American J o u r n a l of Medical Genetics 38552-556 (1991)
A Distinct Type of Hidrotic Ectodermal Dysplasia Fahed Halal, Nora Setton, and Nai-San Wang Division of Medical Genetics, Montreal Children's Hospital (F.H.), Department of Pathology, McGill University ( N . S . W . ) , and Department of Pediatrics, Hopital Notre-Dame, Universite de Montreal (F.H., N . S . ) , Montreal, Quebec, Canada.
Four individuals from 2 generations of a family had a hidrotic type of ectodermal dysplasia (ED).Males and females were similarly affected. They had trichodysplasia, with absent eyebrows and eyelashes; normal teeth, onychodysplasia; normal sweating; mild retrognathia; abnormal dermatoglyphics; and mental retardation. Additional variable manifestations included irregular menses, high implanted or prominent ears, cafe-au-lait spot, keratosis pilaris, supernumerary nipple, and mild hearing loss. Their previously undescribed condition could be classified as an ED of 1-3 (trichoonychial) subgroup of group A according to F'reire-Maia's classification and is inherited as an autosomal recessive trait.
KEY
trichodysplasia, onychodysplasia, autosomal recessive inheritance, dermatoglyphics
CLINICAL REPORTS The patient (Fig. 1,VII-2) was the 1st child of young, unaffected parents. The father was 26 years old and the mother 21 years old. He was born a t term after a n uneventful pregnancy and delivery. Birth measurements were weight 2,710 g, length 48 cm, occipitofrontal circumference 34 cm. Apgar scores were 6 a t 1min and 8 a t 5 min. At the nursery, he was noted to have absent hair, eyebrows, and eyelashes and dysplastic nails in fingers and toes (Fig. 2A-C). One paternal aunt (Fig. 1, VI-4) who had the same clinical manifestations as the patient died at age 5 weeks. A 28-year-old paternal aunt (Fig. 1, VI-5) was born with the same clinical manifestations. Her scalp hair started to grow a little bit a t age 7-8 years to a maximum length of 1 cm. It was sparse and fell out easily when washed or pulled. Eyebiows and eyelashes were absent; nails were dystrophic. After a first menstrual period a t the age of 14 years, her menstrual cycles were irregular, with absence of menstruations sometimes for I
INTRODUCTION Ectodermal dysplasias (EDs) are a large heterogeneous group of diseases comprising more than 100 different entities [Freire-Maia and Pinheiro, 1984, 19881.Initially EDs were subdivided into anhidrotic and hidrotic forms LClouston, 19391. More recently, FreireMaia [1977] proposed a new classification into 2 groups. Group A includes a t least 2 of the following 4 cardinal signs: 1) trichodysplasia, 2) dental anomalies, 3) onychodysplasia, and 4) dyshidrosis (hyper-hypo-anhidrosis). Group B includes a t least one of these signs plus a t least another ectodermal manifestation. Both groups could also include anomalies and malformations of nonectodermal origin. We report a family with a previously undescribed type of hidrotic ED group A, subgroups 1-3 (trichoonychial), inherited as an autosomal recessive trait. Received for publication November 20, 1989; revision received June 14, 1990. Address reprint requests to Dr. Fahed Halal, Division of Medical Genetics, Montreal Children's Hospital, 2300 "upper Street, Montreal, Quebec, Canada H3H 1P3.
o 1991 Wiley-Liss, Inc.
II
Ill
IV
V
VI
VII
f2 Fig. 1. Family pedigree.
