BG06: The phenotypic spectrum of biallelic plectin mutations: findings from the UK epidermolysis bullosa database

G. Petrof,¹ M.-L. Lovgren,² A.E. Martinez,¹ L. Liu,³ M. Ogboli,² J.E. Mellerio,⁴ J.A. McGrath⁵ and C. Moss²

¹Great Ormond Street Hospital, London, UK; ²Birmingham Children’s Hospital, Birmingham, UK; ³Guy’s Hospital, London, UK; ⁴Guy’s and St Thomas’ Hospital, London, UK; and ⁵King’s College London, London, UK

Biallelic mutations in PLEC underlie epidermolysis bullosa simplex (EBS) with muscular dystrophy (EBS-MD) and EBS with pyloric atresia (EBS-PA). The occurrence of PA, extent of skin involvement and age of onset of muscular dystrophy vary between families with no clear genotype–phenotype correlation to date. To characterize these conditions more clearly, we reviewed patients with EBS-MD, EBS-PA and biallelic PLEC mutations identified from the UK National EB database. There were 18 individuals (12 males, six females) with pathogenic biallelic PLEC mutations in themselves or an affected sibling, or – in two cases – the complete absence of plectin on skin biopsy. Six died (three were members of a single family) at a median age of 25 days (range 5 days–6 weeks). These included all five babies with PA (surgically corrected in three cases) and one who did not have PA, although his affected sibling and cousin did. Of those who died, all were preterm, none had evidence of muscle disease, and all had extensive aplasia cutis on all four limbs, mucosal involvement and associated ear abnormalities (low-set, absent or malformed). All five males had abnormal genitalia, while three had dystrophic or absent nails. Twelve were alive (median age 12·5 years; range 11 months–36 years). Of these 7/12 (58%) had some form of muscle involvement. Five had MD in some cases with associated myasthenia. In one case MD was congenital, but otherwise the earliest onset was 8 years. Two (one aged 8 years and one aged 14 years) had early features of fatiguability or ptosis (before the age of 5 years). In the EBS-MD group skin involvement at birth was minimal in three, extensive in three and one patient experienced oral blisters. Five patients were alive with no MD (aged 11 months–26 years) and all had very mild skin fragility, including at birth and no other anomalies, although two experienced mucosal blistering. Mutations in exon 31 occurred in five of seven families with MD, in one of three families with PA and in two of three families with neither. Other mutations were in exons 13, 30 and 32, and intron 12. Our findings suggest that babies with extensive skin involvement at birth, associated ear, genital and nail abnormalities, and biallelic PLEC mutations have a poor outcome, even after surgical correction of PA. Babies with mild skin involvement at birth may develop MD, usually in the second decade; there are no clear predictors of MD, but fatiguability and ptosis appear to be early manifestations. We found no clear genotype–phenotype correlation.