American Journal of Medical Genetics 41:398-404 (1991)
Autosomal Recessive Ectodermal Dysplasia: I. An Undescribed Dysplasia/Malformation Syndrome Tania Bustos, Venancio Simosa, Juan Pinto-Cisternas, William Abramovits, Liliana Jolay, Luis Rodriguez, Luis Fernandez, and Marcos Ramela Centro Nacwnal de Gene‘tica Humana y Experimental, Universidad Central de Venezuela (T.B., V.S.), Laboratorio de GenCtica Humana, Znstituto Venezolano de Znvestigmwnes Cientificas (JP.C.1, and Centro Medico Docente La Trinidad (W.A.), Caracas and Hospital Dr. Agustin R. Hernandez, Juan Griego, Nueva Esparta (L.J., L.R., L.F., M.R.), Venezuela ~~~~
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We describe 27 individuals of 7 families related to each other with high probability who showed manifestations of ectodermal dysplasia and other anomalies affecting females as severely as males with variable expressivity. All parents were normal. These families were detected in a relatively isolated and inbred populationwith very small neighbouring communities from a Carribbean Sea island, Margarita Island, in Northeastern Venezuela (Nueva Esparta State). The clinical picture common to all patients could not be classified within the heterogeneous group of known ectodermal dysplasias and the published cases do not resemble our patients. We believe that this condition constitutes a newly recognized autosomal recessive dysplasia/malformation syndrome of ectodermal dysplasia. KEY WORDS: autosomal recessive inheritance, hydrotic ectodermal dysplasia,cleft lip and palate, pili torti, syndactyly INTRODUCTION The hereditary ectodermal dysplasias (ED) comprise a large and genetically heterogeneous group of disorders usually divided into the hypohidrotic and hydrotic categories although the extent of the deficit of sweat glands may be not easily demonstrated. The first paper concerning these entities were published by Thurman [1848], and later Weech [1929] published on another 2 patients and revised various ED conditions. Received for publication June 29,1989; revision received December 17, 1990. William Abramovits is now Assistant Clinical Professor (Dermatology) Department of Family Practice, University of Texas School of Medicine at San Antonio, Texas. Address reprint request to Tania Bustos and Venancio Simosa, Instituto de Medicina Experimental, Universidad Central de Venezuela, Caracas 1050-A-Apdo, Postal 50587, Venezuela.
0 1991 Wiley-Liss, Inc.
These first observations constitutes cases of hypohidrotic ectodermal dysplasia (HED) X-linked type, a classical and well-known form of ED with defect in sweating, alopecia, and hypodontia in males as minimal diagnostic criteria. Some reports indicate that presumed heterozygous females may show some phenotypic expression including diminution of dermal ridge sweat pores and dental anomalies [ f i i a s and Smith, 1968; Gorlin et al., 1970; Pinheiro and Freire-Maia, 1979; Simosa and Benarroch, 19863. Roselli and Giulenetti [19611 described a recessively inherited condition in 4 patients with HED, cleft lippalate, syndactyly, foot deformity, mental retardation, and genitourinary malformations. Two were brother and sister whose parents were consanguineous. Between 1965 and 1972 many other conditions with apparently distinct forms of HED were reported. Passarge et al. [1966] described a large inbred kindred with HED as a n autosomal recessive trait clinically undistinguishable from X-linked HED save for the hereditary pattern. Gorlin et al. [1970] summarized the findings and the genetic heterogeneity in 18 pedigrees with this type of HED. Other distinct forms of HED were reported by Rapp and Hodgkin [19681, Summit and Hiatt [19711, and Wannarachue e t al. [19721 having lip, palate, or uvula cleft and autosomal dominant etiology as novel characteristics. Bowen and Armstrong [19731 also described 3 of 10 sibs affected with findings similar to those of Rapp and Hodgkin in one family. Bowen and Armstrong [19761 also discussed various syndromes with ED and cleft lip and palate and concluded that their cases and those of Roselli and Giulenetti [19611, with strong evidence of autosomal recessive inheritance, were different from others in which oral clefts, popliteal pterygium, and digital and genital anomalies occur apparently as a pleiotropic dominant trait. It is evident that the ED syndromes are a clinically complex group of disorders some of which are difficult to classify. By around 1984 roughly 117 conditions with ED were recognized in accordance with the definition proposed by Freire-Maia and Pinheiro as “conditions with a t least
Autosomal Recessive Ectodermal Dysplasia one of the signs detected in the first cases reported in the literature (trichodysplasia, onychodysplasia, dental defects and dyshidrosis) plus at least one sign affecting another structure of ectodermal origin.” The same authors in the recent review indicated that the number of ED conditions is now 135 [Freire-Maia and Pinheiro, 1984, 19871. Here we delineate a condition described in 7 families of Caucasian origin with 27 affected individuals. These individuals were detected in an inbred population located in the Nueva Esparta State, Venezuela. This is a Caribbean northeastern area of 1,150 km2consisting of 3 islands named Margarita, Coche, and Cubagua (Fig. 1)with an autochthonous population of approximately 150,000 inhabitants almost all living in Margarita.
