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Veterinary Dermatology 2004, 15, 269 277

Review

Blackwell Publishing, Ltd.

Clinical and genetic aspects of X-linked ectodermal dysplasia in the


dog a review including three new spontaneous cases
ENIO MOURA and SILVANA M. CIRIO
Faculty of Veterinary Medicine, Pontifcia Universidade Catlica do Paran, Curitiba, Brazil
(Received 6 January 2003; accepted 5 April 2004)

Abstract This review presents the clinical, dermato-histopathological and genetic features of canine X-linked
ectodermal dysplasia in previously reported cases and in three new spontaneous cases. The condition is compared
with anhidrotic ectodermal dysplasia in humans and, based on current genetic concepts, we suggest that the two
conditions are caused by the same gene and, consequently, represent a single pathological entity that affects both
humans and dogs.
Keywords: alopecia, conic teeth, dental abnormalities, dog, ectodermal dysplasia, hypotrichosis, oligodontia, X
chromosome.

I N TRO D U CT ION
X-linked ectodermal dysplasia (XLED) is a congenital, sex-linked, recessive disorder, characterized mainly
by a reduction in, or absence of, piloglandular units
over areas of the body. There may also be abnormalities in the teeth and other ectodermal derivatives.1 In
humans it is variably termed hypohidrotic ectodermal
dysplasia, anhidrotic ectodermal dysplasia (EDA) or
ChristSiemensTouraine syndrome,2 and it is the most
common of the 192 ectodermal dysplasias described.3
In mice it is called the Tabby phenotype4 and in cattle
hypotrichosis with anodontia.5,6 In dogs, it has been
described in only four reports in indexed journals and has
been called congenital ectodermal defect,7,8 congenital
ectodermal dysplasia9 and X-linked ectodermal dysplasia.10 (Note that the first publication of Selmanowitz
et al.7 was subsequently presented at a workshop and
republished.9 ) The purpose of this review is to characterize X-linked ectodermal dysplasia both clinically
and genetically, to describe three new spontaneous
cases, to highlight the similarities with EDA and to
propose a common aetiology for the two conditions.

REPO RTED C L INICA L FE AT UR E S


OF XLED
The clinical signs observed by Selmanowitz et al.79 and
Casal et al.10 describe the basic phenotype of canine
XLED. Two male dogs were reported in 1970,7,9 five
Correspondence: E. Moura, Faculty of Veterinary Medicine,
Pontifcia Universidade Catlica do Paran, Curitiba, Brazil. E-mail:
emoura@per.com.br
2004 European Society of Veterinary Dermatology

males and three females in 1977,8 and three males and


two females in 1997,10 totalling 15 cases, all showing
the same pattern of distribution of alopecia and hypotrichosis (Fig. 1a). The dogs also showed an absence or
reduction of piloglandular units and several had dental
abnormalities. Characteristically, there was alopecia
and hypotrichosis which was spread over approximately
two-thirds of the body area7,8,10 with some variation as
to its extent.8,10 In younger dogs, the skin in the alopecic
areas was thin and pinkish-grey or greying brown, leaving the vasculature visible7 but tending to become
pigmented with age. The dogs partially retained their
primary coat, but it was thinner than normal and lacked
sheen. Their secondary hairs were brittle, incomplete
and possibly abnormal.10 Episodic scaling of varying
degrees was observed from the age of 4 months, but
this was independent of the degree of alopecia.7 On
histopathology, there was an absence or reduction of
hair follicles, sweat glands and arrector pili muscles,
depending on the degree of visible alopecia. Independent
of the presence or absence of hair, there was superficial
orthokeratotic hyperkeratosis, foci of spongiosis and
epidermal hyperpigmentation.7 Collagen and elastic
fibres were normal.
Dental alterations affecting the deciduous and permanent dentition of both dental arcades were observed
in some, but not all, dogs. Affected dogs showed various combinations of oligodontia, dental hypoplasia,
persistence of deciduous teeth, delayed eruption of the
permanent dentition and conical teeth.7,8,10 As well as
the cardinal dermatological and dental signs, mild
conjunctivitis and photophobia were common7,10 and
showed spontaneous improvement followed by relapse.
When performed, opthalmoscopic examination and
Schirmer tear tests were normal.7 No abnormalities of
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E Moura and SM Cirio

