Publishers, Copenhagen. Used with permission.)
435
GENETIC AND
CONGENITAL
DISORDERS
436
CHAPTER 1
FIGURE 173. Higher magnification of the buttock. Macules are irregular in size and shape. The circle indicates the
location of the punch biopsy (x 5). (From: Cesarini JP et
al: Hypopigmented macules of sun-unexposed skin in xeroderma pigmentosum. An electron microscopic study. J
Cuton Pothol 2:128-139, 1975. Copyright, 1975, Munksgaard International Publishers, Copenhagen. Used with permission.)
437
FIGURE 175. Buttock: hypo pigmented macule. Melanocyte
containing melanosomes of a lamellar type (~) or granular type
(.) as well as normal-looking melanosomes (x 30,000). (From:
Cesarini JP et al: Hypopigmented macules of sun-unexposed
skin in xeroderma pigmentosum. An electron microscopic study.
J Cutan Patho12:128-139, 1975. Copyright, 1975, Munksgaard
International Publishers, Copenhagen. Used with permission.)
FIGURE 176. Buttock: hypopigmented macule. Melanocyte (M) with indented nucleus. The cell contains few
melanosomes (arrows) (x 11,000) . (From Cesarini JP et
al: Hypopigmented macules of sun-unexposed skin in
xeroderma pigmentosum. An electron microscopic study.
J Cutan Pathol 2:128-139, 1975. Copyright, 1975,
MUnksgaard International Publishers, Copenhagen. Used
with permission.)
GENETIC AND
CONGENITAL
DISORDERS
438
CHAPTER 1
Hypopigmentation in xeroderma pigmentosum reflects an absence of melanocytes. Cesarini et al. [3] suggested that the abnormalities of melanocytes
at the margins of the hypopigmented macules must be independent of sun
exposure because lesions may occur in skin not habitually exposed to sun.
This suggests that xeroderma pigmentosum is characterized by a generalized
cutaneous pigmentary abnormality. The presence of pigmentary abnormalities
in a DNA repair defect disorder and the relationship of psoralen DNA adducts
to melanosome structure [7] and psoralen-induced UVA repigmentation suggest
some unknown relationship between DNA structure and melanosome morphology.
REFERENCES
1. Cleaver JE: Defective repair replication of DNA in xeroderma pigmentosum. Nature 78:652-656,
1968
2. Cleaver
JE:
DNA damage and repair in light sensitive human skin disease. J Invest Dermatol
54:181-195, 1970
NEUROFIBROMATOSIS
Neurofibromatosis is an autosomal dominant disorder appearing in childhood or adolescence and characterized by cafe-au-Iait spots and multiple peripheral nerve tumors. Poliosis has been reported in association with neurofibromas (Fig. 177). Rarely a segmental hypomelanosis may occur [1].
IIi 1968, Kaplan and Shapiro [2] reported a 19-year-old, generally healthy
male with a 15-year history of a slowly enlarging asymptomatic neurofibroma
of the scalp; gray hair localized to the same area had been present for seven
years. Masson-Fontana silver stain revealed some hairs with large quantities
of melanin pigmentation and others with none.
Bradley et al. [3], in 1974, reported in three members of one family the
occurrence of neurofibromatosis, peroneal muscular atrophy, congenital deafness, partial albinism, and the Axenfeld defect. The mother (Fig. 178) had gray
scalp hair. Her two daughters had golden-white hair, pale skin, and numerous
freckles. One daughter also had ocular albinism. The father had premature
whitening of the scalp hair and the investigators suggested he had piebaldism
which his daughters inherited as an autosomal dominant trait. The mother and
one of the daughters had cutaneous signs of neurofibromatosis and the father
was said to have a possible cafe-au-Iait spot on his hip. There was no obvious
439
GENETIC AND
CONGENITAL
DISORDERS
FIGURE 177. Hypomelanosis of the hair and of the face in a child with neurofibromatosis.
FIGURE 178. This 58-year-old woman with typical neurofibromatosis had two daughters with
piebaldism. (From: Bradley WG et al: The familial association of neurofibromatosis. peroneal
muscular atrophy. congenital deafness. partial albinism. and Axenfeld defect. Brain 97:521-532.
1974. Copyright. 1974. Oxford University Press. Used with permission.
440
CHAPTER 1
REFERENCES
1. Berg M, Tarnowski W: Nevus depigmentosus. Arch Dermatol109:920, 1974
2. Kaplan BS, Shapiro L: Poliosis overlying a neurofibroma. Arch Dermatol 98:631-633, 1968
3. Bradley WG et al: The familial association of neurofibromatosis, peroneal muscular atrophy,
congenital deafness, partial albinism and Axenfeld's defect. Brain 97:521-532, 1974
Clinical Features
Incidence
Both types of dyschromatosis are apparently rare; only a few cases have
been reported. Ito [4] found in his clinic between 1925 and 1944 only 16 cases
of dyschromatosis symmetric a, but Costa [8] stated that the disease is frequent
in Brazil.
Race
Although most of the initial cases were reported in Japanese, dyschromatosis has been reported among Europeans [9] and South Americans [8].
Sex
Although precipitating factors are unknown, that dyschromatosis symmetrica is localized to sun-exposed areas suggests a role of ultraviolet radiation.
But dyschromatosis universalis hereditaria is frequently most prominent on
the abdomen and back; while the face may be affected, it is less commonly
involved and, if so, less severely than elsewhere. Thus, light alone is not the
etiologic agent for all dyschromatoses.
Clinical Findings
Onset
Dyschromatosis symmetrica usually appears in infancy or in early childhood. In the young boy reported by Tay et al. [11] the abnormal pigmentation
was initially noted at the age of two. In two cases reported by Sugai et al. [13]
the disease began very soon after birth in one patient and at the age of seven
in the other; both cases could, however, represent vitiligo. Costa [8] reported
two patients in whom the condition was first noted at ages 18 and 22 years.
Ito [4] found the age at which patients were first examined to range from 16 to
40 years.
441
GENETIC AND
CONGENITAL
DISORDERS
442
CHAPTER 1
hyperpigmented macules are numerous, but usually small and discrete. They
range in size from "a grain of rice," to "a pea" or "a bean," and vary in color
from light to dark brown. The hypomelanotic macules may be similar. The
macules assume a round or irregularly patchy pattern. These lesions are irregularly clustered and closely intermingled so that a mottled appearance results.
Hyperpigmented macules are sharply demarcated from hypopigmented lesions.
There seems to be no seasonal variation in the intensity of pigmentation, which
curiously appears not to be stimulated by sun exposure. There are no other
epidermal changes and the lesions are asymptomatic. There is no pruritus,
localized anesthesia, anhidrosis, scaling, scarring, atrophy, inflammation, lichenification, or hyperkeratosis.
The lesions of dyschromatosis symmetrica are symmetrically distributed
TABLE 109. Clinical Features of Dyschromatoses
Dyschromatosis symmetrica
Dyschromatosis
universalis hereditaria
Inheritance
Autosomal dominant
Autosomal dominant
Age of onset
Elementary lesion
None
Extremities of limbs
Dorsa of hands and feet
Sometimes face
Palms and soles usually
spared
Symmetrical
Variable
None
Generalized
Palms and soles usually
spared
Variable
Associated
abnormalities
None
None
Course
Stationary
Benign
Stationary
Benign
Size
Shape
Borders
Grouping
Local symptomatology
Distribution
Extent
over the extremities, particularly the distal hands and feet where spotted hyperpigmentation is mingled with hypopigmentation, and also over the arms
and legs. Occasional involvement of the face with small pigmented macules
resembling freckles has been described. Palms and soles are usually not involved.
In dyschromatosis universalis hereditaria, the lesions are distributed all
over the body, particularly the trunk, abdomen, and limbs. In some cases the
face is involved but usually only slightly and then only in the periauricular
regions. Palms and soles are usually spared, but Suenaga [10] reported involvement of the palms with a few light brown macules in two patients and involvement of the sole in one. The extent and severity of the involvement is
extremely variable.
Neither type of dyschromatosis is progressive, although both do seem less
prominent in younger patients.
Dyschromatosis does not affect the general health of the patient. Nails,
eyes, teeth, and hair are usually normal and there are no neurologic abnormalities. Only isolated patients have been reported to have systemic abnormalities. Suenaga [10], for example, reported a child with dyschromatosis universalis hereditaria, caries of the dorsal spine, coxa vulgae, and signs of nerve
root compression. There is one case of dyschromatosis symmetrica in a patient
with an atypical 47 XYY syndrome. But any significant relationship between
the dermatosis and any of these features is unsubstantiated.
Pathologic Findings
In hyperpigmented skin, Tay et al. [11] found increased melanin pigmentation in the basal layer of the epidermis and a strongly positive dopa reaction.
No comprehensive study of the hypopigmented macules in dyschromatosis
has been done. Sugai et al. [14] studied the hypopigmented macules in one of
their patients and noted decreased melanin pigmentation. Dopa reaction was
negative and there was a sharp demarcation between unmelanized and melanized areas. There were also many clear basal cells considered to represent
inactive epidermal melanocytes [13]. Saunders and Hu [15] suggested, and it
seems likely, that the latter cases represented vitiligo because depigmentation
was present without any hyperpigmented macules and because clinically the
periungual hypomelanosis was characteristic of vitiligo.
Electron microscopy studies of dyschromatosis are not available.
Diagnosis
The clinical presentation and the hereditary pattern suggest the diagnosis.
However, pigmentary lesions of dyschromatosis may simulate ephelides, xeroderma pigmentosum, and various leukomelanodermas characterized by both
hyperpigmentation and hypopigmentation (arsenic dermatosis, incontinentia
pigmenti, Fanconi anemia, vagabond's leukomelanoderma, piebaldism, vitiligo,
443
GENETIC AND
CONGENITAL
DISORDERS
444
CHAPTER 1
Treatment
No effective treatment is available.
REFERENCES
1.
2.
3.
4.
5.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
Matsumoto S: (Acta Dermatol (Kyoto) 2:191, 1923). Quoted by E Meirowski, in Handbuch der
Haut- und Geschlechtskrankheiten. Edited by J Jadassohn. Berlin, Julius Springer, 1933
Komaya G: "Symmetrische Pigmentanomalien" der Extremitiiten. Arch Dermatol Syphilol
(Berlin) 147:389-393, 1924
Toyama I et al: A previously undescribed anomaly of pigmentation: dyschromatosis universalis
hereditaria. Jpn J Dermatol Urol 34:360-364, 1933
Ito M: Dyschromatosis symmetrica. Tohoku J Exp Med 55(suppI1):77-78, 1952
Matsunaga M: Quoted in Ito M: Dyschromatosis symmetrica. Tohoku J Exp Med 55(suppl
1):77-78, 1952
Ikegami Y, Hashiguchi M: On a peculiar depigmentary condition in the islets of Palau and
Saipan, South Sea Islands (abstr). Acta Dermat01 (Kyoto) 11:100, 1928
Ito M: Dyschromatosis symmetrica on the extremities. Tohoku J Exp Med 53:69-75, 1950
Costa OC: Leucopathie symmetrique progressive des extremites. Ann Dermat01 Syphiligr (Paris)
78:452-454, 1951
Siemens HW: Acromelanosis albo-punctata. Dermat010gica 128:86-87, 1964
Suenaga M: Genetical studies on skin diseases VII: Dyschromatosis universalis hereditaria in
5 generations. Tohoku J Exp Med 55:373-376, 1952
Tay CH et al: Dyschromatosis symmetrica in a Chinese with 47-XYY syndrome. Int J Dermat01
11:134-139, 1972
Toyama I, Omori H: (Jpn J Dermatol). Quoted by M Ito: Dyschromatosis symmetrica on the
extremities. Tohoku J Exp Med 53:69-75, 1950
Sugai T et al: Reply to comments on "symmetric acroleukopathy in mother and daughter."
Arch Dermatol 94:252, 1966
Sugai T et al: Symmetric acroleucopathy in mother and daughter. Arch Dermat01 92:172-173,
1965
Saunders TS, Hu F: Symmetric acroleukopathy or vitiligo (letter). Arch Dermatol 93:261, 1966
A Group
Type
445
GENETIC AND
CONGENITAL
DISORDERS
Type II
Type I
C Group
Type I
Type n
Type III
8 Group
FIGURE 179. Demarcation lines of pigmentation (feathered and hyphenated) found in Japanese.
after Miura. Ventral axial lines of inner thigh. to which Group B may correspond. are usually
shown in posterior view. (From: Selmanowitz VJ. Krivo JM: Pigmentary demarcation lines. Br J
Dermatol 93:371-377. 1975. Copyright. 1975. Blackwell Scientific Publications. Used with permission.)
defect lies in the darker area of skin, whereas in pigmentary demarcation lines
the lighter areas are abnormal.
Pigmentary demarcation lines were first described in 1913 [2] among Japanese and have generally been observed in dark-skinned people, particularly
Japanese and blacks. Pigmentary demarcation lines have been found to involve
various areas of the body. In 1953, Kisch and Nasuhoglu [3] described "a
mediosternal depigmentation line" in a great percentage of black patients. Having observed pigmentary demarcation lines in siblings and in several generations of a family, they concluded the condition must be hereditary. In 1965,
Weary and Behlen [4] reported an "unusual familial hypopigmentary anomaly"
in five members of a black family; all showed sharply outlined areas of hypopigmentation in approximately symmetrical locations just inferior to both
clavicles. In 1973, Selmanowitz and Krivo [5] studied these two kinds of hypopigmented markings in blacks and called them "pigmentary demarcation
lines." Miura [6] proposed the following classification of pigmentary demarcation lines based upon the location of the pigmentary disturbance:
446
CHAPTER 1
Subgroups
Location
Group
A
Arms
Legs
(mid perineum straight to
inner popliteal fossa)
Sternum
Back
(downward on either side
of midline)
Chest
(linear from nipples
toward midline)
Clinical Findings
Incidence
Pigmentary demarcation lines are common, particularly in dark-skinned
peoples. A mediosternal depigmentation line has been reported in nearly 40%
of 112 investigated blacks [3]. In a study of 100 blacks [5], a mediosternal
100 Patients
aged 6 mo. to 72 yr.
26 Patients aged 6
mo. to 13 yr.
74 patients aged
13 yr. to 72 yr.
38
(38%)
16
(16%)
18
(69%)
12
(46%)
20
(27%)
(5%)
52 Males
48 Females
22
(42%)
16
(33%)
11
5
(10%)
(21%)
From: Selmanowitz JV, Krivo JM: Hypopigmented markings in Negroes. Int J DermatoI12:229-235,
1973. Copyright, 1973, J. B. Lippincott Co. Used with permission.
447
GENETIC AND
CONGENITAL
DISORDERS
448
CHAPTER 1
Clinical Description
Chest Hypopigmented Macules
The principal lesion is a small hypopigmented but not totally amelanotic
macule, about 1 cm in size. The margins of the lesions are ill defined. The
epidermis is otherwise normal. Hair growth, sweating, and sensation are not
disturbed. In anyone patient there may be from several to 10 macules that may
vary in size and shape. These hypopigmented macules are always bilateral and
usually symmetrical, but there is sometimes an asymmetrical distribution of
lesions (Fig. 180).
Mediosternal Hypopigmentation Lines and Chest Hypopigmented Markings
Chest-wall markings have been variously characterized as "broad and slightly
curved ribbon-like markings with irregular margins and blunt ends," "narrower
markings with tapered ends, somewhat leaf-shaped," and "longer streaklike
FIGURE 180. Bilateral hypopigmented macules (arrows) and mediosternal line (broad arrow).
Right: Periareolar hypopigmented macules. The two macules indicated by arrows have leaf-shaped
configurations. The cause of the mediosternal line (broad arrow) is described in the text. (From:
Selmanowitz VJ. Krivo JM: Hypopigmented markings in Negroes. lnt JDermato112:229-235. 1973.
Copyright. 1973. J. B. Lippincott Co. Used with permission.)
hypopigmentation." Lesions are usually located in the preareolar areas but have
also been observed just below the mid portion of the clavicles, midway between
the clavicles and nipples, and sometimes in a linear fashion from the nipples
toward the midline. The latter were described as Group E pigmentary demarcation lines by Selmanowitz and Krivo [7].
Mediosternal hypopigmentation lines are located on the midline of the
sternum and may extend longitudinally onto the abdominal skin (Figs. 180,
181). In some patients, the hypopigmented band may involve the suprasternal
area with a slight curvature of the band to one side. Sometimes also the hypopigmentation line is not strictly located to the midline but arches away,
sometimes taking a second change in direction. Selmanovitz and Krivo [7]
identified this latter as consistent with the pigmentary demarcation lines of
Group C (Fig. 182) described by Miura [6]. Both types of mediosternal lines
and chest macules can occur in the same individual.
FIGURE 181. Arrows indicate the hypo pigmented streaks. The mediosternal line extends into
the abdominal midline skin (broad arrows). (From: Selmanowitz VJ, Krivo JM: Hypopigmented
markings in Negroes. lnt J Dermato112:229-235, 1973. Copyright, 1973, J. B. Lippincott Co. Used
with permission.)
449
GENETIC AND
CONGENITAL
DISORDERS
450
CHAPTER 1
FIGURE 182. The arrow points to a pronounced typical brachial demarcation line of pigmentation
(Group A). A prominent line is also seen on the other arm. The ends of the "V" on the chest abut
a Type II mediosternal line (Group C) which arches from xiphisternal midline and returns to
midline superiorly. (From: Selmanowitz VJ. Krivo JM: Pigmentary demarcation lines. Br J Derrnatol
93:371-377. 1975. Copyright. 1975. Blackwell Scientific Publications. Used with permission.)
Diagnosis
In some individuals the markings are so clear as to cause little doubt of
their presence to an aware physician. However, sometimes even in dark-skinned
individuals they are very faint and can easily be overlooked. In the latter case,
Wood's light examination may be useful.
As pointed out by Selmanowitz and Krivo [5], the mediosternalline is not
likely to be confused with anything else.
In a patient with hypopigmented chest macules, relevant history and the
absence of other cutaneous lesions help to exclude postinflammatory hypopigmentation. The presence of normal sensation on the hypopigmented macules
excludes Hansen disease. Tuberous sclerosis also may be present with a similar
ash leaf-shaped macule, but in tuberous sclerosis the depigmentation is usually
not an isolated finding and the depigmented patches are more numerous, widely
distributed, and not bilaterally symmetrical.
Significance
It is most probable that pigmentary demarcation lines are a dominantly
inherited trait [1,4,5] and represents, as suggested by Selmanowitz and Krivo
[7], a duality in the population of melanocytes.
These demarcation lines cause very slight cosmetic disfigurement and require no treatment.
REFERENCES
1. Ito K: The peculiar demarcation of pigmentation along the so-called Voigt's line among the
Japanese. Dermatologia Internatl 44:45-47,1965
2. Matzumoto S: Ober eine eigentumliche Pigmentverteilung in den Voigtshen Linien (Beitrag zur
Kenntnis der Voigtschen Grenzen). Arch Dermatol Syphilol (Berlin) 118:157-164, 1913
3. Kisch B, Nasuhoglu A: A mediosternal depigmentation line in Negroes. Exp Med Surg 11:265-267,
1953
4. Weary PE, Behlen CH: Unusual familial hypopigmentary anomaly. Arch Dermatol 92:54-55,
1965
6. Miura 0: On the demarcation lines of pigmentation observed among the Japanese, on inner
sides of their extremities and on anterior and posterior sides of their medial regions. Tohoku J
Exp Med 54:135-140, 1951
7. Selmanowitz VI. Krivo JM: Pigmentary demarcation lines-comparison of Negroes with Japanese. Br J Dermotol 93:371-377, 1975
8. Fletcher PH: A peculiarity of pigmentation of the upper arm of Negroes. Science 88:570-571,
1938
9. Vollum DI: Skin markings in Negro children from the West Indies. Br J Dermotol 86:260-263,
1972
451
GENETIC AND
CONGENITAL
DISORDERS
452
CHAPTER 1
Darier-White Disease
Darier-White disease is an uncommon autosomal dominant disorder of
keratinization characterized by small hyperkeratotic papules usually located
on the face, extremities, chest, and back. Palms and soles, nails, and mucous
membranes may be involved. Spontaneous mutation is responsible for many
cases. Electron microscopic studies show a structural defect in the tonofilament-desmosome complex.
There are only a few scattered reports of leukoderma in Darier-White
disease [1]. Goodall and Richmond [2], in 1965, reported a 24-year-old woman
with many macules of leukoderma on the upper extremities and trunk; it is
possible that these represented postinflammatory changes. Cornelison et al. [3],
in 1970, described guttate leukoderma associated with Darier-White disease.
Based on the presence of these widespread white macules among three of 15
patients with keratosis follicularis, Cornelison et al. [3] concluded that guttate
leukoderma with keratosis follicularis is more common than the scant attention
afforded it in the literature would indicate. These patients, two males and one
female, respectively aged 21, 49, and 32, had had depigmented lesions since
childhood. None had a positive family history for the disease. In all three
patients, the white macules were numerous, 1 to 5 mm in diameter, asymptomatic, and randomly distributed around as well as between the hair follicles
on the trunk and extremities. None of the white macules occurred on the face.
According to the patients, no other lesions preceded the appearance of the
white macules. Dystrophic nail changes and characteristic keratotic papules in
the typical distribution were also noted. Histologic examination of white macules of two patients revealed decreased to absent epidermal melanin. However,
the typical histologic features of the disease, namely dyskeratosis, corps ronds
or grains, were absent in these sites.
Cattano [4] reported a postinflammatory leukoderma in keratosis follicularis. Histologic studies showed epidermal thinning, atrophy, and flattening of
rete ridges. Dopa-silver nitrate stain revealed a virtual absence of melanocytes.
Many hyperpigmented hyperkeratotic papules were present in this
patient.
Rozycki et al. [5] described a syndrome of congenital deafness with profound sensorineural hearing loss, muscle wasting, short stature, hyperreflexia,
achalasia, and vitiligo in two children of parents who were also first cousins.
In both, depigmented patches are described on their necks and trunks. Both
453
GENETIC AND
CONGENITAL
DISORDERS
FIGURE 183. a: Small hypomelanotic macules scattered over the lateral neck. (Courtesy of D. L.
RozyckL) b, c: Small hypomelanotic macules scattered over the lateral neck. (Courtesy of D. L.
RozyckL)
454
CHAPTER 1
c
FIGURE 183 (Continued)
Muscle wasting involving the hands (a) and feet (b) of affected individuals. (From:
Rozycki DL et al: Autosomal recessive deafness associated with short stature. vitiligo. muscle
wasting and achalasia. Arch Otolaryngol 93:194-197. 1971. Copyright. 1971. American Medical
Association. Used with permission.)
FIGURE 184.
455
GENETIC AND
CONGENITAL
DISORDERS
~I..n
ot M - IIIItJ 't
"'''' -''11
"t OIfO "'l I~ '
o
T
I-Ill
DIAD
( MIIl o-t ...
S4!1 .... ~
FIGURE 185.
FIGURE 186.
456
CHAPTER 1
also had abnormal EEGs, slightly elevated beta and gamma globulins, decreased
alpha globulins, and abnormal cephalin flocculation and thymol turbidity tests
(Figs. 183, 184, 185, 186).
457
GENETIC AND
CONGENITAL
DISORDERS
FIGURE 187. Multiple areas of anetoderma and hypopigmentation of buttocks, legs, and thighs
at birth. (From: Gottlieb SK et al: Focal dermal hypoplasia. Arch Dermatol 108:551-553, 1973.
Copyright, 1973, American Medical Association. Used with permission.)
458
CHAPTER 1
FIGURE 188. Multiple areas of anetoderma, hypopigmentation of posterior thighs and knees at
age nine. (From: Gottlieb SK et al: Focal dermal hypoplasia. Arch Dermatol108:551-553, 1973.
Copyright, 1973, American Medical Association. Used with permission.)
The macules varied from 1 to 16 mm in diameter and from brown to light tan
in color. None of the macules depigmented totally. The macules, which had
sharply demarcated borders, were scattered over most of the body, but were
sparse or absent on the acral portions of the body, including the head, neck,
nipples, elbows, knees, genitalia, hands, and feet (Fig. 189). Fontana-Masson
silver stain showed melanin granules in the hypopigmented epidermis with
occasional small collections of melanophages in the upper dermis.
Hair, mucous membranes, and irides were normally pigmented. In addition, flat-topped hypopigmented keratotic papules were present on the palms,
soles, and dorsolateral fingers and toes. This patient also had a G6PD deficiency.
Other members of the family (maternal grandfather, mother, and three
brothers) all also had the same dermatologic features. The authors suggested
an autosomal dominant pattern of inheritance.
459
GENETIC AND
CONGENITAL
DISORDERS
FIGURE 189. Sharply demarcated irregular hypomelanotic macules that were scattered all over
the body in a patient with punctate keratosis of the palms and soles. (From: Cole MLA: Hypopigmentation with punctate keratosis of the palms and soles. Arch Dermatol112:998-1000. 1976.
Copyright. 1976. American Medical Association. Used with permission.)
460
CHAPTER 1
REFERENCES
1. Cohen-Hadria M: Maladie de Darier (premier cas publie en Afrique du Nord); debut tras
precoce; lesions zoniformes; leukodermie residuelle. Bull Soc Fr Dermotol Syphiligr
46:1478-1481, 1939
2. Goodall JWO, Richmond QMS: A case of Darier's disease. Br J Clin Proct 19:475-476, 1965
3. Cornelison RL et al: Guttate leukoderma in Darier's disease. Arch Dermotol102:447-450, 1970
4. Cattano AN: An unusual case of keratosis follicularis. Arch Dermotol 98:168-174, 1968
5. Rozycki DL et al: Autosomal recessive deafness. Arch Otoloryngol 93:194-197, 1971
6. Goltz RW et al: Focal dermal hypoplasia syndrome. Arch Dermotol101:1-11, 1970
7. Gottlieb SK et al: Focal dermal hypoplasia. Arch Dermotol108:551-553, 1973
8. Marchionini A, Besser F: Ober Poikilodermia atrophicans vascularis Uacobi). Arch Dermotol
Syphilol (Berlin) 165:431-442, 1932
9. Cole LA: Hypopigmentation with punctate keratosis of the palms and soles. Arch Dermotol
112:998-1000, 1976
10. Freire-Maia N et al: A syndrome of hypohidrotic ectodermal dysplasia with normal teeth,
peculiar facies, pigmentary disturbances, psychomotor and growth retardation, bilateral nuclear cataract and other signs. J Med Genet 12:308-310, 1975
11. Berlin C: Congenital generalized melanoleukoderma associated with hypodontia, hypotrichosis, stunted growth, and mental retardation occurring in two sisters. Dermotologico
123:227-243, 1961
FANCONI SYNDROME
Fanconi syndrome is vitamin-D-resistant rickets or osteomalacia with hypophosphatemia, glucosuria, generalized aminoaciduria and generally chronic
acidosis, hypouricemia, and hypokalemia. It may occur early (infantile form)
or later (adult form) in life.
Fanconi syndrome may be idiopathic or associated with cystinosis, Lowe
syndrome, or tyrosinemia. In a series of 24 patients reported by Cowie [2], 19
patients had cystinosis, four had cirrhosis and no cystinosis, and one had
neither. Both groups of patients were found to have significantly fairer hair
electrospectrophotometrically than their siblings or than age-matched controls.
Schneider and Seegmiller [3] noted that although these patients with increased intracellular cystine often have blond hair and are significantly fairer
than their parents, they have much less tendency to sunburn than would be
expected for their degree of pigmentary dilution.
461
GENETIC AND
CONGENITAL
DISORDERS
462
CHAPTER 1
ROTHMUND-THOMSON SYNDROME
Rothmund-Thomson syndrome is a rare, autosomal recessive disease which
is characterized by acquired erythematous patches that develop atrophy, telangiectasia, hypo- and hyperpigmentation, and sometimes warty keratosis [4,5].
Other features include alopecia, photosensitivity, bilateral cataracts, short stature, small skull, sometimes with birdlike features, and hypogonadism. Life
expectancy appears to be normal. Premature canities is an inconstant feature
of Rothmund-Thomson syndrome; it sometimes appears in adolescence and
progresses rapidly.
DYSTROPHIA MYOTONICA
Canities occurring in the second or third decade may be seen in dystrophia
myotonica [6], an entity that was first described in 1909 by Steinert [7]. This
rare disorder, which is inherited as an autosomal dominant disease, usually
appears in the second or third decade and is characterized by myotonia, severe
muscle wasting, cataracts, premature frontal baldness, and characteristic lugubrious physiognomy. Testicular atrophy, various disorders of ovarian function, and low basal metabolic rate are frequently observed. Few of these patients
survive beyond the sixth decade and death is often attributed to aspiration
pneumonia or to cardiac conduction defects.
Patients with Werner syndrome have a characteristic habitus with a beakshaped nose, stocky trunk with slender extremities, and short stature first apparent in adolescence. A weak, high-pitched voice is characteristic. The skin
and subcutaneous tissues are atrophic with circumscribed hyperkeratosis. Indolent ulcers often develop over malleoli of ankles, Achilles tendon, heels and
toes. Most of the patients develop juvenile cataracts. Hypogonadism and diabetes mellitus are frequently observed. Generalized arteriosclerosis, osteoporosis, calcifications of ligaments, tendons, and subcutaneous tissues may develop prematurely. The incidence of malignancy is increased and the life
expectancy is decreased.
Diagnosis
atrophic and wrinkled. This child and another patient were subsequently reported by Gilford [13], who first used the name "progeria."
Progeria is a rare condition occurring equally in both sexes. The primary
defect responsible for the disease is unknown.
Pigmentary Disturbances
In progeria, the hair is sparse and prematurely gray. DeBusk [14] noted
that sparse, downy blond or white fuzz was present even if the original hair
was black.
Other Clinical Features
Patients with this disease usually appear normal at birth. During the first
year of life there is a profound failure to meet normal growth markers and
463
GENETIC AND
CONGENITAL
DISORDERS
464
CHAPTER 1
during the second year of life the characteristic facies (plucked-bird appearance
with craniofacial disproportion, micronathia, and prominent eyes), alopecia,
loss of subcutaneous fat, stiffness of joints and bones, skeletal abnormalities
(pyriform thorax, coxa valga), cutaneous changes (diminution of subcutaneous
fat and sclerodermatous skin), and abnormal dentition become apparent. Motor
and mental development is normal. There is insulin resistance and increased
basal metabolic rate. Early death results from severe generalized arteriosclerosis.
Diagnosis
FISCH SYNDROME
Fisch [15] described a family with deafness and early, pronounced graying
of the hair. Among 21 members of this family, two of the 10 who had early
graying also had deafness. Two other young children had only deafness and
two others partial heterochromia irides. Fisch observed similar cases and believed this a genetically distinct syndrome. Soussi Tsafir [16], arguing that none
of the 13 affected members of this family had dystopia canthorum, drew the
same conclusion and distinguished this condition from Waardenburg syndrome, which has a penetrance of 40% to 99%. Other possible cases include
those of Ballantyne [17] who noted that many of his patients with progressive
high-tone deafness, among them a father and daughter and a brother and sister,
had strikingly light blond hair and light blue eyes.
in one family, nine individuals were involved. In these cases, graying of scalp
and body hair appeared during the second decade or earlier, but did not affect
the eyebrows and eyelashes [19].
465
GENETIC AND
CONGENITAL
DISORDERS
466
CHAPTER 1
PROLIDASE DEFICIENCY
Prolidase deficiency, a very rarely reported inborn error of metabolism,
has important and severe dermatologic manifestations, especially ulcers of the
lower extremities. Poliosis or premature graying of hair has been found in
several of these patients [26].
