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Twelve patients from 7 different families have been reported [Andersen and Pindborg, 1947; Epps et al., 1977;
Fuks et al., 1978; Gorlin et al., 1978; Shapira et al., 1982;
Wajntal et al., 1982; Gagliardi et al., 1984; Silva, 1984;
hpton and Gorlin, 1984; Manouvrier-Hanu et al., 19871.
We give detailed reports of the same patients previously
reported by Epps et al. [19771 and Wajntal et al. [19821
and mentioned in Freire-Maia and Pinheiro [1984].
FAMILY HISTORY
The family is of Brazilian ancestry, from the state of
Ceara (northern Brazil), and lives in Sao Paulo, Brazil.
The patients have been followed a t the Hospital das
Clinicas, University of Sao Paulo, for the last 23 years.
Their parents are multiply consanguineous (Fig. 1).In
1976, when they were referred for genetic evaluation,
the mother (IV-10) was 53 years old, the father (IV-9)
was 56 years old, patient 1 07-41 was 27 years old, and
patient 2 (V-8)was 20 years old. Both parents were short
(mother 143 cm, father 155 cm) and, except for the sensorineural hypoacusia of the mother, they were normal.
Three of the maternal sisters have hearing deficits and 2
have short stature. One of the patients sisters is also
short (137 cm). Both father and mother are the product
of a consanguineous marriage, but the exact degree of
consanguinity could not be established between the fathers parents. Thus the patients have a minimum coefficient of inbreeding of 1/16 (Fig. 1).
CLINICAL REPORTS
Patient 1
INTRODUCTION
History. Patient 1 (V-4, ADA) was born at term
GAPO is an acronym coined by Tipton and Gorlin
after a n uneventful pregnancy and home delivery. His
[19841 to refer to a syndrome of growth retardation (G),
alopecia (A),pseudoanodontia (P),and optic atrophy (0). birth weight and length were not recorded but were
similar to those of his normal sibs. At birth his skin was
thick and he had generalized atrichia. His teeth never
erupted. There was initial delay in motor development,
Received for publication June 28,1989; revision received Novembut
school performance was normal. The available
ber 20, 1989.
growth data are: when he was 12 years old (Fig. 2a), his
Address reprint requests to Anita Wajntal, Unidade de Aconselhamento Genetico, Departamento de Biologia, Instituto de Bio- height was 108 cm (<3rd centile), weight 18,300 g (<3rd
cihcias, Universidade de Sao Paulo, Caixa Postal 11461-CEP centile), OFC 51.5 cm (<50th centile), and he had a bone
05499, S&o Paulo, S.P., Brazil.
age of 7 years. When he was 14 years old his height was
0 1990 Wiley-Liss, Inc.
214
Wajntal et al.
I
/I
II I
I
O A
10
I V
10
21-28
11-20
V
I
Fig. 1. Pedigree
Fig. 2. Patient 1 at 12 years old (a)and 27 years old (b).(Photo b reproduced from Freire-Maia and
Pinheiro, 1984, with permission of the publisher.)
215
biopsies of scalp and axillae were performed. Scalp biopsy showed a thin epidermis with lack of epithelial
ridges. The papillary dermis contained clumps of homogeneous amorphous hyaline material and collagen fibers. Residual hair follicles were surrounded or filled
with homogeneous eosinophilic material. Axillary skin
showed the characteristic dermis with sparse hair follicles and normal apocrine glands with areas of the same
amorphous material in papillary dermis. The described
hyaline material was periodic acid-Schiff (PAS)positive,
diastase resistant, and was not stained by the Congo red
stain for amyloid. The elastic fibers, evaluated by resorcin-fuchsin stain, were almost absent in the reticular
dermis where the eosinophilic material was present.
When palm sweating was induced a t age 12 years there
was absence of sweat production. Reduced sweating was
present on the 2nd and 5th phalanges.
Radiologic manifestations
Head. Reduced density of calvaria and sclerosis of
the cranial base. Absence of pneumatization of the maxillary sinuses. Apneumatic hypoplasia of mastoid apophysis and facial sinuses with a marble-like aspect (Fig.
4a,b). Planigraphic cuts showed clouding of the median
ear which was small. Nasal cavities were of diminished
caliber because of excess soft tissue, but permeability
was preserved bilaterally.
Chest. Demineralization of vertebral bodies, alteration of the discal surface with Schmorls nodules, disc
calcification of Cg and Cg reduced intervertebral distance.
