Acta Dermato-Venereologica 99-2CompleteContent | Page 30

238 SHORT COMMUNICATION Phenotypic Features of Epidermolysis Bullosa Simplex due to KLHL24 Mutations in 3 Italian Cases May EL HACHEM 1 , Sabina BARRESI 1 , Andrea DIOCIAIUTI 1 , Renata BOLDRINI 2 , Angelo Giuseppe CONDORELLI 1 , Ettore CAPOLUONGO 3 , Vittoria PROTO 4 , Giulietta SCUVERA 5 , Cristina HAS 6 , Marco TARTAGLIA 1# and Daniele CASTIGLIA 4# Genetics and Rare Diseases Research Division, 2 Pathology Division, Bambino Gesù Children’s Hospital-IRCCS, Piazza S. Onofrio 4, IT- 00165 Rome, 3 Laboratory of Clinical Pathology and Advanced Molecular Diagnostics, Istituto Dermopatico dell’Immacolata, IDI-IRCCS, and Università Cattolica del Sacro Cuore, Fondazione Policlinico Universitario Agostino Gemelli, 4 Laboratory of Molecular and Cell Biology, Istituto Dermopatico dell’Immacolata, IDI-IRCCS, Rome, 5 Pediatric Highly Intensive Care Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, Milan, Italy, and 6 Department of Dermatology, University Medical Center, Freiburg, Germany. E-mail: [email protected] # These authors contributed equally. 1 Accepted Sep 18, 2018; E-published Sep 18, 2018 Epidermolysis bullosa simplex (EBS) is a phenotypically and genetically heterogeneous type of EB characterized by skin fragility and cleavage within the epidermis (1). The most common subtypes of EBS are due to dominant mutations in the KRT5 (keratin 5) and KRT14 (keratin 14) genes, but genetic defects in 10 additional genes are responsible for different variants. KLHL24 cau- sative mutations have been identified in a novel EBS form characterized by denuded skin areas at birth and improvement in skin fragility with age (2, 3). KLHL24 encodes a member of the kelch superfamily, which in- cludes proteins with variable tissue expression patterns involved in ubiquitination and proteaso- mal degradation of different substrates, including epidermal keratins (3, 4). It is notable that all of the 29 KLHL24 mutation-positive patients reported to date carried a heterozygous mutation in the first codon affecting translation ini- tiation. The causal mutation shows a do- minant pattern of inheritance in affected pedigrees or occurs as a de novo event (2, 3, 5–7). At present, the spectrum of clinical features and natural history of this EBS subtype remains incompletely characterized. We report here on 3 ad- ditional children with de novo KLHL24 codon 1 mutations, providing evidence for a wider clinical spectrum associated with these mutations. scarring (Fig. 1a–c), and the patient did not show new blisters. Congenital erosive and vesicular dermatosis healing with reti- culated supple scarring was diagnosed. In the following years, the patient developed occasional trauma-induced erosions, follicular atrophy, and dystrophy of toenails, which appeared thinned, brittle with longitudinal ridging and onycholysis. At 7 years of age, fol- lowing informed consent, the patient was enrolled in the Ospedale Pediatrico Bambino Gesù “Undiagnosed Patients Program”, and a trio-based whole exome sequencing analysis, together with a novel skin biopsy, was performed (for methods, see Appendix S1 1 ). Variant filtering, annotation and prioritization allowed to identify the de novo c.2T>C (p.Met1?) in KLHL24 (NM_017644) as the https://www.medicaljournals.se/acta/content/abstract/10.2340/00015555-3046 1 CASE REPORTS Case 1. Male, born from healthy parents at 37 weeks of gestation weighing 2,650 g. At birth, he presented extensive areas of denuded skin involving the limbs, buttocks, left mam- mary region, and oral lesions. The course was complicated by Serratia marcescens sepsis. Both immunofluorescence antigen mapping (IFM) and electron microscopy (EM) of a skin biopsy performed in a reference centre for EB showed normal expression of epithelial adhe- sion proteins in the absence of skin cleavage, and were thus considered uninformative. Skin erosions healed within the first month, leaving hypochromic, atrophic and raised linear-stellate doi: 10.2340/00015555-3046 Acta Derm Venereol 2019; 99: 238–239 Fig. 1. Clinical features. Case 1: (a) hypopigmented polymorphic scars on the back, (b) hypopigmented, atrophic, and stellated scars on the calf, and (c) raised stellated scarring intermingled with skin atrophy on hand dorsum at the age of 7 years. Case 2: (d, e) residual skin erosions on the knees, legs and left wrist at 14 days of age, (e) note the hypoplastic nail of the third finger; (f) atrophic scarring, milia, and follicular atrophoderma on the forearm and hand dorsum at 2 months of age. This is an open access article under the CC BY-NC license. www.medicaljournals.se/acta Journal Compilation © 2019 Acta Dermato-Venereologica.