Ectodermal Dysplasia: A New e p e
553
Fig. 2. A-C: The patient.
as long as 3 months. Her teeth and breasts were normal. She sweats normally. She had bilateral moderate prominence of auricles and mild retrognathia (Fig. 3A-C). Her dermatoglyphics showed radial loop on right finger 5, TRC of 160, and distal axial triradius t” bilaterally. Complete blood count was normal. Audiogram showed mild right hearing loss at 51 KHz, with conductive component. Orthopantomogram showed discrete periodontitis (2 molars have been extracted). Skeletal survey showed a n increased interpedicular distance and
spina bifida occulta of L,-L, and spina bifida of sacrum. Skin histology revealed normal sweat glands and scarce pilosebaceous apparatus. Scalp hair ultrastructure study by scanning electron microscopy (SEM) is shown in Figure 4A-F. I& testing showed moderate mental retardation, with a global I& of 50 (nonverbal 54; verbal 56). Another 22-year-old paternal uncle (Fig. 1,VI-7) was similarly affected. His scalp hair started to grow a t age 6-7 years to a maximum length of 3 mm and with the
Fig. 3. A-C: Paternal aunt VI-5.
554
Halal et al.
Fig. 4. A,B: SEM of normal scalp hair and of individual VI-5. C-F: Progressive atrophy of cuticular scales from the proximal portion of the hair (c) to its distal portion (0,where they are almost absent, scales are atrophic clumped and lifted up (e). Original magnification x 1,000.
same characteristics a s those of his older sister. Beard and pubic hair were similar to scalp hair. Chest and axillary hair would grow only to the surface of the skin. His eyebrows, eyelashes, and upper and lower limb hair were absent. His nails were dystrophic. He had one cafeau-lait spot (10 cm in diameter) in the left axillary region, keratosis pilaris on upper and lower limbs, and a supernumerary left nipple. His teeth were normal. He sweats normally. He had a long oval face, high-implanted ears, and mild retrognathia (Fig. 5A-D). His dermatoglyphics showed 9 whorls on finger tips, TRC of 165, bilateral interdigital triradius B-C, and bilateral distal axial triradius t", with hypothenar pattern (L, ulnar loop; R, whorl). Complete blood count, audiogram, orthopantomogram, and skeletal survey were normal. Skin histology was similar to his sister's (VI-5). SEM of scalp hair is shown in Figure 6A-E. I& testing revealed mild mental retardation, with a global I& of 70 (nonverbal 81, verbal 66). The patient's unaffected parents are first cousins. Unaffected paternal grandparents are second cousins once removed (Fig. 1). The family is of Portuguese descent (San Miguel, Azores).
DISCUSSION The most common type of ED is usually inherited either as a n X-linked recessive trait (McKusick [19881 No. 305101, with affected males showing hypotrichosis and absence of teeth and sweat glands (anhidrotic) and heterozygous women showing reduction or malformation of teeth and mild abnormalities of sweat glands and breasts, or as a n autosomal dominant trait (McKusick [19881No. 129501,where affected individuals have total alopecia, dystrophic nails, hyperpigmentations, and normal teeth and sweat function (hidrotic). An autosomal dominant form of anhidrotic ED phenotypically similar to the X-linked form has been described in a very few families (McKusick [19881 No. 22490) [Gorlin et al., 1970; Passarge et al., 19661. Another form of autosomal recessive ED was reported by Mikaelian et al. [19701in a brother and sister of consanguineous parents. They had hidrotic ED with deafness, which could be classified a s a n ED of the 1-2 (trichoodontal) subgroup of group A. Other manifestations included camptodactyly of fifth fingers and thoracic kyphosis (McKusick [19881 No. 22480). Affected individuals had normal eyebrows, eyelashes, and nails. One affected individual had carious teeth.
Ectodermal Dysplasia: A New v p e
555
Fig. 5. A-D: Paternal uncle VI-7
TABLE I. List of Ectodermal Dysplasias Group A Subgroup 1-3, With Indication of Cause* Condition
AD
AR
XL
Heterogeneity AD AR XL
_
?
_
Unknown AD? AR? XL?