Figure 1. Confirmed and possible cases of canine XLED (described in the literature as hypotrichosis or congenital alopecia). (a) Distribution
pattern of alopecia and hypotrichosis in canine XLED. The areas in red indicate the distribution of alopecia and hypotrichosis. The range of
this distribution may vary depending on the patient. (b f ) Note, in red, the distribution of alopecia or hypotrichosis in the described cases,
compared with the distribution of XLED. All were male, except (e) and had no piloglandular units in the affected areas or had them in reduced
numbers. In addition, there were dental defects in (e). The drawings were made from written clinical descriptions or photographs presented with
each report.

the nails were recorded. One of the poodles described


by Selmanowitz et al.7 had an umbilical hernia.
Based on the above information, the following criteria
should allow a diagnosis of XLED to be made relatively easily:
1 characteristic distribution of congenital alopecia
and hypotrichosis;
2 histological absence of piloglandular units in the
areas of alopecia;
3 dental alterations;
4 generally the male is affected, although heterozygous
females may show mild signs of dysplasia.8,10

F U RTH ER POSSI B L E CA SE S
O F XLED
In addition to the cases described above, there are a
number of reports in the literature of cases in several
breeds that are referred to as having congenital hypotrichosis or congenital alopecia and which were probably XLED but were not described as such. Prior to
Selmanowitz et al.7 there were at least two reports by
Thomsett in 196111 (whippet) and Kral & Schwartzman

in 196412 (cocker spaniel). These reports described dogs


with a phenotype that corresponds to what is now
consistent with canine XLED (Fig. 1b,c). Subsequently
a further three reports by Muller & Kirk13 in 1976 (Belgian shepherd), Kunkle14 in 1984 (Labrador retriever)
and Grieshaber et al.15 in 1986 (Bichon frise) described
dogs with a similar phenotype. All the dogs had congenital alopecia, the distribution of which, despite
certain differences as to its extent, essentially corresponded to that seen with XLED (Fig. 1df ). However,
in the majority of these cases, no dental abnormalities
were reported. This does not necessarily mean that
another type of dysplasia was present. It may just be a
variation within the phenotypic spectrum of XLED.
An absence of dental abnormalities was observed in
some of the cases reported by Selmanowitz et al.7 and
it is worth remembering that, in humans, different
studies have confirmed allelic heterogeneity.1621 If variable expressivity due to allelic heterogeneity occurred
in dogs, it could be a plausible explanation for the
variations as to the extent and degree of the cutaneous
and dental alterations. Furthermore, all the dogs in the
above reports were male, except that reported by Kunkle,14 which was a female with hypotrichosis and alopecia with a similar distribution to that seen in males,
albeit less intensely, a reduction in piloglandular units
and a partial lack of teeth. It is possible that this was a
spontaneous case of canine XLED in a female because

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in humans there are many cases of women who are
carriers of the EDA allele and show clinical signs,
although their clinical condition is not as serious as in
men. This situation can be explained by the phenomenon
of inactivation of the X chromosome (lyonization),22
or by the acceptance of X-linked semi-dominant inheritance.23 Such a situation would be possible if the
mother was an asymptomatic carrier (Kunkle stated
that the genitors were normal) or if there was a gene
mutation in the maternal or paternal X chromosome.
Thus, the female would be affected as long as there was
sufficient inactivation of the parental X chromosome,
allowing for the clinical expression of the mutation.

THREE NEW CASES OF CANINE XLED


Over the last 15 years, we have observed three further
cases of male dogs with congenital alopecia, absence of

271

piloglandular units and dental defects consistent with


XLED.

Case 1
A mixed-breed miniature pinscher with a brown and
white hair coat was initially examined in 1989 at the age
of 2 years with the following clinical signs. There was
alopecia in the frontaltemporoparietal region, in the
sacral region and over the ventral regions of the trunk
(Fig. 2). Hypotricosis was present over the face, and
the thoracic and pelvic limbs, especially over the proximal two thirds. Secondary hairs were virtually absent.
Hyperpigmented patches were distributed over the skin
surface. The skin appeared thin, and there was intermittent scaling over the dorsum, the sacral region and
especially the limbs, which also showed mild erythema
on the distal thirds. There was oligodontia, conic and
irregularly distributed teeth. Chronic mild conjunctivitis
was also present, punctuated by periods of improvement.

