BG06 Beyond keratin: when simplex is not so simple

Abstract Epidermolysis bullosa simplex (EBS) is a heterogeneous, congenital, mucocutaneous fragility syndrome, characterized ultrastructurally by cleavage within the basal keratinocyte. Seventy-five per cent of cases are attributable to mutations in KRT5 and KRT14, vast majority which dominant negative mutations, resulting impaired keratin intermediate filament dynamics layer epidermis. The presenting phenotype, including extracutaneous manifestations overall severity, often closely linked underlying genetic mutation; however, genotype–­phenotype correlation poorly resolved minority cases, there an approximately additional 15% patients whom abnormalities not identified. However, recent advances next-generation sequencing technologies have expanded mutational database. We describe two EBS with rare distinct clinical phenotypes. A 46-year-old man presented widespread blistering primarily affecting his hands, feet, elbows knees since childhood. He had unaffected, consanguineous parents one three siblings was affected. Other features included dystrophic nails, focal plantar keratoderma, truncal mottled pigmentation large areas hypopigmentation on back. considered diagnosis ‘EBS pigmentation’, but autosomal recessive mode inheritance nails were atypical. DNA whole-exome (WES) bidirectional Sanger revealed novel homozygous PLEC mutation [c.94dupG p.(Ala32GlyfsTer3)]. Pathogenic variants known cause EBS, Ogna type (MIM131950), muscular dystrophy (MIM226670) pyloric atresia (MIM612138). To date, our patient has manifested any signs progressive muscle weakness, age can vary. second 30-year-old woman who her flexures, hands friction sites 4 months. She eight unaffected siblings. WES confirmatory identified nonsense DST [c.3370C>T p.(Gln1124Ter)]. encodes epithelial isoform bullous pemphigoid antigen-1, present skin, neuronal tissues. Only 11 mutation-induced been reported date. cutaneous phenotype be blisters, postinflammatory dyspigmentation, scarring, nail dystrophy, keratoderma hyperhidrosis. If affected exon isoforms tissue, neurological symptoms expected. Unlike elsewhere harbours exactly same mutation, no issues These highlight importance unravelling genotype–phenotype forms possible implications for future prognosis management.