Epidermolysis Bullosa Simplex with Mottled Pigmentation and Migratory Circinate Erythema: Distinct Subtypes or a Continuum?

Abstract

Epidermolysis bullosa simplex with mottled pigmentation (EBS-MP) or with migratory circinate erythema (EBS-MCE) are rare clinical subtypes, typically associated with KRT5 pathogenic variants. A clinical and molecular analysis was conducted on 49 patients from 21 unrelated families in Argentina with suspected EBS-MP or EBS-MCE. Forty-eight individuals carried KRT5 variants, with the most frequent being c.1649del, found in 44 patients from 16 families. All affected individuals inherited the variant from one parent, and shared ancestry was traced to a restricted region in northeastern Argentina. Clinical data showed early-onset blistering, followed by generalized mottled pigmentation, and progressive nail dystrophy. Migratory erythema was observed in 18 patients, resolving by age 4 in most cases. Strikingly, 3 families showed intra--familial phenotypic variability: some individuals developed only MP, while others exhibited early MCE that later evolved into MP. This suggests a dynamic phenotypic spectrum potentially influenced by modifier factors. Additionally, a novel pathogenic variant in KRT14 and a large KRT5 exon 8 deletion were identified. This study represents the first report on the molecular epidemiology of EBS-MP in a South American population with an uncharacterized genetic background, contributing novel insights into genotype-phenotype correlations and natural history of EBS-MP and EBS-MCE.