Palmoplantar Keratoderma And Congenital Alopecia 1

A number sign (#) is used with this entry because of evidence that palmoplantar keratoderma and congenital alopecia-1 (PPKCA1) is caused by heterozygous mutation in the GJA1 gene (121014) on chromosome 6q22.

Description

Palmoplantar keratoderma and congenital alopecia-1 (PPKCA1) is a rare autosomal dominant disorder characterized by severe hyperkeratosis and congenital alopecia. Nail changes occur in some patients (summary by Castori et al., 2010).

Also see PPKCA2 (212360), an autosomal recessive disorder characterized by congenital alopecia and progressive hyperkeratosis resulting in sclerodactyly, severe contractures and tapering of the digits, and pseudoainhum formation.

Clinical Features

Stevanovic (1959) described a family with congenital alopecia, hyperkeratosis of the palms and soles, and mild dystrophic changes of the fingernails inherited in an autosomal dominant pattern.

Basaran et al. (1995) reported a family in which 3 members had congenital hypotrichosis, characterized by trichorrhexis nodosa and trichoptilosis (splitting of the hair), dry skin, keratosis pilaris, and leukonychia totalis. They also developed a progressive form of palmoplantar keratoderma with hyperkeratotic lesions on the knees, elbows, and perianal region. There was male-to-male transmission (Castori et al., 2010).

Stratton et al. (1993) reported a 10-year-old girl, born of unrelated Hispanic parents, with trichodysplasia, onychodysplasia, hyperpigmented lesions on her shins, and hyperkeratosis of the soles, consistent with an ectodermal dysplasia. She had erythema of the soles with hyperkeratosis since age 1 year. She had sparse scalp and eyebrow hair, erythematous palms and soles, and wide, flat, peeling nails. Scanning electron microscopy of the hair showed spiraling longitudinal grooves with apparent absence of the normal cuticle. Sweating and intelligence were normal, and there was no family history of a similar disorder. Stratton et al. (1993) proposed that the phenotype was similar to Alves syndrome (601701). However, the patient reported by Stratton et al. (1993) did not have cataracts or scoliosis, prompting Castori et al. (2010) to suggest that this patient had the less severe autosomal dominant form of palmoplantar keratosis with congenital alopecia.

Wang et al. (2015) described a 25-year-old Chinese man who was noted at birth to have 20-nail leukonychia totalis and alopecia of the scalp hair, eyebrows, and eyelashes. At age 2 years, he developed hyperkeratosis of the perianal area, auricles, knuckles, knees, and ankles, which gradually spread to his trunk, extremities, hands, and feet. Examination showed diffuse keratosis pilaris on his trunk and extremities, coalescing into dark plaques with sharp demarcation on friction areas. Hyperkeratosis was particularly prominent on his ankles, elbows, and popliteal fossae, with multiple spiky horn-like lesions reminiscent of ichthyosis hystrix (see 146600). Focal palmoplantar keratoderma was present primarily on weight-bearing areas and was transgredient over the dorsa of hands and feet. All 20 nails were chalk-white, without dystrophic changes or subungual hyperkeratosis. Sparse, short, brittle hair was present on the scalp and axillae, and body hair was scant. Skin biopsy from the trunk showed orthohyperkeratosis with follicular plugging and perivascular lymphocytic infiltration in the papillary dermis. Scanning electron microscopy of hair shafts revealed multiple pits with cuticular weathering. His 4-year-old daughter had a nearly identical clinical presentation, albeit with milder hyperkeratosis. Wang et al. (2015) also studied a 27-month-old Chinese boy, born to nonconsanguineous healthy parents, whose clinical features closely resembled those of the affected members of the first family.

Molecular Genetics

In a Chinese family in which a father and daughter had palmoplantar keratoderma with congenital alopecia, Wang et al. (2015) performed whole-exome sequencing and identified heterozygosity for a missense mutation in the GJA1 gene (G8V; 121014.0023). The mutation segregated with disease in the family and was not found in 212 ethnically matched controls. In a similarly affected Chinese boy, Wang et al. (2015) directly sequenced the GJA1 gene and identified heterozygosity for the same G8V mutation.