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.

Fig. 1

Family pedigree and age-related phenotypic features in patients with KRT5:c.1649del. (A) Pedigree of Family 5. Unfilled symbols: unaffected individuals. Filled black symbols: affected individuals with only mottled pigmentation. Filled symbols with red border: affected individuals with both migratory circinate erythema and mottled pigmentation. Grey symbols: affected individuals with no data available regarding disease course. Patients with genetically confirmed KRT5:c.1649del variant are numbered. (B) Neonatal blisters in patient 5.9. (C) Migratory circinate erythema in patient 5.9 at 2 months of age. (D) Mottled pigmentation in patient 5.7 at age 5. (E) Mottled pigmentation in patient 5.7 at age 10. (F) Mottled pigmentation at age 20. (G) Mottled pigmentation at age 40. (H) Dystrophic nails in a patient aged 7 years.

Fig. 2

Sequential progression of migratory circinate erythema into mottled pigmentation in patient 12.4.

Fig. 3

Phenotypic features. Patient with KRT5 exon 8 deletion (patient 4.1): (A) Diffuse alopecia. (B) Residual hyperpigmented macules on the hands. (C) Residual hyperpigmented macules on the legs. (D) Plantar keratoderma. Patient with KRT14:c.1121_1162dup variant (patient 21.1): (E–F) Mottled pigmentation on the trunk. (G) Mottled pigmentation on the legs. (H) Dystrophic toenail.