REFERENCES
1. Book JA: Clinical and genetical studies of hyperdontia. I. Premolar aplasia, hyperhidrosis and
canities prematura. A new hereditary syndrome in man. Am J Hum Genet 2:240-263, 1950
2. Cowie V: Hair colour in the infantile Fanconi syndrome. Ann Hum Genet 21: 170-176, 1956
3. Schneider JA, Seegmiller JE: Cystinosis and the Fanconi syndrome, in Metabolic Basis of
Inherited Disease, 3rd ed. Edited by JB Stanbury et al. New York, McGraw-Hill, 1972, pp
1581-1604
4. Rook A, Wells RS: Genetics in dermatology, in Textbook of Dermatology. Edited by A Rook
et al. London, Blackwell, 1969, pp 57-60
5. Tannhauser SJ: Werner's syndrome (progeria of the adult) and Rothmund's syndrome: two
types of closely related heredofamilial atrophic dermatoses with juvenile cataracts and endocrine features. A critical study of five new cases. Ann Intern Med 23:559-626, 1945
6. Touraine A: (Progres Medical 73:47, 1945). Quoted in Ebling EJ, Rook A: Premature canities,
in Textbook of Dermatology. Edited by A Rook et al. London, Blackwell, 1969, pp 1413-1414
7. Steinert H: Myopathologische Beitrage I. Dber das klinische und anatomische Bild des Muskelschwunds der myotaniker. Dtsch Z Nervenh 37:58-104, 1909
8. Werner 0: Dber Katarakt in Verbindung mit Sclerodermie. Doctoral Dissertation, Kiel University. Kiel, Schmidt and Klaunig, 1904
9. Epstein DJ et al: Werner's syndrome. Medicine (Baltimore) 45:177-221, 1966
10. Rook A: Disorders of connective tissues, in Textbook of Dermatology. Edited by A Rook et al.
London, Blackwell, 1969, pp 1287-1288
11. Gilkes JJH et al: The premature aging syndromes. Br J Dermatol 91:243-262, 1974
12. Hutchinson J: Congenital absence of hair and mammary glands. Medico-Chirurg Trans 69:473,
1886. Quoted by Gilkes JJH et al: The premature aging syndromes. Br J Dermatol 91:243-262,
1974
13. Gilford H: Progeria: a form of senilism. Practitioner 73:188-217,1904
14. DeBusk FL: The Hutchinson-Gilford progeria syndrome. J Pediatr 80:697-724, 1972
15. Fisch L: Deafness as part of an hereditary syndrome. J Laryngol Otol 73:355-382, 1959
16. Soussi Tsafir J: Light-Eyed Negroes and the Klein-Waardenburg Syndrome. London, MacMillan, 1974
17. Ballantyne JC: Deafness. London, Churchill, 1960
18. Bernier GM et al: Kappa chain deficiency. Blood 40:795-805, 1972
19. Hare HJH: Premature whitening of hair. J Hered 20:31-32, 1929
20. Seckel HPG: Bird-Headed Dwarfs. Basel, S Karger, 1960
21. Fitch N et al: A form of bird-headed dwarfism with features of premature senility. Am J Dis
Child 120:260-264, 1970
22. Tay CH et al: A recessive disorder with growth and mental retardation, peculiar facies, abnormal
pigmentation, hepatic cirrhosis and aminoaciduria. Acta Paediatr Scand 63:777-782, 1974
23. Lopez B et al: Trastornos de la pigmentaci6n, in Actas Del VI Congresso Ibero-Latino Americano
de Dermatologia (Barcelona, Spain, 1967). Barcelona, Editorial Cientifico Medica, 1970, pp
157-179
24. Porter PS, Lobitz WC: Human hair: a genetic marker. Br J Dermatol 83:225-241, 1970
25. Breg WR: Abnormalities of chromosomes 4 and 5, Endocrine and Genetic Diseases of Childhood
and Adolescence. Edited by 11 Gardner. Philadelphia, Saunders, 1975, pp 1505-1515
26. Der Kaloustian VM et al: Prolidase deficiency: an inborn error of metabolism with major
dermatological manifestations. Dermatologica 164:293-304, 1982
2
Hypomelanoses Associated with
Nutritional and Metabolic Disorders
KWASHIORKOR
Kwashiorkor is a result of dietary deficiency of protein in the weaning and
early postweaning stage of childhood. In underdeveloped nations it remains a
significant cause of death among children from one to four years of age.
Credit for the first description of kwashiorkor is generally given to Williams
[1], who, in 1953, reported five "Gold Coast children," four of whom died. The
origin of the term "kwashiorkor" is not precisely known.
Kwashiorkor has been reported in every part of Africa, and also in China,
India, Malaya, Indonesia, Fiji, the Philippines, Caribbean Islands, Hungary,
Italy, and various parts of South America. Henington et al. [2], in 1958, reported
four cases from Louisiana. The general prevalence of kwashiorkor is 0.5% to
1.5% in various community surveys [3]. It is said to be much higher in primitive
cultures.
Depigmentation in Kwashiorkor
Clinical Description
467
468
CHAPTER 2
Banerjee and Dutta [4] noted that there may be generalized pallor with
extensive hypo- and hyperpigmentation, the latter mostly in the diaper area,
buttocks, back, thighs, and elbows-as opposed to the sun-exposed areas of
pellagra.
Dyschromic hair is a common feature of kwashiorkor. Mukherjee and Jelliffe [5] found the changes minimal in India compared to those seen in Africa,
where hypochromotrichia is pronounced. Others [6] reported only 13% with
hair discoloration, yet Jelliffe [7] reported as high as 82% among African infants
in Jamaica. In the latter, curled jet black hair is replaced by sparse dry hair
varying from red-brown to gray in color.
Henington et al. [2] noted golden to reddish coloration at the ends of
normally black hair in their four black patients. There is often such minimal
dilution of color-a fringe effect-and the color may be brown, red, golden,
gray, or white. The "signe de bandera" or "flag sign"-which is striped hairmay represent a recurrence. Thinning of eyebrows or loss of the outer thirds
may occur. The hair also becomes dry, thin, and brittle and may be removed
painlessly with little effort [8]. Partial or total alopecia may result. Hair production is 59 /-Lm 3 per follicle in kwashiorkor vs. 514 /-Lm 3 for controls [9].
Cystine levels are also reduced but return to normal after therapy.
Histology of Depigmentation
"Crazy-pavement" dermatitis
Bullae, ulceration
Purpura
Mucous membrane
Angular stomatitis
Cheilosis
Nails
Eyes
Xerophthalmia
Bitot's spots
Blepharitis, conjunctivitis, photophobia
Systemic changes
Growth retardation
Psychic disturbances and mental retardation
Muscle wasting
Edema
Gastrointestinal disorders (anorexia, diarrhea)
Hepatomegaly
Laboratory findings
Hypoalbuminemia
Anemia
Hypovitaminosis
Diagnosis
Leukoderma is not a primary or essential feature of kwashiorkor, the diagnosis of which is based on the history of malnutrition in an infant from an
endemic area plus the presence of the many clinical features noted. Bands of
de pigmented or dyschromic hair may correspond to relapses and those of repigmentation to treatment. Other nutritional deficiency syndromes may also
be present.
Treatment
Kwashiorkor responds to dietary protein and the skin is said to repigment
slowly [4].
469
HYPOMELANOSES
ASSOCIATED
WITH
NUTRITIONAL
AND METABOLIC
DISORDERS
470
CHAPTER 2
hypopigmented macules in the diaper area, upper legs, and lower abdomen.
During the next two months, similar lesions continued to appear on the trunk
and spread to the distal extremities. No inflammation preceded the hypopigmented eruption but the father and an older sister had a history of infantile
eczema.
Examination revealed a generalized mottling of the skin which had irregularly scattered hyperpigmented and hypopigmented macules.
As poor dietary intake and recurrent diarrhea had been present in the first
months of life, the author suggested that the dyschromia may result from malnutrition. However, amino acid, copper, and vitamin B12 studies were not done.
OF THE GUT
COPPER DEFICIENCY
Acquired copper deficiency is discussed with Menkes kinky hair syndrome
(see "Copper Deficiency" in Chapter 1).
REFERENCES
1. Williams CD: Kwashiorkor. JAMA 153:1280-1285, 1953
2. Henington VM et al: Kwashiorkor. Arch Dermatol 78:157-170, 1958
3. Ebrahim GJ: The skin in malnutrition, in Essays on Tropical Dermatology. Edited by J Marshall.
Amsterdam, Excerpta Medica, 1972, vol 2, pp 124-128
4. Banerjee BN, Dutta AK: Malnutrition in the tropics: dermatoses in nutritional disorders, in
Clinical Tropical Dermatology. Edited by 0 Canizares. Oxford, Blackwell, 1975, pp 273-277
5. Mukherjee KL, Jelliffe DV: Clinical observations on kwashiorkor in Calcutta. J Trop Pediatr
1:61-66, 1955
Report of the Second Inter-African [CCTA) Conference on Food and Nutrition, Gambia. London, Her Majesty's Stationery Office, 1954, p 215
14. Petrozzi JW: Unusual dyschromia in a malnourished infant. Arch Dermatol103:515-519, 1971
15. Rook A: Nutritional, metabolic, and chemical influences of hair colour, in Textbook of Dermatology. Edited by A Rook et al. London, Blackwell, 1969, pp 1631-1632
471
HYPOMELANOSES
ASSOCIATED
WITH
NUTRITIONAL
AND METABOLIC
DISORDERS
472
CHAPTER 2
16. 8ilverblatt CW, Brown HE: "Kwashiorkor-like" syndrome, associated with burning feet syndrome, in one adult male. Am J Med 28:847-854, 1960
17. Mellinkoff 8M: Temporary redness of the hair in ulcerative colitis. Am J Dig Dis 2:738-739,
1957
18. Tasker P, Polunin I: Extreme anaemia with recovery associated with pigmentary changes in
the hair (case report). Br Med J 2:465, 1954
19. Wintrobe MM: Pernicious anemia and related macrocytic anemias, in Clinical Hematology,
6th ed. Philadelphia, Lea & Febiger, 1967, pp 502-576
20. Dawber RPR: Integumentary associations of pernicious anemia. Br J Dermatol 82:221-223,
1970
21. Wintrobe MM: Pernicious anemia and related macrocytic anemias, in Clinical Hematology.
London, Kimpton, 1967, p 509
3
Hypomelanosis Associated with
Endocrine Disorders
HYPERTHYROIDISM
The association of vitiligo and Addison disease has been discussed (see
"Vitiligo" in Chapter 1).
CUSHING SYNDROME
Brooks and Richards [3] reported depigmentation in two black women with
Cushing syndrome. In both patients, depigmentation occurred on the exposed
areas (extensor surfaces of the hands and feet) but returned to normal after
adrenal surgery.
The authors suggested the depigmentation may be due to suppression of
melanocyte-stimulating hormone (MSH) by high circulating levels of cortisol.
But as only two cases are reported, any association must be considered tentative.
473
474
HYPOGONADISM
CHAPTER 3
Male eunuchs have pale skin [4]. One eunuch who failed to tan after sun
exposure has been reported. Five months later, after administration of testosterone, deep pigmentation developed in the normally sun-exposed areas [5].
This suggests that testosterone deficiency decreases melanin pigmentation and
decreases the capacity of the melanin pigmentary system to respond to solar
stimulation. However, while orchidectomy has been reported to decrease melanin pigmentation of the skin in men [6], there are experimental results which
suggest that testosterone has no effect on the melanin pigmentation of the skin
[4].
REFERENCES
1. Freinkel RK, Freinkel N: Dermatologic manifestations of endocrine disorders, in Dermatology
in General Medicine. Edited by TB Fitzpatrick et al. New York, McGraw-Hill, 1971, pp 1434-1459
2. Sheehan HL: Simmond's disease due to post-partum necrosis of the anterior pituitary. Q JMed
8:277-309, 1939
3. Brooks VEH, Richards R: Depigmentation in Cushing's syndrome. Arch Intern Med 117:677~80,
1966
4. Lorincz AL: Pigmentation, in Physiology and Biochemistry of the Skin. Edited by S Rothman.
Chicago, Univ of Chicago Press, 1954, pp 515-563
5. Hamilton JB, Hubert G: Photographic nature of tanning of the human skin as shown by studies
of male hormone therapy (letter). Science 88:481, 1938
6. Edwards EA et al: Cutaneous vascular and pigmentary changes in castrate eunuchoid men.
Endocrinology 28:119-128, 1941
7. Fields JP et al: Hypoparathyroidism, candidiasis, alopecia and vitiligo. Arch Dermatol
103:687-689, 1971
8. Fisher M, Fitzpatrick TB: Candidiasis, vitiligo, Addison's disease and hypoparathyroidism.
Arch Dermatol102:110-111, 1970
9. Goldmann PJ, Thiess AM: Berufsbedingte Vitiligo durch para-tertiar Butylphenol, eine Ames
Trias von Vitiligo, Hepatose und Struma. Hautarzt 27:155-159, 1976
10. Rodermund DE, Wieland H: Vitiligo, Hepatosplenopathie und Struma nach Arbeit mit paratertiiirem Butylphenol. Dtsch Med Wochenschr 100:2216-2222, 1975
4
Hypomelanosis Secondary to
Irradiation and Physical Trauma
Melanocytes are vulnerable to nonspecific trauma. In animals or in humans,
dark skin or hair may lose pigment in areas exposed to various types of injury
(x-rays and ionizing radiations, ultraviolet rays, thermal burns, freezing, physical traumas) (Fig. 190).
X-rays have long been known to cause changes in melanin pigmentation.
In animals, x-ray exposure causes depigmentation of feathers [1,2] or hair [3-6].
In humans, cutaneous depigmentation with atrophy may follow x-ray therapy
[7]. Human hair color changes following x-radiation were reported just after
the turn of this century [8,9]. Regrowth of white hair has been observed in
white or black children [10,11] following epilating doses of x-rays for the treatment of tinea capitis.
X-ray depigmentation results from a loss of functioning melanocytes. Straile
[12] observed that x-ray irradiation decreases the number of melanocytes in
the hair follicles of mice. Other changes included alterations of the length of
the dendrites, decrease in the transfer of pigment granules, alteration in the
distribution of melanin in the hair, and changes in the color of melanin granules.
However, the mechanism by which follicular melanocytes seem to disappear
after irradiation is unknown.
The epithelium target theory suggests that x-rays alter the epithelium of
the hair follicle [13]; subsequently, there is either a failure of the induction of
follicular melanogenesis or a disturbance in the regulation of the differentiation
of the secretory melanocytes at the beginning of the hair growth cycle. Cohen
[14] suggested from studies of tissue culture of irradiated growing feathers
and transplant experiments that the action of x-rays is upon the melanoblast-ectoderm relationship. Chase et al. [6] observed radiation effects remote
from the site of original exposure; depigmentation was delayed until the second
growth cycle after irradiation. They concluded that there is an indirect effect
of x-rays on melanocytes.
The melanocyte theory suggests that melanocytes are individually and
directly killed or inactivated by x-rays [13].
Still another theory is that proposed by Straile [12], who suggested a more
475
476
CHAPTER 4
FIGURE 190. Top: Clip in position on the shaved back of the rat. Bottom: One month after
application of the clip. the hair in the previously ischemic area is white and longer than in the
surrounding areas where regeneration after shearing is irregular and slow. (From: Selye H: Ischaemic depigmentation. Experientia 23:524.1967. Copyright. 1967. Birkhauser Verlag. Used with
permission.)
REFERENCES
1. Cole LJ, Finley HE: Production of somatic mutations in the pigeon with x-rays. Anat Rec
[Suppl] 81:48-49, 1941
2. Espinasse PC: The responses of some developing feathers to x-ray. J Embryol Exp Morphol
7:165-172, 1959
3. Chase HB: Graying of hair. I. Effects produced by single doses of x-rays on mice. J Morphol
84:57-80, 1949
4. Chase HB: Number of entities inactivated by x-rays in graying of hair. Science 113:714-716,
1951
5. Chase HB, Raugh H: Graying of hair. II. Response of individual hairs in mice to variations in
x-irradiation. J Morphol 87:381-392, 1950
6. Chase HB et al: Evidence for indirect effects of radiation of heavy ions and electrons on hair
depigmentation. Ann NY Acad Sci 100:390-399, 1963
7. Ladanyi E: Nach Riintgenbestrahlung entstandene, "White Spot Disease." Hautarzt 21:328-330,
1970
8. Danysz J: De I'action du radium sur les differents tissus. C R Acad Sci (Paris) 136:461-464,
1903
9. Ellinger F: Medical Radiation Biology. Springfield. Ill. Thomas. 1907. p 173
10. Hazen H: Results of repeated epilation with roentgen rays in tinea tonsurans. Arch Dermatol
56:539-540, 1947
11. Zeligman I: Graying of hair following epilating doses of x-rays. Arch Dermatol 66:627-628,
1952
12. Straile WE: A study of the hair follicle and its melanocytes. Dev Biol10:45-70, 1964
13. Selye H: Ischemic depigmentation. Experientia 23:524, 1967
14. Cohen J: The nature of the effect of x-irradiation in depigmentation. Ann NY Acad Sci 100:400-412,
1963
15. Moshman J, Upton A: Depigmentation of hair as a biological radiation dosimeter. Science
119:186-187, 1954
16. Taylor AC: Survival of rat skin and changes in hair pigmentation following freezing. J Exp
2001110:77-112, 1949
477
HYPOMELANOSIS
SECONDARY TO
IRRADIATION
AND PHYSICAL
TRAUMA
5
Chemical Hypomelanosis
480
CHAPTER 5
0
0
OH
0
OH
OH
Hydroquinone
OOH
OH
CH. C CH.
CH.
p-tertiary
Butylcatechol
CH,
Monobenzylether
of
Hydroquinone
0
OH
CH.
Monomethylether
of
Hydroquinone
0
OH
CH. C CH.
CH.
p-tertiary
Butylphenol
0
OH
CH. C CH.
CH,
CH.
p-tertiary
Amylphenol
COMPARED TO
o
OH
CH,
NH, CH COOH
Tyrosine
481
CHEMICAL
HYPOMELANOSIS
482
CHAPTER 5
Product
Bactophene
Beaucoup
Chlorocide
Galahad
Listophene
Matar
Microphene
Phenocide
Phenomycin
Staphene
i-Stroke Vesphene
Tergisyl
Tri-Kem
Ves-Phene
Ves-Phene 0
a
Manufacturer
Sanfax Corporation
Huntington Laboratories
Center Chemicals
Puritan Chemical
Enterprise Paint Manufacturing
Huntington Laboratories
Sanfax Corporation
Center Chemicals
Franklin Division of Purex
Vestal Laboratories
Vestal Laboratories
Lehn and Fink Division, Sterling Drug
Airwick Industries
Vestal Laboratories
Vestal Laboratories
Source: Fisher AA: Vitiligo due to contactants. Cutis 17:431--437,1976. Copyright, 1976, Donneley Publishing Corporation. Used with permission.
PHENOLIC COMPOUNDS
The basic structural requirements for a depigmenting phenolic compound
seem to be hydroxylation of the benzene ring, particularly in the para-position,
and a nonpolar side chain in the one position [13]. The presence of an ether
link at the 1 position increases the effective depigmenting potency [13]. Many
of these phenol derivatives resemble tyrosine or dihydroxyphenylalanine in
their molecular structure.
Clinical Features
The leukodermas arising from chemical exposure are clinically similar.
Chemical exposure of as little as two weeks' duration may cause depigmentation, but four to six months is a more commonly cited exposure period.
Manufacturer
Sanfax Corporation
Sanfax Corporation
Lehn and Fink Division, Sterling Drug
Center Chemicals
483
CHEMICAL
HYPOMELANOSIS
Contact dermatitis may precede whitening but is not necessary for development
of depigmentation. Depigmentation begins as confetti-like or small, round to
oval macules which may be more or less grouped in a particular anatomic
region. Predisposed sites are a function of direct occupational contact, so that
the hands, forearms, perioral skin, neck, and lower legs are among the first to
depigment. Satellite lesions (Fig. 193) may occur in areas not directly exposed
to the chemical. In extensive cases, which certainly resemble vitiligo, genital
and perianal skin may be affected. Extensive and symmetrical depigmentation
of the trunk may also occur. A leukomelanoderma may result. Graying of scalp
and body hair is rare. Eye color is unchanged. Repigmentation may occasionally
occur from the margins or from hair follicles after the chemical is withdrawn,
but more often depigmentation is permanent.
484
CHAPTER 5
Hydroquinone (HQ)
Oettel [28], in 1936, noted that black-haired cats developed reversible graying of hair after six to eight weeks of hydroquinone (HQ) feedings. Martin and
Ansbacher [29] noted that achromatrichia developed after four to 20 weeks of
oral HQ in mice. HQ fed to guinea pigs did not cause depigmentation, whereas
subcutaneous injection resulted in depigmentation at the injection sites [18].
Workers exposed to large amounts of HQ do not develop depigmentation, but
depending on the length of exposure may develop a reddish discoloration of
hair and exposed skin, particularly on the palms and soles [30]. This may result
from oxidation and polymerization of absorbed HQ [30] or from conversion of
HQ to a melanin-like product similar to that in the conjunctivae in ochronosis
[31]. HQ has also been found to be a quite effective de pigmenting agent but,
unlike MBEH, it does not cause satellite depigmentation and the depigmentation is usually reversible once application of HQ is discontinued (Fig. 194).
Furthermore, total depigmentation has never been reported. Large quantities
of HQ creams have been used in Africa for over 15 years; no reports of vitiligolike depigmentation have been reported despite annual sales of several million
dollars.
Jimbow et al. [32] found evidence of destruction of melanocytes with HQ;
there was decreased formation of melanosomes, alteration of internal structure,
increased melanosome degradation, and destruction of membranous organelles.
485
CHEMICAL
HYPOMELANOSIS
486
CHAPTER 5
FIGURE 194. a: Patient with melasma before treatment with hydroquinone. b, c: Same patient
during and after treatment. The hypomelanosis is much less apparent.
487
CHEMICAL
HYPOMELANOSIS
488
CHAPTER 5
pet plant workers had had a dermatitis on their upper arms prior to the appearance of depigmentation. Leukoderma appeared following a few months' to
four years' chemical exposure. The amelanotic macules were confined to the
hands and forearms in only one patient, whereas the others also had remote
areas involved. One worker was 75% depigmented. Patch testing gave positive
results in three of four patients, one of whom subsequently developed an area
of depigmentation at the site of patch testing.
Another worker exposed to PTBC was studied. It was observed that patch
tests to 0.01% and 0.5% PTBC were both positive, but only with the 0.5% did
depigmentation occur. This developed two weeks after patch testing. The same
worker was also patch test-positive to PTBP but depigmentation did not occur.
Histologic studies show decreased melanin, a decreased number of dopa-positive melanocytes, and melanophages in the dermis. After three years, improvement was noted but some depigmentation remained. Phase contrast and electron microscope studies of guinea-pig ear melanocytes treated with PTBC show
the changes in more detail. These changes included decreased melanocyte size,
a beaded dendritic pattern, and some melanocytes rounded-up in shape; many
of these changes were reversible once PTBC was washed out. PTBC exposure
also caused transition from smooth melanocyte contour to irregular outlines
and melanin pigmentary clumping. In cell culture, half the cells were killed,
but among remaining cells, no lightening occurred. Thus, cell killing would
appear to be the mechanism for PTBC depigmentation. An alternative mechanism for depigmentation is inhibition of tyrosine oxidation as has been observed in vitro [43].
In another industrial investigation in a Dutch factory, inhalation was implicated. Patch testing of 16 of these workers to multiple phenol derivatives
including PTBP revealed universally negative results and no depigmentation
at sites of application of the testing materials. Wild-type colored guinea pigs
and black cats fed up to 10 months a tube feeding mixture of phenols, including
PTBP, PTBC, and others did not develop hypomelanosis of hair [44a].
Depigmentation of hands and arms occurred in seven employees of a Denver hospital [12] who were exposed to Vesphene, a PTAP-containing disinfectant. PTAP was observed to cause depigmentation in the absence of an antecedent dermatitis. In some patients and test subjects, the depigmentation
disappeared in six months, whereas in others it persisted more than one year.
PTBP-depigmented skin lacks melanin granules and contains only occasional melanocytes with few melanosomes [44]. In four of five patients in
another series, no melanocytes were identified in the involved skin and the
rare melanocytes found contained swollen mitochondria, many vacuoles, and
premelanosomes with "an abacus" type of pigment distribution [44a].
Occupational leukoderma from the alkylphenols has also been reported
[38,45].
4-Isopropylcatechol (4-IPC)
Dihydroxydiphenylmethane
Depigmentation due to adhesive tape has been attributed to contact with
a natural rubber-base adhesive containing a derivative of dihydroxydiphenylmethane [4].
p-Cresol
A compound in laundry ink, p-cresol, has been shown to induce permanent
hair depigmentation in CBA/J mice [47]. p-Cresol appeared to be toxic to melanocytes during the early anagen phase of the hair cycle. Superficially the coat
appeared pigmented until the hair was parted to reveal depigmentation of 90%
of the hair, which in fact retained pigment only at the tips. The area of depigmentation corresponded to the area of application of p-cresol.
Butylated Hydroxytoluene
Vollum [48] found two black children who developed hypopigmentation
at the site of application of a polyethylene film containing an antioxidant,
butylated hydroxytoluene. After four weeks one showed no signs of repigmentation; the other had repigmented in eight weeks.
Mechanism of Action
Bleehen et al. [46] suggested seven possible mechanisms for exogenous
depigmentation with an agent such as 4-IPC:
1. Selective action on the melanocyte-as metabolic antagonists or respiratory inhibitors-through formation of free radicals that disrupt melanocyte
function
2. Competitive inhibition with tyrosinase
3. Block of enzymatic oxidation of tyrosine to dopa, for example, by reduction of dopaquinone to an orthodihydroxyphenol compound, which may
then inhibit melanin pigmentation
489
CHEMICAL
HYPOMELANOSIS
490
CHAPTER 5
491
CHEMICAL
HYPOMELANOSIS
492
CHAPTER 5
4-HA was noted to produce keratinocyte pseudopods into the dermis, whereas
nontoxic 2-HA and 3-HA had no, or a much slower, effect, respectively. This
effect is reversed once application is discontinued.
The mechanism of PTBP is not understood, but it induces changes in the
cresolase activity of tyrosinase [37,55]. McGuire and Hinders concluded that
paratertiary butylphenol depigmentation may result from competitive inhibition of tyrosinase [50].
493
CHEMICAL
HYPOMELANOSIS
day for over four months achieved complete depigmentation [58]. An average
of only two to three months of therapy was required to notice any change. After
completely depigmenting, two patients observed small macules of repigmentation; these macules were readily erased with further applications of Benoquin.
All patients who depigmented fully were very pleased with the results.
Side effects of MBEH therapy are not uncommon. Dermatitis, burning [59-61],
and pruritus [7] are the most frequent complaints. Contact dermatitis, varying
from mild asymptomatic erythema to a painful vesicular eruption, has been
reported in 13% of treated patients; in some of these cases dermal or epidermal
hyperpigmentation resulted [22]. In 3816 patch tests on 578 subjects (200 Indians, 316 Zulus, and 62 mixed whites and blacks) with 1% to 75% hydroquinone or MBEH, reactions varied from erythema to vesiculation as a function
of concentration. Hyperpigmentation, never depigmentation, followed [62].
Two-thirds of the 18 patients treated at the Massachusetts General Hospital
complained of burning or itching, erythema, dryness, or warm sensation. One
patient developed a contact dermatitis and was unable to use Benoquin [58]
and one of the authors has since observed another such patient.
Other pigmentary abnormalities, including leukomelanoderma, satellite
depigmentation (Fig. 196), and hypermelanosis, may occur. Hyperpigmentation
with MBEH-containing Neoprene has been reported [8], and such hyperpigmentary responses tend to be permanent [63]. According to a study of Becker
494
CHAPTER 5
and Spencer [9], among 25% of patients responding to 1% to 20% MBEH application, the response was unpredictable in extent and degree. Among Japanese women using MBEH, a vitiligo-like leukomelanoderma developed remote
from the sites of direct application [59]. Development of completely depigmented macules outside the treated area was noted in two South American
patients [23]. Total depigmentation was common among blacks and Asiatics
but not among Caucasians [23]. Curiously, in another 185 patients, neither
hyper- nor hypo pigmentation was noted; this suggested possible patient misuse
or careless transfer by fingers [22] was responsible for the satellite depigmentation reported by others. The variation in reactions to patch testing of 43 normal
black males [2], one of whom discontinued MBEH because of a disseminated
eczematous eruption, confirms a spectrum of MBEH reactions. Twenty-three
developed inflammation at the site of MBEH application, and after four months
26 had leukoderma. Five, in fact, developed leukoderma within the time of
application, and in seven the leukoderma continued to progress for six months
after application. Four years after application had been discontinued, nine
subjects continued to be depigmented. MBEH depigmentation is, however, not
necessarily permanent. But a few months to years may be required for repigmentation to occur. Such repigmentation may be partial or complete. In two
of seven volunteers who underwent 30-day patch testing with 10% to 30%
MBEH, perifollicular repigmentation was observed a month after the end of
the experiment [18]. Another group of Caucasians treated with MBEH did not
develop leukoderma, but the test sites would not tan for several years.
Other effects are rarely reported. A halo nevus has been reported to develop
in an MBEH-treated patient [64J. Hair loss has been observed in one case [3J.
While the incidence of side effects is high, these do not usually limit the
proper use of Benoquin. The only clinical use of MBEH is for those vitiligo
patients who wish, above all, to be one color and who can accept the emotional
and physical limitations of being totally amelanotic. Once therapy has resulted
in hypomelanosis, irreversible depigmentation (amelanosis) should be expected to follow and remain. And, after full depigmentation, the patient must
495
CHEMICAL
HYPOMELANOSIS
496
CHAPTER 5
SULFHYDRYL COMPOUNDS
Depigmentation has been found to occur with 2-mercaptoethylamine (MEA),
N-(2-mercaptoethyl)-dimethylamine (MEDA), cystamine dihydrochloride, 3mercaptopropylamine hydrochloride, and sulfanolic acid. Sulfhydryl compounds were first observed to cause depigmentation in goldfish [69]. Topical
application of these compounds was later found to depigment mammalian skin
[46,70].
With black guinea pigs, MEDA was found to be a more potent depigmenting
agent than MEA, and sulfanilic acid, like hydroquinone, was found to induce
barely perceptible hypopigmentation [71]. In MEDA-treated epidermis, only
rare melanocytes could be identified. Those present contained many vacuoles,
swollen mitochondria, and imperfectly melanized melanosomes. Some small
vacuoles resembled coated vesicles; larger ones containing electron-dense material resembled malformed melanosomes. The depigmented skin contained
some normal melanosomes similar to those in the untreated epidermis [71], a
normal complement of Langerhans cells, and unidentified cells lacking desmosomes, melanosomes, or Langerhans granules. Although sulfhydryl-induced
depigmentation has not been clearly documented in humans, several patients
ingesting sulfhydryl-containing compounds have developed hypopigmentation. Depigmentation was observed in a black patient treated with thiouracil
for hyperthyroidism [72]. Chronic administration of BAL (2,3-dimercaptopropanol) is said to cause graying of hair [73].
It was concluded that MEDA is a cytotoxic agent which alters or blocks
the formation of melanin by tyrosinase inhibition. The selective action on
melanocytes suggested that thiol compounds attach to the melanocyte components by both covalent and ionic bonds, such that functional activity is
disrupted. These thiols may interfere directly with enzymes, including tyrosinase, and may attach to microsomal particles thought to be templates for
protein synthesis. Riley [13] suggested sulfhydryl compounds may decrease
the cellular capacity to inactivate a potentially harmful free radical.
CINNAMIC ALDEHYDE
Several cases of perioral leukoderma simulating vitiligo from use of a
toothpaste containing cinnamic aldehyde have been observed [73a].
