Cancer, Alopecia, Pigment Dyscrasia, Onychodystrophy, And Keratoderma

A number sign (#) is used with this entry because of evidence that cancer, alopecia, pigment dyscrasia, onychodystrophy, and keratoderma (CAPOK) can be caused by homozygous mutation in the SASH1 gene (607955) on chromosome 6q24. One such family has been reported.

Heterozygous mutation in the SASH1 gene results in dyschromatosis universalis hereditaria-1 (DUH1; 127500).

Description

CAPOK syndrome is characterized by onset of symptoms in the first year of life, with the development of progressive alopecia, hypo- and hyperpigmented macular skin lesions, palmoplantar keratoderma, and nail dystrophy. Beginning in the third decade of life, patients develop recurrent squamous cell carcinomas. Some patients may have brittle teeth resulting in tooth loss, and multinodular goiter has been observed (Courcet et al., 2015).

Clinical Features

Courcet et al. (2015) reported a Moroccan brother and sister with alopecia, dyschromatosis, nail dystrophy, palmoplantar keratoderma, and squamous cell carcinomas (SCCs). The 32-year-old brother developed progressive alopecia at 8 months of age, and at 1 year presented with diffuse hyperpigmented macular lesions, palmoplantar keratoderma, and alopecia. He also had brittle teeth, and experienced complete tooth loss in the second decade of life. At age 20, he had 2 SCCs, on his left palm and in the right popliteal fossa; at age 30, he had SCC of the right fourth finger that required amputation of the distal phalanx; and at age 31 he had another SCC, of the right thumb. Dermatologic examination showed generalized hypo- and hyperpigmented macules that were larger and more irregular, with a reticulated appearance, towards the distal extremities. The proband also exhibited diffuse palmoplantar keratoderma with ill-defined margins and thick squama, as well as diffuse alopecia of the scalp, eyelashes, and eyebrows, nail dystrophy, and conjunctival telangiectasia. In addition, he had multinodular goiter. Ocular examination and x-rays of long bones were normal. The proband's 39-year-old sister was similarly affected, with alopecia at 6 months of age followed by palmoplantar desquamation and the progressive appearance of hypo- and hyperpigmented macules and nail dystrophy. The macules occurred primarily on the dorsa of her hands and feet, with slight hyperpigmentation limited to the legs and forearms, but no pigmentation defects on the remainder of the body; she noted that in contrast to her affected brother, she had stayed out of the sun since early childhood. At age 35 years, she had squamous cell carcinoma of the right forearm, requiring amputation. Pubic and axillary hair was normal in both sibs, and unlike her brother, the sister had normal dentition.

Molecular Genetics

By genomewide homozygosity mapping and exome sequencing in a Moroccan brother and sister with CAPOK syndrome, Courcet et al. (2015) identified homozygosity for a missense mutation in the SASH1 gene (E617K; 607955.0004) that segregated with disease in the family and was not found in local exomes or public variant databases.