Ectodermal Dysplasia 10b, Hypohidrotic/hair/tooth Type, Autosomal Recessive

A number sign (#) is used with this entry because of evidence that autosomal recessive hypohidrotic ectodermal dysplasia-10B (ECTD10B; HED/EDA) is caused by homozygous or compound heterozygous mutation in the ectodysplasin anhidrotic receptor gene (EDAR; 604095) on chromosome 2q13.

Description

Some ectodermal dysplasias are here classified as congenital disorders characterized by abnormal development in 2 or more ectodermal structures (hair, nails, teeth, and sweat glands) without other systemic findings.

Hypohidrotic, or anhidrotic, ectodermal dysplasia is characterized by a triad of signs comprising sparse hair (hypotrichosis), abnormal or missing teeth (anodontia or hypodontia), and inability to sweat (anhidrosis or hypohidrosis). Typical clinical manifestations also include dryness of the skin, eyes, airways, and mucous membranes presumably due to the defective development of several exocrine glands. Hypohidrotic ectodermal dysplasia can be associated with dysmorphic features (forehead bumps, rings under the eyes, everted nose, and prominent lips) and occasionally with absent nipples (summary by Cluzeau et al., 2011).

Clinical Features

Shimomura et al. (2004) reported a 24-year-old Japanese woman with autosomal recessive hypohidrotic ectodermal dysplasia. Her parents were unaffected and there was no consanguinity. She had heat intolerance, sparse hair, periorbital wrinkling, and oligodontia, and reported recurrent fevers as a child. A skin biopsy showed absence of hair follicles and hypoplastic eccrine sweat glands. Molecular analysis identified compound heterozygosity for 2 mutations in the EDAR gene (604095.0007 and 604095.0008).

Naeem et al. (2005) reported 2 consanguineous Pakistani families with autosomal recessive hypohidrotic ectodermal dysplasia. Affected individuals had classic features of the disorder, including sparse hair, absent eyebrows and eyelashes, missing teeth, decreased sweating, dry, thin skin, periorbital wrinkling and hyperpigmentation, prominent lips, and a saddle-shaped nose. Molecular analysis showed that affected members of each family had a homozygous mutation in the EDAR gene (see, e.g., 604095.0012).

Megarbane et al. (2008) described an 18-year-old Lebanese woman, born to first-cousin parents, who had a severe form of autosomal recessive anhidrotic ectodermal dysplasia with unusual clinical manifestations including absence of breasts, a rudimentary extranumerary areola and nipple on the left side, and marked palmoplantar hyperkeratosis. Molecular analysis identified homozygosity for a mutation in the EDAR gene (604095.0013) that results in a total absence of EDAR.

Inheritance

A rare autosomal recessive form of anhidrotic ectodermal dysplasia was suggested by the findings of Passarge et al. (1966) in inbred people of eastern Kentucky. Phenotypically the features were indistinguishable from those in males with the X-linked form. The existence of an autosomal recessive form was further supported strongly by the report by Gorlin et al. (1970) of a female with the full-blown syndrome and by their review of reported cases in females and of parental consanguinity and by Crump and Danks (1971) who reported a boy and girl in a family with hypohidrotic ectodermal dysplasia.

Kabbaj et al. (1998) reported a large consanguineous Moroccan family in which 14 individuals, both male and female, were affected.

Molecular Genetics

Monreal et al. (1999) identified mutations in the EDAR gene in 3 HED families displaying recessive inheritance (see, e.g., 604095.0001) and in 2 HED families with autosomal dominant inheritance (604095.0005).

In an 18-year-old Lebanese woman with a severe form of autosomal recessive anhidrotic ectodermal dysplasia with unusual clinical features including absence of breasts, extranumerary areola and nipple on the left side, and marked palmoplantar hyperkeratosis, Megarbane et al. (2008) identified a novel homozygous splice site mutation in the EDAR gene (IVS9+G-A; 604095.0013). RT-PCR analysis performed on whole skin biopsies and genes known to be expressed in skin appendages indicated that the mutation severely impairs EDAR cDNA splicing, resulting in total absence of EDAR transcripts and consequently of the EDAR protein. Megarbane et al. (2008) hypothesized that the mutation leads to the loss of EDAR/NF-kappa-B signaling. They speculated that the mutation impairs Wnt (see 164820)/B-catenin (116806) downregulation, which may modify the balance between signals necessary to mammary gland development.

Genotype/Phenotype Correlations

Van der Hout et al. (2008) identified mutations in the EDAR gene in 5 (28%) of 18 EDA-negative probands with hypohidrotic ectodermal dysplasia. Four families showed autosomal dominant inheritance. In 1 family, 2 affected boys with a severe phenotype were compound heterozygous for 2 mutations (R89H, 604095.0002; D110A, 604095.0009). The unaffected father carried the D110A mutation. However, the mother, who was heterozygous for the R89H mutation, was mildly affected with hypohidrosis and few permanent teeth. Van der Hout et al. (2008) concluded that some presumably 'recessive' mutations may show phenotypic expression in carriers. In the study overall, patients with dominant mutations were less severely affected compared to patients with recessive mutations.