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MATERIALS AND METHODS I’ Our data were obtained between 1986 and 1988 as part of a program of genetic assistance to the medical personnel of Nueva Esparta. A clinicopathologicalregistry of genetic diseases was set up on Margarita consisting of patients suspected of chromosomeabnormalities, mental retardation, malformations, and clearly hereditary traits. All families reported here were ascertained through a 17-year-old proposita detected in this program with manifestations of ED. The following individuals were identified in successive visits a t the schools, homes, and hospitals with a careful physical examination and a family interview. With the information obtained 7 genealogies were assembled. At present 20 individuals have been diagnosed as I affected and another 7 (4 of them deceased) were identified by photos and information given by their relatives Fig.1. Geographic localization of Margarita island in Northeastern as presumably having the same syndrome. Venezuela. The clinical examination was performed on all propositi, parents, and sibs by 3 physicians, 2 geneticists, and one pediatrician and later by a dermatologist and a dentist-specialist in human genetics. In a second approach this (a)coefficient was also estiAnthropometric data included height, weight, OFC, and other craniofacial measurements. Dental examina- mated through isonymy and taking into account the tions also were performed in almost all affected individ- geographic origin of the most remote ancestors. uals (n: 18) and some relatives (n: 42). A chi square ($1 analysis of homogeneity for each sex In special cases radiologic evaluations were performed separately and a heterogeneity (x2)test “eel and Schull, in the hospitals of the region. Traits such as sweating; 19541 were done on observed and expected members of hair color and type; skin and eye color; eyelashes, eye- affected and unaffected subjects in 18sibships under the brows, ears, nose, lips, nails; and palm and sole charac- assumption of a recessive Mendelian segregation of 3 teristics were determined in as much detail as possible, (norma1):l (affected). and samples of hair and nail were collected. RESULTS Sweat pore counts and dermatoglyphic studies were A total of 27 affected individuals, 15 females and 12 attempted by using palmar prints of white plastic glue as a modification of the technique proposed by Frias and males, were ascertained in 7 families of Caucasian deSmith [19681; however, an adequate analysis was not scent. Their ages ranged from 3 months to 65 years; 15 possible due to the hypoplasia of ridges and hyper- were brothers and sisters. Our cases had the following general characteristics (Table I): triangular faces with keratosis of palms. The levels of inbreeding were estimated through the prominent auricles and malar hypoplasia present from coefficient of inbreeding (F) of each family in each ge- infancy; sparse, brittle, short, fine, and dry hair with nealogy and with these values the mean coefficient (a), reduced tensile strength; ring-shaped and microscopic which measures the probability that 2 genes taken at structural alterations very similar to pili torti present random in one individual may be identical by descent, from birth and affecting all hair-bearing areas identiwas calculated in genealogy for all families of affected. cally in all affected individuals; absence of hair on the
400
Bustos et al. TABLE I. Clinical Manifestation in 20 Patients With Autosomal Recessive Ectodermal Dysplasia
72 Characteristics Sex F F Normal sweating . . Face Unusual . . Triangular - Anteverted pinnae + + Malar hypoplasia - Cleft lip-palate - _ Abnormal philtrum” - + Cleft lip onlyb + Teeth Conical crowns + + Delayed eruption + + Hypodontia + + - Anodontia Microdontia + + Hair Sparse . . Short . . Brittle . . Hypotrichosis + + Scanty eyebrows and lower eyelashes + + Palms and soles Hyperkeratosis . . Onychondysplasia + + Cutaneous syndactyly + +
6
3
7 8
Case 9 10 11 12 13 14 15 16 17 18-19 20
%
M F F M F M F F F M F M M F M M M M 50M 50F . . . . . . . . . . . . . . . . . . 100
. . + + + + + + - -
. + + +
+
+
-
-
-
+ + + + . . . + . +
+ + + . . . + . + -
. +
+
-
. + + ++
+
-
-
-
-
+ + + + . . . + + . + +
+ + + + . . . + + . + +
. + +
+
-
-
. + + +-
. + + +-
. + --
+
-
-
-
-
-
. + + -
-
-
. . . . . + + + + - + + + + + + + + -
+
+
-
-
-
-
-
+ -
-
-
-
-
. . . + - + + - + - +
- -
-
+ - -
+ + + - - - + - + + + + - + + + - - - + - + + + - - + + + - - + + - + - + - - - - - + + - + - - - + + + + + - - + + - + + + + - . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . + - + + - + - + + - + + + + + + + + + + + + + + + + + + . . . . . . . . . . . . . . - - + + - + - + + - - + + + - + + + + - - + + + - -
100 70 75 70 35 25 5 70 65 60 25 75 100 100 100 70 100
100 60 65
“Subjects without cleft. bBilateral cleft lip.
