Erythrokeratodermia Variabilis Et Progressiva 3

A number sign (#) is used with this entry because of evidence that erythrokeratodermia variabilis et progressiva-3 (EKVP3) is caused by heterozygous mutation in the gene encoding connexin-43 (GJA1; 121014) on chromosome 6q22.

Description

Erythrokeratodermia variabilis et progressiva is a rare skin disease. Patients with EKVP3 have normal skin at birth but develop hyperpigmentation and scaling at sites of friction in childhood, with progression to near-confluent corrugated hyperkeratosis, palmoplantar keratoderma, and transient figurate erythema (summary by Boyden et al., 2015).

For a discussion of genetic heterogeneity of EKVP, see EKVP1 (133200).

Clinical Features

Boyden et al. (2015) reported 3 unrelated patients with erythrokeratodermia variabilis. The first was a 2.5-year-old boy who at 5 months of age developed thick, brown-gray scales on frictional surfaces, as well as progressive darkening of his dorsal hands, arms, legs, and face. The palmoplantar surfaces and digits became pink and then markedly hyperkeratotic, and migrating areas of transient figurate erythema overlay the generalized scaling. The second patient was a 6-year-old girl, adopted from Guatemala, who at 8 months of age developed darkening and scaling of frictional surfaces and dorsal hands as well as progressive thickening of palms and soles. At 13 months of age, she had hyperpigmented, hyperkeratotic plaques of the axillae, elbows, and inner thighs, which became confluent by 2 years of age, with sparing of the cheeks and upper chest. She had intermittent annular red patches that faded within hours of onset. The third patient was a 30-year-old woman in whom darkening of the inner thighs was noted at 6 months of age, followed by development of thick scales on the knees, elbows, hands and feet, which progressively spread up the legs and arms. At 10 years of age, she developed pink to deep-red transient erythematous patches, associated with a burning sensation. In all 3 patients, erythema was induced by stress and warm conditions. In addition, all 3 exhibited enlarged porcelain-white lunulae, which extended from the cuticle to the free edge of the nail in 2 of the patients, as well as darkening of the periorificial areas. Histology of the most severely affected skin in each case showed papillomatosis, acanthosis, hypergranulosis, and compact orthohyperkeratosis with retained nuclei. Less severely affected skin showed acanthosis, papillomatosis, orthohyperkeratosis, and follicular plugging.

Molecular Genetics

By exome sequencing in 3 unrelated patients with erythrokeratodermia variabilis et progressiva, Boyden et al. (2015) identified heterozygosity for 2 de novo missense mutations in the GJA1 (CX43) gene, E227D (121014.0024) and A44V (121014.0025). The mutations were not present in any of the unaffected parents available (1 patient was adopted), in approximately 2,500 control exomes, or in public databases of human genetic variation. Immunostaining of patient skin and transfected HeLa cells showed that, in contrast to wildtype CX43, mutant CX43 did not localize to the membrane but appeared to be retained in the Golgi apparatus.