Erythrokeratodermia Variabilis Et Progressiva 2

A number sign (#) is used with this entry because of evidence that erythrokeratodermia variabilis et progressiva-2 (EKVP2) is caused by heterozygous mutation in the gene encoding connexin-30.3 (GJB4; 605425) on chromosome 1p34.

Description

Erythrokeratodermia variabilis et progressiva-2 is a genodermatosis characterized by persistent plaque-like or generalized hyperkeratosis and transient red patches of variable size, shape, and location. The severity and dominating features of the disease vary strikingly within families and also during an individual's course of disease. The erythematous component usually prevails in young children, whereas hyperkeratosis is the dominant or sole feature in adults. Some patients with EKVP2 display lesions resembling erythema gyratum repens (summary by Richard et al., 2003). EKVP was previously thought to be separate disorders: erythrokeratodermia variabilis (EKV) and progressive symmetric erythrokeratodermia (PSEK) (van Steensel et al., 2009).

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

Clinical Features

Macari et al. (2000) studied 8 affected and 3 healthy individuals over 3 generations of an Israeli family of Kurdish origin with the migratory form of EKVP, originally described by Hacham-Zadeh and Even-Paz (1978). The dermatosis started at birth or shortly thereafter, but the patients were usually in good general health. Migratory erythematous lesions tended to turn gradually into more or less fixed keratotic plaques. In some patients, these erythematous lesions appeared as erythema gyratum repens, characterized by rapidly migrating figurata erythema 1 to 2 cm wide in an annular, garland, or spiral arrangement (Braun-Falco et al., 1991), which Macari et al. (2000) stated had not previously been reported in EKV. Generally, the palms and soles were spared. Lesions started to become worse in summer and to improve in winter. In 1 patient, lesions worsened during pregnancy. Audiograms in 2 affected patients were normal.

Richard et al. (2003) studied 57 patients with the migratory form of EKVP from 13 unrelated families. The hyperkeratosis was confined to localized plaques in 10 families, and individuals from the remaining 3 families had more widespread involvement. In 3 families, patchy or diffuse glove-like palmoplantar keratoderma (PPK; see 144200) was observed. In 2 families, children but not adults displayed rapidly changing erythematous patches with prominent circinate or gyrate borders (erythema gyratum repens). Richard et al. (2003) observed highly variable intrafamilial phenotypes, suggesting the strong influence of modifying genetic and epigenetic factors.

Mapping

Macari et al. (2000) performed linkage analysis in an Israeli family of Kurdish origin with the migratory form of EKVP, associated with erythema gyratum repens in some patients, originally described by Hacham-Zadeh and Even-Paz (1978). Macari et al. (2000) mapped the disorder to chromosome 1p35-p34, obtaining a maximum 2-point lod score of 2.343 (theta = 0) with marker D1S472, and noted that all affected individuals shared a common allele.

Molecular Genetics

In affected members of an Israeli family of Kurdish origin with the migratory form of erythrokeratodermia (EKV), originally described by Hacham-Zadeh and Even-Paz (1978), in which some patients displayed erythema gyratum repens, Macari et al. (2000) identified heterozygosity for a missense mutation in the GJB4 gene (F137L; 605425.0001).

Richard et al. (2003) analyzed the GJB4 gene in 13 unrelated families with EKV who were known to be negative for mutation in GJB3, and identified 6 distinct mutations (605425.0001-605425.0006) in 5 families and a sporadic patient. The F137L substitution, previously identified in an Israeli family of Kurdish origin with EKV and erythema gyratum repens by Macari et al. (2000), was found in 2 families: the identical 409T-C transition was detected in a family with typical EKV, whereas in a 2-year-old boy with EKV and erythema gyratum repens, a 411C-A transversion that also resulted in the F137L substitution was identified (605425.0002). No mutations were found in the remaining 7 families; Richard et al. (2003) stated that they did not observe any discriminatory or consistently deviant clinical features of EKV that would allow clinical differentiation of these patients from others harboring mutations in the GJB3 or GJB4 genes.

In 2 unrelated Dutch patients diagnosed with PSEK, van Steensel et al. (2009) identified heterozygosity for the G12D mutation in the GJB4 gene (605425.0004) that had previously been found in affected members of a Dutch family with typical EKV by Richard et al. (2003). Haplotype analysis of the 2 PSEK patients and 3 patients from the EKV family showed a shared haplotype extending over 2 Mb including the GJB4 gene. Van Steensel et al. (2009) concluded that PSEK and EKV can be manifestations of the same genetic defect and proposed the designation 'erythrokeratodermia variabilis et progressiva' to indicate the protean nature of the disorder.