crown of young patients and total alopecia by the 5th decade; scanty or absent lateral eyebrows and eyelashes from birth, mainly lower eyelashes; axillary and pubic hypotrichosis; small teeth (microdontia) with delayed eruption, hypodontia (anodontia in adults), persistence of deciduous and conical incisors; thick skin on palms and soles with hypoplastic dermatoglyphics and progressive hyperkeratosis; mild variable onychodysplasia; spontaneous normal sweating and normal tolerance to tropical heat; partial cutaneous syndactyly of fingers and toes 2-3; variable cleft lip-palate and alterations in length and shape of uvula and soft palate; normal growth, sexual and psychomotor development, and life expectancy in most of cases. The affected young persons and adults were unmarried and none had offspring except one 65-year-old woman who had 2 abortions in a first-cousin marriage (IV-13, family A); thus, nothing is known a t present about the fertility of the patients. The pedigree are shown in Figures 2-8. Although audiometric studies were not performed, the affected individuals and obligatory heterozygotes were clinically normal except for one 6-year-old affected girl (VI-19, family B) who had a apparently mild, notcongenital partial deafness. The values of the coefficient (a)for each genealogy were 0.00195 for genealogy A, 0.02119 for B; 0.01562 for C; 0.03125 for D; 0 for genealogies E and F; and 0.0625 for G . The values of (a)for all families of affected individuals in 7 genealogies were 0.01296 and 0.01513. The first value corresponds to an F between second cousin and
second cousin once removed and the second value is similar to the F value for second cousins. The (x2)homogeneity and ($1 heterogeneity analysis for sex in 18 sibships of different generations showed a relation of unaffected/affected persons not statistically different from the expected 3:l Mendelian recessive proportion (26 normal and 13 affected maled30 normal and 14 affected females). The parents and other relatives were unaffected;however, some small alterations of facial, oral, profile, soft palate, and tooth characteristics in some relatives (10 out of 18parents and 19 out of24 sibs) may be related to this entity.
DISCUSSION It seems clear that the total pattern of defects present in our cases constitutes an ectodermal dysplasidmalformation syndrome apparently not previously described. In recent years many attempts to classify the EDs have been made [Freire-Maia and Pinheiro, 1984,1987, 1988; Jorgenson and Dowben, 19871 and many “new” entities have been listed. Our patients apparently have a condition different from that of any other report. A MEDLINE search (December,1988)and a search of The London Dysmorphology Database also failed to turn up a recessive syndrome similar to our cases. The occurrence of this syndrome in sibs of opposite sex with unaffected parents in a small community, the proportion unaffected/affected sibs in 18 sibships, and the value of the inbreeding coefficient all indicate autosomal-recessive inheritance. Marriage patterns on this island, low levels of eccle-
Autosomal Recessive Ectodermal Dysplasia I I I
Ill
I V
V
VI
VII
Fig. 2. Family A.
w
I
II
Ill
IV
V
VI
VI I 1
2
Fig. 3. Family B.
I
I
It
It
Ill
Ill
IV
IV 1
V
6-63 1
2
3
Fig. 4. Family C.
V
m
1-3
4
5
Fig. 5. Family D.
Fig. 2-8. Legends for Figures 2 and 4-8 are: 0 ,affected individuals; 0 (3, obligate carriers; 0 0, normal individuals. Legend for Figure 3 is: 0 , affected individuals of ED; 0 0, normal individuals; 0 (3, obligate carriers of ED; 0 0, affected individuals of MPS 111; El @, obligate carriers of MPS 111.
401
Bustos et al.
402
copolysaccharidoses 111. They were closely related to the ED cases in the same family. In accordance with what is now known about some mucopolysaccharidoses and other rare recessive syndromes in Venezuela [Arias and Zimmer, 1961; Arias et al., 1982; Simosa, 19811, these also have a focal distribution and a relatively high probability of a founder effect of Hispanic origin. According to the nomenclature proposed by Herrmann et al. [19771, our cases may be classified into the group of malformationldysplasia syndromes and, according to the taxonomic approach proposed by FreireMaia [1971,1973,1977,19821andFreire-Maia and Pinheiro [1984,1987], into the “A” group with the following signs: trichodysplasia; dental defects in shape, size, number, and structure; hyperkeratosis of palms and soles; cleft lip-palate; syndactyly of fingers and toes; and onychodysplasia (Figs. 9-13). In some relatives of affected patients we detected anomalies that may or may not be related to the syndrome. These anomalies may be classified in 3 different groups:
111
IV
1
-2
3-4
Fig. 6. Family E.
I
II
Ill
IV
d d t
V
1
2
3
Fig. 7. Family F.
I
II
Fig. 9. Frontal view of the index case. Scanty eyebrows and eyelashes and repaired cleft lip. Note frontal sweating.
