Acta Dermato-Venereologica 98-4CompleteContent | Page 9

411 CLINICAL REPORT Epidermolysis Bullosa (EB) Acquisita in an Adult Patient with Previously Unrecognized Mild Dystrophic EB and Biallelic COL7A1 Mutations Liliana GUERRA 1 , Angelo Giuseppe CONDORELLI 2 , Paola FORTUGNO 1 , Valentina CALABRESI 1 , Cristina PEDICELLI 3 , Giovanni DI ZENZO 1# and Daniele CASTIGLIA 1# Laboratory of Molecular and Cell Biology and 3 1 st Dermatology Division, Istituto Dermopatico dell’Immacolata-IRCCS, and 2 Genetic and Rare Diseases Research Area, Bambino Gesù Children’s Hospital-IRCCS, Rome, Italy #These authors share last authorship. 1 Circulating anti-type VII collagen autoantibodies are frequently detected in patients with recessive dys- trophic epidermolysis bullosa (RDEB). However, evi- dence supporting their pathogenic role in inducing epi- dermolysis bullosa acquisita (EBA) has been provided for only one individual with dominant dystrophic epi- dermolysis bullosa (DDEB). We describe here a patient who presented with dystrophic toenails since early childhood and developed trauma-induced skin blis- ters and oral erosions at age 26 years. Direct immu- nofluorescence showed IgG deposits with a u-serra- ted pattern along the cutaneous basement membrane zone, while no change in the expression of collagen VII could be detected by antigen mapping. High-titre anti-collagen VII antibodies were detected by enzy- me-linked immunoassay (ELISA). In parallel, sequen- cing of epidermolysis bullosa (EB) genes identified compound heterozygous COL7A1 missense c.410G>A (p.Arg137Gln) and splicing c.3674C>T (p.Ala1225_ Gln1241del) mutations, previously unrecognized in dystrophic epidermolysis bullosa (DEB). Thus, our pa- tient had RDEB “nails-only” and developed mechano- bullous EBA in adulthood. These data support a patho­ genic role of circulating autoantibodies to collagen VII in inducing EBA in selected patients with DEB. Un- foreseen worsening of skin symptoms in DEB should prompt laboratory investigations for EBA. Key words: dystrophic epidermolysis bullosa; type VII collagen; autoantibodies. Accepted Nov 24, 2017; Epub ahead of print Nov 28, 2017 Acta Derm Venereol 2018; 98: 411–415. Corr: Daniele Castiglia, Laboratory of Molecular and Cell Biology, Istituto Dermopatico dell’Immacolata (IDI)-IRCCS, via dei Monti di Creta 104, IT-00167 Rome, Italy. E-mail: [email protected] T ype VII collagen (C7) is the major constituent of an- choring fibrils, microstructures that connect the basal lamina to the underlying mesenchymal tissue. It is formed from 3 identical alpha-chains, each consisting of a cen- tral collagenous triple helix flanked by non-collagenous domains (NC), named NC1 at the N-terminus and NC2 at the C-terminus. The large NC1 domain is subdivided into modules with similarity to adhesive proteins: 2 motifs with homology to von Willebrand factor type A domain (vWFA1 and vWFA2) and 9 to fibronectin type III (1, 2). In addition, a NC1 cysteine-rich region next to the collagen triple helix domain is recognized (1, 2). NC1 subdomains interact with many extracellular matrix proteins, including collagens I and IV, and laminin-332 (2, 3). The crucial role of C7 in mediating dermal-epidermal adhesion is underlined by 2 subepidermal skin blistering diseases with partially overlapping clinical features, but different aetiology: dystrophic epidermolysis bullosa (DEB) and epidermolysis bullosa acquisita (EBA) (1, 4). The former is caused by dominant or recessive mu- tations in the gene, COL7A1, that encodes C7, while the latter results from an autoimmune reactivity mediated by circulating and tissue-bound immunoglobulin G (IgG) antibodies to C7, mainly recognizing the NC1 domain (4). In most cases DEB manifests at birth, while EBA onset usually occurs in adulthood (1, 4). These features can help in distinguishing the 2 diseases, nevertheless a large fraction of patients with recessive DEB (RDEB) develop circulating anti-C7 antibodies, as detected by enzyme-linked immunoassay (ELISA) and/or immu- noblotting assays (5–7). However, these patients lack the major immunodiagnostic criterion for EBA, i.e. a linear deposition of IgG along the dermal–epidermal junction in a u-serrated pattern, as detected by direct immunofluorescence (4, 8). We report here the first case of EBA developing in a individual with RDEB with previously unrecognized pathogenic mutations affecting NC1 subdomains. METHODS Patient samples, immunofluorescence, and ultrastructural analyses Following ethical approval and informed consent, skin biopsies from the patient and blood samples from the patient, her parents and child were obtained for standard histological and electron microscopy examinations, direct immunofluorescence (DIF), im- munofluorescence (IF) antigen mapping, indirect IF (IIF) on salt- split skin, ELISA assays, immunoblotting, keratinocyte cultures, and for genetic analysis. The study was conducted in compliance with the principles of the Declaration of Helsinki. Enzyme-linked immunosorbent assays ELISAs for detection of anti-BP230, -BP180 and -C7 circulating autoantibodies were performed using commercial kits (MBL, Naka-Ku Nagoya, Japan). This is an open access article under the CC BY-NC license. www.medicaljournals.se/acta Journal Compilation © 2018 Acta Dermato-Venereologica. doi: 10.2340/00015555-2851 Acta Derm Venereol 2018; 98: 411–415