A number sign (#) is used with this entry because of evidence that erythrokeratodermia variabilis et progressiva-6 (EKVP6) is caused by heterozygous mutation in the TRPM4 gene (606936) on chromosome 19q13.

EKVP6 is characterized by erythematous hyperkeratotic plaques that develop within the first year of life, beginning on distal extremities and progressing to involve the face, wrists, and ankles, with sparing of volar surfaces. Intrafamilial variation in severity has been observed, and most affected individuals experience slowly progressive spontaneous remission after puberty (Wang et al., 2019).

For a general phenotypic description and discussion of genetic heterogeneity of EKVP, see EKVP1 (133200).

Wang et al. (2019) studied 2 unrelated 4-generation Chinese families segregating an autosomal dominant form of progressive symmetric erythrokeratodermia, and 1 sporadic patient of Han Chinese ethnicity. All affected individuals developed erythematous hyperkeratotic plaques on the dorsal aspect of their distal extremities within the first year of life. During childhood, the lesions progressed to involve the wrists, ankles, and the periorificial areas, most prominently on the face; volar aspects of extremities were mostly spared. Severely affected individuals experienced mild pruritus, and there was wide variation in disease severity among affected individuals from both families, ranging from generalized erythrokeratodermia to lesions restricted to the dorsum of hands and feet. Teeth, hair, and nails were normal, and skin lesions showed no seasonal variation. Most patients noted slowly progressive spontaneous remission after puberty. Histopathology of lesional skin showed psoriasiform hyperplasia of the epidermis with focal parakeratosis and mild perivascular lymphocytic infiltration in the superficial dermis. None of the affected individuals reported symptoms of cardiac arrhythmias or history of cardiac disorders, and no arrhythmias were detected on repeated electrocardiograms in 3 affected individuals.

The transmission pattern of EKVP6 in the families reported by Wang et al. (2019) was consistent with autosomal dominant inheritance.

In 2 unrelated 4-generation Chinese families segregating autosomal dominant progressive symmetric erythrokeratodermia, Wang et al. (2019) identified heterozygosity for a missense mutation in the TRPM4 gene (I1040T; 606936.0007). In a Han Chinese girl similarly affected with erythrokeratodermia, they identified heterozygosity for a de novo missense mutation in TRPM4 (I1033M; 606936.0008). The proband from 1 of the families (family 1) was screened for mutation in known EKVP-associated genes and no causative mutations were found.