Ill
IV
1
2
3
4
5
Fig. 8. Family G.
siastic registration due to illegitimacy, and incomplete family names made it impossiblet o relate all families to a common ancestor. However there is a high probability that all families belong to a single genealogy. It is possible that a founder effect took place through Caucasian immigrants of Spanish origin, since this group of islands was one of the first sites of entrance and establishment of the Spanish in Venezuela around 1500 and a very important center of trade in pearls from Cubagua island. The pedigree B (Fig. 3) shows 4 subjects from mu-
Fig. 10. Sparse, short, and dry hair.
Autosomal Recessive Ectodermal Dysplasia
403
a. Cranial and facial anomalies: mild asymmetry, micrognathia; retrognathia and malar hypoplasia. b. Cleft-related phenotype: unusual philtrum with congenital labial scar-like shape; anatomical alteration in soft palate and hypernasality. c. Tooth anomalies: hypodontia (mainly upper lateral incisors) and size-shape alterations.
Fig. 11. Note similar changes in a one-year-old infant.
Whether these manifestations are a variable expression of the gene in single dose is unclear; however, it is possible to comment on 2 facts: first, it has been known that any anatomical alteration in shape or size of soft palate andlor uvula may be considered as a microform or “predisposition”to clefting [Shapiro et al., 1971;Huston et al., 1985; Lehman and Artz, 1976; Heckler et al., 19791,and second, minor manifestations in normal relatives of affected subjects have been described in other ED syndromes [Passarge and Fries, 1977; Soderholm and Kaitila, 19851. We will attempt to clarify these facts in subsequent communications. The inbreeding value showed a level of inbreeding of some importance in the families of the affected individuals, especially when it was recalculated based on isonymy and common geographical origin of some ancestors. These values are higher than others found in Venezuelan populations, and this fact suggests that the affected subjects belong to an endogamous group within the general population of Nueva Esparta State.
REFERENCES
Fig. 12. tYlY.
hyperkeratosis, hypoplastic ridges, and syndac-
Fig. 13. Dental anomalies.
Arias S, Zimmer E (1981):The Canarian origin of most mucopolysaccharidoses in Venezuela, and their focal distribution in the country. 6th Int Congr Hum Genet (abstr.). Jerusalem: Israel, pp 198. Arias S, Zimmer E, Pinto-Cisternas J , Quero J (1982):Phenotypic and population features of MPS IH in Quibor, Venezuela. In Papadatos CJ,Bartsocas CS (eds): “Skeletal Dysplasias.” New York: Alan R. Liss, Inc., pp 487-489. Bowen P, Armstrong HB (1973):Cleft lip-palate, ectodermal dysplasia, hand-foot anomalies and OliPoDhrenia. In Bergsma D (ed): Birth Defects. Atlas and CompendTum.New York Aran R. Liss, Inc., for the National Foundation-March of Dimes, p 262. Bowen p, Armstrong HB (1976): Ectoderma1 dysplasia, mentalretardation, cleft lip and palate and other anomalies in three sibs. Clin Genet 9:35-42. Freire-Maia N (1971):Ectodermal dysplasia. Hum Hered 21:309-312. Freire-Maia N (1973): Dysplasias ectodermicas-um grupo nosol6gico com contornos ma1 delineados. Acta Biol Paranti 2:3-8. Freire-Maia N (1977):Ectodermal dysplasia revisited. Acta Genet Med Gemellol (Roma) 26:121-131. Freire-Maia N (1982):Malformacoes, sindromes e displasias. Actas V Congr Latinoam Genet (Chile), pp 35-43. Freire-Maia N, Pinheiro M (1984):“Ectodermal Dysplasias. A Clinical and Genetic Study.” New York Alan R. Liss, Inc., pp 189-193. Freire-Maia N, Pinheiro M (1987):Ectodermal dysplasias. A review of the conditions described after 1984 with a n overall analysis of all the conditions belonging to this nosologic group. Rev Brasil Genet X:403-414. Freire-Maia N, Pinheiro M (1988):Ectodermal dysplasias. Some recollections and a classification. BD:OAS XXIV(2):3-14. Frias JL, Smith DW (1968): Diminished sweat pores in hypohidrotic ectodermal dysplasia. A new method for assessment. J Pediatr 72:606-610. Gorlin RJ, Sedano 0, Cervenka J (1968): Popliteal pterygium syndrome. A syndrome comprising cleft lip-palate, popliteal and intercrural pterygia, digital and genital anomalies. Pediatrics 41503509. Gorlin FtJ, Old T, Anderson VE (1970):Hypohidrotic ectodermal dys-
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plasia in females. A critial analysis and argument for genetic heterogeneity. Z Kinderheilkd 108:l-11. Heckler FR, Oesterle LG, Jabaley ME (1979): The minimal cleft lip revisited Clinical and anatomical correlations. Cleft Palate J 16:240-247. Herrmann J, Gilbert EF, Optiz J M (1977): Dysplasia, malformations and cancer, specially with respect to the Wiedemann-Beckwith syndrome. In Nichols U’W, Murphy DG (eds): “Regularisation of Cell Proliferation and Differentiation.” New York: Plenum. Huston JP, Bixler D, Yu P (1985): Velopharyngeal variations in relatives of cleft-affected individuals. J Craniofac Genet Dev Biol 5167-173. Jorgenson RJ, Dowben SL (1987): Autosomal dominant ectodermal dysplasia. J Craniofac Genet Dev Biol 7:403-412. Lehman JA, Artz J S (1976): The minimal cleft-lip. Plast Reconstr Surg 58:306-309. Nee1 JV, Schull WJ (1954):“Human Heredity.” Chicago: University of Chicago Press, pp 214-215. Passarge E, Nuzum CT, Schubert WK (1966): Anhydrotic ectodermal dysplasia as autosomal recessive trait from a n inbred kindred. Humangenetik 2:181-185. Passarge E, Fries E (1977): Autosomal recessive hypohidrotic ectoderma1 dvsulasia with subclinical manifestation in the heterozvsote. New qoik: Alan R. Liss, Inc., for the National Foundation-Mirch of Dimes. BD:OAS XIII(3C):95-100. Pinheiro M, Freire-Maia N (1979): Christ-Siemens-Touraine syndrome. A clinical and genetic analysis of a large Brazilian kindred. 111. Carrier detection. Am J Med Genet 4:129-134.