METALS
Mercurials have been widely used as depigmenting agents. However, use
of mercurials has been banned because cutaneous absorption of mercury may
cause nephrotoxicity [67].
HYDROGEN PEROXIDE
Hydrogen peroxide is a very popular topical bleaching agent for hair. Keratin is irreversibly altered by oxidation of combined cysteine. The cysteic acid
formed causes a significant change in the distribution of electrostatic crosslinks [74]. Electron microscopy studies of bleached human scalp hair reveal
that bleaching is associated with destruction and dissolution of the melanin
granules. There were no premelanosomes in bleached hair [75]. There is no
evidence for a depolymerization of the melanin polymer.
Benzoyl peroxide contained in antiacne preparations can also bleach hair.
GUANONITROFURACIN
Cutaneous depigmentation was observed in Japan after the use of a topical
solution or ointment containing 5-nitro-2-furfurylidene aminoquaridine (guanonitrofuracin) for the treatment of conjunctivitis and blepharitis. One to eight
months after cessation of the therapy, depigmentation of the eyelid and eyelashes occurred in about 20% of the cases; in some, cutaneous depigmentation
remote from the sites of application of the compound was also observed. Halo
nevi have been reported. No patients had a history of preceding inflammatory
changes [76]. The involved skin was normal except for the absence of melanin;
dopa reaction was negative.
Absence of sweating in the leukodermatous macules has been described
and is said to precede appearance of the depigmentation. This observation has
led to the hypothesis that guanonitrofuracin-induced leukoderma is precipitated by some neuropathic process. The eccrine sweat glands are histologically
normal.
Guanonitrofuracin has been shown to interact with several components of
the melanogenesis pathways. Guanonitrofuracin inhibits potato tyrosinase. This
inhibition can be reversed by the addition of copper; it has been demonstrated
spectrophotometrically that guanonitrofuracin interacts with cupric sulfate.
However, guanonitrofuracin does not inhibit the dopa reaction of normal human skin, and has only a 10% inhibitory effect on human melanoma tyrosinase.
But according to Ito [77], since guanonitrofuracin is a competitive inhibitor of
497
CHEMICAL
HYPOMELANOSIS
498
CHAPTER 5
MEPHENESIN CARBAMATE
Mephenesin, an aromatic glycerol ether, a,~-dehydroxY-"Y-(2-methylphen
oxy)propane, which has been used for the treatment of multiple sclerosis, exerts
a depressant effect on synoptic transmission at spinal, brain stem, and subcortical levels and in addition possesses anesthetic and anticonvulsant properties. Spillane [78] reported depigmentation of scalp hair in six patients (four
females and two males) using this drug. Five were suffering from multiple
sclerosis and one from a posttraumatic hemiplegia. The degree of depigmentation seemed proportional to the dosage of the drug and to the duration of the
treatment. In the most striking cases, in which the patients were taking 10 g
daily, the hair turned from dark brown to blond in three months. The mechanism of this depigmentation is unknown. No cutaneous depigmentation was
observed.
TRIPARANOL (MER-29)
Triparanol (MER-29), 1-[p-(~-diethylaminoethoxy)phenyl]-1-(p-tolyl)-2-(p
chlorophenyl)ethanol, a drug that principally blocks the conversion of demosterol to cholesterol [79], was, for a short time, employed therapeutically to
reduce cholesterol levels. Change of hair color was one of the complications
noted with use of MER-29. Achor, Winkelmann, and co-workers [80,81] reported loss of hair color in two males, and Minton and Bounds [82] observed
in one of 12 patients treated by MER-29 that the hair changed from dark brown
to light brown. Winkelmann et a1. [81] observed two patients in whom examination of the hair shaft showed abrupt color change. Alopecia, ichthyosis,
and cataracts were other undesirable side effects of this drug. Since MER-29
is known to disturb the formation of the horny layers in rat epidermis, it is
likely that the pigmentary changes are secondary to disturbed keratinization
which results from interference with cholesterol synthesis [83].
DINITROCHLOROHENZENE (DNCH)
Holzegel [84] observed two patients with permanent depigmentation on
the sites of an epicutaneous test with DNCB (dinitrochlorobenzene). Grosshans
et a1. [85] also observed several instances of such depigmentation. Holzegel
[84] found this depigmentation could not be differentiated clinically or histologically from vitiligo.
ARSENIC
Chronic arsenical ingestion [86,87] can induce a cutaneous leukomelanoderma which may occur without an antecedent dermatitis and may develop
several to many years after arsenical use. The hyperpigmentation may be diffuse, but more frequently the presence of small depigmented macules gives a
freckled or "raindrop" appearance. The hypopigmented macules vary in size
from several millimeters to a few centimeters, are round to oval, usually not
confluent, and asymptomatic.
Diagnosis is made by the history of therapeutic or industrial use of arsenic,
by the association of the other clinical signs of the disease, namely, loss of
hair, transverse whitish discoloration ofthe fingernails (Mees' lines), and, later,
keratotic lesions of palms and soles which can evolve into skin tumors, and
by the finding of elevated arsenic levels in urine, hair, and nails.
The mechanism of the hypopigmentation is unknown.
CORTICOSTEROIDS
Depigmentation can follow either topical or intralesional injection of corticosteroids.
Kestel [89] first reported hypopigmentation associated with the use of corticosteroid tape. The tape alone (without the steroid preparation) did not produce the hypopigmentation, which was restricted to the sites of use of the
corticosteroid tape. In this case, the skin remained hypopigmented for about
one week, then slowly repigmented. Another patient applied flurandrenolide
tape to the side of her neck two times for 10 to 12 hours each. Approximately
one month later, hypopigmentation appeared in the area of previous application
and remained unchanged for five months. A 21-year-old female found herself
unable to tan in sites where triamcinolone acetonide cream had been applied
three times a day for one month. Arnold et al. [90] found topical depigmentation
to be fairly rapid, incomplete and reversible. Amelanosis does not occur.
Hypopigmentation may also complicate corticosteroid injections [91,92].
499
CHEMICAL
HYPOMELANOSIS
500
CHAPTER 5
BUTYROPHENONE
Butyrophenone
(4-(3-azaspiro/5 ,5/undec-3/yl)-4' -fluorobutyrophenone),
which has been used as an antipsychotic agent, may induce depigmentation
of hair. Simpson et al. [99] observed hair color changes in four of 10 patients
receiving large doses of butyrophenone (45 to 300 mg daily) for two or three
weeks. During treatment, these four Caucasoid patients developed a peculiar
501
eyelashes. eyebrows. beard. and pubic hair. None of the three black patients
or the two Puerto Ricans of this group was affected.
All these disturbances proved reversible once butyrophenone was discontinued. Although the exact mechanism of this depigmentation is unknown. it
seems likely that it is related to disturbances in keratinization. probably induced
by an interference of the drug with cholesterol metabolism. Decreased cholesterol blood levels were found in several of these patients during the treatment.
CHLOROQUINE DIPHOSPHATE
Amelanosis of hair following the administration of chloroquine was first
reported by Alving et al. [100] in 1958 (Fig. 197). This phenomenon occurred
in blond subjects taking 0.3 g daily. Another subject developed the same changes
on a weekly dose of 0.5 g; the decreased hair color reversed spontaneously
when the dosage was reduced. In three blond patients with lupus erythematosus
treated with 0.5 to 0.75 g of chloroquine diphosphate daily. decreased hair
CHEMICAL
HYPOMELANOSIS
502
CHAPTER 5
color occurred from three to seven weeks after the treatment was instituted;
not only the scalp but also the eyebrows were involved in some patients. Lanugo
hair was unaffected. The hair returned to normal color about three weeks after
treatment was discontinued. Other similar cases have been reported [101-104].
Although chloroquine-induced hair depigmentation occurs mainly in patients with blond hair, Schoch [104] observed it in a brown-haired woman. He
later mentioned a young woman who was blond until age 20, when her hair
spontaneously darkened; while taking chloroquine, her hair again became blond.
Sharvill [105] also reported a brown-haired patient in whom the scalp hair and
the eyebrows turned white. Depigmentation of the hair of red-haired individuals has also been reported [106]. Saunders et al. [107] reported 10 cases of
dilution of reddish or blond hair color following chloroquine diphosphate
therapy. Similar alteration of hair color has been reported in patients ingesting
hydroxychloroquine sulfate [108].
Hypopigmentation of the skin as well as of the hair has been observed in
one patient [109] ingesting chloroquine.
The mechanism by which chloroquine diphosphate induces pigmentary
changes in the hair is unknown. Chloroquine has been found to have little or
no in vitro effect on mammalian tyrosinase. Although there was a significant
lengthening of the induction period for tyrosine oxidation, this could not account for the observed clinical effects [107]. Chloroquine feedings to flies or
to guinea pigs failed to produce any color changes. However, instillation of
chloroquine into the yolk sac [107] depigmented feathers of the Rhode Island
Red chick. No change in the pigmentation in the Black Minorca chick could
be induced by the same procedure [107]. The latter results suggest that chloroquine diphosphate induces a block in the synthesis of pheomelanins but not
in the eumelanin pathway. The exact site of the block in the metabolic pathway
is unknown.
ESERINE
Four cases of depigmentation of the eyelids due to use of eserine ophthalmic
ointment have been reported [110]. A possible potentiation of the effect of
acetylcholine may be responsible, but the mechanism of the depigmentation
is unknown.
EPINEPHRINE
Injection of epinephrine into pigmented rats caused a local alopecia areata
and subsequent regrowth of white hair [111]. Epinephrine must have an effect
on melanin production; in rats, when hair had been plucked prior to injection
of epinephrine, the regrown hairs were amelanotic [112].
It has also been suggested that an oxidation product of epinephrine is the
inhibitor of melanogenesis [111]. Since ischemia has been shown to induce
depigmentation in animals [113], it is possible that epinephrine-induced vasoconstriction destroys hair bulb melanocytes.
503
CHEMICAL
HYPOMELANOSIS
PHOTOTOXIC DRUGS
In Japan, leukomelanoderma frequently occurs in patients treated with
chlorothiazide. The pigmentary abnormalities occur mainly on exposed skin.
As chlorothiazide is a well-known phototoxic and photoallergic agent, it is
possible that this leukomelanoderma is a phototoxic reaction and that the
pigmentary changes are postinflammatory.
Tetracycline, another phototoxic drug, has been reported to induce pigmentary changes (Fig. 198). Tanioku and Ono [114] reported a 36-year-old
female patient who, three days after tetracycline administration, developed a
phototoxic eruption which resolved in seven days. One month later, she developed leukomelanoderma on the face and dorsa of the hands and feet.
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CINNAMIC ALDEHYDE
73a. Mathias CGT et al: Perioral leukoderma simulating vitiligo from use of a toothpaste containing
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HYDROGEN PEROXIDE
74. Wolfram LJ et al: The mechanism of hair bleaching. I Soc Cosm Chern 21:875-900, 1970
75. Mahrle G, Orfanos CE: Haarfarbe und Haarpigment. Elektronenmikroskopische Untersuchungen am natiirlichen und gebleichten Haarpigment. Arch Dermoto! Forsch 248:109-122, 1973
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MEPHENESIN CARBAMATE
78. Spillane JD: Brunette to blonde: depigmentation of human hair during oral treatment with
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TRIPARANOL (MER-29)
79. Goodman OS et al: The metabolism of demosterol in human subjects during triparanol administration. J Clin Invest 41:962-971, 1962
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DINITROCHLOROBENZENE (DNCB)
84. Holzegel K: Vitiligo als Dauerfolge von Epikutantestungen. Dtsch Gesundheitsw 28:133-136,
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85. Grosshans E et al: Criteres du diagnostic clinique du vitiligo. Bull Soc Fr Dermato! Syphiligr
81:519-526, 1974
ARSENIC
86. Cannon AB, Karelitz MB: Vitiligo from arsphenamine dermatitis and from arsenic of unknown
origin. Arch Dermato! Syphilo! 28:642-681, 1933
87. Jeghers H: Pigmentation of the skin. N Eng! J Med 231:122-136, 1944
CORTICOSTEROIDS
89. Kestel JL Jr: Hypopigmentation following the use of Cordran tape. Arch Dermato!103:460-461,
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90. Arnold J et al: Depigmenting action of corticosteroids. Dermatologica 151:274-280, 1975
91. Di Stefano V, Nixon JE: Steroid-induced skin changes following local injection. Clin Orthop
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92. Morris WJ: Undesirable side effects following intralesional corticosteroid therapy. Calif Med
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96. Dupre A, Fournie A: Leucodermies secondaires 11. des injections de corticoides. Bull Soc Fr
Dermatol Syphiligr 80:616-618, 1973
507
CHEMICAL
HYPOMELANOSIS
508
CHAPTER 5
97. Rimbaud P et al: Complications dermatologiques locales second aires aux injections cortisonees.
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Langue Fran"aise. Ajaccio, 1976
BUTYROPHENONE
99. Simpson GM et al: Cutaneous effects of a new butyrophenone drug. Clin Pharmacol Ther
5:310-321, 1964
CHLOROQUINE DIPHOSPHATE
100. Alving AS et al: Studies on the chronic toxicity of chloroquine. J Clin Invest 27:60-64, 1958
101. Fuld H: Chloroquine and bleaching of hair (letter). Br Med J 2:300, 1956
102. Payne RS: Personal communication to the authors, in Saunders TS et al: Decrease in human
hair color and feather pigment of fowl following chloroquine diphosphate. J Invest Dermatol
33:87-90, 1959
103. Schoch AB: Bull Assoc Milit Dermatol 4:16, 1955. Quoted in Saunders TS et al: Decrease in
human hair color and feather pigment of fowl following chloroquine diphosphate. J Invest
Dermatol 33:87-90, 1959
104. Schoch AG: Personal communication to the authors, in Saunders TS et al: Decrease in human
hair color and feather pigment of fowl following chloroquine diphosphate. J Invest Dermatol
33:87-90, 1959
105. Sharvill DF: Bleaching of hair by chloroquin. Br Med J 1:1035, 1950
106. Tye MJ et al: Chronic discoid lupus erythematosus. Treatment with Daraprim and chloroquine
diphosphate (Aralen). N Engl J Med 251:52-55, 1954
107. Saunders TS et al: Decrease in human hair color and feather pigment of fowl following
chloroquine diphosphate. J Invest Dermatol 33:87-90, 1959
108. Scherbel AL et al: Further observations on the use of 4-aminoquinoline compounds in patients
with rheumatoid arthritis or related diseases. Cleve Clin Q 25:95-111,1958
109. Marriott P, Borrie PF: Pigmentary changes following chloroquine. Proc R Soc Med 68:535-536,
1975
ESERINE
110. Jacklin HN: Depigmentation of the eyelids in eserine allergy. Am J Ophthalmol 59:89-92,
1965
EPINEPHRINE
111. Munam LP: Depigmentation of hair by oxidized adrenaline solutions (letter). Lancet 1:600,
1953
112. Selye H: Ischemic depigmentation. Experientia 23:524, 1967
113. Shelley WB, Ohman S: Epinephrine induction of white hair in AcI rats. J Invest Dermatol
53:155-158, 1969
PHOTOTOXIC DRUGS
114. Tanioku K, Ono K: Phototoxic and photoallergic problems in Japan, Sunlight and Man:
Normal and Abnormal Photobiologic Responses. Edited by MA Pathak et al. Tokyo, University
of Tokyo Press, 1974, pp 483-493
6
Hypomelanosis Associated with
Inflammation
LUPUS ERYTHEMATOSUS
Hypopigmentation with or without marked cutaneous atrophy is frequently
observed in sites of resolving discoid lupus erythematosus (Fig. 201). Depigmentation can also be observed in systemic lupus erythematosus; Tuffanelli
and Dubois [4] found localized depigmentation in 4.8% of 520 patients with
509
510
CHAPTER 6
spongiosis
and edema
~J
decreased secretion
of melanosomes
re lated to structural
alterations in
kerat inocytes
FIGURE 200.
511
HYPOMELANOSIS
ASSOCIATED
WITH
INFLAMMATION
FIGURE 201. a, b: Hypopigmented macules in two patients with discoid lupus erythematosus.
Lesions are atrophic.
512
CHAPTER 6
systemic lupus erythematosus. The depigmentation was most commonly postinflammatory. The mechanism is unknown but may be a transfer block.
ACHROMIC GUTTATE PARAPSORIASIS
Achromic guttate parapsoriasis, first described by Lortat-Jacob and Fernet
[5], is not uncommon. The lesions are small, white, round macules 1 ern in
diameter, scattered on the neck, trunk, and limbs (Fig. 202). Sometimes they
almost invariably absent. This is a chronic disease that lasts from several months
to five to 10 years with occasional remissions of variable duration.
Since the hypo pigmentation occurs only in sites involved with or previously involved with typical papules of guttate parapsoriasis, the depigmentation in achromic guttate parapsoriasis is likely postinflammatory.
In the presence of hypopigmentation and typical lesions diagnosis is easy.
When hypopigmentation is the only cutaneous finding, history of the disease
is helpful but leukoderma of secondary syphilis, achromic tinea versicolor, and
other postinflammatory hypomelanoses must be excluded.
No effective treatment is available.
PSORIASIS
Three types of hypo pigmentation have been seen with psoriasis. These
include postinflammatory hypomelanosis, vitiligo, and Woronoff's ring.
Postinflammatory hypopigmentation, which is the most common, appears
after the disappearance of the typical psoriatic plaque (Fig. 203). Increased
keratinocyte turnover may interfere with the transfer of melanosomes from
melanocytes to keratinocytes (Fig. 204). More recent views of the role of cyclic
AMP, both in epidermal turnover and in melanogenesis, may give further in-
FIGURE 203. Postinflammatory hypomelanosis in a patient with psoriasis. Woronoff's ring may
be seen on the left arm.
513
HYPOMELANOSIS
ASSOCIATED
WITH
INFLAMMATION
514
CHAPTER 6
CONVEYOR BELT -
- - - ff.
abnormal
melanosome transfer
..
,
'
.-.-.
.-
FACTORY
(melanocyte)
increased speed
of conveyor belt
(increased turnover
of kerat inocytes)
sight into this problem. It is also possible that the depigmentation may, at least
in part, result from topical steroid therapy.
Vitiligo has been reported in patients with psoriasis. Both are, of course,
common problems, but in some patients the vitiligo and the psoriasis involve
the same skin surfaces; or different areas may be involved . This problem has
been discussed (see "Vitiligo" in Chapter 1).
In 1926, Woronoff [6] described hypomelanotic halos surrounding indi-
FIGURE 205. Appearance of psoriatic lesions and hypo pigmented halos (arrow points to most
prominent one) prior to treatment. (From: Koplon BS et al: The Woronoff ring of psoriasis: study
of a patient. Int J Dermato1 10:235-238, 1971. Copyright, 1971, J. B. Lippincott Co. Used with
permission.)
515
HYPOMELANOSIS
ASSOCIATED
WITH
INFLAMMATION
516
CHAPTER 6
PITYRIASIS ALBA
Pityriasis alba is a common entity consisting of slightly scaling, round to
oval, often poorly circumscribed macules of mild to moderate (1 to 2 + hypopigmentation).
History
The initial cases of pityriasis alba described by Fox [10,11] involved partial
depigmentation of the face of several black children [10-12]. In 1924, PardoCostello and Dominguez [13] described a similar but more extensive dermatosis,
"achromia parasitaria," from which Aspergillus was isolated in six of 36 cases.
The various names that have been used to describe the disease include pityriasis
streptogenes, pityriasis corporis, pityriasis simplex facei, erythema streptogenes [14], pityriasis impetigo furfuracia, chronic impetigo, pityriasis sicca
facei, pityriasis alba facei, and achromatous pityriasis facei. The name "pityriasis alba" suggested by O'Farrell [15] was thought by Wells et al. [16] to be most
suitable, for the name is morphologically appropriate and etiologically noncommittal.
Common
Sex
Female = male
Age of onset
Elementary lesion
Color
Shape
Size
Borders
Local symptomatology
Distribution
Course
Race
Pityriasis alba occurs in all races. Although it may involve whites [18,19],
it is considered more frequent in blacks [16]. However, as the disease is primarily of cosmetic importance, and as a depigmenting process is more visible
in dark-skinned people, this increased incidence among blacks may be more
apparent than real. That all 67 cases collected at the Mayo Clinic over 10 years
were Caucasoid is hardly surprising because the Mayo Clinic population at
large is 99% white.
The disease is found worldwide; series are reported from North America
[16], South America [13], Europe [20], and Africa [17].
Sex
Both sexes are probably equally affected. Of 67 cases, 37 were females and
30 males [16]. A marked male prevalence of up to 78% has been reported [17,21].
Age
Pityriasis alba is a disease of childhood and adolescence. Among 200 patients with pityriasis alba [17], 90% were between six and 12 years and about
10% between 13 and 16 years of age. Wells et al. [16] noted a predominance
of the condition among children in the prepuberal age group. However, adults
may also be affected [16]; onset at 39 and 41 years of age has been reported.
Precipitating Factors
Various seasonal and climatic factors have been reported to influence pityriasis alba. O'Farrell [15] observed that pityriasis alba becomes more apparent
517
HYPOMELANOSIS
ASSOCIATED
WITH
INFLAMMATION
518
CHAPTER 6
FIGURE 207.
a, b: Typical lesion of pityriasis alba. The surface of the macules has a filmy, scaly,
or whitish, dry, powdery appearance, sometimes with slightly raised borders.
Clinical Description
The primary lesion is a pale pink, round, oval, or irregular, scaling macule
with ill-defined borders (Figs. 207, 208). The lesions usually vary in size from
5 to 30 mm, but larger lesions may occur. Usually, there are only two or three
lesions; however, there may be from one to 20 lesions or more. The early lesions
are erythematous; after a few weeks the erythema fades and the cutaneous
surface assumes a whitish, dry, powdery appearance, sometimes with slightly
raised, pink or reddish borders. The scale is characteristically fine or powdery.
The face is the most frequent site of involvement. In 20 cases, the following
sites of facial predilection predominated: midforehead, 64%; malar ridge, 56%;
angles of the mouth, 37%; lateral periorbital area, 35%; paranasal area, 18%;
and lateral supraorbital area, 14%. Macules of pityriasis alba occur less commonly on other parts of the body, namely the neck, trunk, back, limbs, and
scrotum. In 200 cases [17], involvement of the legs was noted in four patients
and involvement of the extensor surfaces of the arms and forearms in two
FIGURE 208. a: A child with a few hypomelanotic macules on the face. The contrast between
the involved skin and the normal surrounding skin is subtle and the borders poorly defined. b:
Large hypomelanotic macules distributed on the arm of another patient.
519
HYPOMELANOSIS
ASSOCIATED
WITH
INFLAMMATION
520
CHAPTER 6
Histology
Histologic examination [15] shows a nonspecific dermatitis. There are varying degrees of hyperkeratosis and parakeratosis. Silver stain shows reduced
pigment in the basal layer of the epidermis. There is a moderate dilatation of
the vessels in the superficial dermis, a slight perivascular lymphocytic infiltrate,
and edema of the upper dermis. Appendages are normal. Split-dopa and electron microscopy studies have not been reported.
Pathogenesis
Although pityriasis alba has been said to arise from lack of cleanliness
[22], vitamin deficiencies [23], or unknown nutritional factors [24], the etiology
remains unknown. Pityriasis alba has also been considered a form of seborrhea,
eczema [25], or an abortive form of impetigo. Search for microbial or fungal
agents has been unrewarding. Dobes and Jones [19] noted cultured J3-hemolytic
streptococcus from five of seven patients. On the other hand, Wells et al. [16]
found Staphylococcus aureus in only one case and nonpathogenic staphylococci in two cases. Bassaly et al. [17] consistently found negative bacterial
cultures in 68 cases.
Aspergillus has been reported to cause pityriasis alba [13], but Wells et al.
[16] and Bassaly et al. [17] found fungal studies consistently negative. Bassaly
et al. [17] did find several fungi (Aspergillus-Trichophyton spadix) in a small
number of their cases but considered this fortuitous contamination. No bacteria
or fungi can be implicated in the pathogenesis of pityriasis alba.
The pathogenesis of the primary lesion remains unknown. O'Farrell [15]
concluded that pityriasis alba is eczematous dermatosis of complex etiology.
Wells et al. [16] consider pityriasis alba to originate from a nonspecific erythema
with a mild dermal inflammatory infiltrate which somehow results in localized
hypopigmentation, possibly because of ultraviolet screening by the hyperkeratotic and parakeratotic epidermis. Bassaly et al. [17] observed that in Egypt
pityriasis alba seemed to disappear in Mayor June and then reappear in the
same areas in November or December, and they speculated that hot summer
sun stimulated seborrheic and sudoriparous activity and cleared pityriasis alba.
Diagnosis
In a young patient, the presence of hypomelanotic slightly scaling macules
with poorly defined margins suggests a diagnosis of pityriasis alba. Lesions are
usually larger than those of tinea versicolor, which can be excluded by a scraping for fungus. Trichrome vitiligo usually has discrete margins and is accompanied by typical amelanotic lesions elsewhere. Postinflammatory hypomelanosis must be excluded by history.
Treatment
No effective treatment is available. Topical hydrocortisone combined with
exposure to ultraviolet radiation may be effective. Emollients seem to be as
effective as anything else [16,17].
REFERENCES
J Invest Dermatol
45:465-474, 1965
Sarrat H, Nouhouayi Y: Les modifications du pigment melanique cutane rencontrees chez
l'Africain au caves de diverses dermatoses. Int J Dermatoll0:44-60, 1971
Pinkus H et al: The symbiosis of melanocytes and human epidermis under normal and abnormal
conditions, in Pigment Cell Biology. Edited by M Gordon. New York, Academy, 1959, pp
127-138
Tuffanelli DL, Dubois EL: Cutaneous manifestations of systemic lupus erythematosus. Arch
Dermatol 90:377-386, 1964
Lortat-Jacob L, Fernet P: Quoted by Degos R: Dermatologie, Dyschromies. Paris, Editions Medicales Flammarion, 1953, pp 126-127
Woronoff DL: Die peripheren Veriinderungen der Haut urn die Effloreszcizen Psoriasis vulgaris
und Syphilis corymbosa. Dermatol Wochenschr 82:249-257,1926
Penneys NS et al: Pathogenesis of Woronoff ring in psoriasis. Arch Dermatol 112:955-957,
1976
Bettman S: Kapillarmikroskopishe Untersuchungen bei Psoriasis. Derm Wschr 83:1223, 1926
Herrmann F, Kanof ND: The flourescein pattern of dermatoses. J Invest Derm 8:421-432, 1947
Koplon BS et al: The Woronoff ring of psoriasis: study of a patient. Int JDermatoll0:233-236,
1971
Warin AP, Greaves MW: Woronoff's rings with PUVA therapy. Arch Dermatol115:105, 1979
Fox H: Partial depigmentation of the face of a Negro. Arch Dermatol Syphiloll0:78-79, 1924
Fox H: Partial depigmentation of the face and arms. Arch Dermatol Syphilol12:753-754, 1925
Fox H: Partial depigmentation; chiefly on the face in Negro children. Arch Dermatol Syphilol
7:268-269, 1923
Pardo-Castello V, Dominquez M: Achromia parasitaria. Arch Dermatol Syphilo19:82-95, 1924
Weidman F: Quoted by Dobes WI, Jones J: Erythema streptogenes. Arch Dermatol Syphilol
53:107-114, 1946
O'Farrell MM: Pityriasis alba. Arch Dermatol 73:376-377, 1956
Wells B et al: Pityriasis alba: a ten year survey. Arch Dermatol 82:183-189, 1960
Bassaly M et al: Studies on pityriasis alba. Arch Dermatol 88:272-275, 1963
2.
3.
4.
5.
6.
7.
8.
8a.
9.
9a.
10.
11.
12.
13.
14.
15.
16.
17.
521
HYPOMELANOSIS
ASSOCIATED
WITH
INFLAMMATION
522
CHAPTER 6
18. Wise F: In discussion of Fox H: Partial depigmentation; chiefly on the face in Negro children.
Arch Dermatol Syphilol 7:268-269, 1923
19. Dobes WI, Jones J: Erythema streptogenes. Arch Dermatol Syphilol 53:107-114, 1946
20. Pautrier LM: Quoted in Brand A, Tas J: Pityriasis simplex faciei (dartre volante). Dermatologica
105:145-153, 1952
21. Gaul LE, Underwood GB: Relation of dew point and barometric pressure to chapping of normal
skin. J Invest Dermatol19:9-19, 1952
22. Brand A, Tas J: Pityriasis simplex faciei (dartre volante). Dermatologica 105:145-153, 1952
23. Bacarini I, Diniz 0: Dartre volante: an account of its etiology and treatment (abstr). Excerpta
Medica 5:414, 1951
24. Tas J: Pityriasis simplex (dartre volante). Dermatologica 108:202-208, 1954
25. Unna PG: Quoted by Tas J: Pityriasis simplex (dartre volante). Dermatologica 108:202-208,
1954
7
Infectious and Parasitic
Hypomelanosis
LEPROSY
Leprosy is a chronic and contagious human disease that mainly affects the
skin and the peripheral nervous system, but which may also involve the mucous
membranes of the upper respiratory tract, the eye, the superficial lymph nodes,
the testes, and other organs. Hypopigmentation is one of the main cutaneous
features of leprosy (Figs. 209, 210).
Clinical Features
Etiology and Epidemiology
The disease is widespread in tropical and subtropical countries and endemic in some temperate zones.
Race
No race is spared.
Sex
523
524
CHAPTER 7
FIGURE 209.
FIGURE 210.
chella.)
525
INFECTIOUS AND
PARASITIC
HYPOMELANOSIS
526
Age
CHAPTER 7
Heredity
There may be a genetic predisposition in leprosy.
Classification
The current classification of leprosy is based on the degree of host resistance
[2].
Many bacilli
Tuberculoid or
occasionally
sarcoidal
structure
None-a few during
reaction
Positive
Nonspecific
inflammatory
reaction
Absent or few
Positive or negative
Unstable-regress
or progress into
more definite
types
Histopathology
Bacilli
Lepromin test
Course of the
disease
Stable
None. or as in
tuberculoid
leprosy
Association of
tuberculoid and
lepromatous
structures
Dryness-slight
scaling or atrophy
Negative or weakly
positive
Unstable
Stable to
progressive
Negative
Lepromatous
infiltrate with
Virchow cell
(foamy
macrophages)
Abundant bacilli
None
None
Variable
Variable
None
None
Pronounced
anesthesia
Alopecia
Hypesthesia
Sensory
changes
Alteration of
hair
Other skin
changes
Asymmetricwidespread
Asymmetricexposed areas
Multiple
Macules
Lepromatous
Variable
Large
Ill-defined.
indistinct
Symmetricextremities.
buttocks. face.
sparing of
warmer regions
Slight anesthesia
Distribution
Variable
Small
Ill-defined
Variable
Small
Well-defined with
raised borders
Asymmetricextremities. back.
buttocks. face
Usually single or a
few
Variable
Small
Ill- or well-defined
Number
Shape
Size
Borders
Macules
Macules or infiltrated
plaques
Multiple
Borderline or
dimorphous
Macules or
infiltrated plaques
Single to few
Tuberculoid
Type
Indeterminate
TABLE 116.
oga:>
cn .... Z
Cilno
~~@
"J:j
.z. .
o
tEl
E!::'"tIQ
tEl:> ......
:x
.'"tI. :
en
N
"'I
528
Lepromatous Leprosy
CHAPTER 7
529
INFECTIOUS AND
PARASITIC
HYPOMELANOSIS
Indeterminate Leprosy
In indeterminate leprosy, the macules are usually hypopigmented but may
also be erythematous. There is usually a single lesion, but there may be more.
