Ectodermal Dysplasia 4, Hair/nail Type

A number sign (#) is used with this entry because of evidence that ectodermal dysplasia-4 (ECTD4) is caused by homozygous mutation in the KRTHB5 gene (KRT85; 602767) on chromosome 12q13.

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. Ectodermal dysplasia of the hair/nail type is a rare congenital condition characterized by hypotrichosis and nail dystrophy without nonectodermal or other ectodermal manifestations.

Clinical Features

Calzavara-Pinton et al. (1991) reported a family with an autosomal recessive form of hidrotic ectodermal dysplasia involving the hair and nails. Affected members had scalp, beard, axillary, and pubic hairs 1 to 10 mm long. The hair was brittle and easily broken, and showed twisting on scanning electron microscopy (EM). Eyebrows, eyelashes, and body hair were completely absent. Nails were distally dystrophic. No teeth abnormalities were found.

Naeem et al. (2006) described a large consanguineous Pakistani family in which 4 males and 4 females had ectodermal dysplasia of the hair and nails with total alopecia and nail dystrophy present at birth. Affected individuals were born completely devoid of eyebrows and eyelashes, had no scalp, face, chest, arm, or leg hair, and never developed axillary or pubic hair. The nails of all digits were dystrophic. Affected individuals were in good general health, sweated normally, and were of normal intelligence.

Shimomura et al. (2010) analyzed 2 consanguineous Pakistani families with hair and nail ectodermal dysplasia. In family A, affected individuals showed sparse hair and diffuse follicular papules on the scalp, and facial and body hair was less dense overall. The scalp hair was brittle and showed inconsistent thickness of the hair shaft on scanning EM. In family B, affected individuals displayed complete alopecia with diffuse follicular papules on the scalp. Facial and body hair was also absent, and the tips of the nails showed severe deformities. Affected individuals in both families showed normal facial features, teeth, and sweating, and they did not show palmoplantar hyperkeratosis.

Inheritance

The disorder in the families reported by Calzavara-Pinton et al. (1991) and Naeem et al. (2006) segregated in an autosomal recessive fashion; obligate carriers had normal hair and nails.

Mapping

Using a candidate gene approach, Naeem et al. (2006) performed linkage analysis in a large consanguineous Pakistani family with ectodermal dysplasia of the hair and nails and found linkage at the type II keratin gene cluster on chromosome 12q13.13. A maximum 2-point lod score of 4.54 was obtained at D12S398 (theta = 0); multipoint analysis yielded a lod score of 8.2 at that marker. The 3-unit support interval and region of homozygosity was flanked by markers D12S291 and D12S90, defining a 16.6-cM (15.0-Mb) region known to contain 6 type II hair keratin genes.

Molecular Genetics

In a large consanguineous Pakistani family with ectodermal dysplasia that had been mapped to a 15.0-Mb region on chromosome 12q13.13, Naeem et al. (2006) sequenced 6 candidate type II hair keratin genes and identified homozygosity for a missense mutation in the KRTHB5 gene (602767.0001) in all affected individuals. The mutation was present in heterozygosity in obligate carriers within the family and was not found in 200 chromosomes from Pakistani controls.

In 2 consanguineous Pakistani families with hair and nail ectodermal dysplasia mapping to a 1.26-Mb region on chromosome 12, Shimomura et al. (2010) identified homozygous mutations in the KRT85 gene: the same missense mutation (602767.0001) identified by Naeem et al. (2006) and a truncating mutation (602767.0002). The family with the truncating mutation (family A) had a less severe phenotype.