Rapp RS, Hodgkin WE (1968): Anhidrotic ectodermal dysplasia. Autosoma1 dominant inheritance with palate and lip anomalies. J Med Genet 5269-272. Roselli D, Giulenetti R (1961): Ectodermal dysplasia + cleft lip and palate. Br J Plast Surg 14:190-204. Shapiro BL, Meskin LH, Cervenka J , Pruzansky S (1971): Cleft uvula, a microform of facial clefts and its eenetic basis. New York: Alan R. Liss, Inc., for the National Found&ion-March of Dimes. BD:OAS VII(7):80-82. Simosa V (1981): “Hiperfenilalaninemias en Retrasados Mentales Institucionalizados en Venezuela.” MsC thesis. C.E.A. IVIC. Caracas, Venezuela. Simosa V, Benarroch L (1986): Displasia ectodermica hipohidr6tica en mujeres. Analisis clinic0 genetic0 de tres casos. Acta Med Coll 11(5):253-257. Soderholm A-L, Kaitila I (1985): Expression of X-kinked hypohidrotic ectodermal dysplasia in six males and their mothers. Clin Genet 28:136-144. Summit RL, Hiatt RL (1971): Hypohidrotic ectodermal dysplasia with multiple associated anomalies. New York Alan R. Liss, Inc., for the National Foundation-March of Dimes. BD:OAS VII(8):121-124. Thurman J (1848): Two cases in which the skin, hair and teeth were very imperfectly developed. Med Chir P a n s 31:71-82. Wannarachue N, Hall Bd, Smith DW (1972): Ectodermal dysplasia and multiple defects. J Pediatr 81:1217-1218. Weech AA (1929): Hereditary ectodermal dysplasia (congenital ectodermal defect). A report of two cases. Am J Dis Child 37:766-790.
Autosomal Recessive Ectodermal Dysplasia: I. An Undescribed Dysplasia/Malformation Syndrome Tania Bustos, Venancio Simosa, Juan Pinto-Cisternas, William Abramovits, Liliana Jolay, Luis Rodriguez, Luis Fernandez, and Marcos Ramela Centro Nacwnal de Gene‘tica Humana y Experimental, Universidad Central de Venezuela (T.B., V.S.), Laboratorio de GenCtica Humana, Znstituto Venezolano de Znvestigmwnes Cientificas (JP.C.1, and Centro Medico Docente La Trinidad (W.A.), Caracas and Hospital Dr. Agustin R. Hernandez, Juan Griego, Nueva Esparta (L.J., L.R., L.F., M.R.), Venezuela ~~~~
~
~
~
We describe 27 individuals of 7 families related to each other with high probability who showed manifestations of ectodermal dysplasia and other anomalies affecting females as severely as males with variable expressivity. All parents were normal. These families were detected in a relatively isolated and inbred populationwith very small neighbouring communities from a Carribbean Sea island, Margarita Island, in Northeastern Venezuela (Nueva Esparta State). The clinical picture common to all patients could not be classified within the heterogeneous group of known ectodermal dysplasias and the published cases do not resemble our patients. We believe that this condition constitutes a newly recognized autosomal recessive dysplasia/malformation syndrome of ectodermal dysplasia. KEY WORDS: autosomal recessive inheritance, hydrotic ectodermal dysplasia,cleft lip and palate, pili torti, syndactyly INTRODUCTION The hereditary ectodermal dysplasias (ED) comprise a large and genetically heterogeneous group of disorders usually divided into the hypohidrotic and hydrotic categories although the extent of the deficit of sweat glands may be not easily demonstrated. The first paper concerning these entities were published by Thurman [1848], and later Weech [1929] published on another 2 patients and revised various ED conditions. Received for publication June 29,1989; revision received December 17, 1990. William Abramovits is now Assistant Clinical Professor (Dermatology) Department of Family Practice, University of Texas School of Medicine at San Antonio, Texas. Address reprint request to Tania Bustos and Venancio Simosa, Instituto de Medicina Experimental, Universidad Central de Venezuela, Caracas 1050-A-Apdo, Postal 50587, Venezuela.