The lesions are asymmetrically distributed, mostly on the exposed areas, but
also on the trunk, limbs, or buttocks. The borders, which are well- or ill-defined,
are flat and not infiltrated; the hair is normal. The macules may be hypesthetic
or anesthesic and the histamine test may show sympathetic dysfunction. These
lesions may regress spontaneously or may evolve into one of the more definite
types of leprosy.
Histology
530
CHAPTER 7
531
INFECTIOUS AND
PARASITIC
HYPOMELANOSIS
FIGURE 214.
FIGURE 215.
532
CHAPTER 7
activity but they were unable to identify the cause of this alteration in the
melanocyte.
Electron Microscopy Studies
Breathnach et al. [6] observed that melanocytes appeared ultrastructurally
normal in nine patients with leprosy. In two cases of hypopigmented lesions
of indeterminate leprosy studied by Job et al. [8] the number of melanocytes
was greatly reduced. Some of these cells showed vacuolization or atrophy,
fewer showed mitochondria and a dilated endoplasmic reticulum. In some
others, the number of melanosomes was decreased, the endoplasmic reticulum
was reduced, and the Golgi apparatus barely apparent. Retraction of the cytoplasm of some melanocytes from adjacent keratinocytes was observed and
the space thus provided was filled with a granular material. Folding and replication of the basement membrane were found in areas of contact with several
basal melanocytes. Job and Mathan [9] also noted that melanosomes were poorly
melanized. Various findings have been reported concerning Langerhans cells.
Breathnach et al. [6] found normal numbers. Richter [10] found that, in early
cases of leprosy, the number of Langerhans cells was greatly reduced and most
showed degenerative changes. Job et al. [8] reported an increased number of
Langerhans cells, which generally were of normal appearance, although some
were atrophic or also showed a retraction of the cytoplasm.
Pathogenesis of Hypomelanosis
The mechanism of hypopigmentation in leprosy is unknown.
Having observed no histologic or ultrastructural alterations in the melanocytes, Breathnach et al. [6] concluded that hypopigmentation in leprosy is
probably just a postinflammatory hypomelanosis. This does not explain the
histologic and electron microscopic findings reported by Job et al. [8].
Shira saki [11] concluded that the depigmentation of the epidermis could
be considered a direct sequela of the invasion of lepra bacilli at the melanocyte
level or the peripheral nerve. Shirasaki suggested that melanocytes and peripheral nerves, because of their common neuroectodermal origin, show a peculiar susceptibility to lepra bacilli.
Prabhakaran et al. [12-16] observed that M. leprae contains an enzyme
similar to the tyrosinase of melanocytes. Like plant phenolases and unlike
mammalian tyrosinases, this M. leprae enzyme was able to act on catechols
and dopa. With fairly purified concentrates of M. leprae from lepromatous
nodules, in vitro oxidation of dopa to indole-5,6-quinone was observed. The
investigators suggested that the lepra bacillus converts dopa to a quinone, so
that dopa is unavailable for melanin production. However, there is no correlation between the degree of hypomelanosis and the presence or absence of M.
leprae [17]. The palest areas of skin often have remarkably few bacilli present,
whereas lepromatous nodules with many bacilli frequently show no pigmentary
changes.
Associated Findings
Various features of leprosy may be associated with the cutaneous hypopigmentation.
In indeterminate leprosy, hypopigmented macules are the only cutaneous
finding. There is usually no associated nerve enlargement.
In lepromatous leprosy, hyperpigmented or erythematous macules may be
associated with the achromic ones and are usually the earliest manifestations
ofthe disease. As the disease progresses, plaques, nodules, or diffuse infiltration
appear. Hypopigmentation usually does not persist to this stage.
In tuberculoid leprosy, erythematous plaques may be associated with the
hypopigmented lesions. Enlarged superficial nerves are present, sometimes in
the vicinity of the lesions.
In borderline or dimorphous leprosy, erythematous macules, nodules, or
plaques, which are succulent with a smooth surface and a brownish or a violaceous hue, may be associated with the hypopigmented lesions.
Diagnosis
The diagnosis of leprosy is based on the history (endemic area or familial
exposure to leprosy), on the clinical appearance and the demonstration of
hypesthesia of a skin lesion, and by the presence of enlarged, hard, and tender
nerve trunks at the sites of predilection or near a hypopigmented area of the
skin.
M. leprae can be demonstrated in a skin smear or stained by the Ziehl-Nielsen
method. The diagnosis can be made by biopsy of a skin lesion which may show
typical granuloma or M. leprae on Ziehl-Nielsen stain. Enlarged lymph nodes
may contain M. leprae. In the presence of skin lesions, nerve biopsy is usually
not necessary. The histamine test or sweat test (pilocarpine) is helpful. The
lepromin skin test (Mitsuda) has no diagnostic value but is useful for classification.
533
INFECTIOUS AND
PARASITIC
HYPOMELANOSIS
534
Treatment
CHAPTER 7
YAWS
Yaws is a treponematosis caused by Treponema pertenue and found in
impoverished isolated areas, particularly in Central Africa, where warm humid
conditions prevail. The World Health Organization estimates that 50 million
people over the world are afflicted. Yaws is most common in childhood and
among men more than women.
The disease is acquired through direct contact with fomites or an infected
carrier, usually through an open wound; occasional transmission is attributed
to the Hippelates fly.
Clinical Description
The primary stage, called "protopianoma," "bubo madre," or "mamanpian"
develops at the site of inoculation. An asymptomatic, erythematous, infiltrated
plaque is formed; this ulcerates and may be covered by yellow exudate. The
lesion enlarges centrifugally or by satellites or forms a raised, rounded ulcer
or a raspberry-like vegetation. Fever, malaise, arthralgias, or adenopathy may
occur. After two to six months, the ulcers leave large atrophic and depressed
scars with hypochromic or achromic centers, sometimes surrounded by a dark
halo.
An uncommon presentation of the second stage involves lenticular or hypochromic macules considered to be an id reaction. These are called "babides,"
"framboesides," or "pianides." Headache, fever, bone and joint pain, and generalized adenopathy may occur.
Tertiary yaws features hyperpigmentation, shininess, and chronic thickening of the skin. Because the leukoderma usually follows tertiary yaws, treatment of the latter prevents development of leukoderma. Untreated, the hyperpigmentedskin develops macules of hypopigmentation (Fig. 216). These macules
enlarge until an entire area becomes depigmented. There are no other epidermal
changes.
Browne [19] found depigmentation to be uncommon among those with
yaws-affecting 686 of 45,035, none of whom were under nine and only six of
whom were between 10 and 19 years of age. Of those under 30 years of age,
0.11 % of males and 0.13% of females had leukoderma as opposed to 4.42% of
males and 9.63% of females over 50. Browne suggested the female prevalence
535
INFECTIOUS AND
PARASITIC
HYPOMELANOSIS
FIGURE 216. a, b: Patchy hypomelanosis following tertiary yaws and involving the hands. (Courtesy of S. G. Browne.)
may relate to the fact that the female who is less hairy than the male may have
embryologically different follicular melanocytes that are more susceptible to
treponemal toxins.
There is a characteristic pattern of involvement. Lesions are usually symmetrically placed. The most commonly affected areas are the anterior wrists
(40%), often having a triangular macule the apex of which points inferiorly;
dorsal hands (21 %); and metacarpophalangeal and interphalangeal joints (17%).
Involvement of the feet and legs is much less common (Fig. 217).
Mottled palmar dyschromia is often associated with typical frambesial
hyperkeratosis and contracture, especially of the fourth and fifth digits. Pigment
loss over the dorsal hand is usually patchy and irregular, although it may be
complete over small bony prominences. The olecranon process may be depigmented as may be the fibular head, either side of the tibial crest, anterior ankle,
536
CHAPTER 7
and occasionally large areas of the leg and thigh. Normally deeply pigmented
areas, such as female areolae, scrotum, and penis, may be affected if general
pigment loss is severe. There are only a few affected sites in anyone patient.
In 87 patients, 137 locations were found [19].
Two examples of generalized achromia of limbs have been reported to
follow widespread secondary yaws.
Treatment
Penicillin is the treatment of choice. Treatment prior to the tertiary stage
prevents the development of leukoderma.
PINTA
Pinta, also called "mal del pinto," "carate," "cute," or "cativa," is a chronic,
non venereal treponematosis, caused by Treponema carateum and characterized by partial or complete loss of pigment.
The causative agent, T. carateum, is microscopically identical to the treponemas of syphilis and yaws. Penetration occurs usually through a minute
abrasion or wound.
FIGURE 218.
537
INFECTIOUS AND
PARASITIC
HYPOMELANOSIS
538
CHAPTER 7
and, after some time, "slate blue," show gradations of depigmentation throughout, around the periphery, or in small areas. The presence of alternating macules
of erythema, pigmentation, and leukoderma may give the pintides a mottled
appearance (Fig. 219). Finally, they may become completely depigmented (Fig.
220). Pintides may occur at the same site as the primary lesion but extensive
dissemination may be observed. Although depigmentation occurs in most cases
six months to one year after the appearance of pintides, it may be seen within
two or three months. Leukoderma, or "white pinta," is characteristic of the late
stage of the disease. The occurrence of leukoderma in a patient with pinta
reflects the rate of regression of the lesions rather than the duration of the
disease [21]. Some patients may develop achromic lesions within a few months
(late pinta) while others may require many years to develop depigmented macules (intermediate stage).
The depigmented macules in late pinta may be localized or generalized
and vary in size, shape, and distribution. Near total cutaneous depigmentation
may occur. Depigmented macules are seen on the bony prominences such as
the knuckles, elbows, knees, and ankles. Involvement of the flexor wrist is
common [22,23]. Bilateral symmetry is the rule. The contours of the lesions
are irregular but well defined and are marked by peripheral brownish hyperpigmentation. The color may be white. Sometimes there is also an intermingling
of all varieties of dyschromia, hypochromia, and achromia. Usually, this variant
is extensive and found on the back and extremities. Sometimes, on the flexor
aspect of the upper extremities, especially the forearms, reticulated areas are
observed mixed with pinhead-sized depigmented macules and brownish hy-
FIGURE 219. Mottled pigmentation and depigmentation of the dorsa of the hands of a patient
with pinta. (From: Canizares 0 (Ed): Clinical Tropical Dermatology. London. Blackwell. 1975.
Plate 9. Copyright. 1975. Blackwell Scientific Publications . Used with permission.)
539
INFECTIOUS AND
PARASITIC
HYPOMELANOSIS
FIGURE 220. Late achromic lesions in pinta with peculiar bilateral and symmetric distribution.
(From: Marquez F: Pinta, in Clinical Tropical Dermatology. Edited by 0 Canizares. London, Blackwell, 1975, p 91. Copyright, 1975, Blackwell Scientific Publications. Used with permission.)
Histology
In newly developed primary or secondary lesions, there is spongiosis,
migration of lymphocytes into an acanthotic and spongiotic epidermis, liquefaction degeneration of the basal layer, and loss of melanin. In the papillary
540
CHAPTER 7
FIGURE 221. a-c: Hypopigmentation is associated with thinning. wrinkling. alopecia. and dryness of the involved skin.
Mechanism
The hypomelanosis in pinta may be postinflammatory. In light of the fact
that hypopigmentation is associated with many treponematoses, it must also
be postulated that treponemas may have an inhibitory effect on melanocytes.
541
INFECTIOUS AND
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HYPOMELANOSIS
FIGURE 221
(Continued)
542
CHAPTER 7
Treatment
Either PAM or benzathine penicillin given intramuscularly is the treatment
of choice. Primary or secondary dyschromic lesions disappear after treatment
in four or six months without the occurrence of hypochromia. Rein et al. [21]
observed that penicillin therapy resulted in a complete repigmentation of leukoderma of short duration except for macules over bony prominences. In these
areas, there was only a spotty repigmentation or a reduction in the size of the
patches of leukoderma. In patients with long-standing achromic lesions, repigmentation is rarely observed.
ENDEMIC SYPHILIS
Bejel or endemic nonvenereal syphilis is a treponematosis said to affect
about a million people in the world, particularly in certain districts of Central
America, Ghana, Nigeria, the Middle East, Lower Mongolia, and Tibet. Bejel
affects poverty-striken regions where hygiene is poor. Bejel appears usually in
children over the age of two but may also be seen in adolescents and adults.
There is no racial predisposition and girls are more frequently affected than
boys.
The disease tends to be familial and is usually acquired by nonvenereal
childhood contact from infected children or from articles in daily use and is
transmitted subsequently to adolescents and adults. Most authors think that
the infective agent is Treponema pallidum.
Clinical Description
Hypomelanosis
Other Features
Diagnosis
Epidemiology, other cutaneous features, skeletal lesions, and serologic tests
with treponemal antigens distinguish bejel from pinta, vitiligo, and piebaldism.
Treatment
Treatment is intramuscular penicillin.
Clinical Features
Leukoderma syphiliticum, found frequently on the lateral neck of women,
has been called the "necklace of Venus." It occurs about three months after
infection when roseola is fading, but may be seen sometime later within the
543
INFECTIOUS AND
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HYPOMELANOSIS
544
CHAPTER 7
Treatment
Resolution follows treatment with intramuscular penicillin.
HERPES ZOSTER
A tuft of white hair can mark the site of herpes zoster of the scalp. McCarthy
[29] shows a picture of localized graying of the hair that followed herpes zoster
TINEA VERSICOLOR
Tinea versicolor, a disease which may cause marked hypopigmentation of
the skin, is a chronic, mild, usually asymptomatic infection of the stratum
corneum and is caused by a lipophyllic yeast, Pityrosporum orbiculare, formerly known as Malassezia furfur.
History
Tinea versicolor was first described in 1846 by Eickstedt [30] and in 1847
by Shuyter [31]. Hypopigmentation in tinea versicolor was first described by
Ehrmann [32] in 1908. Later, in 1929, Gougerot et al. [33] found the achromia
of tinea versicolor to be particularly frequent after sunlight exposure. About
this time, many reports of such cases accumulated in the European and American literature [34-38]. That the hypochromia reflected true hypopigmentation
and not a pseudoachromia or contrast phenomenon was clearly established by
Gougerot et al. [39-41] and by Wise and Sulzberger [42], who observed that in
North African or in black patients the involved skin became much lighter and
contained less pigment than the normal surrounding skin.
Several hypotheses were proposed to explain the hypopigmentation.
Wertheim [43], in 1923, studied the role of ultraviolet radiation. In 1927, Kistiakovsky [44] and, in 1936, Lewis and Hopper [45] suggested that hypopigmentation results from obstruction of ultraviolet radiation by the fungus so that
delayed tanning does not occur. On the other hand, in 1933 Ruete [46] suggested
that the depigmentation in tinea versicolor results from some direct interaction
between the fungus and melanocytes.
545
INFECTIOUS AND
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HYPOMELANOSIS
546
CHAPTER 7
Frequent
Sex
FIM
Age of onset
Clinical description
Configuration
Color
Size
Border
Surface
Distribution
Symptoms
Course
Associated cutaneous
findings
1:1
white so that the involved skin appears moderately hypopigmented but not
totally depigmented (Figs. 222, 223). While the contrast between the hypopigmented infected skin and the surrounding normal skin is striking in darkskinned patients, in light-skinned people Wood's light examination may be
required to locate the lesions. The borders of macules are usually sharp to
slightly fuzzy. The scaling may not be very apparent on casual inspection but
may be obvious with a hand lens or when the involved skin is scratched with
a glass slide. Depigmentation without any scaling may remain for months after
spontaneous remission of the actual scaling lesions. Occasionally the lesions
appear slightly raised. Although the lesions are usually asymptomatic, some
patients complain of mild pruritus.
Most commonly, the hypopigmented macules are distributed randomly
over the upper anterior and posterior trunk (Fig. 224). However, involvement
of the proximal extremities, the lower abdomen, and the neck and face may
occur [49] (Fig. 225). Jelliffe and Jacobson [50] described white, depigmented,
scaly, circumscribed macules on the face and perineal and gluteal regions of
black infants with tinea versicolor. A blotchy, somewhat rounded island of
depigmentation, extending as a scattered archipelago onto the abdominal wall
anteriorly and onto the lower back posteriorly was observed in these patients.
Blumenthal [51] reported multiple hypopigmented scaly macules on the penis
in a 63-year-old black man. Palms and soles are never affected.
These macules, once established, do not change. In winter the macules
547
INFECTIOUS AND
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HYPOMELANOSIS
FIGURE 222. Characteristic lesions in achromic tinea versicolor. There are multiple punctate
scaly hypomelanotic macules.
Histology
El Gothamy et al. [52] used histochemical techniques to study melanin
formation in the involved skin of tinea versicolor. In seven patients, although
there was no hypo pigmentation clinically, there was decreased density of melanin granules in keratinocytes and a decreased dopa reaction. Split-dopa preparations of hypopigmented epidermis in another study [53] showed no change
in the density of dopa-positive melanocytes, but the melanocytes appeared
larger and more intensively stained than those of uninvolved areas (Fig. 227).
548
CHAPTER 7
FIGURE 223. a, b: Close-up view of hypomelanotic macules in tinea versicolor. The contrast
between the involved and the normal skin is not striking in fair-skinned patients.
549
INFECTIOUS AND
PARASITIC
HYPOMELANOSIS
FIGURE 224. a: Extensive involvement of the chest, one of the most commonly affected sites in
tinea versicolor. b: Close-up view of raised margin of affected and normal skin.
550
CHAPTER 7
FIGURE 225.
FIGURE 226. The contrast between hypomelanotic macules of tinea versicolor and normal skin
increases after sun exposure.
551
INFECTIOUS AND
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HYPOMELANOSIS
FIGURE 227. Top: Involved skin: Keratinocytes showing paucity of melanosomes within the
cytoplasm. N = nuclei. (x 4500) Bottom: Involved skin: stratum spinulosum melanin aggregation
within dendrite of melanocyte. K = keratinocyte. (x 4500) (From: Charles CR et al: Hypopigmentation in tinea versicolor: a histochemical and electromicroscopic study. Int J Dermato112:43-53,
1973. Copyright, 1973, J. B. Lippincott Co. Used with permission.)
The keratinocyte turnover time did not differ significantly from that of normal
uninvolved skin.
552
CHAPTER 7
Normal
Normal or decreased
Marked "melanin loading" with melanosomes
Melanosomes in melanocytes
Number
Size
Shape
Inner structure
Melanization
Increased
Decreased
Normal (ellipsoidal) and abnormal (round)
Normal (lamellar) and abnormal (granular)
Decreased
Melanosomes in keratinocytes
Number
Distribution pattern
Degradation
Decreased
Variable: no melanosomes in some, complexes in
others
Possibly increased
Transfer of melanosomes to
keratinocytes
Decreased
Other abnormalities
of these cells also showed marked "melanin loading" compared to the dendrites
in normal skin. Melanosomes were irregularly distributed within keratinocytes.
While some of these cells, scattered in the basal and spinous layers, were
overloaded with melanosomes, others showed little or no melanin uptake.
Melanosome packaging was different from normal uninvolved skin; melanosomes were aggregated rather than dispersed. Dark collapsed cells were also
observed scattered throughout the stratum spinulosum. There was a suggestion
that "melanin loaded" cells observed in the basal and spinous layers became
the dark collapsed cells of the upper spinous layer and at the same time lost
their melanosome complexes. The extracellular glycogen granules described
by Keddie [54] were not found.
On the basis of their electron microscopic findings, Charles et al. [53]
suggested the following interpretation of the cellular and subcellular events
that result in hypopigmentation in tinea versicolor: production of abnormally
small melanosomes; partial block in melanosome transfer to keratinocytes; and
possible increased melanosome degradation in lysosomal complexes resulting
in degeneration of keratinocytes,
Similar electron microscopic findings of affected hypopigmented epidermis were observed by Grupper et al. [55] who also found decreased or absent
melanin synthesis, aggregation of mature melanosomes, and structural abnor-
553
INFECTIOUS AND
PARASITIC
HYPOMELANOSIS
554
CHAPTER 7
FIGURE 228. a, b: Electron microscopy shows decreased melanin synthesis with abnormal first
stage melanosomes (small, round, with granular matrix.) I = indeterminate cell; M = melanocyte;
mb = basement membrane. (From: Grupper C et al: Pityriasis versicolor achromiant. Etude ultrastructurale. Note preliminaire a propos de 3 cas. Bull Soc Fr Dermatol Syphiligr 82:114-117,1975.
Copyright, 1975, Masson & Cie, Paris. Used with permission.)
In whitish macules, Wood's light examination shows the skin to be only hypopigmented. In pink to brown macules, the golden-green fluorescence is characteristic. The diagnosis of tinea versicolor may be confirmed by histologic
examination of the scrapings of any of the lesions regardless of their color. The
hyphae seen in epidermal scales are 2.5 to 4 (.Lm in diameter, short, curved and
bent, rarely branching. They are associated in clusters with spherical cells
which have rather thick walls and may reach a diameter of 8 (.Lm. However,
the hyphae may be difficult to demonstrate in old lesions or in the patient who
has been using a fungicide.
Achromic tinea versicolor may be confused with vitiligo, postinflammatory
hypopigmentation, or chronic parapsoriasis. However, history, Wood's light,
and examination of the scales with potassium hydroxide readily differentiate
the hypopigmentation of tinea versicolor from that of other hypomelanoses.
Treatment
There is no one specific drug that will clear the lesions of tinea versicolor
and prevent recurrence of the infection. Sulfur, salicylic acid, or a combination
of both will clear the skin temporarily. Sodium hyposulfite 25% solution or
5% selenium sulfide lotion applied to the skin for five to 15 minutes once daily
for two to four weeks is satisfactory. Clotrimazole and miconazole are also said
to be effective.
To treat the hypomelanosis, EI Gathamy et al. [52] used meladinine (three
tablets, each composed of amoiden 0.01 g and amiden 0.005 g) in a single dose
two hours before exposure to ultraviolet radiation and after local application
of sodium thiosulfate. The incidence of hypo pigmentation was 54.5% in 33
patients treated with this combination, whereas it was 56% in 25 treated with
sodium thiosulfate and ultraviolet radiation alone and 66.7% in 21 patients
treated with sodium thiosulfate only. Hence, the addition of 8-methoxypsoralen to the treatment regimen produced minimal improvement in results.
The authors suggested that the small dose of 8-methoxypsoralen given to the
patients and the fact that the psoralen therapy was administered at the same
time as the specific treatment for the fungus may explain these poor results.
One of our patients treated with PUV A for six weeks failed to respond until
antifungal therapy was given. The role of psoralens is in accelerated tanning
once the fungal infection has been effectively treated. Successful melanogenesis
with natural sunlight alone or with psoralen therapy implies the tinea versicolor
has been adequately treated. Recurrences, however, are not at all unusual.
ONCHOCERCIASIS
Onchocerciasis or blinding filarial disease is caused by Onchocerca volvulus and transmitted to humans by black flies. It most typically affects the
skin, subcutaneous tissue, and the eye.
Onchocerciasis is endemic to sectors of Africa (Senegal to Ethiopia, Angola,
Tanzania), Yemen, the Sudan, and America (Guatemala, Dominican Republic,
Mexico, and Columbia).
555
INFECTIOUS AND
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HYPOMELANOSIS
556
Depigmentation
CHAPTER 7
557
INFECTIOUS AND
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HYPOMELANOSIS
FIGURE 229. a: Typical bilateral depigmentation of the anterior mid tibial region in a patient with
onchocerciasis. b: Symmetrical depigmentation of the chest. (Courtesy of S. G. Browne.
558
Histology
CHAPTER 7
Early Lesions
Many microfilariae are found close to rete pegs, and nearby melanoblasts
of the germinal layer may be slightly disturbed. The moderate round cell dermal
infiltrate does not seem directly related to the microfilariae.
Late Stage
Rete ridges become flattened and micro filariae more numerous. Acanthosis
and hyperkeratosis may appear. Cells of rete pegs may be normal or have a
shrivelled appearance and pyknotic nuclei. Melanocytes may have disappeared, have abnormally shaped melanin granules, or normal granules abnormally distributed. Increased transport of melanin from the basal to the reticular
layer is apparent. The only identifiable melanin present may be at the tips of
the rete ridges.
Final Stage
This is marked by the absence of melanin, thinned epidermis, dermal
fibrosis with increased elastic tissue and collagen, near or complete absence of
microfilariae, total flattening of rete ridges, and a slight lymphohistiocytic infiltrate.
Mechanism
terial infection. This is most common over the trunk, hips, shoulders, and
extensor thighs and arms.
"Mal morado" are localized, nonpitting, violaceous, edematous, oval plaques
associated with massive dissemination from gravid females.
Cutaneous papillomas, regional lymphadenitis, scrotal nodules, hydrocele,
and elephantiasis may occur.
Nodules, which begin as subcutaneous infiltrations, may be movable or
adherent to deeper structures, even within muscle, and vary from several millimeters to 2 to 5 cm in diameter. These firm, painless lesions are found most
commonly on affected Africans, where the trunk is primarily involved, whereas
in Americans the lesions are usually scant in number and localized to the head.
Nodules, which may be calcified, have been reported on scrotal skin.
Microfilariae in the anterior chamber of the eye are diagnostic of onchocerciasis. Chamois iris, acute or chronic iritis, posterior synechiae with secondary glaucoma, punctate keratitis, and tigroid retina have been described.
Diagnosis
Patients from endemic areas with the ocular and cutaneous findings described should have slit-lamp examinations to identify micro filariae in the
anterior chamber of the eye. Mazzotti's test is positive in 92% of parasitologically confirmed cased [63]. Swimming microfilariae may be identified on Tiersch
skin biopsy suspended in saline on a glass slide.
Treatment
There is little to suggest that leukoderma responds to any treatment except
excision of onchocercomata. Browne [62] found that in one-third of those in
whom all onchocercomata were removed, repigmentation occurred from the
margins of normally pigmented skin. The failure of others to repigment may
occur because a depigmenting agent remains in undetected extranodular or
unencapsulated adult filariae or because such a factor has permanently suppressed melanocyte function.
Antitreponemal therapy and oral or topical 8-methoxypsoralen are generally ineffective in repigmenting onchocerciasis, although Browne [62] did
notice slight repigmentation of smaller macules (not the larger dead-white ones)
with the latter.
POSTKALAAZAR DERMATOSIS
Post-kala-azar dermatosis, a post-kala-azar dermal leishmaniasis, may present with hypopigmented macules.
Post-kala-azar dermatosis occurs in patients with untreated or incompletely
559
INFECTIOUS AND
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HYPOMELANOSIS
560
CHAPTER 7
treated chronic kala-azar and may appear one to five years after the initial
infection. The causative agent is the parasite Leishmania donovani, which
infests the skin to produce insidious, nonulcerative granulomas containing the
protozoa. 1. donovani is transmitted by the sandfly.
Post-kala-azar dermatosis is found commonly in India and Bangladesh,
less frequently in the Sudan and East Africa, rarely in China, and virtually
never in Mediterranean countries or South America, despite the fact that kalaazar itself occurs in all these regions. Attempts to eradicate the sandfly have
decreased the incidence of post-kala-azar dermatosis in the world [64].
Sen Gupta and Bhattacharjee [68] described the histology of these hypopigmented macular lesions. A slight decrease in basal layer pigmentation was
the only epidermal change. In the dermis, there is an infiltrate of histiocytes,
lymphocytes, and a few plasma cells in the upper dermis around proliferated
blood vessels and deeper around hair follicles, sebaceous glands, and sweat
ducts. Leishmanias are present in small number and are difficult to demonstrate
within histiocytes. Biopsy of another patient [64] showed a dense bandlike
infiltrate in the upper dermis with histiocytes, plasma cells, and lymphocytes.
561
INFECTIOUS AND
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HYPOMELANOSIS
FIGURE 231. Post-kala-azar dermal leishmaniasis. Hypomelanotic lesions (patient of Dr. Lahiri).
(From: Banerjee BN. Dutta AK: The cutaneous manifestations of kala-azar and post-kala-azar dermatosis. in Clinical Tropical Dermatology. Edited by 0 Canizares. London. Blackwell. 1975. Plate
17. Copyright. 1975. Blackwell Scientific Publications. Used with permission.)
Other Features
The two other cutaneous features include erythematous macules and yellow to pink nodules. A butterfly erythema of the face involving the nose and
cheeks as well as the chin and the perioral skin may also extend to other parts
of the body, particularly those areas that typically become hypopigmented. The
yellowish pink nodules, often compared to xanthoma and varying from pinhead
to plum size. either replace the earlier lesions of hypopigmentation or erythema
or may appear de novo. The face, earlobes, trunk, and genitalia are frequently
involved. Involvement of palms and soles, as well as mucous membranes, may
also be observed. When these nodules disappear, they do not scar or leave
pigmentation abnormalities.
562
CHAPTER 7
Otherwise, patients are healthy, afebrile, and without any sign of visceral
involvement.
Treatment
Systemic treatment with antimonials or diamidines (especially pentamidine-Iomidaine) is effective. Patients with mild disease and few organisms in
lesions may respond better to therapy and tend less to relapse than those with
severe disease and many organisms. Post-kala-azar dermatosis must be treated
with pentavalent antimonials. It is almost impossible to obtain total repigmentation of hypopigmented areas.
TUBERCULOSIS
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66. Napier LE, Das Gupta CR: A clinical study of post-kala-azar dermal leishmaniasis. Indian Med
Gaz 65:249-257,1930
67. Banerjee BN, Dutta AK: The cutaneous manifestations of kala-azar and post kala-azar dermatosis, in Clinical Tropical Dermatology. Edited by 0 Canizares. Oxford, Blackwell, 1975,
pp 197-205
68. Sen Gupta PC, Bhattacharjee B: Histopathology of post-kala-azar dermal leishmaniasis. J Trop
Med Hyg 56:110-116,1953
69. Pearson CA: Hypochromia as a clinical sign of tuberculosis in the tropics. Tubercle 59:111-119,
1978
565
INFECTIOUS AND
PARASITIC
HYPOMELANOSIS
8
Leukoderma Acquisitum Centrifugum:
Halo Nevus and Other
Hypomelanoses Associated with
Neoplasms
The partial or complete regression of benign and malignant tumors is of interest for
it is evident that if on rare occasions forces within the human organism can bring
about spontaneous regression of a tumor, the intellect will some day master the
mechanism of the process.
Rohdenburg, 1927 [1]
HALO NEVUS
Halo nevus [5], also referred to as "Sutton's nevus" or "Sutton's disease,"
is the most common form of leukoderma acquisitum centrifugum. Halo nevus
can be defined as a benign nevus cell nevus undergoing spontaneous resolution
and surrounded by leukoderma (Fig. 232).
History
The first description of halo nevus was not found in the medical literature
but rather was painted by Grunewald, a 16th century artist [6]. On a panel of
567
568
CHAPTER 8
the Isenheimer Altar ("The Temptation of Saint Anthony"), one of the demons
has numerous colored spots surrounded by light areas typical of Sutton nevi.
The first mention in the medical literature of the phenomenon of a macule
of depigmentation surrounding a preexisting pigmented nevus was in an 1874
textbook by Hebra and Kaposi [7], who called this "vitiligo." Additional repdrts
did not appear until the early 20th century. Hyde [8], in 1906, presented a case
of "vitiligo with a central mole." Cases of halo nevus were recorded in 1910
by Rolleston [9] in a jaundiced patient with abdominal carcinomatosis and in
1915 by Almkvist [10], who used the term "nevus anemicus" to describe the
depigmented halo. However, it was Sutton, in 1916 [11], who first recognized
"depigmentation around a brown center resembling a pigmented nevus" as a
distinct entity; he named this "leucoderma acquisitum centrifugum." Stokes
[12], in 1923, first recognized the central tumor to be a nevus cell nevus. The
natural course was elaborated by Kuske [6] who noted that in some enlarging
lesions, the central nevus seems to be gradually obliterated. Gougerot and
Carteaud [13] observed complete disappearance of the central mole. Sutton
recognized the presence of an infiltrate of cells histologically, which he interpreted to be endothelial in nature. Shelmire [14] and Bunch [15] later made
similar observations. There has been much discussion about the nature of the
depigmented macule surrounding the central nevus. Feldman and Lashinsky
[16] suggested the achromic area to be a nevus anemicus and proposed the term
"halo nevus" to describe what they considered to be a nevoid entity composed
of two components, namely, nevus anemicus and nevus cell nevus.