_
_
^
_
_
_
_
_
X 1. Hairy elbows dysplasia x x? 2. Palmoplantar hyperkeratosis and alopecia X 3. Curly hair-ankyloblepharon-naildysplasia (CHANDS) X 4. Onychotrichodysplasia with neutropenia X 5 . Pili torti and onychodysplasia 6. Agammaglobulinemia-dwarfism-ectodermaldysplasia X X 7 . Trichoonychodysplasia with xeroderma 8. Skeletal anomalies-ectodermal dysplasia-growth and mental retardation X 9. Sabinas brittle hair and mental deficiency syndrome X 10. Syndrome of accelerated skeletal maturation, failure to thrive, and peculiar face X 11, Congenital lymphedema, hypoparathyroidism, nephropathy, prolapsing mitral valve, and brachytelephalangy x XR X 12. Bartsocas-Papas syndrome Total 1 6 0 1 1 ? 0 1 0 3 1 *AD, autosomal dominant; AR, autosomal recessive; XL, X-linked; XR, X-linked recessive. Adapted from FYeire-Maia and Pinheiro [1988], with
permission of the authors.
~
556
Halal et al.
Fig. 6. A-D: SEM of scalp hair from individual VI-7, showing the same atrophy of cuticular scales as in individual VI-6. Original magnification x 1,000.E: Difference in size ofhair shaft between individual VI-7 (large) and VI-6 (small). Original magnification x 200.
The affected individuals in the present family had trichodysplasia, with absent eyebrows and eyelashes; normal teeth; onychodysplasia; normal sweating; mild retrognathia; and mental retardation. Although the sweating capacities of the affected individuals were not quantitated, they seem to be clinically euhidrotic, and there are no episodes of unexplained fever or heat intolerance; also, histologically the skin showed normal sweat glands. Additional variable manifestations included irregular menses, high implanted or prominent ears, cafe-au-lait spot, keratosis pilaris, supernumerary nipple, mild hearing loss, and abnormal dermatoglyphics such as excess of whorls on fingertips, radial loop on finger 5, interdigital triradius B-C, thenar exit of triradius A line, distal axial triradius t”and hypothenar pattern. The findings in affected individuals of the present family fit the criteria required to classify their condition as an ED of the 1-3 (trichoonychial) subgroup of group A according to Freire-Maia’s classification [ Freire-Maia, 1971, 1977; Freire-Maia and Pinheiro, 1984, 19883. According to the updated classification and list of EDs [Freire-Maia and Pinheiro, 19881, subgroup 1-3 of group A includes 1 2 conditions none of which is similar to the one described in the present family (Table I). We conclude that affected individuals in this family have a
distinct type of ED. Since the parents of affected individuals are unaffected and consanguineous, autosomal recessive inheritance of the trait is very likely.
REFERENCES Clouston HR (1939):The major forms of hereditary ectodermal dysplasia. Can Med Assoc J 4O:l-7. Freire-Maia N (1971): Ectodermal dysplasias. Hum Hered 21:309-312. Freire-Maia N (1977):Ectodermal dysplasia revisited. Acta Genet Med Gemellol 26121-131. Freire-Maia N, Pinheiro M (1984):“Ectodermal Dysplasias: A Clinical and Genetic Study,” New York: Alan R. Liss, Inc. Freire-Maia N, Pinheiro M (1988):Ectodermal dysplasiassome recollections and a classification. In Salinas CF, Opitz JM, Paul NW (eds): “Recent Advances in Ectodermal Dysplasias.” New York: Alan R. Liss, Inc., for the National Foundation-March of Dimes. BD:OAS 24(2):3-14. Gorlin FLJ, Old T, Anderson VE (1970): Hypohydrotic ectodermal dysplasia in females. A critical analysis and argument for genetic heterogeneity. Z Kinderheilk 108:l-11. McKusick VA (1988): “Mendelian Inheritance in Man. Catalogs of Autosomal Dominant, Autosomal Recessive, and X-Linked Phenotypes. Ed 8.” Baltimore: The Johns Hopkins University Press. Mikaelian DO, Der Kaloustian VM, Shahin NA, Barsoumian VM (1970): Congenital ectodermal dysplasia with hearing loss. Arch Otolaryngol 92:85-89. Passarge E, Nuzum CT, Schubert WK (1966): Anhidrotic ectodermal dysplasia as autosomal recessive trait in a n inbred kindred. Humangenetik 3:181-185.