Figure 2. Case 1 at 2 years of age. Compare the distribution of alopecia shown in this patient (a c) with the drawings in Fig. 1(a).
(d) Oligodontia, conic teeth and dental malalignment.
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E Moura and SM Cirio

Figure 3. Case 2 at 4 months of age. Compared with Fig. 2, the degree of alopecia is slightly less, but there is essentially the same pattern of
distribution. Note in (a) and (b) the presence of an umbilical hernia. (e) Dentition at 8 months of age. There is oligodontia and spaced conic
teeth as well as the persistence of one deciduous upper incisor. The lower canine and incisor teeth were also deciduous.

The sire, dam and siblings were all normal. No information was available for the grandparents.

Case 2
A crossbreed with a brown and white hair coat was
examined initially in 1999 at the age of 4 months with
the following clinical signs. There was alopecia in the
frontal temporal regions and over the ventral region of
the trunk (Fig. 3). Hypotrichosis was present in the
sacral region and over the proximal two thirds of the
thoracic and pelvic limbs. On the lateral and dorsal
regions of the trunk, the hypotrichosis was localized.
Secondary hairs were virtually absent. The skin was
thin, with hyperpigmented patches all over the body.
There was generalized, intermittent scaling and mild
erythema on the distal thirds of all limbs. Oligodontia,
conic and widely spaced teeth were present. The dog
had conjunctivitis, but Schirmer tear tests were normal
(right eye, 13 mm/min; left eye, 11 mm/min). The dog also
had an umbilical hernia. No family history was available.

Case 3
A mixed Pekingese with a brown hair coat was examined
initially in 2001 at the age of 2 months with the following
clinical signs. There was thin skin with alopecia in the

frontal and temporoparietal regions, over the lumbosacral


region, over the proximal two-thirds of all four limbs and
over the ventral region of the trunk (Fig. 4). Secondary
hairs were rare. There was oligodontia, widely spaced
and conic teeth. Conjunctivitis was present but Schirmer
tear tests were normal (right eye, 10 mm/min; left eye,
15 mm/min). As in case 2, the dog had an umbilical
hernia. The sire and dam were unaffected, as were the
paternal grandparents. No information was available
concerning the maternal grandparents. From the same
gestation there was a normal male and female sibling.
According to the owner, there was also a normal halfsister from a previous gestation and a half-brother
with a similar phenotype to that of the patient (Fig. 5).
Histopathological changes were similar in all three
cases. There was absence of hair follicles, arrector pili
muscles, sweat glands and sebaceous glands with epidermal hyperpigmentation and orthokeratotic hyperkeratosis (Fig. 6). Collagen fibres were normal.
Some interesting points can be highlighted from the
above three cases. First, in all three cases, the dental
abnormalities were more accentuated in the lower
arcade; second, in two cases (1 and 2), periodic scaling
was observed as described by Selmanowitz et al.,7 as
well as erythema over the limbs; third, in all three cases,

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Figure 4. Case 3 at 4 months of age showing alopecia with characteristic distribution


since birth. Note the signs of conjunctivitis in (b), the visible vasculature and the presence
of an umbilical hernia in (d). (e) At 17 months of age. (f ) Dentition at 13 months of age.
There is oligodontia, conic teeth and persistence of some deciduous teeth.

there was mild conjunctivitis, but tear production was


normal in those tested (cases 2 and 3). Finally, in two
of the dogs (cases 2 and 3) an umbilical hernia was
found, as observed by Selmanowitz et al.7 The significance of these findings is not yet clear.
Case 1 was examined periodically throughout its life
and showed no change in its dermatological condition
until it died in May 2000 from prostate cancer. Cases 2
and 3 are still alive and being observed.

CLIN ICAL SI M IL AR IT I E S B E T WE E N
XLED AN D E DA
Canine XLED and human EDA are clinically similar,
showing the same cardinal signs, i.e. trichodysplasia,
dental abnormalities and a lower number of sweat and

sebaceous glands. The following similarities and differences deserve to be highlighted.