Many others have considered this condition to be a variant of vitiligo.
Montpellier [3] and Petges [17] used the term "perinevoid vitiligo" and Narducci [2] that of "perinevic vitiligo" to emphasize that vitiligo may coincidentally surround moles. In fact, Weber [18] suggested that vitiligo tends to form
around preexisting nevi. Crawford [19] based his assertion that this entity was
a variant of vitiligo on the observation that both presented with hyperpigmented
borders, an observation not confirmed by later studies. Leider and Cohen [4]
concluded that "vitiligo, perinevic vitiligo, leukoderma associated with
syphilis, and psoriasis have a common physiochemical mechanism of inhibition of pigment formation." Leider and Fisher [20] followed the disappearance
569
LEUKODERMA
ACQUISITUM
CENTRIFUGUM
FIGURE 232. a, b: Typical halo nevi composed of a central pigmented nevus surrounded by a
depigmented halo.
570
CHAPTER 8
of the central mole and postulated the nevus also could be involved in a
"vitiliginizing" process. But Poor [21] felt that the presence of islands of pigment
in the epithelium of the halo area differentiate the disease from vitiligo, in
which he considered depigmentation to be total. Kuske [6] also agreed that
there were important clinical differences between the two conditions. Even
today this issue is not well resolved. Many authors consider halo nevus as an
entity sui generis. Stokes [12] believed that central nevus may play an important
role in the pathogenesis of depigmentation, which may result from physiochemical inhibition of melanogenesis. Niles [22] removed the central nevus
and observed no changes in the surrounding halo. He concluded erroneously
that the halo is nevoid in character.
Rohdenburg [1] first suggested an immunologic basis for halo nevus. There
is now considerable evidence to support this hypothesis.
Incidence
Frequency (Tables 120, 121)
Halo nevus does not appear to be uncommon, but its exact frequency has
never been reported. Since over 20% of vitiligo patients (1% to 2% of population) have halo nevi and many have halo nevi without vitiligo, the general
incidence of halo nevus must be about 1% or greater.
Sex
that the latter study from the Armed Forces Institute of Pathology (A.F.I.P.)
would be expected to be biased towards males.
No. of patients
with halo nevus
% with Vitiligo
14
35
100
23
7
21.4
25.7
1.0
47.8
42.8
No. of patients
with vitiligo
62
3.2
545
62
2.9
6.4
50
0.5
14
1.0
10.0
200
348
100
30
Race
Cases have been reported from all parts of the world. No race is spared.
All the 100 patients of Wayte and Helwig [5] were Caucasoids, but this appears
to reflect the A.F.I.P. population which is predominantly Caucasoid. There are
numerous reports concerning halo nevus in black patients [35,37,38]. In the
Kopf et a1. series [24], the black to white ratio of 1:16 shows an insignificant
black predominance compared to the general clinic ratio of 1:19.
Age
Halo nevi have been observed to arise in patients from three to 50 years
of age. In the series of Wayte and Helwig [5], the age of male patients varied
from five to 50 and that of females from eight to 40, the average age being 17
and 18, respectively. The patients of Frank and Cohen [23] were from five to
37 years of age, and those of Kopf et a1. [24] from three to 42 years of age. The
peak incidence is in the second decade-44% [5], 40% [24], and 42.8% [23].
Seventy-five percent of the eight patients of Findlay [36], 86.9% of the patients
of Copeman et a1. [25], and 71.4% of the 14 patients of Frank and Cohen [23]
were under the age of 20. In two series, 85% [5] to 92.8% [23] of halo nevi
occurred within the first three decades of life. No congenital halo nevi have
been reported.
Familial History
Familial cases have been noted but they are uncommon. Kopf et a1. [24]
noted halo nevi among sisters. Another girl with halo nevus and vitiligo has a
sister with multiple halo nevi (personal observation of the authors). Two of the
100 patients reported by Wayte and Helwig [5] had a positive family history
for halo nevus. One of the patients of Kopf et a1. [24] had a positive family
history of vitiligo.
Kopf and Petratos [39] reported a patient's father to have developed premature graying of the hair by 17 years of age and his sister to have a solitary
macule of leukoderma and a caUi-au-Iait spot.
571
LEUKODERMA
ACQUISITUM
CENTRIFUGUM
572
Clinical Features
CHAPTER 8
FIGURE 233. a, b: There is no apparent relationship between the size of the central nevus and
the size of the halo.
scaling, and erythema may follow sunburn but otherwise do not occur. The
depigmented macules do not tan. Most patients are otherwise healthy.
573
LEUKODERMA
ACQUISITUM
CENTRIFUGUM
574
CHAPTER 8
a, b: Multiple halo nevi. Note that not all the nevus cell nevi are surrounded by a
halo of depigmentation.
FIGURE 234.
575
LEUKODERMA
ACQUISITUM
CENTRIFUGUM
FIGURE 235. Anatomic distribution of 108 halo nevi. (From: Wayte DM, Helwig EG: Halo nevus.
Cancer 22:69-90, 1968. Copyright, 1968, J. B. Lippincott Co. Used with permission.)
The Nevus
Most patients with halo nevi specifically observed the involved nevi had
been present many years prior to the development of the halo. In some instances, the nevi are congenital [24,40,44,45]. Never does the nevus develop
in a preexisting macule of leukoderma; in the 100 cases reported by Wayte and
Helwig [5], none observed the pigmented nevus to have developed at the same
time as or after the halo. However, in one of Sutton's two original cases, the
patient's mother stated that the central spot had not been present before the
onset of depigmentation, but this observation is open to question.
Halo Formation
576
CHAPTER 8
FIGURE 236. Trichrome hypopigmented halo around a pigmented nevus. (From: Dupre A et al: Une variante
du vitiligo trichrome de Fitzpatrick. Bull
Soc Fr Dermatol Syphiligr 81:530-532,
1974. Copyright, 1974, Masson & Cie,
Paris. Used with permission.)
577
LEUKODERMA
ACQUISITUM
CENTRIFUGUM
578
CHAPTER 8
1 to 2 cm and resembling the halo nevi in shape and color, but without the
Precipitating Factors
For the majority of patients, no obvious precipitating cause is apparent.
Sunlight, chemical exposure, and familial predisposition have all been suggested.
579
LEUKODERMA
ACQUISITUM
CENTRIFUGUM
FIGURE 240.
Wayte and Helwig [5], noting that the majority of their cases often were
first seen during the months of July and August, suggested solar irradiation to
be a significant factor in the pathogenesis of halo nevi. Four patients of Kopf
et al. [24] and six of the 100 of Wayte and Helwig [5] reported a sunburn
preceding the onset of halo nevus. Another 14-year-old patient first became
aware of his perinevic depigmentation after a severe sunburn sustained while
he was water skiing [43]. However, the broad geographic distribution of the
occurrence of halo nevus makes the relationship of halo nevus to a specific
environmental factor, such as sunlight, extremely difficult to evaluate. It is
likely that sunlight, tanning the normal skin and burning the unmelanized
halo, causes patient awareness.
Chemical exposure may be a significant factor in some cases. Acquired
halo nevi-like lesions attributed to Benoquin [37] and Guanofurocin [48] have
been reported.
There is scant evidence to suggest halo nevus is a genetic disorder. Although most patients have no family history of halo nevus or of other pigmentary disturbances, several observations raise the question of a genetic predisposition. Chisa [49] reported two siblings in whom multiple halo nevi appeared
at nearly the same age. Fitzpatrick and Mihm [50] also observed two siblings
with halo nevus without vitiligo.
580
CHAPTER 8
FIGURE 241.
Associated Disorders
581
LEUKODERMA
ACQUISITUM
CENTRIFUGUM
Vitiligo
Vitiligo and halo nevus occur in the same patient with significant frequency. Between 1% and 47.8% of patients with halo nevus are reported to
have vitiligo, and between 0.5% and 50% of patients with vitiligo are reported
to have concomitant halo nevus (Fig. 241). This concomitant vitiligo is not
thought to represent resolved halo nevi, although the latter are clinically, histopathologically, and ultrastructurally [32] indistinguishable from ordinary vitiligo. The exact sequence of appearance of these two dermatoses varies; the
halo nevus may occur before, during, or after the appearance of the vitiligo.
There are also examples of the occurrence of vitiligo and halo nevus in different
members of the same family.
The relationship between vitiligo and halo nevus (Table 122) is controversial. Halo nevus was initially considered to be a peculiar variety of vitiligo;
some early authors considered halo nevus only the incidental occurrence of
vitiligo around a preexisting mole. Lerner [51] still considers the halo nevus
to be a form of vitiligo. To support his thesis, he cites the seeming scarcity of
nevi other than halo nevi in vitiligo patients, the similar histology in the two
conditions, and the greater occurrence of halo nevi in patients with generalized
vitiligo.
Ito and Yoshida [52] suggested that in vitiligo there is dysfunction in the
region of spinal ganglia; the depigmentation has a corresponding symmetrical
or unilateral quasidermatomal array. But in Sutton disease the neural disturbance is limited to the area of the nevus, resulting in a circumscribed perinevic
lesion with little tendency to extension.
A number of observations support the concept of halo nevus and vitiligo
as separate and distinct entities. Vitiligo and halo nevus certainly do not always
coexist. Those nevi present in vitiligo patients rarely become inflamed and do
not undergo the specific retrogressive inflammatory changes characteristic of
TABLE 122.
Evidence for
Both are pure-white in color.
The histology is similar.
There is an increased incidence
of halo nevi in patients with
generalized vitiligo.
582
CHAPTER 8
halo nevi. Pigmented nevi may even exist in long-standing vitiliginous areas.
Stegmaier [53] found no vitiligo in his 11 cases of halo nevus. The lymphocytic
infiltrate seen in halo nevi usually is absent in vitiligo. Halo nevi lack a hyperpigmented border that may be seen in vitiligo. The course of vitiligo may
occasionally be marked by repigmentation, which is rarely adequate, but halo
nevi do not repigment before resolution of the nevus. In cross-transplantation
studies, no specific resolution or typical inflammatory response could be found
in nevi transplanted into a macule of leukoderma [43].
More recently, Copeman and co-workers [25,54] have suggested that vitiligo
associated with halo nevus is different from ordinary vitiligo and results from
an immune phenomenon directed against both nevus cells and normal melanocytes. But there is no clinical evidence that vitiligo with halo nevus is any
different from that not associated with halo nevus.
In summary, the association between halo nevus and vitiligo appears to
be statistically significant, but concrete evidence to support a common pathogenesis remains elusive.
Leukotrichia
Graying of hair may be observed in the white macule or in the nevus cell
nevus [55]. Graying of hair remote from the site of the halo nevus also occurs
(Fig. 242). Premature graying of the entire scalp has been reported [39]. Several
patients with the triad of leukotrichia, vitiligo, and halo nevus have been reported [42,56].
Melanoma
True halo nevus may accompany melanoma. This is separate and distinct
from the halo occasionally reported around the melanoma itself. Epstein et al.
[57] reported the appearance of multiple prominent halo nevi in five patients
who had undergone surgical excision of a primary melanoma. Clark et al. [58]
also observed multiple halo nevi to occur randomly, unrelated to the site of
the primary or of recurrent metastatic melanoma. The prognostic significance
of this phenomenon is unknown.
Donaldson et al. [59] noted a patient to develop halo nevus, vitiligo, and
uveitis following BCG vaccination immunotherapy for metastatic melanoma.
However, since no skin biopsy was performed, that the central tumor of the
"halo nevus" was a metastatic melanoma cannot be excluded.
Chorioretinitis
Chorioretinitis has been reported in one patient with halo nevus [3].
Pernicious Anemia
Among 125 cases of pernicious anemia, Dawber [60] found four with halo
nevus; one of these also had vitiligo. In all four cases, the central nevus was
583
LEUKODERMA
ACQUlSITUM
CENTRIFUGUM
FIGURE 242. Nevus cell nevus of the scalp with white hair arising in the depigmented halo.
clinically a benign pigmented nevus. No cases of halo nevus were found among
132 controls. The association between pernicious anemia and halo nevus seems
statistically significant.
Histologic Findings
The histopathology of halo nevus is that of a dermal or compound nevus
in an epidermis with reduced or absent melanin content. The appearance of
any given biopsy is a function of the stage at which the biopsy is taken [61,62)
(Fig. 243).
Halo Epidermis
:>
:;:>'
PRIMARY
FACTOR
7J UNKNOWN
,.::- 0:-'~[!)
i!)0 0
~~~
<i)
FIGURE 243.
\_
f)G>
ey@e 6
o (9C1
G
80
(5::)
DH
8(%.
6) ' .
cD
(!)
DH
'--y-----J
~:~J.
('J
@(;e{5), ~_
;~.q;;
,:;'i
~ (;), ~e 0
~__~(9:CD~
LYMPHOCYTES
AND
MACROPHAGES
I.
0>
:;0
~
~
en
The thickness of the epidermis overlying the nevus may be normal, decreased, or increased [5,24,36]. Acanthosis is often associated with nevus cells
at the dermal-epidermal junction [24,35]. Keratinocytes are normal in number
and appearance. According to Wayte and Helwig [5], hyperkeratosis and follicular plugging are frequently observed.
Wayte and Helwig [5] reported that there is no exocytosis or migration of
nevus cells into the upper levels of epidermis. Findlay [36] reported a case
with a thick gelatinous basement membrane, but the basement membrane is
usually normal. The melanin content in the region of the nevus is usually
normal or increased. The dopa reaction may be strongly positive [24,40,43],
but later negative [24]. Few lymphocytes may be seen [43].
Epidermis Surrounding the Depigmented Skin
The transition between the depigmented halo and the surrounding normal
epidermis is histologically abrupt. There is no increased melanogenesis at the
border [5,24] of normal and depigmented skin.
The Central Nevus
The central nevus is a dense nevus cell nevus in the superficial dermis
with deeper extension perpendicular to the involved surface of the skin. Rare
perifollicular extension has been observed. Melanin and tyrosinase activity are
usually found only in the uppermost cluster of epithelioid cells [36] and the
dopa reaction decreases with the depth of the nevus; dopa-negative nevus cells
are located in the mid and lower dermis.
The nevus may be junctional, dermal, or compound but Wayte and Helwig
[5] and Stegmaier et al. [43] found all the nevi to be compound nevi. Nests of
nevus cells are most commonly found in the most superficial areas of the nevus
[5] and isolated small nests in the deepest parts. In the late resolution stage,
nevus cells disappear [23,36].
The morphology of the nevus cells is a function of their location. The most
superficial tend to be polygonal and relatively large (type A nevus cells) [43],
but in the deeper areas the cells are epithelioid or fusiform in shape.
The nevus cells show intense diphosphopyridine nucleotide diaphorase,
lactic, and succinic dehydrogenase activity [5] only in the upper part of the
nodule. Hexokinase and G-6-PD (glucose-6-dehydrogenase) [5] and cholinesterase [43] are negative. Histiocytes within the tumor show maximal acid phosphatase activity.
The nevus cells are not markedly hyperchromic. Pleomorphism and mitotic
figures are unusual [5,24]. Although Wayte and Helwig [5] and Stegmaier et
al. [43] observed no structural changes in the nevus cell nevus, Findlay [36]
described cytologic damage and impending cell death. Kopf et al. [24] also
observed various degrees of nevus cell damage. Nuclear changes including
swelling, chromatin clumping and condensation, pyknosis, and karyorrhexis
vacuolization have been described. Cytoplasmic changes include intracellular
edema, basophilia, and vacuolization [24].
585
LEUKODERMA
ACQUISITUM
CENTRIFUGUM
586
CHAPTER 8
Electron Microscopy
Halo Epidermis
Melanocytes
Although Stegmaier et al. [43] reported the same number of melanocytes
in the halo as in the normal epidermis, melanocytes are decreased in number
[40,64,65] or totally absent [40,63,66,67]. In the remaining melanocytes, the
number of melanosomes is usually decreased and these are mainly stage I
melanosomes [40,66,68].
Hashimoto [65] observed a decreased number of basal melanocytes and a
number of degenerated melanocytes in the upper epidermis in the progressively
depigmented area surrounding a compound nevus. These cells were observed
even in the granular layer and showed various degenerative changes such as
vacuolization, coagulation, segregation of part of the cytoplasm, and autophagocytosis of melanosomes. Serial sections did not show any anatomic connection of these "high level melanocytes" to the basal layer (Figs. 244, 245).
Gauthier et al. [26] noted an abundance of cytoplasmic filaments around the
nucleus in some melanocytes, but the significance of this finding is unknown.
At the ultrastructural level, the depigmentation appears to result from an absence of melanocytes or a markedly reduced number of melanocytes and impaired production of melanin in the remaining melanocytes.
FIGURE 244. Melanocyte M, shows severe vacuolar and coagulation degeneration. M2 also contains many vacuoles and remains in the same position between M, and Langerhans cell L2. It does
not extend toward the basal layer. L2 contains a large number of L cell granules (arrow in inset).
Keratohyaline granule (K) containing granular cells, and horny cells (H) are just above these cells.
Not only the intercellular edema but also severe degenerative changes (*) are seen in malpighian
cells. The rectangle at L2 indicates the area enlarged in the inset. N2 = nucleus of L2 (x 8,000).
Inset x 61,000. (From: Hashimoto K: A case of halo nevus with effete melanocytes. Acta Derm
Venereol (Stockh) 55:87-95, 1975. Copyright, 1975, Society for the Publication of Acta DermatoVenereologica. Used with permission.)
587
LEUKODERMA
ACQUISITUM
CENTRIFUGUM
588
CHAPTER 8
FIGURE 245. Pyknotic nucleus (N) is visible in the same cell (Md shown in Fig. 244. A part of
the cytoplasm is enlarged in the inset and broad arrows in both pictures point to the same area.
Melanosomes in various stages of maturation are seen (broad arrows). Many immature ones appear
to be degenerating in vacuoles. Coagulation necrosis (cn) or dense homogenization of the cytoplasm
is enlarged in the inset. This melanocyte is located among granular cells which contain cytoplasmic
(kJ and intranuclear (thin arrows) keratohyaline granules (x 1200). (Inset x 60,000) (From Hashimoto K: A case of halo nevus with effete melanocytes. Acta Derm Venereol (Stockh) 55:87-95,
1975. Copyright, 1975, Society for the Publication of Acta Dermato-Venereologica. Used with
permission.)
Langerhans Cells
An increased number of Langerhans cells has been observed at the basal
layer [40,63,65,67,69,70]. Studies of Mishima et al. [67] show the total number
of Langerhans cells in the entire epidermis is normal. Usually the Langerhans
cells appear normal. However, Hashimoto [65] observed a few vacuolated cells.
Cesarini et al. [64] described Langerhans cells with "feather-like bodies" (considered to be debris of melanosomes or of Langerhans cell-specific granules),
stage IV melanosomes, and dense vesicles containing pseudomyelin structures,
limited by a unit membrane, perhaps of lysosomal origin. Ebner and Niebauer
[69] observed melanin granules in the cytoplasm of Langerhans cells.
Indeterminate Cells
Zelickson and Mottaz [68] observed the same number of "indeterminate
cells" in the hypopigmented epidermis as in normal epidermis, but Mishima
et al. [67] found an increased number. Well-established older halos may have
no indeterminate cells.
Keratinocytes
Except for pigmentary changes, the keratinocytes are normal. Usually the
number of melanosomes in keratinocytes is decreased [40,63,66] or totally
absent. Stegmaier et al. [43] observed that keratinocytes contained a normal
number of melanosomes and melanosome complexes. Hashimoto [65] described degenerative changes in the keratinocytes. A few lymphocytes have
also been observed in the hypopigmented epidermis [66].
Epidermis Overlying the Nevus
Melanocytes
Melanocytes in the epidermis overlaying the nevus are usually normal in
number and contain numerous melanized melanosomes [40,64]. Tyrosinase
activity is slightly increased [40]. Hashimoto [65] described vacuolated and
shriveled pigmented cells in the upper layers of epidermis, but could not
determine whether these high-level effete cells originated from normal melanocytes or from nevus cells (Fig. 246).
Langerhans Cells
Langerhans cells are normal in number [40,64] and in morphology.
Keratinocytes
Keratinocytes are usually unaffected, except that they may be overloaded
with pigment and contain many melanosomes or melanosome complexes
589
LEUKODERMA
ACQUISITUM
CENTRIFUGUM
590
CHAPTER 8
FIGURE 246. Advancing border of depigmentation. No nevus cells forming a nest are seen.
Transferred melanin pigment is visible in the basal cells and lower malpighian cells but not in
clear cells. Several shrunken clear cells (*) are present near the granular cell layer. Some of the
basal clear cells are vacuolated (x 400). (From: Hashimoto K: A case of halo nevus with effete
melanocytes. Acta Derm Venereol (Stockh) 55:87-95, 1975. Copyright, 1975, Society for the Publication of Acta Dermato-Venereologica. Used with permission.)
[40,64,66]. Cesarini et al. [64] observed a thinning of the epidermis with significant intercellular edema and Jacobs et al. [71] described disruption of some
keratinocytes.
The Nevus
591
LEUKODERMA
ACQUISITUM
CENTRIFUGUM
592
CHAPTER 8
The dermis contained only occasional nevus cells, disrupted mast cells, lymphocytes, and pigment-laden macrophages.
The inflammatory infiltrate is predominantly lymphocytic (Fig. 248). Swanson et al. [63] observed small lymphocyte-like cells, particularly in the deeper
portions of the nevus, and suggested these cells could also represent Type B
nevus cells. Gauthier et al. [26] distinguish the lymphocyte-like cells from the
Type B nevus cells, as only the former have very dense chromatin and unipolar
mitochondria. Although Jacobs et al. [71] considered most inflammatory cells
infiltrating the nevus to be antigenic ally activated lymphocytes, Gauthier et al.
FIGURE 248. Advanced clinical stage. Infiltrate in the deeper dermis. Different types of cells can
be observed: lymphocyte-like cells (Ly), macrophages (Ma), mast cells (Me), and fibroblasts (Fi)
(x 2000). (From: GauthierY et al: Uitrastucture of halo nevi. J Cutan Pathol 2:71-81, 1975. Copyright, 1975, Munksgaard International Publishers, Copenhagen. Used with permission.)
[26] noted that only a few of the inflammatory cells showed ultrastructural
FIGURE 249. Superficial nest of nevus cells in the epidermis [Ep). Nevus cells [Nc) are seen in
contact with several lymphocyte-like cells [Ly) (x 9000). (From: Gauthier Y et al: Ultrastructure
of halo nevi. J Cuton Potho12:71-81, 1975. Copyright, 1975, Munksgaard International Publishers,
Copenhagen. Used with permission.)
593
LEUKODERMA
ACQUISITUM
CENTRIFUGUM
594
CHAPTER 8
FIGURE 250. Close contact between a small mononuclear cell with a deeply clefted nucleus (N)
and a fibroblast-like cell (Fi) (x 25,000). (From: Gauthier Y et al: Ultrastructure of halo nevi. J
Cutan Pathol 2:71-81, 1975. Copyright, 1975, Munksgaard International Publishers, Copenhagen.
Used with permission.)
served that when lymphocytes and nevus cells are in contact, the involved
cells have thickened cell membranes with small ruptures along the points of
contact.
Other types of cells observed include numerous melanophages, some plasma
cells, and a few mast cells. Langerhans cells have been observed in the dermal
infiltrate of halo nevus [70].
Gauthier et al. [26] described multiplication of the basement membrane
and a swollen unmyelinated nerve close to the epidermis, similar to vitiligo.
Neurofibroma
Leszczynski [73] first described halos around multiple neurofibromas in a
healthy 48-year-old woman. Kopf et al. [24] also reported that in one of their
cases the central tumor was not a nevus cell nevus but was a neurofibroma. A
patient with multiple halo neurofibromas and probably Recklinghausen disease
has been reported [74].
The histology surrounding the neurofibroma is essentially that of the halo
of a nevus cell nevus.
Flat Warts
Two patients with depigmented halos around involuting flat warts have
been described [75]. The warts had been unresponsive to three-and-one-half to
five months of topical salicylic acid-propylene glycol gel (Keralyt) usage before
the depigmentation appeared. In both cases all warts with depigmentation
regressed in three to eight weeks. In one of the patients depigmentation appeared around only three of the warts and these were the only warts to disappear. Patch testing with Keralyt applied to normal skin for four to six months
did not induce any depigmentation.
Histologic studies of one lesion showed mononuclear cell infiltrate in the
central lesion with exocytosis of mononuclear cells into the epidermis. Necrosis, spongiosis, and hyalinized epithelial cells were prominent in the epidermis.
The upper epidermis showed lymphocytic infiltration around subpapillary blood
vessels, few histiocytes, edema, dilated papillary and subpapillary vessels, and
focal hemorrhage. Masson silver stain demonstrated absence of melanin in the
halo epidermis.
Neurotized Nevus
Kopf et al. [24] observed two cases in which the central tumor was a neuroid
nevus; most of the nevus cells closely resembled neuroid structures. In both
cases, the tumor within a protruding area of the papillary dermis was amelanotic
595
LEUKODERMA
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596
CHAPTER 8
Blue Nevus
Kopf et al. [24] observed a halo around a lesion that had the typical histologic features of a blue nevus. Apart from a mild perivascular leukocytic
infiltrate in the upper dermis outside the tumor area, the lesion was remarkably
free of inflammatory infiltrate. Iijima and Kanazawa [76] described a similar
case and noted that blue nevus cells were dopa-positive whereas the epidermis
was not.
Garment Nevus
Ridley [41] reported a case of giant congenital nevus that underwent considerable spontaneous resolution (Fig. 251). In the chronically depigmented
skin, there were no residual nevus cells and no inflammation. The dermis
contained some melanin-containing macrophages. Berger and Voorhees [40]
also described a middle-aged woman with a giant pigmented nevus with a wellmarked halo.
Melanoma
Several types of cutaneous depigmentation have been associated with cutaneous melanomas (Table 123). They may occur at the site of the tumor (Fig.
252) or its metastases or at sites distant from the tumor or its metastases.
There are many reports of appearance of the halo phenomenon around a
primary melanoma or cutaneous metastases. Merklen and Pelbois [77] pre-
597
LEUKODERMA
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598
CHAPTER 8
FIGURE 252. Circumscribed area of depigmentation within a primary malignant melanoma. Lesion has been encircled with ink. (From: American Academy of Dermatology Melanoma Home
Study Program. Compiled by TB Fitzpatrick et al. Copyright, 1974, Syntex Laboratories, Palo Alto,
California. Used with permission.)
sen ted a case first thought to represent a benign halo nevus but subsequently
found to be a halo around a melanoma [78). Champion [79) reported as "malignant Sutton's nevus" a central nodular melanoma surrounded by a pale zone
which in turn was almost completely encircled by a zone of senile lentigines.
Stehlin [80) observed a primary melanoma of the foot with a surrounding halo
which appeared after the limb was perfused with chemotherapeutic agents.
Several months later, other pigmented lesions appeared on the patient's back
and depigmented halos developed around these also. Kopf et al. [24) followed
an elderly man with disseminated melanoma who developed depigmented
halos around many of his cutaneous metastases; thereafter, spontaneous resolution of the metastases ensued so that only macular areas of depigmentation
remained. Shapiro and Kopf [81) reported a nine-year-old girl who developed
widespread lymphadenopathy, visceral metastases, and a depigmented halo
around a pigmented cutaneous tumor; histologic studies of the cutaneous tumor
and axillary metastases suggested melanoma. Goldman et al. [82) observed
perilesionalleukoderma appearing suddenly around metastatic melanomas in
many areas of the skin. Other cases have also been recorded [5,58,59,83,84).
The frequency of occurrence of partial or complete halos of depigmentation
around primary or metastatic melanoma has not been firmly established; examination of melanoma patients with a Wood's light may assist in revealing
subtle examples of this phenomenon [82,85).
Depigmentation may be observed at the sites of spontaneous, total or partial
regression of the primary melanoma. In some patients with metastases, cir-
PATHOGENESIS
Over time, halo nevus has been considered to be a neurotrophic, postinflammatory, or an immunologic disorder.
That the leukoderma surrounding a nevus results from a neurotrophic
599
LEUKODERMA
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600
CHAPTER 8
FIGURE 253. Malignant melanoma with hypomelanosis on the dorsum of the foot. remote from
the site of the tumor. (From: Frenk E: Depigmentation vitiligineuse chez des patients atteints de
melanome malin. Dermatologica 139:84-91. 1969. Copyright. 1969. S. Karger A.G. Used with
permission. )
601
LEUKODERMA
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CENTRIFUGUM
602
CHAPTER 8
Sinclair swine probably represent an animal model for halo nevus. Millikan
et al. [96] observed that a large number of melanocytic nevi occur in Sinclair
swine (Fig. 258). The pathology of these lesions and the organ distribution of
metastases mimics human melanomas [97]. Some of these tumors regress dramatically. Regression accompanied by depigmented halos around the tumors
begins with an inflammatory infiltrate and leads to depigmentation and fibrosis.
Ultrastructurally, regressed lesions show an almost complete absence of melanocytes.
The inflammatory infiltrate, which is predominantly lymphocytic in nature, seems to be composed of antigenically activated lymphocytes [26,71]. In
situ immunocytochemical identification by antihuman T or B lymphocyte antigens show that most of the inflammatory cells are T lymphocytes [97a]. Contact
between these cells and degenerating nevus cells or melanocytes has been
observed [57]. Reed et al. [98] suggested that atypical nuclear changes commonly seen in halo nevi prove the existence of melanocytic dysplasia. They
further concluded that the halo reaction more likely results from an abnormal
clone of melanocytes than from the action of an abnormal clone of lymphocytes
against nevus cell nevus.
A number of studies have attempted to demonstrate the presence of a
circulating factor in those with halo nevi. Sumner and Foraker [90] transfused
whole blood from a patient with spontaneously regressing primary and metastatic melanoma into a man with similar lesions. Thereafter, all of the lesions
of the latter disappeared and, following regression of a scalp tumor nodule, the
overlying hair became depigmented while the rest of his hair remained black.
Melanoma-specific protein, immunologically related to altered nevus cell
603
LEUKODERMA
ACQUISITUM
CENTRIFUGUM
FIGURE 257. Vitiligo-like depigmentation involving face and neck as well as circumscribed areas
of otherwise normal skin surrounding each pair of BCG vaccination scars in both deltoid areas in
a patient with metastatic malignant melanoma. There is a halo of depigmentation around an
intradermal lesion in the left supraclavicular area.
cytoplasm has been detected not only in melanoma patients but also in patients
with actively developing halo nevi [99]. Although Kopf et al. [24] were unable
to detect prefixed or 7S gamma globulin antibodies directed against tumor cells
in halo nevi, Copeman and coworkers [25,54] found circulating antibodies
against the melanoma cell cytoplasm in 15 of 23 patients with halo nevi. Antibody cound be detected while the nevi were actively regressing cytologically,
but usually disappeared after this stage so that the halo itself could be present
for some time after the cytoplasmic antibody could no longer be detected. This
antigenic link between halo nevus and melanoma raised the possibility that
benign halo nevus, although all other clinical and histopathologic features
suggest it is benign, may be a manifestation of a seldom seen interim stage of
rejection of an early melanoma arising in such a nevus. The halo nevus must
be just an exaggerated expression of a natural protective mechanism in which
the entire nevus tumor mass rather than perhaps just a few selected cells
undergoes a dramatic, rapid, and massive rejection.