Pelvis. Small with normal articulation.
Long bones. Reduced density, bowing of diaphyses,
and elongation of distal metaphyses, especially in femora and tibiae (Fig. 5a,b).
Hands and feet. Short metacarpals, metatarsals,
and phalanges with wide diaphyses (Fig. 6).
Autopsy, Macroscopic findings showed a thickened
arachnoid membrane over the brain convexity and
thickened pericardium with a verrucous appearance,
coarse and whitish, similar to grated coconut. This
coarse material was also present on the epicardium (Fig.
7) along the coronary vessels. There was atrial dilatation with elongated pectineus muscles and prolapse of
the 3 tricuspid valve leaflets and of the 2 mitral valve
leaflets (Fig. 8). There were hardened plaques in the
coronary lumen narrowing i t up to 10% of its original
size in the anterior descending and the circumflex arteries. On the visceral pleurae there was the same material as on the epicardium and pericardium. The peritoneum was also thickened with whitish lumps on the
liver and the spleen; the liver had a thickened capsule
and widening of the portal spaces, which were joined by
whitish septa.
Microscopic examination using hematoxylin and eosin staining showed a n increase of a n amorphous hyaline substance in all organs and interstitia. In the
hepatic parenchyma, this substance was responsible for
the thickening of the portal spaces, forming bridges
which joined the portal spaces. The same changes were
present in the lymph nodes, spleen, entire digestive
tract, gallbladder, mesentery, and the endocrine gland
216
Wajntal et al.
217
epidermis and of cutaneous adnexa which were surrounded and frequently replaced by the amorphous material and collagen. The dermis studied with resorcinfuchsin staining showed a small number of elastic fibers.
The fibrous and hyaline material, which replaced the
cutaneous adnexa, was strongly stained by Masson trichromic and was PAS positive and diastase resistant.
The thin fibrillar amorphous material, which was present in the papillary dermis, between the thickened collagen fibers and also next to the cutaneous adnexa,
showed metachromasia when stained by toluidine blue
a t pH 7.0, being composed of mucine and probably hyaluronic acid. This material was almost completely digested by hyalozyme, suggesting the presence of hyaluronic acid in this material. Congo red staining was
negative, thus excluding a n amyloid origin of the hyaline storage. Staining with scarlet-R was equally negative, excluding a fatty origin of this material.
Dermatoglyphics
Digits: left hand: WD (131, A", L" (5),L" (121, Ws (8);
right hand: WD(141, A", L" (51,L" (8), L" (13). Mainline
formula: left hand: 9.-7-9.9.5'. 13.t'-A.A/LR.0.L.W",
right hand: 9.-9.9. 7.5' -5'.13.t'-A.A./LR.L.L.L.
There
was a n incomplete simian crease on both hands.
Fig. 7. Patient 1, necropsy of heart showing the presence of verrucous coarse material on the epicardium (arrows).
Patient 2
History. Patient 2 (V-8, MMA), the sister of patient
1,was first seen when 4 years old. She was born a t term
after a n uneventful pregnancy and home delivery. Her
birth weight and length were not recorded, but were said
to be normal. Neuromotor development was normal and
she had normal black hair on her scalp, which she lost
progressively after age one year; there was complete
alopecia a t age 2 years. She had choanal stenosis which
caused respiratory problems. Breast development and
menarche occurred a t age 15;her menstrual cycles have
always been irregular with amenorrheic episodes of 2 or
3 months and, later, for up to 12 months; she has not had
menses for 3 years and is receiving hormone replacement.
218
Wajntal et al.
Fig. 9. Patient 1 necropsy, showing increase of hyaline amorphous substance in the testis interstitia
(arrowheads). Hematoxylin and eosin. x 1000.
Fig. 10. Patient 1necropsy, showing optic nerve. a:normal histology of the nerve (open arrow) Hematoxylin and eosin. x 250. b: Optic nerve (open arrow) surrounded by thickened dura (arrowheads).Hematoxylin and eosin. x 50.
219
Fig. 11. Patient 1,necropsy of skin. a: Severe atrophy of epidermis (arrow) and cutaneous adnexa with
storage of amorphous material. Hematoxlyin and eosin. x 40. b: Sebaceous glands and hair follicles
partially replaced by fibrous material (arrowheads).Hematoxylin and eosin. x 100.c: Hair follicle completely replaced by fibrous and hyaline material (open arrow). Hematoxylin and eosin. x 100. d Fibrillar
and amorphous material present in reticular dermis. Hematoxylin and eosin. x 250.
