Keratosis Linearis With Ichthyosis Congenita And Sclerosing Keratoderma

A number sign (#) is used with this entry because of evidence that keratosis linearis with ichthyosis congenita and sclerosing keratoderma (KLICK) is caused by homozygous mutation in the POMP gene (613386) on chromosome 13q12.

Clinical Features

Pujol et al. (1989) described 4 Spanish sibs with an autosomal recessive keratinizing disorder thought to represent an entity that should be classified among congenital syndromes. The most striking feature of the patients' skin was the early appearance of linear hyperkeratosis without evidence of Koebner phenomenon.

Vahlquist et al. (1997) described an isolated case of what was thought to be the same disorder, which they referred to as KLICK syndrome (keratosis linearis with ichthyosis congenita and sclerosing keratoderma). The 32-year-old patient had a moderate, nonblistering ichthyosis since birth and longstanding palmoplantar keratoderma with pseudoainhum and a sclerosing flexion deformity of the fingers. Longitudinal, noninflamed keratotic striae, which had appeared spontaneously, were seen around his wrists, in the armfolds, and behind the knees. The patient was otherwise physically and mentally healthy and had no history of dental, nail, hair, or mucous membrane problems. The parents were nonconsanguineous, and all 5 of his half sibs were healthy and without skin symptoms. The condition improved on oral etretinate therapy. On light microscopy, the involved epidermis showed marked acanthosis with hypergranulosis and hyperkeratosis. Electron microscopy disclosed numerous large keratohyaline granules in superficial keratinocytes. Vahlquist et al. (1997) suggested that the condition is due to a genetic defect in the formation of keratohyaline granules.

Inheritance

Vahlquist et al. (1997) suggested that KLICK syndrome is an autosomal recessive disorder. Dahlqvist et al. (2010) confirmed autosomal recessive inheritance of the disorder.

Mapping

Dahlqvist et al. (2010) performed whole-genome SNP analysis on DNA from 3 Spanish sibs and 3 Swedish sporadic cases with KLICK syndrome and identified a 1.5-Mb homozygous candidate region on chromosome 13q. Microsatellite marker analysis further refined the critical region to an approximately 0.8-Mb interval spanning 10 annotated genes and 2 pseudogenes.

Molecular Genetics

In 12 patients from 8 European families with KLICK syndrome mapping to chromosome 13q, Dahlqvist et al. (2010) analyzed candidate genes and identified homozygosity for a 1-bp deletion in the POMP gene (613386.0001). Segregation analysis showed that the 6 available parents were heterozygous and the 5 available healthy sibs were either heterozygous or noncarriers for the deletion, which was not found in 280 Swedish control chromosomes. Immunohistochemical staining of patient skin biopsies revealed an altered distribution of POMP and proteasome subunits during formation of the horny layer, suggesting that KILCK syndrome is caused by proteasome insufficiency at a specific stage of epidermal differentiation.