604
CHAPTER 8
FIGURE 258. In many of the Sinclair swine. the first sign of regression of pigmented tumors is
the appearance of depigmented hair around the lesions. These changes in the hair coat allow one
to look deep into the hair to find an involuting lesion. Here we can see some whitening and
keratosis of this lesion. This could be considered as the animal model of human leukoderma
acquisitum centrifugum. (From: Millikan LE et al: Gross and ultrastructural studies in a new
melanoma model: the Sinclair swine. Yale JBiol Med 46:631-645.1973. Copyright. 1973. Academic
Press. Inc. Used with permission.)
common. Rather, the common factor between the two might be the processes
of involution and cell destruction and not malignancy. Apparently a primary
unknown event alters melanocytes and/or nevus cells, and initiates a progressively destructive self-limited immunologic process.
Cytotoxic lymphocytes have been noted in patients with halo nevi [101).
Roenigk et a1. [102) studied tumor immunity by cell inhibition (microcytotoxicity) assay in 11 patients with halo nevus (Fig. 259). The target cells in this
study were derived from cultured melanoma cell lines. Actively regressing halo
nevi showed a high percentage of cell inhibition, whereas inactive halo nevi
had low levels of cell inhibition and of blocking factor. With indirect immunofluorescent microscopy, tumoral antibodies against the cytoplasmic melanoma cell antigen could be demonstrated in five of 11 patients with halo nevi.
They concluded that perhaps cellular cytotoxicity against melanoma cells may
be more important than tumoral antibodies. Clark, Leung, and Mastrangelo
(unpublished data) and Mastrangelo et a1. [103) have also observed that the
lymphocytes of patients with halo nevi with or without melanoma are cytotoxic
to allogenic melanoma cell lines.
Five patients with primary melanoma and multiple halo nevi that developed after the melanoma was excised were subjected to skin testing; these
patients were found to have normal to increased cellular immunity [57). All
four cases evaluated displayed cellular immunity in at least one in vitro test
(lymphocyte stimulation, migration inhibitory factor production, or rosetteforming lymphocytes). Only two of four patients had antibodies cytotoxic to
melanoma cells. It has been demonstrated that cultured lymphocytes from
patients with halo nevi quickly attach to several different lines of cultured
human melanoma cells, after which the tumor cells swell, become vacuolated,
and die [104) .
Stegmaier et a1. [43) proposed the following hypothesis: Dermal nevus cells
become antigenic, attract lymphocytes, and a delayed hypersensitivity reaction
occurs. A soluble substance cytotoxic to melanocytes is produced and attaches
to the nevus cells and to epidermal melanocytes in areas not protected by nevus
cells. There is progressive destruction of nevus cells, active epidermal melanocytes above the nevus cells, and inactive melanocytes beyond the nevus.
60
c:
.2
-:;
:;
FIGURE 259. Comparison of percent
of cell inhibition in patients with halo
nevus (regressing and persisting) and
normal controls scoring greater than 40%
cell inhibition against melanoma target
cells. (From: Roenigk HH Jr et al: Microtoxicity and serum blocking factors
in malignant melanoma and halo nevus .
Arch Dermatol 111:720-725, 1975.
Copyright, 1975 , American Medical Association. Used with permission.)
c.
o
40
11.
'0
'E
e
CD
20
11.
o
5
Normal
Halo Nevus
Halo Nevus
Regressing
Persisting
605
LEUKODERMA
ACQUISITUM
CENTRIFUGUM
606
CHAPTER 8
DIAGNOSIS
The diagnosis of leukoderma acquisitum centrifugum is based on identification of a nevus or tumor with a perilesional hypomelanotic halo. There is
no other clinical entity that is characterized by a central pigmented tumor
surrounded by a symmetrical halo of depigmentation. However, particularly
in fair-skinned individuals, Wood's light examination may be required to detect
those lesions that are inapparent under ordinary light. Macules of depigmentation around senile verruca [105], papular sarcoid [12], vascular nevus [72],
dilated pores [106] and comedones (personal observation by the authors) have
also been noted.
The appearance of a halo of hypo pigmentation around any pigmented
tumor should always lead to a careful clinical scrutiny of the central lesion
(Table 124). The only clinical problem is to be certain the central tumor is not
a melanoma and this distinction is usually not difficult. The age of the patient
TABLE 124. Features of Leukoderma Acquisitum
Centrifugum That May Be Associated with Melanoma
Eccentric placement of tumor
Irregular margin of halo
Pruritus of lesion
Bleeding of lesion
Growth of tumor
Red, white, and blue color of tumor
Appearance in older adult
Note: The primary melanoma may anatomically be elsewhere
Benign Halo Nevus
607
LEUKODERMA
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CENTRIFUGUM
TREATMENT
Patients and particularly the parents of young involved children will need
to be reassured the lesions are not malignant. Typical halo nevi require no
treatment. The natural course is for spontaneous resolution, although this sometimes requires years. In all the cases where there is a clinical suspicion of
melanoma, removal of the entire nevus for histologic examination should be
performed. Patients with one halo nevus are probably at increased risk of
developing more and of developing vitiligo.
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608
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25. Copeman PWM et al: Immunological associations of the halo nevus with cutaneous malignant
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1958
38. Cornbleet T et al: Observations on leukoderma acquisitum centrifugum. Arch Dermotol
82:1011-1012, 1960
39. Kopf AW, Petratos M: Leukoderma acquisitum centrifugum, leukotrichia, and leukoderma
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40. Berger RS, Voorhees JJ: Multiple congenital giant nevocellular nevi with halos. Arch Dermotol
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44. Brownstein MH et al: Halo congenital nevus. Arch Dermotol113:1572-1575, 1977
45. Garcia RL, Gano SE: Halo congenital nevus. Cutis 23:338-339,1979
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39:163, 1939
48. Yamada M: Studies on Guanofuracin leukoderma. Jpn J Dermotol VenereoI65:187-202, 1955
49. Chisa N: Multiple halo nevi in siblings. Arch Dermotol 92:404-405, 1965
50. Fitzpatrick TB, Mihm MC Jr: Abnormalities of the melanin pigmentary system, Dermotology in General Medicine. Edited by TB Fitzpatrick et al. New York, McGraw-Hill, 1971,
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51. Lerner AB: Vitiligo. J Invest Dermotol 32:285-310, 1959
52. Ito M, Yoshida Y: Malignant melanoma. Tohoku J Exp Med 55(suppll):60-71, 1952
53. Stegmaier OC: Transplantation of melanocytic nevi into vitiliginous skin. J Invest Dermotol
36:47-54, 1961
54. Lewis MG, Copeman PWM: Halo nevus: a frustrated malignant melanoma. Br Med J 2:47-48,
1972
55. Kawamura T et al: Gray hair on the nevus cell nevus. Jpn J Dermotol [B] 73:305-308, 1963
56. Perlman HH: Vitiligo, leukoderma acquisitum centrifugum, nevus pilosus, premature graying.
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59. Donaldson RC et al: Uveitis and vitiligo associated with BCG treatment for malignant melanoma. Surgery 76:771-778, 1974
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63. Swanson JL et al: Ultrastructure of halo nevi. I Invest Dermotol 50:434-450, 1968
64. Cesarini JP et al: Le halo-naevus (naevus de Sutton): etude structurale. Ann Dermotol Syphiligr
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65. Hashimoto K: A case of halo nevus with effete melanocytes. Acto Derm Venereol (Stockh)
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66. Hori Y: Quoted in Smith WE, Moseley JC: Multiple halo neurofibromas. Arch Dermotol
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67. Mishima Y et al: Dendritic cell dynamics in progressive depigmentations. Arch Dermotol
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68. Zelickson AS, Mottaz JH: Epidermal dendritic cells: a quantitative study. Arch Dermotol
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69. Ebner H, Niebauer G: Elektronenoptische Befunde zum Pigmentverlust beim Naevus Sutton.
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76. Iijima S, Kanazawa T: The relationship between blue nevus and vitiligo. Tohoku J Exp Med
57:144, 1953
77. Merklen FP, Pelbois F: Cas type de maladie de Sutton vraie: leucodermie centrifuge acquise
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1949
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94. Perrot H et al: Vitiliginous achromia with malignant melanoma. Tyrosinase activity and
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95. Jhung JW et al: Multiple halo nevi developing after oxymetholone treatment of "aplastic
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96. Millikan LE et al: Gross and ultrastructural studies in a new melanoma model: the Sinclair
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99. Cooke KB et al: Melanoma specific protein: occurrences in the urine of patients with halo
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1925
106. Nelson LM: Acquired depigmentation around a dilated pore. Arch Dermatol 74: 549-551,
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107. Mihm MC Jr et al: Early detection of primary cutaneous malignant melanoma. N Engl J Med
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611
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9
Miscellaneous Hypomelanoses
SARCOIDOSIS
Sarcoidosis is an idiopathic systemic granulomatous disease that frequently presents with cutaneous manifestations of which leukoderma is one
of the less commonly observed. Although sarcoidosis was first described in
1875 by Hutchinson [1], the associated leukoderma was first mentioned by
Mayock et al. [2] in 1963. It was later described by Harmon and Peterson [3]
in a patient with asthma and generalized lymphadenopathy, by Kotler and Zwi
[4] in a review from South Africa, and by Cornelius et al. [5] in four additional
patients. A series of eight cases was assembled by Clayton et al. [6] who also
performed ultrastructural studies.
The general incidence of sarcoidosis is estimated to be from 20:100,000
(Great Britain) to 200:100,000 [7]. Sarcoidosis in general involves females more
than males and is especially predominant among blacks but is not uncommon
among Caucasians from the southeastern United States or Scandinavia. Peak
incidence is in the third or fourth decade.
Hypomelanosis
Clinical Picture (Fig. 261)
The true incidence of leukoderma in sarcoidosis is unknown, but the observation of hypo pigmentation in 6% of the series of Mayock et al. [2] suggests
it must not be rare. Yet, in the patients of eight series [1,8-14] there is no
mention of hypo pigmentation. Emphasis on systemic involvement and on other
cutaneous features may have led to underreporting in earlier series.
Analysis of seven cases of hypopigmentation associated with sarcoidosis
(six from the literature and one presented to the New England Dermatology
Society, November 12, 1975) [15] (Table 125) makes it possible to characterize
these lesions. All patients were in the third or fourth decade when first seen;
in two of five the hypopigmented macules were the presenting complaint and
in another two the macules appeared within two years after the diagnosis ot
613
614
CHAPTER 9
FIGURE 261.
sarcoidosis was established. All patients were black, and the female to male
ratio was 5:2, both features probably reflecting the general sarcoidosis population. The lesions are described as circumscribed or poorly marginated macules or plaques that vary from 1 to 3 cm in diameter and mayor may not be
indurated. Two patients had papules within the white macules and one had
raised borders with a central violaceous hue. Lesions were most common on
arms and legs but also occurred on the face in two patients and on the trunk
in one. The lesions have no epidermal component other than hypo pigmentation
and are asymptomatic. Spontaneous repigmentation is reported in one case.
This generally agrees with the report of Clayton et ai. [6] who described
eight black patients with hypopigmented lesions of sarcoidosis. The female to
male ratio was 5:3. Six patients had dermal nodules surrounded by hypopigmentation and four had hypopigmented macules, both mostly located on the
thighs and upper arms. The nodules were dark red-brown centrally and light
tan peripherally. Most were 1 to 6 cm in diameter. Margins were indiscrete,
sometimes with perifollicular macules of pigmentation. None were symptomatic but some nodules were tender.
The hypopigmented macules appear to carry no specific prognostic significance. In one case, the white macules were the only feature of sarcoidosis.
However, in four patients with hypomelanotic macules, all had hilar adenopathy, three had pulmonary abnormalities, and two had arthritis or arthralgias
(Table 125). Clayton et ai. [6] were unable to correlate the cutaneous lesions
with any systemic features of sarcoidosis. Several patients developed the lesions while on oral corticosteroid therapy.
Histopathology
615
MISCELLANEOUS
HYPOMELANOSES
Mlblackl31
Flblackl33
Mlblackl32
Harmon and
Peterson
[3]
Cornelius
et al. [5]
Cornelius
et al. [5]
Series
Sex/race/
age at
diagnosis
Knees, anterior
thighs
Cheeks, arms,
trunk, legs (7)
Nonindurated,
"slightly"
depigmented
Circumscribed
macules, some
indurated
with eruptive
papules and
nodules
Indurated
Morphology of
hypopigmented
lesions
Nodules
upper
eyelids, left
nasal alae
Other
cutaneous
features
Calcified nodes,
interstitial fibrosis,
cardiomegaly with
congestive heart
failure, pulmonary
hypertension
Asthma, pulmonary
infiltrates, hilar
adenopathy,
generalized
lymphadenopathy,
hepatosplenomegaly
Noncutaneous
features
Site of
hypomelanotic
lesion
(duration in yrs)
TABLE 125.
Treated with
40-60 mg
prednisone but
no mention of
cutaneous
response
Topical steroids
flattened
nodules but
resulted in no
repigmentation
Skin lesions,
pulmonary
functions
markedly
better on 3week trial of
60mg
prednisone
q.d.
Comment
CD
..==
Flblackl37
Flblackl30
Flblackl22
Flblackl34
Cornelius
et al. [5)
Cornelius
et al. [5)
Rhodes [15)
Hubler [16)
Arms
Upper arms
bilaterally
enlarged to 3
cm
Circumscribed
macules or
plaques with
irregular
borders and
1-3 cm
violaceous
center
Multiple 1- to
15-cm poorly
marginated
patches. some
mildly
indurated
Patches. some
with 2--4
papules
Nodule on
nose
Hypertrophic
scar
Hilar adenopathy
History of arthralgias.
increased
pUlmonary markings
Hilar adenopathy.
mediastinal
adenopathy at aortic
arch
C/)C/)
ell
"'I
@O
t<:IC
...
Z~
~~
~~
~~
Treated with
Plaquenil but
no comment
about response
of
hypomelanosis
No therapy.
some
spontaneous
clearing
No therapy
Papules
responded to
intralesional
triamcinolone.
chest x-ray
normal. biopsy
of skin
showed
sarcoidal
granulomas
618
Electron Microscopy
CHAPTER 9
Clayton et al. [6] examined two patients. Although some melanocytes appeared normal, others had abnormalities which included cytoplasmic vacuolation, marked dilatation of rough endoplasmic reticulum, and degenerative
changes of mitochondria. Melanosomes appeared morphologically normal. The
number of melanosomes in keratinocytes was decreased; those observed were
packaged as singles. Intercellular fluid and intracellular vacuolation were observed in one patient. Examination of the dermis showed melanin-laden macrophages, granulomatous infiltration, mast cells, and some Schwann cells with
ingested melanosomes. Dilated lymphocytes and exudate in the region of the
dermal-epidermal junction were observed in one patient.
Diagnosis
The presence of macules of leukoderma on arms or legs, particularly in
association with somewhat indurated plaques in a black patient with uveitis,
hilar adenopathy, and peripheral adenopathy, should suggest a diagnosis of
sarcoidosis.
Certain laboratory studies may be helpful. Sarcoidosis may be associated
with hypochromic and microcytic anemia, eosinophilia, leukopenia, and hypergammaglobulinemia. The sedimentation rate is elevated in two-thirds of the
patients and, if present with erythema nodosum, may rise and fall as the erythema no do sum exacerbates and remits. Alkaline phosphatase levels may rise
with or without clinical granulomatous invasion of bone or liver. Hypercalcemia, hypercalcuria, and increased hydroxyproline excretion may be noted
in some patients. IgA may be very elevated and IgG somewhat elevated. Delayed
hypersensitivity is often impaired. A positive Kveim test has been reported in
75% of patients with sarcoidosis [18].
In difficult cases in which the diagnosis of sarcoidosis is entertained, careful examination of the patient (with a Wood's light in Caucasians) may reveal
the presence of hypopigmented macules, the biopsy of which will establish
the diagnosis and obviate the need for biopsy of nodes, liver, muscles, nerves,
or bronchial mucosa.
macules of another patient treated with similar dosages. None of the lesions
Systemic
Intrathoracic
Mediastinal or hilar adenopathy
Parenchymal changes with or
without adenopathy
Uveitis
Peripheral lymphadenopathy
Splenomegaly
Bone cysts
Arthritis
Coronary, CNS, renal abnormalities
Clinical Findings
Incidence
Despite the fact that in two years McDaniel and Richfield [21] observed
only 17 patients with idiopathetic guttate hypomelanosis, it appears to be a
very common disorder. In a survey of 452 randomly selected patients (mostly
blacks) at Charity Hospital, Louisiana, the incidence was found to be 47%;
619
MISCELLANEOUS
HYPOMELANOSES
620
CHAPTER 9
among another 500 patients, 68% were found to have idiopathic guttate hypomelanosis [22].
Race
The incidence among various races varies with the series reported. Idiopathic guttate hypomelanosis has been reported as both more and less common
among blacks compared to whites [19,23]. In one series, among 123 black males
the incidence was 58%, whereas it was only 20% in 107 white males. But the
incidence was nearly the same for black and white women, 54% of 117 blacks
and 53% of 105 whites, respectively [19]. On the other hand, Whitehead et al.
[22] reported an incidence of 74% among 322 Anglo-Saxons, 62% among 81
Northern Europeans, 69% among 36 Southern Europeans, and 30% among 30
blacks, and concluded that the condition is most common among Anglo-Saxons
and Europeans. That idiopathic guttate hypomelanosis was not observed among
the six Asiatics examined does not exclude its occurrence in Mongoloids or
other Orientals.
Hair Color, Eye Color, Skin Type
While idiopathic guttate hypomelanosis appears to occur among patients
of all hair and eye colors, there seems to be a preponderance of brown eyes
and brown hair. Among 17 patients, 10 tanned deeply, six moderately, and one
lightly [21].
Sex Distribution
Males and females are probably equally affected. Arguelles-Casals and
Gonzales [23] found no sex predominant. However, McDaniel and Richfield
[21] reported all of their patients were women. Cummings and Cottel [19] found
the incidence of idiopathic guttate hypomelanosis to be higher in women (53%
vs. 20%) among whites, and slightly higher in men (58% vs. 54%) among blacks.
Among 339 patients, Whitehead et al. [22] found an incidence of 44.2% in
males and 55.8% in females. It seems doubtful that idiopathic guttate hypomelanosis is more common in females; the apparent increase reported probably
results from the increased cosmetic disfigurement perceived by women compared to men.
Age
Idiopathic guttate hypomelanosis is a disease of adulthood and senescence
[23] and is probably more prevalent with increasing age. However, onset as
young as five years of age has been reported [22]. The age of patients in McDaniel
and Richfield's series [21] ranged from 14 to 63, and peak incidence was in the
thirties and forties. Whitehead et al. [22] observed only two cases below age
10, and found the disease usually appearing after age 30. The data of Cummings
32
37
30
39
62
78
93
81
010
1020
2030
3040
4050
5060
6070
70+
I!
10
20
30
40
50
80
70
80
90
100
FIGURE 262. Incidence of idiopathic guttate hypomelanosis in white and black. male and female patients (452 cases). This
demonstrates increased prevalence with age. (From: Cummings K. Cottel W: Idiopathic guttate hypomelanosis. Arch Dermatol
93:184-186. 1966. Copyright. 1966. American Medical Association. Used with permission.)
Number of Patients
Screened
Age Group
0000
@O
t'lC
Z~
t'"t'"
~~
21 a:::
"'t:J00
...
Cl
N
622
CHAPTER 9
and Cottel [19] support an increased incidence of the condition with age (Fig.
262).
The etiology is unknown. Trauma has been suggested. McDaniel and Richfield [21] first thought idiopathic guttate hypomelanosis was induced by shaving with a safety razor; this was thought to cause a localized impairment in
the functional ability of the melanocytes. But since many patients used only
depilatories or electric shavers, this hypothesis seems too narrow in scope. Nor
could it explain the localization of the disease on the arms, or trunk, areas not
commonly shaved, or its occurrence in males.
Since there is an increased incidence with age and the lesions tend mostly
to occur on sun-exposed areas of skin, ultraviolet radiation may be implicated
[19,21,22]. Most patients appeared to be enthusiastic sunbathers and the majority of them were from the sunny regions of the United States. The unfolding
of the keratin layer observed in areas of the hypopigmentation supports this
hypothesis, but the precise pathogenesis of the unfolding of the keratin layer
is unclear. Since some lesions may occur in areas never exposed to the sun,
there must be other significant factors.
Clinical Description
The typical lesion is a small, discrete, smooth, depigmented macule of
porcelain-white color (Fig. 263). Sometimes small black dots are irregularly
distributed in the white macules [23]. The shape of the macules may be round
(guttate) or angular [22], and they may be delineated by the skin furrows. They
vary from 0.2 to 6 mm, with occasional larger lesions [22]; the average size is
0.5 cm. Once present, these lesions do not change in size. Multiple lesions
(several to 10 and sometimes more than 50) are a frequent occurrence and the
number of macules increases with age. The borders are very sharply defined,
as if pasted on, and there is no peripheral hyperpigmentation (Fig. 264). The
macules are not confluent. The surface of the lesions is smooth, not infiltrated,
and without scarring or atrophy. One patient with a slight hyperkeratosis detachable by scratching has been described [24].
The lesions are most common on the sun-exposed areas of the skin, particularly on the anterior surface of the lower extremities and the lower abdomen.
Whitehead et al. [22] found that male subjects had an increased percentage of
lesions on the arms (Table 127). Facial involvement has also been described;
Whitehead et al. [22] found involvement of preauricular skin in some patients
and McDaniel and Richfield [21] observed a depigmented macule around the
mouth of one patient. Involvement of normally sun-protected skin may occur.
The lesions are totally asymptomatic. Uninvolved skin is normal and patients with this disorder are usually in good health.
Idiopathic guttate hypomelanosis is a slowly progressive disorder. Usually
the lesions do not increase in size, but their number increases with age (Table
128). No spontaneous repigmentation has been observed.
623
MISCELLANEOUS
HYPOMELANOSES
FIGURE 264. Close-up of lesions in which the sharp margins of the hypomelanosis are evident.
(From: Fitzpatrick TB et al (Eds): Dermatology in General Medicine. New York, McGraw-Hill,
1971, Plate XXVII, 4b. Copyright, 1971, McGraw-Hill Book Company. Used with permission.)
624
CHAPTER 9
Number of lesions
1-10
11-50
Over 50
Males
Arms
Legs
Arms and legs
Face
Face, arms, and legs
39
11
14
1
3
12
3
13
0
0
8
3
14
0
3
Females
Arms
Legs
Arms and legs
Face
Face, arms, and legs
27
11
14
0
5
0
3
20
0
7
7
5
35
6
9
Distribution of idiopathic guttate hypomelanotic lesions in 124 males and 149 females
in whom the distribution was recorded.
b Source: Whitehead WJ et al: Idiopathic guttate hypomelanosis. Arch Dennatol
94:279-281, 1966. Copyright, 1966, American Medical Association. Used with permission.
a
Pathology
Except for decreased melanin the skin is usually normal. Generally the
epidermis is normal in thickness, but an increased thickness of the keratin
layer of the depigmented patches has also been reported [24]. The dopa reaction
in the hypopigmented macules is decreased [21, N. Soter, Y. Hori, T. B. Fitzpatrick, unpublished data]. Only a few melanocytes are seen in the hypopigmented macules. Usually there is no dermal change, pigmentary incontinence,
or inflammation. When thickening and fibrosis of the papillary dermis have
been observed in lesions of idiopathic guttate hypomelanosis, similar changes
TABLE 128. Age and Number of LesionsG in Idiopathic
Guttate Hypomelanosis"
Number of lesions
0
1-10
11-50
Over 50
Males
No. of patients
Average age
97
19.2 yr
83
31.8 yr
32
40.0 yr
35
57.4 yr
Females
No. of patients
Average age
64
14.0 yr
72
29.7 yr
47
42.4 yr
70
53.5 yr
Males (247) and females (253) grouped by age and number of lesions.
Source: Whitehead WJ et al: Idiopathic guttate hypomelanosis. Arch Dennatol
94:279-281,1966. Copyright, 1966, American Medical Association. Used with
permission.
FIGURE 265. Melanocytes are present in the hypomelanotic macules. They contain melanosomes with a reduction in the amount
of melanin deposition in comparison with the melanosomes in the control skin. (From: Soter NA. Hori Y. Fitzpatrick TB:
Unpublished data. Used with permission.)
~a:::
~~
~O
tr:IC:
Otr:l
ZZ
tr:I r
r
r
a:::R
o~
"'-
'"en
626
CHAPTER 9
also have been found in normally pigmented skin [19]. In one case, there was
a slight suggestion of some edema between the basement membrane and the
immediate subjacent epidermis. Some investigators [19] have noted a mild
perivascular infiltrate of chronic inflammatory cells.
At the electron microscopic level, the melanocytes contain melanosomes
that are not fully melanized (Fig. 265). Another study suggests that there is a
progressive loss of epidermal melanocytes in a later stage of this disorder [24a].
Diagnosis
The diagnosis can usually be readily established on the basis of characteristic morphology, distribution, and clinical course of the lesions (Table 129).
The small size, porcelain-white surface, and sharp margins are usually diagnostic.
The differential diagnosis may include such hypopigmentary disorders as
vitiligo, lichen sclerosis et atrophicus, atrophie blanche en plaque, leukodermic
guttate parapsoriasis, tinea versicolor, tuberous sclerosis, achromic planar warts,
tinea alba, leprosy, syphilis, chemical depigmentation, and postinflammatory
hypopigmentation.
TABLE 129. Clinical and Histologic Features of Idiopathic Guttate
Hypomelanosis
Incidence
Sex
Age
Clinical features
Configuration
Shape
Color
Size
Number
Border
Localization
Progression
Local symptoms
Repigmentation
Pathologic features
Number of melanocytes
Dopa reaction
Melanization of
melanosomes
Macular
Round or angular
Dull-white or porcelain-white
0.2 to 6 mm (average about 5 mm). occasionally larger
Usually multiple (several to 10); may be 50 or more
Very sharply circumscribed
Sun-exposed areas
Extremities
Lower abdomen
Face (preauricular)
Increase in number but not usually in size with age
None
Usually none
Decreased
Decreased
Decreased
Treatment
No treatment is available. McDaniel and Richfield [21] treated one patient
with 20 mg 8-methoxypsoralen daily for two months and observed an estimated
two-thirds repigmentation. However, no further improvement occurred and
with cessation of therapy a gradual loss of pigment again was observed.
In general, the cosmetic disfigurement is usually mild. As sunlight may be
a precipitating factor, sunbathing should be discouraged and use of topical
sunscreens encouraged.
VOGT-KOYANAGI-HARADA SYNDROME
Vogt-Koyanagi-Harada syndrome (VKHS) is a rare multisystem disorder,
the most consistent feature of which is uveitis, and the variable features of
which include alopecia, poliosis, vitiligo, and dysacousia.
Historical Background
Although Vogt [26], in 1906, described a case of idiopathic atraumatic
uveitis, poliosis, and alopecia, earlier descriptions of what would later become
known as VKHS had been made. The 12th century physician Mohammed al
Ghafigi regarded eyelash poliosis as a disease. In 1873, Schenkl [27] reported
a case of silvery-white eyelashes associated with sympathetic ophthalmia. One
year later, Jacobi [28] reported a similar patient with canities of the upper and
lower eyelids. Similar cases were observed by Tay [29], Bock [30], and Nettleship [31], who considered the concurrence of white eyelashes and sympathetic
ophthalmia no mere coincidence. Peters [32] reported in 1912 six cases of
sympathetic ophthalmia associated with deafness. In 1892, in the course of the
presentation of a case of eyelash poliosis and severe deafness, Hutchinson [33]
referred to another patient with atraumatic destructive uveitis, partial hair loss,
and poliosis of scalp and axillary hair. Cramer [34], in 1913, described a case
that evolved following extraction of a luxated lens.
627
MISCELLANEOUS
HYPOMELANOSES
628
CHAPTER 9
In 1911, Komoto [35] presented his first case of the syndrome but recalled
that some seven years earlier at an ophthalmologic meeting he had presented
a case of sympathetic ophthalmia with circumscribed vitiligo of the forehead.
In the same periodical is another case consistent with VKHS characterized by
vitiligo, poliosis, and chronic nontraumatic choroidal inflammation [36]. Erdmann [36] considered this a type of heterochromic inflammation and attributed
the vitiligo to a similar process.
Gilbert [37], in 1910, observed a patient who developed the concomitant
onset of vitiligo and bilateral optic neuritis resulting in iridocyclitis. He attributed this to ocular herpes; 20 years later he implicated endocrine factors.
Harada [38], in 1926, described five cases of bilateral posterior uveitis and
retinal detachment. Severe headaches and CSF pleocytosis were also frequently
present. A similar disorder was described by Tagami [39] in 1931.
In 1914 Koyanagi [40] reported a syndrome of uveitis and poliosis; in 1929
[41] he completed the description of what has become known as the VKHS.
The features described in his 16 cases included headache, fever, dysacousia,
vitiligo, poliosis, alopecia, and bilateral anterior uveitis with occasional exudative retinal detachment.
The first review in the English literature was that of Parker [42] in 1931;
he associated the syndrome with both idiopathic uveitis and sympathetic
ophthalmia.
Although Ogawa [43] used the names of Vogt and Koyanagi to refer to the
syndrome of "idiopathic uveitis with poliosis and leukoderma," it was Babel
[44] who first called this syndrome the "Vogt-Koyanagi syndrome."
The terms "uveoencephalitis" [45], "oculocutaneous syndrome" [46], "idiopathic neuraxitis" [47], and "uveomeningoencephalitis" [48] have also been
used to describe VKHS.
Classification
For a long time, Vogt-Koyanagi syndrome and Harada disease were considered separate entities. Idiopathic uveitis with leukoderma and poliosis was
classified as either Harada type, Vogt-Koyanagi type, or transitional type (Harada progressing to Vogt-Koyanagi type), mainly on the basis of the ophthalmologic findings [49].
The criteria for the diagnosis of Harada disease included bilateral retinal
detachment beginning in the macular area, hyperemia of the optic disc, inflammation of the vitreous and aqueous humors, and ocular "sunset glow fundus" or cutaneous depigmentation. It was later suggested that Vogt-Koyanagi
syndrome might represent Harada disease in its late, chronic stage.
In the Vogt-Koyanagi type, the uveitis was considered anterior in location
and retinal detachment did not occur, while in Harada disease the uveitis was
posterior and accompanied by retinal detachment.
Most recent authors have been aware that alopecia and poliosis are not
features of Vogt-Koyanagi syndrome alone and that retinal detachment may
occur following any anterior uveitis, not just that of Harada disease. Since these
Incidence
VKHS is a rare disorder. By 1953, only 116 cases had been reported in the
world literature [50].
Any race may be affected. All the initial cases were among Japanese. Reed
et al. [51] and Aita [52] suggested VKHS is a disease of pigmented races, particularly blacks and Orientals (Fig. 266). But, as cases have also been reported
from the United States, the West Indies, Mexico, South America, Egypt, Europe,
and China, it appears that no race is spared [53,54].
Males and females are equally affected [54]. In one series there were 25
males and 20 females [53], and in another 23 males and 24 females [55].
629
MISCELLANEOUS
HYPOMELANOSES
630
CHAPTER 9
VKHS seems to be most frequent in the third decade [56] or between the
ages of 30 and 40 [53], but occurrence in patients from 10 [57] to 57 [58] years
of age has been reported. The average age of onset in one series was 30.3 years
[59]. VKHS has also been reported in children [60].
Social and hereditary factors do not seem to be important [53,59]. One
familial case has, however, been reported [61]. Consanguinity is unusual; it
has been noted in only one instance [62].
631
MISCELLANEOUS
HYPOMELANOSES
FIGURE 267. Vogt-Koyanagi-Harada syndrome. Scleral infection and poliosis. (From: Howsden
SN et al: Vogt-Koyanagi-Harada syndrome and psoriasis. Arch Dermatol 108:395-398, 1973.