1 Both conditions are characterized by hypoplasia
or aplasia of the follicular units, resulting in a quantitative reduction of hair follicles and consequently,
hypotrichosis or areas of alopecia. The hair is dry,
possibly brittle and lacks sheen.
2 Dental abnormalities occur in both species and include
conic, pointed teeth, oligodontia, persistence of deciduous teeth and delayed eruption of permanent teeth.
In men, the lower arcade is more commonly affected,23
as was the situation in the three cases presented here.
3 In both humans and dogs,1,23 the skin is thin and
dry and there may be hyperpigmented patches.

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dysplasia, phenotypically indistinguishable from Xlinked ectodermal dysplasia. A similar situation
occurs in mice, in that similar phenotypes are
caused by mutations in the X-linked locus (Tabby
phenotype) and in the autosomal locus (crinkled
and downless phenotype).24 Therefore, it is possible
that the same situation might occur in dogs.

G E N E T IC A N D M O L E C U L A R
A SP E C T S O F X L E D A N D E DA
Figure 5. Pedigree from Case 3. Note that the two affected
individuals (III-1 and III-5) are males. As the condition involves Xlinked recessive inheritance, the allele responsible for the phenotypes
can only be inherited from the mother (II-2) because they have
normal male genitors. As the mother was also normal, it can be
assumed that she was a heterozygote, in other words, a carrier.
 = normal male;  = normal female;  = affected male;
= indicates the proband.

Figure 6. Cutaneous histopathology in canine XLED. Skin of


the dog shown in Fig. 4 (Case 3). There is an absence of hair
follicles, arrector pili muscles, sweat glands and sebaceous glands.
Hyperpigmentation of the epidermis with orthokeratotic
hyperkeratosis is also present. Collagen fibres are normal. The
same characteristics were observed in clinical Cases 1 and 2. Mallory
stain, 40.

4 In humans, the nails are generally normal,1,23 as


was the case in dogs reported to date.
5 In humans there may be a reduction in the function of the lacrimal glands, photophobia and aplasia or hypoplasia of the lacrimal ducts.1,23 In dogs,
conjunctivitis and photophobia are common,
although tear production seems to be normal
when assessed by Schirmer tear tests.
6 Both conditions are determined by the recessive
allele of a gene on the X chromosome.1,8,10,23
7 In both humans and dogs, female carriers may
show mild signs of dysplasia.1,8,9,23
8 It is important to remember that in humans there
is a rare form of autosomal recessive ectodermal

The inheritance pattern for canine XLED was definitively established by the work of Casal et al.10 20 years
after the pioneering crossings involving segregation
analysis carried out by Selmanowitz et al.8 Canine
XLED is caused by a recessive allele of a gene located
on the X chromosome. As males have only one X chromosome, they are always hemizygotes for the gene and
may or may not be affected. Females, however, may
be dominant homozygotes, which are normal; recessive
homozygotes, which are affected; or heterozygotes,
which may be normal or have some degree of dysplasia,
depending on the degree of lyonization.22 Affected
males never pass the allele on to their male offspring,
but do pass it on to all their female offspring, resulting
in heterozygotes, i.e. carriers. With each gestation, carriers bred with a normal male run a 25% risk of having
affected male offspring and a 25% risk of bearing a
female carrier (Fig. 5). If a carrier is crossed with an
affected male, the result will be 25% normal males, 25%
affected males, 25% normal females or females with
some degree of dysplasia (manifesting heterozygotes or
carriers) and 25% markedly affected females (recessive
homozygotes).
As happens with other rare X-linked recessive traits,
XLED occurs more frequently in male individuals.
Markedly affected females are only possible by crossing carriers and affected males or affected females and
affected males. These unions would be improbable in
random crossings that involve rare traits. Lyonization
may permit some female carriers to show signs of
dysplasia to varying degrees and extents.22 These are
heterozygous females who are phenotypically as if they
were affected hemizygotes, depending on the percentage of somatic cells with inactivation of the X chromosome of the normal allele.
As different mammals share a basic genome, it is to
be expected that certain genodermatoses are not exclusively human. It is estimated that humans and dogs
share over 80% of their DNA sequences.25 One point of
this aspect which deserves attention is the evolutionary
conservation of the X chromosome, maintaining a high
similarity of the G bands in both species.26,27 Some
genes mapped on the proximal region of the long arm
(Xq) of the human X chromosome, such as the genes
of the choroideraemia, the androgen receptor, the
phosphoglycerate kinase and the gene responsible for
severe combined X-linked immunodeficiency were also
located in the corresponding region of the canine X

