Ectodermal Dysplasia-Syndactyly Syndrome 1

A number sign (#) is used with this entry because ectodermal dysplasia-syndactyly syndrome-1 (EDSS1) is caused by homozygous or compound heterozygous mutation in the PVRL4 gene (NECTIN4; 609607) on chromosome 1q23.

Description

Ectodermal dysplasia-syndactyly syndrome (EDSS) is characterized by sparse to absent scalp hair, eyebrows, and eyelashes, hypoplastic nails, tooth enamel hypoplasia, conical-shaped teeth, palmoplantar keratoderma, and partial cutaneous syndactyly (summary by Raza et al., 2015).

Genetic Heterogeneity of Ectodermal Dysplasia-Syndactyly Syndrome

Ectodermal dysplasia-syndactyly syndrome-2 (EDSS2; 613576) maps to chromosome 7p21-p14.

Clinical Features

Brancati et al. (2010) studied 2 unrelated families displaying hair and teeth abnormalities associated with cutaneous syndactyly of the hands and/or feet. One family, originally described by Boudghene-Stambouli and Merad-Boudia (1991), had 4 affected sibs born to first-cousin, healthy Algerian parents. The other family had 2 affected sibs, born to nonconsanguineous healthy parents of Italian origin. All affected individuals manifested partial cutaneous syndactyly variably involving fingers 2-3 and 3-4 and toes 2-3 and 4-5. In the young patients, hair over the entire scalp was sparse and coarse, with a tendency to break at an early age. Eyebrows, eyelashes, and body hair showed identical abnormalities. Progressive hair loss manifested in the second decade of life with patchy areas of alopecia over the scalp and progressed toward complete alopecia. Hair morphologic abnormalities included twists at irregular intervals (pilli torti) and swelling along the shafts, particularly associated with areas of breakage. Dental findings consisted of abnormally widely spaced teeth, with peg-shaped and conical crowns. All patients had normal sweating.

Jelani et al. (2011) reported a large 5-generation consanguineous family from a remote area of the Punjab province in Pakistan in which 10 individuals in the last generation had EDSS1. All had sparse scalp hair, sparse to absent eyebrows and eyelashes, conical and cylindrical teeth with enamel hypoplasia, hypoplastic nails, and cutaneous syndactyly of the third and fourth fingers and second and third toes. Most also had hyperkeratosis of the palms. None had hypo- or hyperhidrosis, cognitive impairment, or other systemic involvement. The clinical features in this family were similar to those described by Brancati et al. (2010), except that the hair did not show pili torti morphology.

Fortugno et al. (2014) reported 3 sibs, born of first-cousin parents of Afghan origin, who had cutaneous syndactyly and hair and teeth abnormalities. All affected individuals showed abnormally widely spaced and hypoplastic teeth. Hair morphologic abnormalities included pili torti, and there was progressive hair loss that manifested in the second decade of life, resulting in complete alopecia. Cutaneous syndactyly was variable, but involved fingers 2 to 4 and toes 2 to 5. Intolerance to heat was reported in 1 affected individual.

Raza et al. (2015) studied a large 5-generation consanguineous family, belonging to a tribe residing in a region at the border of India and Pakistan, in which 2 sibs and their first cousin once removed exhibited ectodermal dysplasia and syndactyly. All 3 presented a similar pattern of congenital hypotrichosis, with thin and sparse to absent scalp hair, sparse to absent eyebrows and eyelashes, and absent axillary and body hair; in the adult male patient, mustache and beard hair were missing. Light microscopy revealed a hair abnormality suggestive of pili torti. Severe dystrophic palmoplantar keratoderma was observed, and palm biopsy showed orthohyperkeratosis and complete absence of sweat gland units. Scalp biopsy showed epidermal hyperkeratosis and acanthosis, with a marked reduction in the density of hair follicles. Affected individuals had heat intolerance during summer months. Nails of hands and feet were thick, flat, and discolored, with longitudinal ridging and hyperkeratosis. Teeth were conical and cylindrical, with enamel hypoplasia. All 3 patients had partial cutaneous syndactyly up to the proximal interphalangeal joints involving fingers 2 to 4 and up to the distal interphalangeal joint involving toes 2 to 5. The patients also exhibited bilateral deformed pinnae, and all had purulent inflammation of the conjunctivae.

Inheritance

Brancati et al. (2010) demonstrated that ectodermal dysplasia-syndactyly syndrome-1 is an autosomal recessive disorder.

Mapping

In the consanguineous Algerian family with EDSS1 described by Boudghene-Stambouli and Merad-Boudia (1991), Brancati et al. (2010) used a homozygosity mapping approach to map the EDSS1 locus to chromosome 1q23.3 between SNPs rs11265404 and rs16833478 (112.6-158.6 Mb, NCBI36). Two-point linkage analysis gave a maximum lod score of 3.08 at D1S484.

Molecular Genetics

In affected members of the Algerian family with EDSS1 described by Boudghene-Stambouli and Merad-Boudia (1991), Brancati et al. (2010) identified a homozygous mutation in the PVRL4 gene (R284Q; 609607.0001). In affected members of an Italian family with EDSS1, they identified compound heterozygosity for mutations in the PVRL4 gene (T185M, 609607.0002; 906delT, 609607.0003). There was decreased PVRL4 immunostaining in the interfollicular epidermis and hair follicles of 1 patient. There was also highly disorganized cell membrane staining of alpha-catenin (CTNNA1; 116805), beta-catenin (CTNNB1; 116806), E-cadherin (CDH1; 192090), and afadin (MLLT4; 159559) in patient skin.

In affected members of a consanguineous Pakistani family with EDSS1, Jelani et al. (2011) identified a homozygous mutation in the PVRL4 gene (P212R; 609607.0004). The mutation was found after homozygosity mapping identified linkage to chromosome 1q23. The findings implicated a role for cell adhesion molecules in the pathogenesis of the disorder.

In 3 sibs with ectodermal dysplasia and cutaneous syndactyly, Fortugno et al. (2014) sequenced the PVRL4 gene and identified homozygosity for a missense mutation (V242M; 613753.0005) for which their unaffected parents were heterozygous. The authors noted clinical overlap between EDSS1 and cleft lip/palate-ectodermal dysplasia syndrome (CLPED1; 225060), caused by mutation in the PVRL1 gene (NECT1; 600644), and stated that the disorders could be referred to as 'nectinopathies.'

In 3 affected members of a 5-generation consanguineous Pakistani family with EDSS mapping to chromosome 1q23, Raza et al. (2015) identified homozygosity for a nonsense mutation in the PVRL4 gene (Q61X; 609607.0006). The mutation was present in heterozygosity in the unaffected parents and sibs and was not found in 100 ethnically matched controls.