Copyright, 1973, American Medical Association. Used with permission.)
deafness usually occur after the onset of the disease. The eighth nerve defect,
which is of variable degree, is in the high-pitch range and may not be apparent
to the patient. Spontaneous resolution may occur.
Seals and Rise [56] studied three patients with VKHS and hearing loss.
One patient had severe cochlear and vestibular loss. Another had no cochlear
or vestibular response on one side and a nonresponsive right vestibular labyrinth and severe sensorineural hearing loss in the other. The third patient
complained of hearing loss but had normal audiometry.
The convalescent stage, as uveitis begins to abate, is marked by vitiligo,
poliosis, and alopecia which occur from three to nine months after the onset
of the disease. Rosen [55] found 90% with poliosis, 73% with alopecia, and
63% with vitiligo, but none, one, two, or all of these may be seen in anyone
patient (Fig. 268).
Patchy or diffuse hair loss usually follows ocular symptoms by two to three
months, but in two of Koyanagi's cases the loss was seen at three weeks [41].
Early hair loss may be readily overlooked. Hair whitening is probably most
apparent once alopecia has commenced and may or may not be permanent.
Parker [59] noted seven patients who had return of normal hair color over five
to eight months.
White areas may remain scattered through the fundus and be interspersed
632
CHAPTER 9
FIGURE
268. Vogt-Koyanagi-Harada
syndrome. Symmetrical hypomelanosis of
the face with nearly complete poliosis of
eyebrows and lashes. (From: Howsden SN
et al: Vogt-Koyanagi-Harada syndrome and
psoriasis. Arch Dermatol 108:395-398,
1973. Copyright, 1973, American Medical
Association. Used with permission.
Dermatologic Features
Hypopigmentation
The first case of VKHS associated with leukoderma was reported by Gilbert
in 1910 [37]. Depigmentation in VKHS occurs classically in the third phase of
the disease and involves the skin and hair.
Poliosis occurs in 82% [53] to 90% [55] of cases, and may appear abruptly
a few weeks after the onset of the disease; involvement of the eyebrows, eyelashes, scalp, beard, and body hair, particularly in the sacral area [66], may be
patchy or diffuse (Fig. 269). Depigmentation of the eyebrows and eyelashes is
usually accompanied by ipsilateral depigmentation of the iris.
633
MISCELLANEOUS
HYPOMELANOSES
FIGURE 269. Vogt-KoyanagiHarada syndrome. Diffuse whitening and poliosis of seal phair.
Alopecia is said to occur in 53% to 73% of patients and may present after
the apparent onset of the disease. Usually the alopecia occurs as discrete patches
of small areas of hair loss, but the entire scalp may be involved. Regrowth may
634
CHAPTER 9
FIGURE 270. Vogt-Koyanagi-Harada syndrome. Variation in size and degree of pigment loss of
hypomelanotic macules . (From: Howsden SN et al: Vogt-Koyanagi-Harada syndrome and psoriasis.
Arch Dermatol 108:395-398, 1973. Copyright, 1973, American Medical Association. Used with
permission.)
be gray and thinner, shorter and more pointed than the former hair. Regrown
hair may remain white to gray [65]. Some general thinning of the scalp hair
may also be observed.
Massive hives and psoriasis have been reported in patients with VKHS
[67,68] (Fig. 272).
635
MISCELLANEOUS
HYPOMELANOSES
Associated Diseases
Although VKHS usually occurs alone, it has been reported associated with
insomnia, amenorrhea, polyuria, and hypertension [69]; a hypothalmic syndrome with hyperglycemia, hypercholesterolemia, nocturia, polyuria, and diabetes insipidus [70]; pituitary dysfunction [71]; adiposogenital syndrome [72];
Frohlich syndrome [73]; Klippel-Feil syndrome with ear agenesis [67]; mandibulofacial dysostosis [71,74]; facial hemiatrophy and alopecia [75]; and progressive facial hemiatrophy [53].
Pathologic Findings
Eye
Histology
The characteristic lesion is a granulomatous uveitis but nongranulomatous
uveitis has also been observed [58]. Typically, nodular eye lesions show epi-
636
CHAPTER 9
637
MISCELLANEOUS
HYPOMELANOSES
638
CHAPTER 9
aggregation, autophagic vacuoles, fatty degeneration, and pyknosis or homogeneous cytoplasmic degeneration. Most of the nonmelanocytic dendritic cells
were Langerhans cells. Nerve connection to normal and degenerated melanocytes was also observed. Bazex et al. [82] identified 250 A wide particles,
probably alpha-glycogen, well-developed unmyelinated nerve endings, and
lymphoid cells closely approximating dendritic cells which contained internal
granular deposits.
Immunofluorescence
In one patient with VKHS and psoriasis, indirect immunofluorescence was
negative. Direct immunofluorescence was faintly positive with IgG; this was
confined to epidermal intercellular space. Results with IgM and C3 were negative. Sections from skin with psoriasis and vitiligo showed not only these
changes but also yellow-green fluorescence beneath the dermal-epidermal
junction. Immunization of normal or control patient skin was negative [68].
Etiology
Although the etiology of VKHS has not been established, various pathophysiologic mechanisms have been suggested; these include endocrine disturbances [41,83], vitamin deficiency [37], bacterial infection [84], neurotrophic
disturbance, viral infection, and autoimmune disturbance. Brucellosis was suggested as a cause of the uveomeningeal syndrome [48].
Hague [85] mentioned a patient with VKHS and ependymoma compressing
the third ventricle and postulated a neurotrophic factor; he suggested a lesion
of the suprachiasmic region could explain all the features of VKHS. He noted
that VKHS usually follows an upper respiratory infection and suggested as a
precipitating factor a resultant encephalitis, severe emotional trauma, or a tumor compressing the hypothalamus.
Currently only two hypotheses-autoimmune and viral-seem appropriate.
As early as 1910, Gilbert [37] suggested herpes zoster as the cause of VKHS.
Others have suggested herpes to be a neurotrophic virus [83,86-88].
Many observations have been used to support the viral hypothesis. Occurrences and recurrences after paranasal sinusitis are compatible with a viral
(or at least infectious) etiology. Mohan and Gupta [89] suggest the meningeal
phase noted in the initial stage of a majority of cases supports an infectious,
e.g., viral, agent. The presence of pleocytosis in the final stage of the meningeal
phase has been interpreted in favor of this hypothesis. The apparent involvement of the hypothalamus could be implicated in the pathogenesis of the
pigmentary disturbance. Similar significance has been ascribed to atypical epidemic cases in a small French village [90]. Yet this is only one case in the
literature in which a person in contact with a VKHS patient acquired bilateral
uveitis [45].
Japanese investigators attempted to establish a virus as the responsible
etiologic agent. Takahashi [91], in 1930, inoculated rabbit cisterna magna with
sterile vitreous from an enucleated eye afflicted with Harada disease and found
optic neuritis and generalized uveitis in two of five rabbits. Brain material from
one of these injected into normal rabbit vitreous also caused uveitis and optic
neuritis; similar injection of CSF from a VKHS patient gave like results. Tagami
[39] transferred the disease through three rabbit generations. Similar transference results were obtained by others [50,92-94]. Friedenwald and McKee [95]
produced the characteristic lesion and passed the agent from CSF serially through
rabbits, cats, and dogs.
Erbakan [96] isolated a virus from the CSF of a patient with VKHS. Suguira
et al. [97] also isolated a virus from the eyes of patients with VKHS and, with
serum of another patient with the same disease, were able to demonstrate a
positive neutralization test against this virus.
However, although particles resembling virus have also been described in
the involved skin [80], most investigators have been unable to isolate or culture
a virus from VKHS patients. For example, injection of subretinal fluid from
affected patients into the brains of mice did not induce the disease [98]. In
other patients, repeated egg embryo, mouse brain, and rabbit eye inoculations
of VKHS subretinal or spinal fluid have been unsuccessful. Thus, neither the
transfer nor isolation experiments have been completely reproducible. The
possibility exists that because the diagnosis usually was not made early, the
phase in which the virus was present and identifiable had passed when most
of these unsuccessful transfer experiments were attempted. If so, the viral
hypothesis must still be considered viable.
Considerable evidence has accumulated to support an autoimmune hypothesis. Pusey in 1903 [99] and Elschnig in 1910 [100] were the first to suggest
that an allergy was responsible for uveitis associated with pigmentary change.
Elschnig considered sympathetic ophthalmia to result from release of damaged
uveal pigment which had antigenic properties and resulted in formation of
organ-specific antibodies. Thus anaphylactic pigment destruction resulted.
Peters [32] suggested uveitis caused the destruction of choroid pigment
and dissemination of breakdown products which led to sensitization and allergic reactions in other body pigmentary structures.
There are clinical similarities between sympathetic ophthalmia and VKHS.
Sympathetic ophthalmia has been associated with alopecia, poliosis, and deafness [34] and VKHS has been observed after eye surgery [67]. The general
concept of sympathetic ophthalmia is that of a severe traumatic reaction which
causes a uveitis. Subsequent uveal degradation is followed by release of antigens which stimulate antibody formation. Once adequate titers are reached,
sympathetic uveitis occurs in the untraumatized eye. A similar mechanism
may exist for VKHS. A VKHS-like syndrome has been observed in two melanoma patients treated with BCG [101]. Furthermore, the histologic and electron
microscopic ocular and cutaneous findings are consistent with this mechanism.
Various experimental studies support the autoimmune hypothesis. Foreign
protein injected into rabbit eyes produced sensitizing reactions in the contralateral eye [102], but only in pigmented and not in albino rabbits. Friedenwald
[92] found the tissue reaction after intracutaneous injection of uveal pigment
to be similar to sympathetic ophthalmia; this is now considered compatible
with a delayed hypersensitivity response. Others have obtained similar results
639
MISCELLANEOUS
HYPOMELANOSES
640
CHAPTER 9
with VKHS and sympathetic ophthalmia [103,104]. Kahan et al. [105] were
able to correlate skin test results with activity of VKHS and sympathetic
ophthalmia. When combining antibodies were completed by Coombs serum,
uveal pigment-agglutinizing antibodies could be found in sera of patients with
VKHS or sympathetic ophthalmia. Hammer [106] found uveal pigment to stimulate lymphocyte cultures from patients with sympathetic ophthalmia or VKHS.
Furthermore, lymphocytes from patients with VKHS may show microcytotoxicity against allogenic melanoma cells in vitro [107].
Since there is much evidence that cutaneous depigmentation can result
from an immunologic mechanism (see "Vitiligo" in Chapter 1 and "Halo Nevus"
in Chapter 8), it is reasonable that the same pathogenesis may apply to VKHS.
It is further possible that these two hypotheses are not separate and discrete,
but that a viral infection may induce an autoimmune reaction.
Sex incidence
Male
Racial incidence
Nonselective
General incidence
Rare
Clinical description of
depigmentation
Skin
Hair
Associated clinical findings
Dermatologic
Other
Course
female
Vitiligo-like depigmentation
Poliosis of eyelashes, scalp, eyebrows, body
hair
Alopecia
Uveitis, meningeal signs and symptoms,
dysacousia
Self-limited
Treatment
In 1959 and 1961, Cremona, Alezzandrini, and Casal a reported two cases
of facial vitiligo, poliosis, deafness, and tapetoretinal degeneration with lesions
of the macules and specific electroretinograms [108].
In 1964, Alezzandrini [109] reported three patients with unilateral tapetoretinal degeneration, facial vitiligo, and poliosis, all on the same side. Two
of these patients also had perceptual deafness.
Alezzandrini syndrome is probably related to the Vogt-Koyanagi-Harada
syndrome.
SENILE GRAYING OF HAIR
641
MISCELLANEOUS
HYPOMELANOSES
642
CHAPTER 9
Clinical Features
Frequency
This phenomenon is very common and occurs to varying degrees in all
persons.
Age of Onset
The age of onset of physiologic canities seems largely hereditary, but other
factors are probably involved. Graying may begin in the twenties or early thirties, but usually is first seen in the late fourth or early fifth decade [111]. Neither
sex is spared. Keogh and Walsh [112], in an Australian population, found no
significant difference in the age of graying among men and women. They found
22.29% of 2574 men and 23.35% of 698 women between 24 and 35 years of
age had some graying and 0.25% of men and 0.15% of women in these same
populations showed a complete graying (Table 131). Burch et al. [113] noted
some gray hair in dark-haired men between 20 and 24 years of age (Table 132).
Onset as early as the second or as late as the ninth decade is also possible.
Keogh and Walsh [112] concluded from their study that at 50 years of age,
regardless of sex, 50% of people are at least 50% gray (Table 133).
Race
No race is spared, but the age of onset has been reported to vary among
several populations. According to Boas and Michelson [114], the normal age
Age
Males
Females
Males
Females
Males
Females
25+
35+
45+
55+
2574
2157
1493
429
698
627
553
189
22.29
61.38
88.68
94.16
23.35
66.35
88.25
96.30
0.23
2.18
12.59
29.91
0.14
1.59
9.95
29.57
Source: Keogh EV, Walsh RJ: Rate of graying of human hair. Nature 207:877-878, 1965. Copyright, 1965,
MacMillan Journals Ltd. Used with permission.
Percent graying
Dark hair
Percent graying
Miscellaneous
no. with
graying
2643
202
281
306
288
288
311
353
215
233
166
503
83
111
115
77
53
28
23
8
3
2
223
0
0
5
10
23
44
60
30
36
15
95
0
0
0
0
4
2
11
16
29
33
0.0
0.0
4.2
11.5
33.8
62.2
75.5
85.2
95.6
96.0
0.0
0.0
0.0
0.0
5.0
2.7
11.7
29.6
42.6
66.0
0
6
18
81
98
150
170
112
97
26
775
119
164
167
115
93
51
42
9
5
1
766
71
0
0
0
0
1
6
8
11
19
26
0.0
3.5
10.8
41.3
51.6
75.4
80.9
93.1
95.9
98.6
0.0
0.0
0.0
0.0
0.5
2.9
3.6
8.3
15.7
37.1
6
0
0
0
2
1
2
0
0
0
1
100
0
0
1
3
10
19
25
15
16
11
104
0
0
0
0
5
9
14
14
28
34
0.0
0.0
0.0
0.0
3.5
5.5
9.3
19.1
32.6
56.0
IZlIZl
t"lC:::
a~
IZlO
5:5:
t"lr-'
~R
OIZl
"'-
~~
Two communities in the North of England. Fair hair = unaffected hair or eyebrows are blond to light. Dark hair = unaffected hair or eyebrows are brown to black.
Miscellaneous = men whose hair color could not be allocated to either the "Fair" or "Dark" categories; the "None" column of this group records men with wigs.
Partly = some gray hairs clearly seen. Completely = all hairs gray or white.
b Source: Burch PRJ et al: The age-prevalence of arcus senilis, greying of hair and baldness. Etiological considerations. J Gerontol 26:364-372, 1971. Copyright, 1971,
Gerontological Society. Used with permission.
15+
15-19
20-24
25-29
30-34
35-39
40-44
45-49
50-54
55-59
60+
All groups
Any
Any
Age
%
No. graying
No. graying
gray Completely
gray Completely
range Number
completely
gray
None Partly Completely hair
(yr) examined None Partly Completely hair
gray
None Partly Completely
gray
Fair hair
TABLE 132.
c.o
a>
644
Number of patients
at risk
CHAPTER 9
Percent with
any graying
Age
Fair
Medium
Dark
Fair
25+
30+
35+
40+
45+
50+
55+
60+
502
345
333
263
282
205
137
839
674
666
604
510
331
222
26
3872
454
459
444
474
406
312
198
4.6
18.0
37.2
60.5
84.0
92.7
96.4
100.0
45.3
-1
Totals
2083
2765
Percent with
complete graying
Medium
Dark
Fair
Medium
Dark
10.4
32.3
53.2
71.4
83.3
91.2
93.2
100.0
52.9
26.4
49.5
64.0
74.9
90.4
93.3
94.9
100.0
68.1
0.4
0.6
0.9
4.6
8.9
23.9
42.3
50.0
7.6
0.0
0.3
1.2
3.3
8.6
15.4
31.1
23.1
5.2
0.0
0.2
1.1
1.9
8.4
12.8
19.2
16.7
3.3
Source: Keogh EV, Walsh RJ: Rate of greying of human hair. Nature 207:877--878, 1965. Copyright. 1965.
MacMillan Journal Ltd. Used with permission.
of onset of graying in white races is 34.2 B.6 years and in blacks 43.9 10.3
years. In Japanese, canities appears on the average at 35.39 years in females
and 30.34 in males [115]. Among Bantus, gray hair is said to be uncommon
before 40 or 50 years of age [116].
Hair Color
Among Caucasoids, graying appears to begin at a younger age in the darkhaired than in the fair-haired, and more dark-haired than fair-haired subjects
show some degree of graying at a given age [112]. But more fair-haired than
dark-haired subjects appear to be completely gray. The reason for this apparent
contradiction is that the first signs of graying are more obvious against a background of dark than of fair hair and, conversely, compared to fair-colored hair
a few dark hairs will be more noticeable against gray hair background. Hence,
the dark-haired individual is the first to appear somewhat gray and the last to
appear to be totally so.
Boas and Michelson [114] concluded that dark hairs of adult Caucasians,
including a great many patients originally with light hair that darkened over
time, become gray earlier than those whose hair continued to have light hues.
Those individuals whose hair darkened most rapidly have the greatest likelihood of becoming gray at an early age. Regardless of hair color, 50% of people
will be 50% gray by the age of 50 [112].
Correlation between Age and Graying of Hair
Most studies correlate graying of hair with aging [112,117]; the relationship
of prevalence to age fits a simple biologic model of aging [113] (Tables 131,
132, 133).
Clinical Picture
Graying of hair usually becomes evident by the latter part of the fourth
decade or the early part of the fifth decade. Occasionally, hypomelanotic hairs
develop during the early part of the second decade, and in rare instances they
fail to appear except in very small numbers even in the ninth decade.
Graying appears first at the temples, extends to the vertex and, over a period
of years, slowly involves the remainder of the scalp. The rate of progression
appears to be extremely variable. Graying of the beard and of the body hair
usually, but not invariably, follows after an interval of some years. Chest, pubic,
and axillary hairs may retain their pigment even in old age. Fitzpatrick et al.
[111) , in a study of eight octogenarians, found virtually no hypomelanotic hairs
in the axillae, presternum, and pubis.
Graying of hair is ordinarily irreversible, but in certain cases reversal of
hair graying has been known to occur [118) (Fig. 274). Ronchese [119) described
FIGURE 274. Hair showing loss of pigment distally with recovery of normal pigmentation in
proximal hair shaft. (From: Comaish S: White scalp hairs turning black. An unusual reversal of
the aging process. Br J Dermatol 86:813--814, 1972. Copyright, 1972, Blackwell Scientific Publications. Used with permission.)
645
MISCELLANEOUS
HYPOMELANOSES
646
CHAPTER 9
the gradual repigmentation of white hair over the course of a long terminal
illness in a male patient who had shown gray hairs at age 38 [120]. Several
hairs plucked from his scalp showed the remarkable loss of pigment distally
and normally pigmented proximal hair and roots; the transition from black to
white was gradual over a length of nearly 6 mm.
Decreased
Marked vacuolization
Normal
Normal
Normal or structurally altered
Decreased
Decreased
Decreased
Normal
In white hair, melanocytes were scarce or entirely absent and there was
no pigment in the matrix and cortex. No Langerhans cells were seen in the
bulbs, but a single Langerhans cell was observed in the outer root sheath beneath
a sebaceous gland. In the papillae, melanin, melanocytes, and melanophores
were all absent. Melanin-containing melanophores were seen only in pigmented
hairs, and were located outside the glassy membrane, usually along the blood
vessel walls. Thus, the structure of gray scalp hair or pigment cells was different
from that of pigmented hair from the same region.
Orfanos et al. [123] noted white hair usually showed large quantities of
pigment debris and an occasional intact melanin granule. He suggested that
melanocytes in old people produce only a few imperfect melanin granules
which disintegrate in the hair shaft.
Herzberg and Gusek [124] found the number of melanocytes in gray hair
to be greatly reduced or totally absent. Pigment cells were markedly vacuolated;
fewer melanosomes were present and those observed had abnormal structural
changes. Pigment transfer appeared normal, however (Fig. 275).
FIGURE 275. Seventy-year-old individual with gray hair. Melanocyte shows a reduction in the
size and number of melanosomes (M). Mi = mitochondria; V = vacuoles; G = Golgi apparatus;
N = nucleus (x 14,000). (From: Herzberg 1. Gusek W: Das Ergrauen des Kopfhaeres. Arch Klin
Exp Dermatol 236:368-384, 1970. Copyright, 1970, Springer-Verlag. Used with permission.)
647
MISCELLANEOUS
HYPOMELANOSES
648
CHAPTER 9
In 1971, Kukita et al. [125] studied the dendritic cells in the matrix of
human senile white and gray hair. There were no melanocytes in white hair,
but there were Langerhans cells and cells closely resembling indeterminate
cells. In senile gray hair, melanocytes and Langerhans cells were observed, but
indeterminate cells could not be identified. Ultrastructural studies revealed
identical dendritic cell populations in both senile white hairs and white hairs
from vitiliginous macules.
Pathogenesis
The mechanism of senile graying of hair has not been established. Metchnikoff [126] suggested that phagocytosis of melanin causes natural graying of
hair.
According to Orfanos et al. [123], senile graying of hair is due not to
corpuscular color but to a constellation of impressions arising from the actual
color of the hair keratin and from the reflection of light on the boundary surfaces
and islets of infundibulary matrix.
In 1937, Yosikawa [127] compared the copper content of gray and normally
pigmented human hairs from aged individuals. In all cases, the copper content
of gray hair was lower than that of colored hair. But it seems unlikely that such
a common event as senile graying of hair could be related to a disturbance in
copper metabolism, which appears to be rare.
Fitzpatrick et al. [111] suggested a decreased number of melanocytes and
slowed melanogenesis in remaining melanocytes accounted for graying of hair.
In electron microscope studies a number of dopa-positive melanocytes with
partially melanized normal melanosomes were observed but there were no
abortive melanocytes or Langerhans cells with their characteristic granules and
lobulated nuclei. Whether melanogenesis was incomplete in these melanosomes because of a change in the rate of enzyme activity or because tyrosine
was unavailable has not been determined. The presence of melanin granules
in the cortical and medullary cells of gray hairs shows that the melanosomal
transfer mechanism continues to function when melanocytes are present. Ultrastructural findings [124] support this conclusion (Figs. 276, 277).
Animal models suggest that heredity is a significant factor. Kirby [128]
described a related graying in a population of wild-type Australian mice. This
progressive loss of hair pigmentation with aging was inherited as an autosomal
dominant trait; the time course seemed to be determined by the mother (Fig.
278). Similar genetic age-related graying has also been found in black and brown
rats, guinea pigs, rabbits, dogs, sheep, and horses.
Burch and Jackson [129] suggested age-specific prevalence of senile graying
of hair suggests some disturbance of immune tolerance. Although premature
graying of hair has in some instances been reported associated with autoimmune disorders or biologic stigmata of autoimmunity, the "immune intolerance" hypothesis is without firm foundation.
649
MISCELLANEOUS
HYPOMELANOSES
FIGURE 276. Brown hair bulb (Mishima stain. x 512) with melanocytes evident in the upper
part. (From: Herzberg J. Gusek W: Das Ergrauen des Kopfhaeres. Arch Klin Exp Dermatol 236:
368-384. 1970. Copyright. 1970. Springer-Verlag. Used with permission.)
FIGURE 277. Gray hair (Mishima stain. x 512) . (From: Herzberg J. Gusek W: Das Ergrauen des Kopfhaeres. Arch Klin Exp
Dermoto) 236:368-384. 1970. Copyright. 1970. Springer-Verlag. Used with permission.)
<0
~
Q
=
en
651
MISCELLANEOUS
HYPOMELANOSES
FIGURE 278. Female 181 (age 8 1/2 months; genotype aa/BBIGa-) showing gray phenotype of Ga
alongside a 5-week-old progeny that shows normal black (aa/BB) phenotype. (From: Kirby GC:
Graying with age. A coat color variant in wild Australian population of mice. J Hered 65:126-128,
1974. Copyright. 1974. American Genetics Association. Used with permission.)
History and folklore are replete with tales of sudden whitening of hair. For
hundreds of years the curious sudden appearance of white or gray hair as a
response to fear or grief has stirred the interest of physiologists attempting to
explain dramatic changes in a structure that has no blood supply or enervation.
Many have questioned that sudden whitening is even possible.
The term "sudden whitening" here applies to the abrupt appearance of
totally depigmented hair in contradistinction to graying, which is a gradually
developing admixture of pigmented and hypopigmented hairs. In earlier times,
premature graying was considered a result of chronic anxiety whereas "acute
shock" rendered one abruptly white.
652
CHAPTER 9
hair. In a single night it had become as white as that of a woman of seventy. She was
thirty-six.
Two years before his death, General Charles Gordon had been noted to
have dignified streaks of gray hair. Yet, during the long seige of Kartoum by
the Mahdi in 1885, Gordon is said to have been so anxious that he developed
snow-white hair.
John Libeny, convicted of the attempted assassination of Emperor Franz
Josef of Austria, and E. S. Stokes, murderer of financier and former associate
Jim Fiske, both developed dramatic changes in their hair color.
More recent and less illustrious men have been reported to blanch under
stress. The hair of a Viennese man became white one day after his mother was
killed in an air raid [132]. Seven weeks after an accident, a motorcyclist noted
blanching of his hair [133]. Sudden graying was noted in a woman who had
been shipwrecked [134]. Ephraim [135] noted he could find four cases of whitening associated with the horrors of World War I but found none related to
World War II.
Other instances of dramatically rapid graying or whitening of hair have
been reported. A soldier in the Bengalese Army, under the horror and despair
of his inquisition as a prisoner, turned completely gray in 30 minutes [136].
Holzgraefe [137] reported a 58-year-old woman whose husband had suddenly
turned white when his house caught fire and who herself turned gray overnight
after learning her two sons had been poisoned by gas. Ornsteen [138] reported
a woman who in the morning had not a single gray hair and who later in the
day and less than four hours after learning that her son had been in a serious
accident became snow white.
Rarely is sudden whitening reversible [120]. However, Canuto [139] noted
a 20-year-old woman whose hair became gray and whose hair color returned
seven months later.
653
MISCELLANEOUS
HYPOMELANOSES
654
CHAPTER 9
was flame red in color and the remainder white or red-white. Two days later
her red hair became completely white and two weeks later she lost all of her
white hair, but not her normal remaining black hair.
Jelinek [131] described a 21-year-old schizophrenic woman who developed
a 3 cm-wide streak of white hair stretching from her forehead to her left side.
Four days later her hair returned to normal, but the whitening, which recurred
with exacerbation of illness, could be reversed by immersion of the hair in
water (with escape of the observed air bubbles).
In 1954, Hoff [142] reported a 40-year-old miner with chalicosis who, after
a small mine accident, developed what was diagnosed as a "grippe" marked
by chills, syncope, nausea, and increased thirst. The next night he lost much
of his blond hair so that his hair appeared to have become completely white.
Slowly his body hair turned white and his brown irides became very light in
color. With this history and the subsequent appearance of weight loss, decreased libido, decreased hearing, and development of small testes, he was
considered to have had hypothalmic trauma or encephalitis.
Gowers [143], in 1901, reported unilateral sudden whitening of a brown
beard within three days of a contralateral meningeal hemorrhage. Cases of
sudden whitening following hemiplegia, brain tumor, ataxia, and unilateral
headache have also been reported. In addition, five cases of sudden whitening
of cilia have been reported by ophthalmologists.
Ephraim [135] personally observed whitening within six weeks (possibly
as soon as two to three weeks) of an accident. His patient had graying of the
temples and a peppering of white hairs prior to a fall; yet within four weeks
of the injury his hair had become completely white except for a band of black
hair at the base of his neck. Examination of his scalp revealed very few dark
hairs. All hairs were normal on microscopic examination, except that the white
hairs were transparent and had clumps of pigment in the medulla. This patient
is said later to have developed generalized vitiligo.
The true incidence of sudden whitening is unknown, but the curiosity
surrounding its occurrence suggests it is indeed rare. There are no apparent
underlying predisposing factors, including family history. No disease associations are known. Spontaneous reversal has been reported. No therapeutic
attempts to repigment have been reported.
Pathogenesis
That sudden whitening, which is more common than sudden graying,
seems to occur is accepted by many American and British dermatologists.
However, many others have asserted sudden whitening is fictional and not
compatible with known anatomic and physiologic phenomena. von Stieda [144],
in 1910, even suggested that abrupt whitening appeared because neurologically
compromised or grief-stricken patients were no longer able to dye their hair.
Hebra and Kaposi [145] have also doubted this can be other than an evolutionary
type of natural replacement of normally pigmented hairs by gray hairs.
Yet observers cannot agree whether hair turns white throughout the entire
shaft simultaneously (if at all), from the root, or from the distal tip. Ephraim
[135] discussed this with hairdressers who stated they never noted short white
655
MISCELLANEOUS
HYPOMELANOSES
656
CHAPTER 9
vitiligo [135]. Folklore and a few reported cases reveal limited insight into this
curious problem. Perhaps these cases represent vitiligo, alopecia areata, or other
leukodermas associated with canities. Critical clinical observation should provide the next clue.
ALOPECIA AREATA
Alopecia areata, which is an idiopathic, circumscribed, nonscarring alopecia, may be associated with several types of depigmentation. The hair, the
skin, or both may be involved.
During the regrowth phase of alopecia areata, new terminal hairs usually
lack melanin pigment (Fig. 279). Usually the amelanosis is transitory so that
the amelanotic hair is eventually replaced by dark, entirely normal hair [159].
In rare instances, the white hair is permanent. Van Scott [160] observed that
the dermal papillae of hair and its underlying column of connective tissue
contained variable amounts of pigment which he explained was melanin that
Klingmuller [148] reported a patient who rapidly lost all of his pigmented
hair while the gray hair persisted, presumably the result of alopecia areata
involving pigmented hair. Hoff [142] has reported a patient with sudden total
vitiligo and sudden graying of the hair, the latter of which was presumably the
result of diffuse alopecia totalis involving the pigmented hair. Lerner [158]
suggested that accounts of the rapid onset of gray hair may be explained in the
following manner: "Some gray hairs appear with age or because of familial
predisposition. When approximately half of the hair is gray, a diffuse hair loss
may occur, most commonly from a febrile illness or from alopecia areata. Since
dark hair falls out more readily than gray hair, in a few days nearly all the
black hair, but little of the gray, may be lost. Loss of the pigmented hair results
in overall thinning which may not be very noticeable. With only the gray hair
remaining, the patient has turned gray overnight." More recent studies by Ortonne et a1. [161] have confirmed this mechanism in four patients.
Alopecia areata and vitiligo occur together more commonly than would
be expected by chance alone (see "Vitiligo" in Chapter 1).
Alopecia Areata and Pallor of the Skin
Lubowe [162] reported that in a large majority of his patients with alopecia
totalis, hypomelanosis of the scalp and face was present. With corticosteroid-corticotropin therapy this pigment dilution was reversed. The patients
reported by Demis and Weiner [159] to have "alopecia universalis onychodystrophy and total vitiligo" really had more of a "generalized palor" than actual
vitiligo. In fact, one of them still retained some ability to tan. No skin biopsies
were performed in these patients.