Dermatoglyphics
Digits: left hand: WD (lo), A", A", LR(61, L" (4);right
hand: L" (6), As, L" (3), L" (61, L" (4).Mainline formula:
220
Wajntal et al.
Fig. 12. Patient 2 when 20 years old. a:Frontal view. (Reproduced from Reire-Maia and Pinheiro, 1984,
with permission of the publisher.) b: Lateral view.
hand: 9.9.5"-4.13
.t '-A.0.0.
L.V., right hand:
9.9.-9.5".5'.13.t-t'-LU.O.O.L.L.
There was a n incomplete
left
Additional tests (patients 1 and2). Results of routine hematologic and urine tests, total protein level, and
protein electrophoresis were normal, except for prothrombin time that was reduced to 66% in patient 1 and
60% in patient 2, and corrected by vitamin K in both
patients. Acid mucopolysaccharide levels were normal
in urine and blood. Buhot cells were absent in bone
marrow and there was no vacuolization in leukocytes.
Patient 1 had oligoasthenospermia with 30,000,000
spermatozoa in a total volume of 1 ml of ejaculate and
50% of dead spermatozoa one hour after ejaculation.
Basal thyroid hormone levels were normal as was the
function of the adenohypophysis (Table I). Patient 1had
a discrete primary gonadal lesion suggested by oligoasthenospermia and slight elevation of basal folliclestimulating hormone (FSH)levels with conserved function of Leydig cells (basal testosterone = 368 ng/dl and
397 ngidl; after stimulation with hCG = 1,228ngidl).
Patient 2 had high levels of gonadotropin. Chromosomes
were normal in both patients. Electron microscopic
studies of collagen from cultured fibroblasts of patient 2
did not show any collagen abnormalities.
221
DISCUSSION
Our patients have manifestations of the GAPO syndrome (except for absence of optic atrophy), presence of
bilateral keratoconus, and signs of hypogonadism. Optic
atrophy is not a constant manifestation, as 6 of the 12
reported patients did not have this manifestation. In 2
instances a n apparent thickening of the optic nerve was
evident by CT scan of the 3 brothers studied by Gag-
222
Wajntal et al.
TABLE I Results of Functional Studies of t h e Adenohypophysis
Patient 1
Patient 2
Normal basal values
Blood glucose
(mgidl)
-~
B
P
~
~~
94
62
60-100
Cortisol
(kgidl)
GH
(ngiml)
__
B
P
~
~~
34
32
19
34
5-25
27
69
20-40
1,5
2,8
0-5
25
25
>7
PRL
(ngiml)
B
P
-
34
53
5,25
167
84
LH
FSH
TSH
(mIUiml)
B
P
~-
mIUiml)
B
P
( FIUiml)
~~
116
6,3
5-20
921
99
200
6,8
42
4,4
0-7
18
8,7
8-25
135
20
5-20
Abbreviations B basal value FSH follicle stimulating hormone G H , growth hormone, LH luteinizing hormone P peak value dftel stimulation PRL
prolactin TSH thyroid-stimulating hormone
P - After intravenous infusion with insulin tO 1-0 2 U kgl thyrotropin releasing hormone (200 pgl and luteinuing hormone-releaqing hormone I100 pgi
knowledge, a hypoactive collagenase has not been described. Hyaluronidase is present in body fluids and
certainly plays a n important role in turnover of hyaluronic acid and derivatives. The elastases are powerful proteases that can hydrolyze numerous proteins and
might be responsible for the turnover of some of the
extracellular components. Further studies will be necessary to disclose the basic pathways involved in this
pathogenetic mechanism, but at this time, we think that
one of the enzymes involved in the breakdown of the
extracellular components is responsible for the manifestations in the GAPO syndrome.
The histologic data presented here on GAPO syndrome show that this condition should be reclassified as
GAPO dysplasia.
ACKNOWLEDGMENTS
We thank Dr. Consuelo Junqueira for specific collagen
staining studies. Our thanks to Miss Luceleni da Silva
for secretarial assistance. Our special thanks to the Scientific Documentation Department of the Faculty of
Medicine, University of Sao Paulo.
This work was partially supported by the Conselho
Nacional de Desenvolvimento Cientifico e Tecnologico
(CNPq), Brazil.
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