G28 A Novel Missense Mutation in Keratin 1 Underlying Clinically Mild Epidermolytic Ichthyosis Mimicking Epidermolysis Bullosa Simplex Superficialis

Inherited skin peeling may be autosomal recessive (AR) or autosomal dominant (AD). When AR, this can be localised, as in acral peeling skin syndrome (APSS); or generalised, as in peeling skin syndrome (PSS) types A (non-inflammatory) and B (inflammatory). When AD, this can present in association with ichthyosis as either epidermolytic ichthyosis (EI) or superficial epidermolytic ichthyosis (SIE); or as a further, poorly characterised form of AD skin peeling, termed epidermolysis bullosa simplex superficialis (EBSS), previously described in two families. We report 6 affected individuals from 2 generations with generalised AD skin peeling. All presented neonatally with erosions at trauma-prone sites including the axillae, back and thighs, with ongoing skin fragility caused by friction. All 4 affected children reported slightly dry skin in the first decade of life with very mild hyperkeratosis of the axillae and neck. Some individuals had peeling of fingertips and soles, and one adult had mild diffuse plantar hyperkeratosis. There was no erythema, mucosal, nail or hair involvement. Initially, EBSS was considered based on AD inheritance, the generalised distribution, and lack of inflammation and ichthyosis at presentation. A biopsy of rubbed, uninvolved skin from one affected individual showed a thickened stratum corneum but no signs of blistering or ultrastructural abnormalities at the dermal-epidermal junction or within the epidermis. Sequencing of KRT5 and KRT14 (keratins 5 and 14) showed no mutations, but whole exome sequencing demonstrated a heterozygous missense mutation in KRT1 encoding keratin 1, p.Ser338Pro, in the 4 probands tested. This amino acid substitution is located within the L12 linker region, close to where other pathogenic mutations in keratin 1 have been reported in unrelated individuals with EI. Therefore, the most likely diagnosis in this family is EI due to a novel mutation in KRT1. This clinically mild disorder and new KRT1 gene pathology extends genotype-phenotype correlation in EI and underscores the value of next generation sequencing in diagnosing clinically atypical genodermatoses.