0 1991 Wiley-Liss, Inc.
These first observations constitutes cases of hypohidrotic ectodermal dysplasia (HED) X-linked type, a classical and well-known form of ED with defect in sweating, alopecia, and hypodontia in males as minimal diagnostic criteria. Some reports indicate that presumed heterozygous females may show some phenotypic expression including diminution of dermal ridge sweat pores and dental anomalies [ f i i a s and Smith, 1968; Gorlin et al., 1970; Pinheiro and Freire-Maia, 1979; Simosa and Benarroch, 19863. Roselli and Giulenetti [19611 described a recessively inherited condition in 4 patients with HED, cleft lippalate, syndactyly, foot deformity, mental retardation, and genitourinary malformations. Two were brother and sister whose parents were consanguineous. Between 1965 and 1972 many other conditions with apparently distinct forms of HED were reported. Passarge et al. [1966] described a large inbred kindred with HED as a n autosomal recessive trait clinically undistinguishable from X-linked HED save for the hereditary pattern. Gorlin et al. [1970] summarized the findings and the genetic heterogeneity in 18 pedigrees with this type of HED. Other distinct forms of HED were reported by Rapp and Hodgkin [19681, Summit and Hiatt [19711, and Wannarachue e t al. [19721 having lip, palate, or uvula cleft and autosomal dominant etiology as novel characteristics. Bowen and Armstrong [19731 also described 3 of 10 sibs affected with findings similar to those of Rapp and Hodgkin in one family. Bowen and Armstrong [19761 also discussed various syndromes with ED and cleft lip and palate and concluded that their cases and those of Roselli and Giulenetti [19611, with strong evidence of autosomal recessive inheritance, were different from others in which oral clefts, popliteal pterygium, and digital and genital anomalies occur apparently as a pleiotropic dominant trait. It is evident that the ED syndromes are a clinically complex group of disorders some of which are difficult to classify. By around 1984 roughly 117 conditions with ED were recognized in accordance with the definition proposed by Freire-Maia and Pinheiro as “conditions with a t least
Autosomal Recessive Ectodermal Dysplasia one of the signs detected in the first cases reported in the literature (trichodysplasia, onychodysplasia, dental defects and dyshidrosis) plus at least one sign affecting another structure of ectodermal origin.” The same authors in the recent review indicated that the number of ED conditions is now 135 [Freire-Maia and Pinheiro, 1984, 19871. Here we delineate a condition described in 7 families of Caucasian origin with 27 affected individuals. These individuals were detected in an inbred population located in the Nueva Esparta State, Venezuela. This is a Caribbean northeastern area of 1,150 km2consisting of 3 islands named Margarita, Coche, and Cubagua (Fig. 1)with an autochthonous population of approximately 150,000 inhabitants almost all living in Margarita.
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R
I I’
MATERIALS AND METHODS I’ Our data were obtained between 1986 and 1988 as part of a program of genetic assistance to the medical personnel of Nueva Esparta. A clinicopathologicalregistry of genetic diseases was set up on Margarita consisting of patients suspected of chromosomeabnormalities, mental retardation, malformations, and clearly hereditary traits. All families reported here were ascertained through a 17-year-old proposita detected in this program with manifestations of ED. The following individuals were identified in successive visits a t the schools, homes, and hospitals with a careful physical examination and a family interview. With the information obtained 7 genealogies were assembled. At present 20 individuals have been diagnosed as I affected and another 7 (4 of them deceased) were identified by photos and information given by their relatives Fig.1. Geographic localization of Margarita island in Northeastern as presumably having the same syndrome. Venezuela. The clinical examination was performed on all propositi, parents, and sibs by 3 physicians, 2 geneticists, and one pediatrician and later by a dermatologist and a dentist-specialist in human genetics. In a second approach this (a)coefficient was also estiAnthropometric data included height, weight, OFC, and other craniofacial measurements. Dental examina- mated through isonymy and taking into account the tions also were performed in almost all affected individ- geographic origin of the most remote ancestors. uals (n: 18) and some relatives (n: 42). A chi square ($1 analysis of homogeneity for each sex In special cases radiologic evaluations were performed separately and a heterogeneity (x2)test “eel and Schull, in the hospitals of the region. Traits such as sweating; 19541 were done on observed and expected members of hair color and type; skin and eye color; eyelashes, eye- affected and unaffected subjects in 18sibships under the brows, ears, nose, lips, nails; and palm and sole charac- assumption