VAGABOND'S LEUKOMELANODERMA
Vagabond's disease [163-166] is a cutaneous affliction that occurs in older
persons who are unkempt in personal habits, have pediculosis corporis, and
give a history of infrequent bathing or changing of clothes, dietary deficiency,
657
MISCELLANEOUS
HYPOMELANOSES
658
CHAPTER 9
and chronic alcoholism. The description suggests a typical beggar or "vagabond." The disorder is characterized by macules and patches of diffuse lightbrown hyperpigmentation especially noticeable around the wrists and groin,
between the thighs, in the axillae, over the back of the neck, and particularly
the upper back (Figs. 280, 281). The face and the extremities usually appear
less pigmented than the trunk [167). Diffuse hyperpigmentation of the oral
mucosa has also been observed in such patients [168,169] . Vagabond's disease
FIGURE Z80. Vagabond's leukomelanoderma. (From: Grosshans E et al: La leucodermie des vagabonds. Etude anatomopathologique et ultrastructurale. Ann Dermatol Syphiligr (Paris) 99:141-166,
1972. Copyright, 1972. Masson & Cie. Used with permission.)
659
MISCELLANEOUS
HYPOMELANOSES
FIGURE 281. a, b: Close-up view of the hypomelanotic macules in two patients. (From: Grosshans
E et al: La leucodermie des vagabonds. Etude anatomopathologique et ultrastructurale. Ann Dermatol Syphiligr (Paris) 99:141-166,1972. Copyright, 1972, Masson & Cie. Used with permission.)
FIGURE 282. Epidermal depigmentation, spongiosis, and pigmentary incontinence. (Fontana stain, x 64) (From:
Grosshans E et al: La leucodermie des vagabonds. Etude anatomopathologique et ultrastructurale. Ann Dermatol
Syphiligr (Paris) 99:141-166, 1972. Copyright, 1972, Masson & Cie. Used with permission.)
to
=
=
0=
FIGURE 283. Melanocyte in involution in Vagabond's disease. Autophagic vacuoles (VA), multivesicular bodies (cmv), and catabolic debris scattered in the cytoplasm. Square on the upper right
shows a premelanosome. (x 28,600 and 61,000) (From: Grosshans E et al: La leucodermie des
vagabonds. Etude anatomopathologique et ultrastructurale. Ann Dermatol Syphiligr (Paris)
99:141-166, 1972. Copyright, 1972, Masson & Cie. Used with permission.)
661
MISCELLANEOUS
HYPOMELANOSES
662
CHAPTER 9
Horner Syndrome
Sympathetic heterochromia is represented by Horner syndrome which can
be congenital or acquired. The essential features of Horner syndrome are a
moderate miosis, a minimal ptosis, and narrowing of the palpebral fissure.
Other features may include anhidrosis on the affected side of the face, an
"upside down" ptosis (elevation of lower lid), conjunctival congestion, transient ocular hypotonia, and heterochromic irides in congenital Horner syndrome [175]. Heterochromia irides with congenital Horner syndrome is transmitted as an irregular dominant trait; familial cases have been reported [176,177].
Gladstone [174] pointed out that sympathetic ophthalmia permits the differentiation of congenital Horner syndrome from a more recent acute lesion.
Section of the superior cervical ganglion [178] has resulted in change in iris
color in animals. Heterochromia irides in association with Horner syndrome
has also been reported to follow excision of the superior cervical ganglion [178],
or in conjunction with neonatal trauma [179] or cervical ribs [179]. Isolated
cases of hypochromic heterochromia of the iris have also been described following a cervical sympathetic lesion or a cervical sympathectomy [180-185].
Laties and Lerner [186] observed decreased iris tyrosinase activity after decentralization of the superior cervical ganglion in mammalian systems.
HYPOMELANOSIS IN SCLERODERMA
Various disturbances of cutaneous pigmentation have been reported in
patients with localized or systemic scleroderma [187,188]. Vitiligo is not uncommon in patients with systemic or localized scleroderma [189,190]. However, some pigmentary abnormalities, including hyperpigmentation and/or hypo pigmentation appear to be more specifically related to the pathogenesis of
scleroderma [187,191]. Diffuse hyperpigmentation is quite common in patients
with systemic scleroderma and macular hypopigmentation may occur, most
frequently on the upper trunk, arms, forearms, and hands (Fig. 284a) Perifollicular sparing of the epidermal pigmentation loss is typical of these lesions
[192]. Morphea is usually hypopigmented or hyperpigmented.
On split dopa preparations, dopa-positive melanocytes are absent in depigmented skin whereas in hyperpigmented skin the melanocytes are large,
with prominent dendrites, and exhibit intense dopa oxidase activity (Fig. 284b).
In depigmented skin, ultrastructural studies confirmed the disappearance of
melanocytes. At the borders of achromic skin, the melanocytes contain few
melanosomes and show evidence of cytoplasmic degeneration (lipid vacuoles
and autophagocytosis of melanosomes) [191].
Hypomelanosis associated with scleroderma is secondary to the disappearance of melanocytes, and hypermelanosis is due to increased activity of
epidermal melanocytes.
The origin and mechanism of these melanin pigmentary disturbances in
scleroderma are unknown. The following hypothesis has been proposed [191]:
Initially and for unexplained reasons, increased melanogenesis occurs within
the epidermal melanocytes. This results in an increase in the intramelanocytic
content of cytotoxic melanin precursors. During a second stage, cellular organelles are altered, resulting in cell death.
663
MISCELLANEOUS
HYPOMELANOSES
664
CHAPTER 9
FIGURE 284. (a) Systemic scleroderma: this patient with diffuse melanoderma shows depigmented macules on the upper chest. (b) Systemic scleroderma (split DOPA). At the border of the
depigmented macules. a few dopa positive melanocytes are observed. No melanocytes are observed
in the depigmented epidermis.
REFERENCES
SARCOIDOSIS
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665
MISCELLANEOUS
HYPOMELANOSES
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666
CHAPTER 9
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39. Tagami K: Beitrage zur Kenntnis der acuten nicht eitrigen diffusen exsudativen Choroiditis
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40. Koyanagi Y: Alopecia and vitiligo accompanied with uveitis. Acta Soc Ophtha1mo1 Jpn
39:118, 1935. Quoted in Yuge T: The relation between Vogt-Koyanagi syndrome and sympathetic ophthalmia. Am J Ophtha1mol 43:735-744, 1957
41. Koyanagi Y: Dysakusis, Alopecia, und Poliosis bei schwerer Uveitis nicht traumatischen
Ursprunges. Klin Monatsbl Augenheilkd 82:194-211, 1929
42. Parker WR: Uveitis associated with alopecia, poliosis, vitiligo, and deafness: report of 2 cases.
Arch Ophthalmo114:577-581, 1931
43. Ogawa U: Histologic findings in idiopathic uveitis. Acta Soc Ophthalmo1 Jpn 38:1005, 1934.
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44. Babel J: Syndrome de Vogt-Koyanagi, Uveite Bilaterale, Poliosis, Alopecie, Vitiligo et Dysacousie. Schweiz Med Wochenschr 69:1136-1140,1939
45. Cowper AR: Harada's disease and Vogt-Koyanagi syndrome: uveoencephalitis. Arch Ophthalmol 45:367-376, 1951
46. Yuge T: The relation between Vogt-Koyanagi syndrome and sympathetic ophthalmia. Am J
Ophtha1mo1 43:735-744, 1957
47. Kissel P et al: Les uveo-neuraxites virales ou presumees telles. Rev Neurol (Paris) 108:267-294,
1963
48. Riehl JL, Andrews JM: The uveomeningoencephalitic syndrome. Neurology 16:603-609,1966
49. Sugimoto S, Kodama T: Clinical and histologic study of idiopathic uveitis. Acta Soc Ophthalmol Jpn 41:526,1937. Quoted in Yuge T: The relation between Vogt-Koyanagi syndrome and
sympathetic ophthalmia. Am J Ophthalmol 43:735-744, 1957
50. Remky H: Beitrag zur Kenntnis schwerer Formen der Uveo-enzephalitis. Klin Monatsb1 Augenheilkd 123:166-180, 1954
51. Reed H et al: The uveoencephalitic syndrome of Vogt-Koyanagi-Harada disease. Can Med
Assoc J 79:451-458, 1958
52. Aita JA: Neurologic manifestations of several improved infectious diseases. Nebr State Med
J 48:460-464, 1963
53. Carrasquillo HR: Uveitis with poliosis, vitiligo, alopecia, and dysacousia (Vogt-Koyanagi
syndrome). Arch Ophtha1mol 28:385-414, 1942
54. Lewis GM, Esplin BM: Vogt-Koyanagi syndrome; report of a case. Arch Dermato1 Syphilo1
59:526-530, 1949
55. Rosen E: Uveitis with poliosis, vitiligo, alopecia and dysacousia (Vogt-Koyanagi syndrome).
Arch Ophthalmol 33:281-292, 1945
56. Seals RL, Rise EN: Vogt-Koyanagi-Harada syndrome. Arch Otolaryngol 86: 419-423, 1967
57. Rones B: Uveitis with dysacousia, alopecia and poliosis. Arch Ophtha1mo1 7:847-855, 1932
58. Perry HD, Font RL: Clinical and histopathologic observations in severe Vogt-Koyanagi-Harada
syndrome. Am J Ophtha1mol 83:242-254, 1977
59. Parker WR: Severe uveitis with associated alopecia, poliosis, vitiligo and deafness. A second
review of the published records. Arch Ophtha1mo1 24:439-446, 1940
60. Weber SW, Kazdan JJ: The Vogt-Koyanagi-Harada syndrome in children. J Pediatr Ophthalmol 14:96-99, 1977
61. Flynn GE: Bilateral uveitis, poliosis and vitiligo with an hereditary factor, Am J Ophthalmol
35:568-572, 1952
62. Zentmayer W: Severe uveitis with associated alopecia, poliosis, vitiligo and deafness. Arch
Ophthalmol 27:342-344, 1942
63. Leyva AV: Uveomeningitis, uveoencephalitis; Vogt-Koyanagi-Harada syndrome; intra-cranial pseudohypertension. Report of three cases. Arch Hosp Univ (Habana) 11:215-231, 1959
64. Alajouanine T et al: Sur une meningoencephalite avec uveite unilaterale et decollement de
la retine, faisant suite a une hepatite ictenigime a rechute; persistance depuis six mois d'un
syndrome confusionnel avec dilatation ventriculaire et alterations du liquide cephalorachidien. Rev Neurol (Paris) 89:281-285, 1953
65. Johnson WC: Vogt-Koyanagi-Harada syndrome. Arch Dermatol 88: 146-149, 1963
667
MISCELLANEOUS
HYPOMELANOSES
666
CHAPTER 9
ALEZZANDRINI SYNDROME
108. Cremona AC et al: Vitiligo, poliosis and unilateral macular degeneration. Arch Oftalmol
Buenos Aires 36:102-106, 1961
109. Alezzandrini AA: Manifestations unilaterales de degenerescence tapeto-retinienne de vitiligo,
de poliose, des cheveux blancs et d'hypoacousie. Ophthalmologica 147:409-419, 1964
669
MISCELLANEOUS
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670
CHAPTER 9
119. Ronchese F: A comment on even whitening of senile hair. Int J Dermatol11:84-85, 1972
120. Comaish S: White scalp hairs turning black-an unusual reversal of the aging process. Br J
Dermatol 86:513-514, 1972
121. Bloch B: Uber die Entwicklung des Haut- und Haarpigmentes beim menschlichen Embryo
und liber das Erliischen der Pigmentbildung im ergrauenden Haar (Ursache der Canities).
Arch Dermatol Syphilol (Berlin) 135:77-108, 1921
122. Fitzpatrick TB et al: The nature of hair pigment, The Biology of Hair Growth. Edited by W
Montagna, RA Ellis. New York, Academic, 1958, pp 255-303
123. Orlanos C et al: Das weisse Haar alterer Menschen. Arch Klin Exp Dermatol 236:395--405,
1970
124. Herzberg 1. Gusek W: Das Ergrauen des Kopfhaares. Arch Klin Exp Dermatol 236:368-384,
1970
125. Kukita A et al: The electron microscopic study on dendritic cells in the hair matrix of human
white and gray hair. Jpn J Dermatol [BJ 81:326-334, 1971
126. Metchnikoff E: Sur Ie blanchissement des cheveux et des pails. Ann Inst Pasteur Lille 15:215,
1901
127. Yosikawa H: Studies in biochemistry of copper; copper in keratinous appendages of skin.
Jpn J Med Sci II Biochem 3:267-272, 1937
128. Kirby GC: Greying with age: a coat-color variant in wild Australian populations of mice. J
Hered 65:126-128, 1974
129. Burch PRJ, Jackson D: The greying of hair and the loss of permanent teeth considered in
relation to an autoimmune theory of aging. J Gerontol 21:522-528, 1966
150. Vauquelin: Quoted in Ephraim AJ: On sudden or rapid whitening of the hair. Arch Dermatol
79:228-236, 1959
151. Metchnikoff E: On the process of hair turning white. Proc R Soc Lond 69:156, 1901-1902
152. Helm F, Milgrom H: Can scalp hair suddenly turn white? Arch Dermatoll02:102-103, 1970
153. Burton JL: Canities of rapid onset due to diffuse alopecia. Practitioner 205:655--656, 1970
154. Damste TJ: A case of alopecia with acute pigment loss. Dermatologica 136:440, 1968
155. Klingmiiller G: Dber "plotzliches Weisswerden" und psychische Traumen bei der Alopecia
areata. Dermatologica 117:84-92, 1958
156. Lehnert W: Beitrag zur Frage des "plotzlichen Weisswerdens" von Korperhaaren. Dtsch Gesund 26:740-743, 1971
157. Montgomery PR: White overnight? (letter). Br Med J 1:300,1967
158. Lerner AB: Vitiligo. Prog Dermatol 6:1--6, 1972
158a. Guin JD et al: Immunofluorescence findings in rapid whitening of scalp hair. Arch Dermatol
117:576-578, 1981
ALOPECIA AREATA
159. Demis J, Weiner MA: Alopecia universalis, onychodystrophy, and total vitiligo. Arch Dermatol 8:195-201, 1963
160. Van Scott EJ: Morphologic changes in pilosebaceous units and anagen hairs in alopecia areata.
J Invest Dermato! 31:35-38, 1958
161. Ortonne J-p, Jeune R: Hair color and alopecia areata. Arch Dermatol114:1716, 1978
162. Lubowe II: Pigmentation in alopecia totalis. Arch Dermato! 77:593-594, 1958
VAGABOND'S LEUKOMELANODERMA
163. Bondet M: Melanodermic parasitaire. Lyon Med 70:262-264, 1892
164. Habermann R: Paratypishe Pigmentanomalien, in Toxicodermien. Edited by E Guttmann et
a1. Handbuch der Haut- und Geschlechtskrankheiten, IV 2. Berlin, Springer-Verlag, 1933,
pp 854-856
165. Pautrier LM, Levy G: Maladie des vagabonds et melanodermie generalisee. Bull Soc Fr Dermatol Syphiligr 32:172-175, 1925
166. Pautrier LM et al: Maladie des vagabonds et melanodermie generalisee (contribution a I'etude
des melanodermies). Bull Soc Fr Dermatol Syphiligr 34:249-253, 1927
167. Jeghers H: Pigmentation of the skin. N Eng! J Med 231:122-136, 1944
168. Greenhow EH: A case of vagabond's discoloration simulating the bronzed skin of Addison's
disease. Trans Clin Soc Lond 9:44-47, 1876
169. Lanzerberg MP: Maladie des vagabonds, avec pigmentation de la mugueuse buceale. Opposition avec un autre malade atteint de phtiriase et d'un autre type de melanodermie. Bull
Soc Fr Dermatol Syphiligr 39:293-295, 1932
170. Becker SW, Obermayer M: Modern Dermatology and Syphilology. Philadelphia, Lippincott,
1940, pp 3-7
171. Marie P, Guillain G: Melanodermie de cause incertaine (maladie d'Addison ou maladie des
vagabonds). Bull Mem Soc Med Hop Paris 19:198-203, 1902
172. Thiers H et al: Deux cas de melanodermie des vagabonds. Etude des epreuves de fonctionnement surrena1. Bull Soc Fr Dermatol Syphiligr 72:82-83, 1965
173. Grosshans E et al: La leucomelanodermie des vagabonds. Etude anatomopathologique et
ultrastructurale. Ann Dermatol Syphiligr (Paris) 99:141-166, 1972
671
MISCELLANEOUS
HYPOMELANOSES
672
CHAPTER 9
175. Grimson BS, Thompson HS: Drug testing in Horner's syndrome, in Neuroophthalmology.
176. Calhoun FP: Causes of heterochromia irides with special reference to paralysis of the cervical
sympathetic. Am J Ophthalmol 2:255-269, 1919
177. Durham DG: Congenital hereditary Horner's syndrome. Arch Ophthalmol 60: 939-940, 1958
178. Angelucci A: Sulle alterazioni trofiche dell'occhio che nei manniferi seguono Ie estirpazione
del gangl ganglio cervicale superiore de sympatico. Arch Ottalm 1:1-100, 1893
179. Mayou MS: Heterachromia iridis associated with paralysis of the sympathetic in early life.
Trans Ophthalmol Soc UK 30:196-197,1910
180. Bistis J: Etude clinique et experimentale sur Ie r61e du sympathique dans l'etiologie de
l'heterochromie. Arch Ophtalmol 45:569-595, 1928
181. Duke Elder S (Ed): System of Ophthalmology, Vol 3. London, Harry Kimpton, 1964
182. Lazarescu D, Lazarescu E: Heterochromia neurogene de l'iris et syndrome de Claude Bernard-Horner: observation clinique et recherches experimentales. Ann Oculist 170:767-771,
1933
183. Makley TA, Abbott K: Neurogenic heterochromia; report of an interesting case. Am JOphthalmol 59:927-928, 1965
184. Waardenburg PJ: Over ongelijke iristeleur bij verlamming van den nevus sympathicus. Ned
Tijdschr Geneeskd 64:1929-1941, 1920 Quoted in Gladstone RM: Development and significance of heterochromia of the iris. Arch Neurol 21:184-192, 1969
185. Weber E: Ober einen feltenen Fall von heterochromia Iridis. Klin Monatabl Augenheilkd
106:719, 1941
186. Laties AM, Lerner AB: Iris colour and relationship of tyrosinase activity to adrenergic innervation. Nature 255:152-153, 1975
SCLERODERMA
187. Jablonska S: Cutaneous lesions in systemic scleroderma (progressive systemic sclerosis), in
Scleroderma and Pseudoscleroderma. Edited by S Jablonska. Warsaw, Polish Medical Publishers, 1975 pp 243-276
188. Jablonska S: Localized scleroderma, in Scleroderma and Pseudoscleroderma. Edited by S
Jablonska. Warsaw, Polish Medical Publishers, 1975, pp 277-303
189. Szczepanski A: Studies of rheobase and sensory chromaxy in an appraisal of the role of the
nervous system in cases of the coexistence of circumscribed scleroderma with vitiligo. Przegl
Dermatol 60:219-222, 1973
190. Szczepanski A: Clinical and etiopathological appraisal of diffuse scleroderma with skin depigmentation. Przegl Dermatol 60:323-326, 1973
191. Ortonne J-p, Perrot H: Scleroderma: ultrastructural study of the melanin pigmentary disturbances of the skin. Clin Exp Dermatol 5:13-25, 1980
192. Guillaum A et al: A propos de deux cas de sclerodermie generalisee chez l'Africain. Bordeaux
Medical 11:101-105, 1978
IV
Leukodermas without Hypomelanosis
NEVUS ANEMICUS
Nevus anemicus, first described by Vomer [1] in 1906, is a congenital
malformation characterized by macules of varying size and shape which appear
distinctly pallid compared to the surrounding skin.
Clinical Features
Nevus anemicus is rare. Piorkowski [2] observed only seven cases in 19
years. However, as the disease is asymptomatic and causes no cosmetic disfigurement, it is likely that few affected patients seek medical counseling. It is
more frequent in women [3]. The lesion is present at birth. Most patients are
generally in good health, but nevus anemicus has been reported in patients
with von Recklinghausen disease [3,4] and with multiple vascular malformations [5]. But there is no data supporting an increased incidence; the incidence
in the general population is unknown.
Clinical Description
Usually, nevus anemicus appears as a large area of pale skin with sharply
outlined irregular borders surrounded by satellite macules (Fig. 285). Sometimes it appears as a number of grouped small macules "arranged like the fronds
of a maidenhair fern" [6] (Fig. 286). Nevus anemicus is usually located on the
trunk, most commonly on the chest. However, involvement of the face and
extremities has been reported [4,7,8]. A patient with a linear nevus anemicus
on an arm has been described [2].
The epidermis appears otherwise normal and the condition is usually
asymptomatic. There are no local sensory abnormalities.
Several simple tests facilitate the diagnosis: Under the Wood's light, nevus
anemicus seems to disappear. This clearly establishes that the decreased color
of the involved skin is not secondary to decreased melanin content. Pressure
on the border of the lesion with a glass slide renders the area of the nevus
673
674
PART IV
FIGURE 285. Large area of pale skin surrounded by small satellite macules. Even with suninduced pigmentation, in the right part of the picture the nevus anemicus is still apparent.
Histology
The histology is normal [9]. In the affected areas, hematoxylin-eosin-saffran stains reveal normal papillary and subpapillary vasculature. Alkalinephosphatase histochemical preparations show intact vasculature indistinguishable from uninvolved skin [3].
Electron Microscopy
Electron microscopy of involved skin is normal [10].
675
LEUKODERMAS
WITHOUT
HYPOMELANOSIS
FIGURE 286. a, b: Grouped small macules of pale skin with sharply outlined borders "arranged
like the fronds of a maidenhair fern. "
676
PARTlY
Pathogenesis
Nevus anemic us is a vascular phenomenon. Since no anatomic abnormalities have been identified in the vasculature of the involved skin, nevus
anemicus must result from a physiologic vascular abnormality. Nevus anemicus
is fascinating because it is a purely functional congenital disorder. Greaves et
al. [10] suggested that nevus anemicus may justifiably be called "pharmacological nevus."
Inquiry into the nature of the vascular reaction pattern anomaly has provoked some observations and studies. Vomer [1] noted that it was difficult to
produce urticaria factitia within a nevus anemicus. Piorkowski [2] concluded,
from physiologic studies of nevus anemicus, that "the cause of the disease is
a permanent tonic constriction" of the vasculature. Butterworth and Walters
[11) hypothesized that the underlying defect is in the effector cells of the
arterioles. Fleisher and Zeligman [3) noted that intralesional injection of acetylcholine, pilocarpine, histamine, or serotonin failed to produce vasodilatation
in the affected areas and concluded that the defect may be "at the motor endplate
or at the smooth muscle effector cells of the blood vessels, perhaps associated
with an increased stimulation of the vasoconstrictor fibers or of inhibition of
the vasodilator fibers of the arterioles." Greaves et al. [10] concluded that the
immediate cutaneous abnormality is sustained adrenergic vasoconstriction. Abolition of visible evidence of the nevus by a sympathetic block suggested sympathetic vasoconstriction produced the nevoid pallor. The lowered threshold
of the nevus vessels to the blanching effect of levarterenol suggested increased
sensitivity of cutaneous blood vessels to catecholamines as important to the
production of the nevoid pallor. However the possibility of increased adrenergic
sympathetic tone due to increased local catecholamine concentration in nevus
anemic us could not be excluded.
Transplant studies demonstrated donor dominance [9). Transplanted skin
biopsies retained their original characteristics and did not assume those of the
receptor site. The defect seems to be an increased sensitivity of blood vessels
to catecholamines and not increased adrenergic stimulation.
Treatment
Fortunately, nevus anemicus induces only a slight cosmetic disfigurement,
because no effective treatment is available.
Rare
Birth
More frequent in females
Variable: large area with small satellite
spots; grouped small spots
Irregular, sharply outlined
Slightly paler than normal skin
Trunk, face, extremities
Localized
None
No contrast with normal skin
Absence of vasodilatation
Usually none
ANEMIA
Decreased levels of circulating oxyhemoglobin in anemic states induce a
pallor which is most readily detected in areas where there is physiologically
less melanin (palms and soles, mucous membranes). The degree of pallor in
the skin is inversely proportional to the hemoglobin content of the blood. Pallor
also results from decreased cutaneous blood perfusion, as in Raynaud phenomenon. However, nevus anemicus is the only focal leukoderma secondary
to decreased oxyhemoglobin content of the skin that can be confused with
melanin disturbances.
REFERENCES
1.
2.
3.
4.
5.
6.
7.
8.
Vomer H: Uber Naevus anaemicus. Arch Dermatol Syphilol (Berlin) 82:391-398, 1906
Piorkowski FO: Naevus anaemicus (Vomer). Arch Dermatol Syphilol 50:374-377, 1944
Fleisher TL, Zeligman I: Nevus anemicus. Arch Dermatol100:750-755, 1969
Naegeli 0: Naevi anaemici und Recklinghausensche Krankheit. Arch Dermatol Syphilol (Berlin) 121:742-745, 1915
Weber FP: Case of nevus anemicus. Br J Dermatol 41:119-120, 1929
Little EGG: Case of nevus anemicus. Br J Dermatol 33:25-26, 1921
Lane J: Naevus anaemicus. J Cutan Dis 34:602-604, 1916
MacKee GM: Case report presented before the Manhattan Dermatologic Society. J Cutan Dis
36:200-201, 1918
677
LEUKODERMAS
WITHOUT
HYPOMELANOSIS
678
PART IV
Index
Achromic guttate parapsoriasis, 512
Addison disease and vitiligo, 191
Albinism
with hemorrhagic diathesis, 75
and immunodeficiency, 87
ocular, 89
optic pathway abnormalities, 92
Albinism, oculocutaneous, 59
classification, 61
incidence, 63
tyrosinase-negative, 65
tyrosinase-positive, 69
yellow-mutant, 74
Albino, 61
Alezzandrini syndrome, 641
Alopecia areata, 656
Alpha-dendritic cells, see Indeterminate cells
Amelanosis, 37
Arsenic, 499
Ascorbic acid in vitiligo, 237
Ataxia-telangiectasia, 433
other cutaneous features, 433
systemic abnormalities, 434
Basement membrane in vitiligo, 233
Benoquin, therapeutic use in vitiligo, 284
Bird-headed dwarfism, 465
Bleeding times in vitiligo, 241
Bloch-Sulzberger syndrome, 422, 427
Butyrophenone, 500
Canities, 37
Chediak-Higashi syndrome, 79; see also
Depigmentation, chemically indiced
Chemical hypomelanosis, 479
mechanism of action, 489
Chloroquine diphosphate, 501
Clofazimine, therapeutic use in vitiligo, 284
Copper, in vitiligo, 235
679
680
INDEX
Hypomelanosis (cont.)
and endocrine disorders, 52, 473
hereditary, 42, 60
infectious, 523
and inflammation, 509
following irradiation, 475
of Ito, 423, 425
and neurocutaneous disorders, 52
with oculocutaneous albinism, 59
parasitic, 523
pathogenesis, 54
following physical trauma, 475
of scalp hair, 39
theoretical mechanisms, 55
Wood's light examination, 49
Hypomelanotic disorders, 57
with circumscribed hypomelanosis, 129
with generalized decreased pigmentation,
102
genetic and congenital, 59
Hypopigmentation
and microphthalmia, 88
with punctate kerotosis of the palms and
soles, 458
Hypopituitarism and hypomelanosis, 473
Hutchinson-Gifford syndrome, 463
Idiopathic guttate hypomelanosis, 619
Immediate pigment darkening, 27
Incontinentia pigmenti, 422
development anomalies in, 432
diagnosis, 430
hypopigmentation in, 427
nervous system abnormalities in, 431
ocular anomalies in, 431
Incontinentia pigmenti achromians, 411
clinical findings, 412
diagnosis, 425
familial, 412
histology and electron microscopy,
420
incidence, 412
systemic findings, 418
pathogenesis, 421
Indeterminate cells, 7, 232
Inflammation and hypomelanosis, 509
Kappa chain deficiency, 464
Keratinocytes, 1
in vitiligo, 233
Koebner phenomenon, 163
Kwashirokor, 467
associated findings, 469
depigmentation in, 467
diagnosis, 469
histology, 468
pathogenesis, 468
681
INDEX
682
INDEX
Porphyria, 213
Post-kala-azar dermatosis, 559
Premature aging syndromes, 462
Premature graying of scalp hair, 40
and vitiligo, 207
with Waardenburg syndrom, 344
Premolar aplasia, hyperhidrosis and canities
prematura, 461
Progeria, 463
Protein deficiency, 467
Psoralens, 260
absorption spectra, 261
pharmacology, 262
photosensitization, 263
therapeutic use, 267
side effects, 279
Psoriasis, 513
Quinacrine, therapeutic use in vitiligo, 283
Rothmund-Thomson syndrome, 462
Rozycki syndrome, 452
Sarcoidosis, 613
Scleroderma, 663
Seckel syndrome, 465
Senile graying of hair, 641; see also Canities
Sensory function of skin, in vitiligo, 238
Skin temperature in vitiligo, 239
Sudden whitening of hair, 651
Sulfhydryl compounds and depigmentation,
496
Sutton's nevus, see Halo nevus
Sweat secretion in vitiligo, 240
Syphilis
endemic, 542
secondary, 543
Thiambutosine, therapeutic use in vitiligo,
284
Thiamine in vitiligo, 237
Thyroid disease and vitiligo, 182
Tietz syndrome, 123
Tinea versicolor, 545
diagnosis, 555
electron microscopy, 551
histology, 547
treatment, 555
Treacher-Collins syndrome, 465
Trichochrome, 6
Trichopoliodystrophy, 103
Triparanol. 498
Tuberculosis, 562
Tuberous sclerosis, 375
clinical features, 376
diagnosis, 392
histology and electron microscopy, 386
systemic manifestations, 391
Tyrosinase, 5
in vitiligo, 234
Tyrosinase inhibitors, 27
Tyrosine-melanin pathway, 3
Ultraviolet radiation, control of pigmentation
by, 27
Vagabond's leukomelanoderma, 657
Vesicoglobular bodies, 14
Vitamin BI2 deficiency, 471
Vitiligo
and Addison disease, 191
and alopecia areata, 205
animal models, 241
and associated disorders, 182
and atopic dermatitis, 211
auditory changes, 177
and autosomal recessive deafness, 452
biochemical studies, 234
and blood groups, 178
classification, 165
clinical features, 132, 145
composite hypothesis, 257
confusion with leprosy, 129
and diabetes mellitus, 198
diagnosis, 258
distribution of depigmented macules, 153
and dysglobulinemia, 216
familial. 135
functional abnormalities of skin, 238
and gastric function abnormalities, 195
and gastroenteropathies, 219
and hematologic disorders, 217
hepatobiliary disease, 216
histologic findings, 225
history, 129
and hypogonadism, 214
and hypoparathyroidism, 204
and hypopituitarism, 214
and idiopathic heart block, 220
immune hypothesis, 243
incidence, 132
involvement of hair in, 161
isomorphic phenomenon, 163
and lichen planus, 211
and lichen sclerosus et atrophicus, 213
and lupus erythematosus, 213
and malignancies, 217
and multiglandular insufficiency
syndromes, 200
and myasthenia gravis, 220
neural hypothesis, 250
and Parkinson disease, 215
and pernicious anemia, 194
and porphyria, 213
precipitating factors, 140
pregnancy, 144
Vitiligo (cont.)
psoralen and ultraviolet radiation therapy,
260
and psoriasis, 207
psychologic factors, 141
repigmentation, 260, 265
and rheumatoid arthritis, 215
self-destruct hypothesis, 256
and thyroid disease, 182
trauma, 143, 163
treatment, 258
Vitiligo-like leukoderma and melanoma, 208
Vogt-Koyanagi-Harada syndrome, 627
clinical features, 630
diagnosis, 640
etiology, 638
pathologic findings, 635
Waardenburg syndrome, 337
abnormalities in, 341
animal models, 339
deafness in, 356
"deficient neural crest" theory, 357
683
INDEX