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X-linked ectodermal dysplasia

Figure 7. Comparison of the alternating light and dark banding


patterns (G bands, obtained by staining the chromosomes with
Giemsa after treatment with trypsin) of the human (left) and canine
(right) X chromosomes. Note the extensive similarity of the G bands
in the X chromosomes of the two species, including the part where
the gene locus of the EDA (arrow) is situated in the human
chromosome. p = the short arm of the chromosome; q = the long
arm of the chromosome; numbers = numbering of the regions,
bands and subbands starting from the centromere to the telomeres
(extremities); G-banding patterns according to Stone et al.26

chromosome through fluorescent in situ hybridization


(FISH) and other methods.28,29 The canine and human
X chromosomes are so similar that even the G-band
patterns are practically the same26,27 (Fig. 7).
Cytogenetic studies do not show chromosomal
aberrations.10 In humans, rare cases of translocation
between the X and 9 chromosomes associated with
EDA have been described and provided a starting point
for studies into the location of the EDA gene.30,32 Analysis of human genealogies shows that an affected male
may have a family history of EDA, but in most cases he
is the only one affected,2 due to a new mutation. Studies
into new mutations suggest a greater origin in spermatogenesis than in oogenesis (ratio = 3.5:1) as observed
in other X-linked traits.33 Prior to the identification of
the EDA gene, its chromosomal location was determined as Xq12-q13.1 by analysis of chromosomal
aberrations and the genetic linkage analysis of polymorphic markers.2 In cattle, a case was reported of
deletion of the long arm of the X chromosome (Xq
deletion) linked to hypotrichosis and oligodontia, along
with other abnormalities.34 Drogemuller et al. studied
affected cattle, but without Xq deletion. Using microsatellites, they detected a region of the long arm which
they considered a possible site for bovine XLED.6,35

275

Kuiper et al. confirmed this location by FISH mapping


the bovine gene, in a region (Xq22-q24)36 which, in the
human X chromosome is contiguous to the locus of the
EDA gene.
In humans, the gene was finally identified in 1996,
being denominated the EDA gene37 and, later, ED1. In
1998, its product was also identified and characterized
as a transmembrane protein denominated ectodysplasin
A. This protein is present in keratinocytes, hair follicles
and sweat glands,16 and probably plays a fundamental
role in mesenchymalepithelial interaction which regulates the formation of ectodermal derivatives.17 Several
mutations have been reported in the ED1 locus, indicating allelic heterogeneity.1621 In mice, Srivastava
et al.38 and Ferguson et al.39 found the homologue of the
ED1 gene and called it Ta (Tabby), which is expressed
in developing teeth and epidermis of normal individuals,
but not in those of the Tabby phenotype (hypoplasia of
the teeth, hair and sweat glands inherited as a X-linked
recessive trait). Ectodysplasin A has 135 amino acids,
but an isoform (isoform II) with 391 amino acids was
subsequently identified, with 94% similarity with the
Ta protein (murine ectodysplasin) and containing a
collagen-like domain with 19 repetitions of Gly-X-Y in
the presumable extracellular domain. The ectodysplasin of the mouse has been characterized biochemically
and functionally, revealing an oligomeric and glycosylated type-II membrane protein (a single transmembrane domain with a cytoplasmic N-terminus) that
promotes adhesion of the cell to the extracellular
matrix.40 These characteristics include it in the superfamily of the tumour necrosis factor (TNF) ligand.
This represents the first signalling molecule to be
described similar to TNF which is necessary for epithelial morphogenesis.4042 The location of mutations in
the extracellular domain of ectodysplasin A suggests
that the primary cause of EDA is a defect in communication between the cells responsible for the development of the epidermal appendages.43 Ectodysplasin A
contains in its stalk region a sequence of amino acids
which represent the site of cleavage of furin, a proprotein
convertase. Molecular analyses suggest that cleavage in
the furin site is necessary for cell-to-cell signalling which
regulates the morphogenesis of the ectodermal derivatives
and that mutations in this site are the basis of XLED.44
The fact that EDA and canine XLED show similar
clinical characteristics and the same patterns of inheritance and the X chromosome is evolutionally conserved
allows for the hypothesis that these two conditions are
the same aetiological entity affecting different species.
If molecular genetic studies confirm this hypothesis, it
is possible that even the location of the canine XLED
gene is equivalent to the EDA gene (Xq12-q13.1).