of a recessive Mendelian segregation of 3 teristics were determined in as much detail as possible, (norma1):l (affected). and samples of hair and nail were collected. RESULTS Sweat pore counts and dermatoglyphic studies were A total of 27 affected individuals, 15 females and 12 attempted by using palmar prints of white plastic glue as a modification of the technique proposed by Frias and males, were ascertained in 7 families of Caucasian deSmith [19681; however, an adequate analysis was not scent. Their ages ranged from 3 months to 65 years; 15 possible due to the hypoplasia of ridges and hyper- were brothers and sisters. Our cases had the following general characteristics (Table I): triangular faces with keratosis of palms. The levels of inbreeding were estimated through the prominent auricles and malar hypoplasia present from coefficient of inbreeding (F) of each family in each ge- infancy; sparse, brittle, short, fine, and dry hair with nealogy and with these values the mean coefficient (a), reduced tensile strength; ring-shaped and microscopic which measures the probability that 2 genes taken at structural alterations very similar to pili torti present random in one individual may be identical by descent, from birth and affecting all hair-bearing areas identiwas calculated in genealogy for all families of affected. cally in all affected individuals; absence of hair on the
400
Bustos et al. TABLE I. Clinical Manifestation in 20 Patients With Autosomal Recessive Ectodermal Dysplasia
72 Characteristics Sex F F Normal sweating . . Face Unusual . . Triangular - Anteverted pinnae + + Malar hypoplasia - Cleft lip-palate - _ Abnormal philtrum” - + Cleft lip onlyb + Teeth Conical crowns + + Delayed eruption + + Hypodontia + + - Anodontia Microdontia + + Hair Sparse . . Short . . Brittle . . Hypotrichosis + + Scanty eyebrows and lower eyelashes + + Palms and soles Hyperkeratosis . . Onychondysplasia + + Cutaneous syndactyly + +
6
3
7 8
Case 9 10 11 12 13 14 15 16 17 18-19 20
%
M F F M F M F F F M F M M F M M M M 50M 50F . . . . . . . . . . . . . . . . . . 100
. . + + + + + + - -
. + + +
+
+
-
-
-
+ + + + . . . + . +
+ + + . . . + . + -
. +
+
-
. + + ++
+
-
-
-
-
+ + + + . . . + + . + +
+ + + + . . . + + . + +
. + +
+
-
-
. + + +-
. + + +-
. + --
+
-
-
-
-
-
. + + -
-
-
. . . . . + + + + - + + + + + + + + -
+
+
-
-
-
-
-
+ -
-
-
-
-
. . . + - + + - + - +
- -
-
+ - -
+ + + - - - + - + + + + - + + + - - - + - + + + - - + + + - - + + - + - + - - - - - + + - + - - - + + + + + - - + + - + + + + - . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . + - + + - + - + + - + + + + + + + + + + + + + + + + + + . . . . . . . . . . . . . . - - + + - + - + + - - + + + - + + + + - - + + + - -
100 70 75 70 35 25 5 70 65 60 25 75 100 100 100 70 100
100 60 65
“Subjects without cleft. bBilateral cleft lip.
crown of young patients and total alopecia by the 5th decade; scanty or absent lateral eyebrows and eyelashes from birth, mainly lower eyelashes; axillary and pubic hypotrichosis; small teeth (microdontia) with delayed eruption, hypodontia (anodontia in adults), persistence of deciduous and conical incisors; thick skin on palms and soles with hypoplastic dermatoglyphics and progressive hyperkeratosis; mild variable onychodysplasia; spontaneous normal sweating and normal tolerance to tropical heat; partial cutaneous syndactyly of fingers and toes 2-3; variable cleft lip-palate and alterations in length and shape of uvula and soft palate; normal growth, sexual and psychomotor development, and life expectancy in most of cases. The affected young persons and adults were unmarried and none had offspring except one 65-year-old woman who had 2 abortions in a first-cousin marriage (IV-13, family A); thus, nothing is known a t present about the fertility of the patients. The pedigree are shown in Figures 2-8. Although audiometric studies were not performed, the affected individuals and obligatory heterozygotes were clinically normal except for one 6-year-old affected girl (VI-19, family B) who had a apparently mild, notcongenital partial deafness. The values of the coefficient (a)for each genealogy were 0.00195 for genealogy A, 0.02119 for B; 0.01562 for C; 0.03125 for D; 0 for genealogies E and F; and 0.0625 for G . The values of (a)for all families of affected individuals in 7 genealogies were 0.01296 and 0.01513. The first value corresponds to an F between second cousin and
second cousin once removed and the second value is similar to the F value for second cousins. The (x2)homogeneity and ($1 heterogeneity analysis for sex in 18 sibships of different generations showed a relation of unaffected/affected persons not statistically different from the expected 3:l Mendelian recessive proportion (26 normal and 13 affected maled30 normal and 14 affected females). The parents and other relatives were unaffected;however, some small alterations of facial, oral, profile, soft palate, and tooth characteristics in some relatives (10 out of 18parents and 19 out of24 sibs) may be related to this entity.