A Distinct Type of Hidrotic Ectodermal Dysplasia Fahed Halal, Nora Setton, and Nai-San Wang Division of Medical Genetics, Montreal Children's Hospital (F.H.), Department of Pathology, McGill University ( N . S . W . ) , and Department of Pediatrics, Hopital Notre-Dame, Universite de Montreal (F.H., N . S . ) , Montreal, Quebec, Canada.
Four individuals from 2 generations of a family had a hidrotic type of ectodermal dysplasia (ED).Males and females were similarly affected. They had trichodysplasia, with absent eyebrows and eyelashes; normal teeth, onychodysplasia; normal sweating; mild retrognathia; abnormal dermatoglyphics; and mental retardation. Additional variable manifestations included irregular menses, high implanted or prominent ears, cafe-au-lait spot, keratosis pilaris, supernumerary nipple, and mild hearing loss. Their previously undescribed condition could be classified as an ED of 1-3 (trichoonychial) subgroup of group A according to F'reire-Maia's classification and is inherited as an autosomal recessive trait.
KEY
trichodysplasia, onychodysplasia, autosomal recessive inheritance, dermatoglyphics
CLINICAL REPORTS The patient (Fig. 1,VII-2) was the 1st child of young, unaffected parents. The father was 26 years old and the mother 21 years old. He was born a t term after a n uneventful pregnancy and delivery. Birth measurements were weight 2,710 g, length 48 cm, occipitofrontal circumference 34 cm. Apgar scores were 6 a t 1min and 8 a t 5 min. At the nursery, he was noted to have absent hair, eyebrows, and eyelashes and dysplastic nails in fingers and toes (Fig. 2A-C). One paternal aunt (Fig. 1, VI-4) who had the same clinical manifestations as the patient died at age 5 weeks. A 28-year-old paternal aunt (Fig. 1, VI-5) was born with the same clinical manifestations. Her scalp hair started to grow a little bit a t age 7-8 years to a maximum length of 1 cm. It was sparse and fell out easily when washed or pulled. Eyebiows and eyelashes were absent; nails were dystrophic. After a first menstrual period a t the age of 14 years, her menstrual cycles were irregular, with absence of menstruations sometimes for I
INTRODUCTION Ectodermal dysplasias (EDs) are a large heterogeneous group of diseases comprising more than 100 different entities [Freire-Maia and Pinheiro, 1984, 19881.Initially EDs were subdivided into anhidrotic and hidrotic forms LClouston, 19391. More recently, FreireMaia [1977] proposed a new classification into 2 groups. Group A includes a t least 2 of the following 4 cardinal signs: 1) trichodysplasia, 2) dental anomalies, 3) onychodysplasia, and 4) dyshidrosis (hyper-hypo-anhidrosis). Group B includes a t least one of these signs plus a t least another ectodermal manifestation. Both groups could also include anomalies and malformations of nonectodermal origin. We report a family with a previously undescribed type of hidrotic ED group A, subgroups 1-3 (trichoonychial), inherited as an autosomal recessive trait. Received for publication November 20, 1989; revision received June 14, 1990. Address reprint requests to Dr. Fahed Halal, Division of Medical Genetics, Montreal Children's Hospital, 2300 "upper Street, Montreal, Quebec, Canada H3H 1P3.
o 1991 Wiley-Liss, Inc.
II
Ill
IV
V
VI
VII
f2 Fig. 1. Family pedigree.
