Atypical epidermolytic palmoplantar keratoderma presentation associated with a mutation in the keratin 1 gene

Background Epidermolytic palmoplantar keratoderma (EPPK) is an autosomal dominant genodermatosis characterized by epidermolytic hyperkeratosis strictly confined to the palms and soles, and usually associated with mutations in the keratin K9 gene (KRT9). Mutations in the keratin K1 gene (KRT1) have been shown to underlie a variety of phenotypes typically involving generalized epidermolytic hyperkeratosis, but in some cases the phenotype can be more regionally restricted.Objectives To identify the genetic defect in two unrelated families initially presenting with EPPK but where careful examination revealed hyperkeratosis extending on to the proximal wrist flexure.Methods Linkage analysis and DNA sequencing.Results We found that this phenotype is caused by a heterozygous missense mutation in the K1 gene, designated 1479T. This mutation lies in the highly conserved helix termination motif of K1, previously shown to be important for keratin assembly and filament formation. In general, mutations in this region of keratins are associated with more severe disease phenotypes. However, K1 mutations in this region and the 1479T mutation in particular have previously been associated with both severe and mild bullous congenital ichthyosiform erythroderma phenotypes. When further clinical enquiries were made, several affected individuals in the families studied here were found to have had transient flexural peeling and hyperkeratosis in the neonatal period.Conclusions K1 mutations may underlie a phenotype closely resembling EPPK. A history of transient flexural peeling and hyperkeratosis in childhood and palmoplantar keratoderma which extends beyond the boundary of the palmoplantar margins may indicate a K1 mutation rather than a K9 defect. As K1 mutations are also associated with severe widespread phenotypes, with important implications for prognostic and genetic counselling, whole body examination is recommended for patients presenting with EPPK