DISCUSSION It seems clear that the total pattern of defects present in our cases constitutes an ectodermal dysplasidmalformation syndrome apparently not previously described. In recent years many attempts to classify the EDs have been made [Freire-Maia and Pinheiro, 1984,1987, 1988; Jorgenson and Dowben, 19871 and many “new” entities have been listed. Our patients apparently have a condition different from that of any other report. A MEDLINE search (December,1988)and a search of The London Dysmorphology Database also failed to turn up a recessive syndrome similar to our cases. The occurrence of this syndrome in sibs of opposite sex with unaffected parents in a small community, the proportion unaffected/affected sibs in 18 sibships, and the value of the inbreeding coefficient all indicate autosomal-recessive inheritance. Marriage patterns on this island, low levels of eccle-
Autosomal Recessive Ectodermal Dysplasia I I I
Ill
I V
V
VI
VII
Fig. 2. Family A.
w
I
II
Ill
IV
V
VI
VI I 1
2
Fig. 3. Family B.
I
I
It
It
Ill
Ill
IV
IV 1
V
6-63 1
2
3
Fig. 4. Family C.
V
m
1-3
4
5
Fig. 5. Family D.
Fig. 2-8. Legends for Figures 2 and 4-8 are: 0 ,affected individuals; 0 (3, obligate carriers; 0 0, normal individuals. Legend for Figure 3 is: 0 , affected individuals of ED; 0 0, normal individuals; 0 (3, obligate carriers of ED; 0 0, affected individuals of MPS 111; El @, obligate carriers of MPS 111.
401
Bustos et al.
402
copolysaccharidoses 111. They were closely related to the ED cases in the same family. In accordance with what is now known about some mucopolysaccharidoses and other rare recessive syndromes in Venezuela [Arias and Zimmer, 1961; Arias et al., 1982; Simosa, 19811, these also have a focal distribution and a relatively high probability of a founder effect of Hispanic origin. According to the nomenclature proposed by Herrmann et al. [19771, our cases may be classified into the group of malformationldysplasia syndromes and, according to the taxonomic approach proposed by FreireMaia [1971,1973,1977,19821andFreire-Maia and Pinheiro [1984,1987], into the “A” group with the following signs: trichodysplasia; dental defects in shape, size, number, and structure; hyperkeratosis of palms and soles; cleft lip-palate; syndactyly of fingers and toes; and onychodysplasia (Figs. 9-13). In some relatives of affected patients we detected anomalies that may or may not be related to the syndrome. These anomalies may be classified in 3 different groups:
111
IV
1
-2
3-4
Fig. 6. Family E.
I
II
Ill
IV
d d t
V
1
2
3
Fig. 7. Family F.
I
II
Fig. 9. Frontal view of the index case. Scanty eyebrows and eyelashes and repaired cleft lip. Note frontal sweating.
Ill
IV
1
2
3
4
5
Fig. 8. Family G.
siastic registration due to illegitimacy, and incomplete family names made it impossiblet o relate all families to a common ancestor. However there is a high probability that all families belong to a single genealogy. It is possible that a founder effect took place through Caucasian immigrants of Spanish origin, since this group of islands was one of the first sites of entrance and establishment of the Spanish in Venezuela around 1500 and a very important center of trade in pearls from Cubagua island. The pedigree B (Fig. 3) shows 4 subjects from mu-
Fig. 10. Sparse, short, and dry hair.
Autosomal Recessive Ectodermal Dysplasia
403
a. Cranial and facial anomalies: mild asymmetry, micrognathia; retrognathia and malar hypoplasia. b. Cleft-related phenotype: unusual philtrum with congenital labial scar-like shape; anatomical alteration in soft palate and hypernasality. c. Tooth anomalies: hypodontia (mainly upper lateral incisors) and size-shape alterations.
Fig. 11. Note similar changes in a one-year-old infant.
Whether these manifestations are a variable expression of the gene in single dose is unclear; however, it is possible to comment on 2 facts: first, it has been known that any anatomical alteration in shape or size of soft palate andlor uvula may be considered as a microform or “predisposition”to clefting [Shapiro et al., 1971;Huston et al., 1985; Lehman and Artz, 1976; Heckler et al., 19791,and second, minor manifestations in normal relatives of affected subjects have been described in other ED syndromes [Passarge and Fries, 1977; Soderholm and Kaitila, 19851. We will attempt to clarify these facts in subsequent communications. The inbreeding value showed a level of inbreeding of some importance in the families of the affected individuals, especially when it was recalculated based on isonymy and common geographical origin of some ancestors. These values are higher than others found in Venezuelan populations, and this fact suggests that the affected subjects belong to an endogamous group within the general population of Nueva Esparta State.
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Fig. 12. tYlY.
hyperkeratosis, hypoplastic ridges, and syndac-
Fig. 13. Dental anomalies.
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