Erythrokeratodermia Variabilis Et Progressiva 4

A number sign (#) is used with this entry because of evidence that erythrokeratodermia variabilis et progressiva-4 (EKVP4) is caused by compound heterozygous mutation in the KDSR gene (136440) on chromosome 18q21.

Description

Erythrokeratodermia variabilis et progressiva-4 is characterized by severe lesions of thick scaly skin on the face and genitals, as well as thickened, red, and scaly skin on the hands and feet (summary by Boyden et al., 2017).

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

Clinical Features

Boyden et al. (2017) reported 4 unrelated patients with a similar skin phenotype, presenting either at birth or in the perinatal period with thickened red skin with vernix, thickened skin in the diaper area, or tight red skin with deep fissures and collodion membrane. Erythema faded in infancy, and by 4 months of age all 4 probands developed well-demarcated, thickened, scaly lesions on the cheeks and periocular areas, with erythema and thickening of the palms and soles. Most of the patients experienced thickened scaly plaques on the genitals, and 1 patient also had well-demarcated scaly plaques on the torso, legs, and arms. All patients reported exacerbation with cold weather. One patient had a sister with similar skin findings who died of pneumonia at 9 days of age.

Clinical Management

In 2 patients with EKVP4, Boyden et al. (2017) reported that treatment with isotretinoin, a systemic retinoic acid derivative, resulted in nearly complete resolution of their scaling and erythema. The authors noted that retinoic acid increases sphingosine acylation and upregulates sphingomyelinase, thus stimulating the ceramide salvage and sphingomyelinase pathways, which produce ceramides independently of KDSR. Boyden et al. (2017) suggested that retinoic acid therapy might be effective, at least in part, by compensating for a genetic defect in the ceramide de novo synthesis pathway via pharmacologic induction of alternative pathways for ceramide generation.

Molecular Genetics

By exome sequencing in a large cohort of patients with presumed-Mendelian disorders of cornification ('MEDOC' cohort), Boyden et al. (2017) identified 2 probands who were compound heterozygous for mutations in the KDSR gene (136440.0001-136440.0003). Another 2 probands from that cohort were found to be compound heterozygous for a mutation in the KDSR gene (136440.0003 or 136440.0004) and a 346-kb inversion on chromosome 18 that replaces the KDSR upstream promotor, 5-prime UTR, start codon, and first 2 exons, with unrelated sequence.