KDSR – Erythrokeratodermia variabilis

Erythrokeratodermia variabilis (EKV) is a rare genodermatosis characterized by well-demarcated erythematous patches and hyperkeratotic plaques that wax and wane over time (PMID:39513663). EKV has been classically linked to autosomal dominant connexin gene variants, but recent evidence implicates recessive KDSR mutations in a distinct EKV-like presentation.

Biallelic KDSR variants underlie an autosomal recessive form of progressive symmetric erythrokeratoderma, often with minimal extracutaneous manifestations (PMID:39513663). Affected individuals present in infancy with thick, scaly plaques on acral and intertriginous sites and erythematous hyperkeratosis on palms, soles, and facial areas.

Exome and genome sequencing in three probands from two unrelated families identified compound heterozygous and homozygous KDSR variants, including c.413T>G (p.Phe138Cys), c.557A>T (p.Tyr186Phe), a recurrent silent splice-site change causing exon skipping, and a 346 kb inversion disrupting KDSR transcription (PMID:28575652). These variants segregated with disease in affected sibships and were absent in population databases.

Functional assays demonstrate that pathogenic KDSR alleles result in loss of 3-ketodihydrosphingosine reductase activity. Splicing assays confirmed exon exclusion for the silent change, yeast complementation failed to rescue mutant alleles, and immunohistochemistry of patient skin showed reduced ceramide deposition in the stratum corneum. Systemic isotretinoin therapy effectively restored skin integrity in treated probands, consistent with retinoid-mediated upregulation of alternative ceramide synthesis pathways (PMID:28575652).

The concordance of genotype, segregation, biochemical loss of function, and therapeutic rescue supports a loss-of-function mechanism for recessive KDSR variants in EKV. No studies to date dispute this association, and allelic heterogeneity encompasses missense, splice, and structural variants that converge on ceramide deficiency.

Key Take-home

Recessive KDSR mutations cause a loss-of-function form of erythrokeratodermia variabilis, informing genetic diagnosis and enabling targeted retinoid therapy.

References

• The Biochemical journal • 2024 • The genetic and molecular basis of a connexin-linked skin disease. PMID:39513663
• American journal of human genetics • 2017 • Mutations in KDSR Cause Recessive Progressive Symmetric Erythrokeratoderma. PMID:28575652

Evidence Based Scoring (AI generated)