Ectodermal Dysplasia: A New e p e
553
Fig. 2. A-C: The patient.
as long as 3 months. Her teeth and breasts were normal. She sweats normally. She had bilateral moderate prominence of auricles and mild retrognathia (Fig. 3A-C). Her dermatoglyphics showed radial loop on right finger 5, TRC of 160, and distal axial triradius t” bilaterally. Complete blood count was normal. Audiogram showed mild right hearing loss at 51 KHz, with conductive component. Orthopantomogram showed discrete periodontitis (2 molars have been extracted). Skeletal survey showed a n increased interpedicular distance and
spina bifida occulta of L,-L, and spina bifida of sacrum. Skin histology revealed normal sweat glands and scarce pilosebaceous apparatus. Scalp hair ultrastructure study by scanning electron microscopy (SEM) is shown in Figure 4A-F. I& testing showed moderate mental retardation, with a global I& of 50 (nonverbal 54; verbal 56). Another 22-year-old paternal uncle (Fig. 1,VI-7) was similarly affected. His scalp hair started to grow a t age 6-7 years to a maximum length of 3 mm and with the
Fig. 3. A-C: Paternal aunt VI-5.
554
Halal et al.
Fig. 4. A,B: SEM of normal scalp hair and of individual VI-5. C-F: Progressive atrophy of cuticular scales from the proximal portion of the hair (c) to its distal portion (0,where they are almost absent, scales are atrophic clumped and lifted up (e). Original magnification x 1,000.
same characteristics a s those of his older sister. Beard and pubic hair were similar to scalp hair. Chest and axillary hair would grow only to the surface of the skin. His eyebrows, eyelashes, and upper and lower limb hair were absent. His nails were dystrophic. He had one cafeau-lait spot (10 cm in diameter) in the left axillary region, keratosis pilaris on upper and lower limbs, and a supernumerary left nipple. His teeth were normal. He sweats normally. He had a long oval face, high-implanted ears, and mild retrognathia (Fig. 5A-D). His dermatoglyphics showed 9 whorls on finger tips, TRC of 165, bilateral interdigital triradius B-C, and bilateral distal axial triradius t", with hypothenar pattern (L, ulnar loop; R, whorl). Complete blood count, audiogram, orthopantomogram, and skeletal survey were normal. Skin histology was similar to his sister's (VI-5). SEM of scalp hair is shown in Figure 6A-E. I& testing revealed mild mental retardation, with a global I& of 70 (nonverbal 81, verbal 66). The patient's unaffected parents are first cousins. Unaffected paternal grandparents are second cousins once removed (Fig. 1). The family is of Portuguese descent (San Miguel, Azores).
DISCUSSION The most common type of ED is usually inherited either as a n X-linked recessive trait (McKusick [19881 No. 305101, with affected males showing hypotrichosis and absence of teeth and sweat glands (anhidrotic) and heterozygous women showing reduction or malformation of teeth and mild abnormalities of sweat glands and breasts, or as a n autosomal dominant trait (McKusick [19881No. 129501,where affected individuals have total alopecia, dystrophic nails, hyperpigmentations, and normal teeth and sweat function (hidrotic). An autosomal dominant form of anhidrotic ED phenotypically similar to the X-linked form has been described in a very few families (McKusick [19881 No. 22490) [Gorlin et al., 1970; Passarge et al., 19661. Another form of autosomal recessive ED was reported by Mikaelian et al. [19701in a brother and sister of consanguineous parents. They had hidrotic ED with deafness, which could be classified a s a n ED of the 1-2 (trichoodontal) subgroup of group A. Other manifestations included camptodactyly of fifth fingers and thoracic kyphosis (McKusick [19881 No. 22480). Affected individuals had normal eyebrows, eyelashes, and nails. One affected individual had carious teeth.
Ectodermal Dysplasia: A New v p e
555
Fig. 5. A-D: Paternal uncle VI-7
TABLE I. List of Ectodermal Dysplasias Group A Subgroup 1-3, With Indication of Cause* Condition
AD
AR
XL
Heterogeneity AD AR XL
_
?
_
Unknown AD? AR? XL?