T R E AT M E N T A N D P RO G N O S IS
OF XLED
Although the clinical condition is irreversible, the prognosis for survival is good. The absence of sweat glands

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E Moura and SM Cirio

does not carry the same clinical importance as it does


in humans because dogs rely on panting to dissipate heat
rather than cutaneous sweating. Hence, life-threatening
hyperthermia is not seen in dogs as it is in children.45
Cutaneous scaling and conjunctivitis rarely require
treatment and, if necessary, can be controlled by the
use of keratolytic shampoos and the use of tear substitutes and antimicrobial eye drops. Recently, an experimental treatment was successfully tested by Gaide &
Schneider46 in pregnant Tabby mice using a recombinant form of ectodysplasin A1, engineered to cross
the placental barrier. The treatment permanently
impeded the development of the Tabby phenotype in
the descendants. Following birth, it was also possible,
by using this recombinant protein, to induce the development of sweat glands. This could be a potential
future option for the treatment of canine XLED.

C ON CLU SION
With the clinical and genetic information provided in
this review, we hope that it will be possible for other
spontaneous cases of canine XLED to be recognized,
allowing for more detailed clinical and molecular analysis, as the scarcity of reports and studies into this genodermatosis is possibly a reflection of the shortage of
diagnoses rather than the rarity of the phenomenon.

ACKN OWLEDGE ME NT S
The authors wish to thank Dr Newton Freire-Maia
(Department of Genetics at the Federal University of
Paran, Brazil) for reading the manuscript. We would
also like to thank our veterinary colleagues Jos
Lenidas Wagner, Solange Souza da Silva Betenheuser
and Ana Maria Della Torre, as well as dog breeder Mr
Zawadzki (Zaki) for referring the affected dogs to us.
We also thank Mr Hlio A. Moura for his assistance
with the photography.

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Rsum Cette revue prsente les donnes cliniques, histopathologiques et gntiques de la dysplasie ectodermique lie lX chez le chien, en se basant sur les donnes de la littrature et sur trois nouveaux cas. La maladie
est compare la dysplasie ectodermique anhidrotique de lhomme, et en se basant sur les donnes gntiques
actuelles, nous suggrons que les deux maladies sont dues au mme gne, et reprsentent donc entit pathologique
unique, commune au chien et lhomme.
Resumen Esta revisin presenta las caractersticas clnicas, dermatohistopatolgicas y genticas de la displasia
ectodrmica canina ligada a X de casos anteriormente publicados y en tres casos nuevos espontneos. La
enfermedad se compara a la displasia ectodrmica anhidrtica en humanos y, basndonos en conceptos genticos
actuales, sugerimos que las dos enfermedades son causadas por el mismo gen y, consecuentemente, representan
una sola entidad patolgica que afecta tanto a humanos como al perro.
Zusammenfassung Dieser bersichtsartikel prsentiert klinische, dermato-histopathologische und genetische
Merkmale von caniner X-gekoppelter ektodermaler Dysplasie in bisherigen Fallberichten und bei drei neuen
spontanen Fllen. Die Erkrankung wird mit anhydrotischer ektodermaler Dysplasie beim Menschen verglichen
und wir vermuten, basierend auf aktuellen genetischen Konzepten, dass die zwei Krankheiten durch dasselbe
Gen verursacht werden und folglich lediglich eine pathologische Entitt darstellen, die sowohl Menschen als auch
Hunde befllt.

2004 European Society of Veterinary Dermatology, Veterinary Dermatology, 15, 269277