_
_
^
_
_
_
_
_
X 1. Hairy elbows dysplasia x x? 2. Palmoplantar hyperkeratosis and alopecia X 3. Curly hair-ankyloblepharon-naildysplasia (CHANDS) X 4. Onychotrichodysplasia with neutropenia X 5 . Pili torti and onychodysplasia 6. Agammaglobulinemia-dwarfism-ectodermaldysplasia X X 7 . Trichoonychodysplasia with xeroderma 8. Skeletal anomalies-ectodermal dysplasia-growth and mental retardation X 9. Sabinas brittle hair and mental deficiency syndrome X 10. Syndrome of accelerated skeletal maturation, failure to thrive, and peculiar face X 11, Congenital lymphedema, hypoparathyroidism, nephropathy, prolapsing mitral valve, and brachytelephalangy x XR X 12. Bartsocas-Papas syndrome Total 1 6 0 1 1 ? 0 1 0 3 1 *AD, autosomal dominant; AR, autosomal recessive; XL, X-linked; XR, X-linked recessive. Adapted from FYeire-Maia and Pinheiro [1988], with
permission of the authors.
~
556
Halal et al.
Fig. 6. A-D: SEM of scalp hair from individual VI-7, showing the same atrophy of cuticular scales as in individual VI-6. Original magnification x 1,000.E: Difference in size ofhair shaft between individual VI-7 (large) and VI-6 (small). Original magnification x 200.
The affected individuals in the present family had trichodysplasia, with absent eyebrows and eyelashes; normal teeth; onychodysplasia; normal sweating; mild retrognathia; and mental retardation. Although the sweating capacities of the affected individuals were not quantitated, they seem to be clinically euhidrotic, and there are no episodes of unexplained fever or heat intolerance; also, histologically the skin showed normal sweat glands. Additional variable manifestations included irregular menses, high implanted or prominent ears, cafe-au-lait spot, keratosis pilaris, supernumerary nipple, mild hearing loss, and abnormal dermatoglyphics such as excess of whorls on fingertips, radial loop on finger 5, interdigital triradius B-C, thenar exit of triradius A line, distal axial triradius t”and hypothenar pattern. The findings in affected individuals of the present family fit the criteria required to classify their condition as an ED of the 1-3 (trichoonychial) subgroup of group A according to Freire-Maia’s classification [ Freire-Maia, 1971, 1977; Freire-Maia and Pinheiro, 1984, 19883. According to the updated classification and list of EDs [Freire-Maia and Pinheiro, 19881, subgroup 1-3 of group A includes 1 2 conditions none of which is similar to the one described in the present family (Table I). We conclude that affected individuals in this family have a
distinct type of ED. Since the parents of affected individuals are unaffected and consanguineous, autosomal recessive inheritance of the trait is very likely.
REFERENCES Clouston HR (1939):The major forms of hereditary ectodermal dysplasia. Can Med Assoc J 4O:l-7. Freire-Maia N (1971): Ectodermal dysplasias. Hum Hered 21:309-312. Freire-Maia N (1977):Ectodermal dysplasia revisited. Acta Genet Med Gemellol 26121-131. Freire-Maia N, Pinheiro M (1984):“Ectodermal Dysplasias: A Clinical and Genetic Study,” New York: Alan R. Liss, Inc. Freire-Maia N, Pinheiro M (1988):Ectodermal dysplasiassome recollections and a classification. In Salinas CF, Opitz JM, Paul NW (eds): “Recent Advances in Ectodermal Dysplasias.” New York: Alan R. Liss, Inc., for the National Foundation-March of Dimes. BD:OAS 24(2):3-14. Gorlin FLJ, Old T, Anderson VE (1970): Hypohydrotic ectodermal dysplasia in females. A critical analysis and argument for genetic heterogeneity. Z Kinderheilk 108:l-11. McKusick VA (1988): “Mendelian Inheritance in Man. Catalogs of Autosomal Dominant, Autosomal Recessive, and X-Linked Phenotypes. Ed 8.” Baltimore: The Johns Hopkins University Press. Mikaelian DO, Der Kaloustian VM, Shahin NA, Barsoumian VM (1970): Congenital ectodermal dysplasia with hearing loss. Arch Otolaryngol 92:85-89. Passarge E, Nuzum CT, Schubert WK (1966): Anhidrotic ectodermal dysplasia as autosomal recessive trait in a n inbred kindred. Humangenetik 3:181-185.
