Acta Dermato-Venereologica 99-13CompleteContent | Page 33

SHORT COMMUNICATION 1309 Novel PLEC Variant Causes Mild Skin Fragility, Pyloric Atresia, Muscular Dystrophy and Urological Manifestations Manthoula VALARI 1 , Martha THEODORAKI 2 , Ierotheos LOUKAS 3 , Sylvia GKANTSEVA-PATSOURA 2 , Georgia KARAVANA 2 , Vasiliki FALAINA 2 , Lilia LYKOPOULOU 1 , Roser PONS 4 , Ioannis ATHANASIOU 5 , Katarzyna WERTHEIM-TYSAROWSKA 6 , Christina KANAKA-GANTENBEIN 1 and Dimitra KIRITSI 5 * 1 First Department of Pediatrics, Medical School and 4 First Department of Pediatrics, Neurology unit, Medical School, National and Kapodistrian University of Athens, “Agia Sofia Childrens Hospital”, Athens, Greece, 2 Neonatal Intensive Care Unit and 3 Department of Pediatric Surgery, General Hospital of Nikaia “Agios Panteleimon”, Peiraius, Greece, 5 Department of Dermatology, Faculty of Medicine, Medical Center, University of Freiburg, Hauptstr. 7, DE-79104 Freiburg, and 6 Department of Medical Genetics, Institute of Mother and Child, Warsaw, Poland. *E-mail: [email protected] Accepted Sep 12, 2019; E-published Sep 12, 2019 Epidermolysis bullosa (EB) is a clinically and genetically relatively heterogeneous group of inherited blistering dis- orders. The most common subtype is EB simplex (EBS), which is usually associated with mutations in the KRT5, KRT14, DST, EXPH5 and PLEC genes (1). Approximately 8% of patients with EBS are estimated to carry PLEC mu- tations (2). The PLEC gene encodes the large cytolinker protein plectin (3–5). Plectin mutations, inherited in an autosomal recessive pattern, result in distinct phenotypes, including EBS with muscular dystrophy (MD), EBS with pyloric atresia (PA) and EBS with skin lesions only (3, 6). The dominantly inherited EBS-Ogna has a mild course restricted to skin involvement (7). Phenotype–genotype correlations have suggested that EBS-MD is mostly due to genetic variants in the central rod domain of plectin and EBS-PA due to mutations outside this domain (3, 8). Urinary tract involvement has only very rarely been reported in patients with either EBS-PA or EBS- MD (3, 4). To our knowledge only one case of EBS with both PA and MD, due to compound heterozygous PLEC mutations located in exon 32, has been reported (9). That patient had severe skin involvement and died 3 months after birth. We report here a patient with non-lethal EBS with rather mild skin involvement, congenital PA, progressive MD and mild bilateral hydronephrosis, who is compound heterozygous for 2 PLEC genetic variants in exon 32, one of them not having been reported previously. Thus, we extend the phenotypic spectrum of genetic PLEC variants. CASE REPORT On the second day of life, an infant boy was observed to have non-bilious vomiting with blood, without abdominal distention. He had been born at 38 weeks’ gestation, with a weight of 2,400 g. Abdominal X-ray showed a large gastric air bubble with no gas distally (Fig. 1A). An upper gastrointestinal tract examination with contrast material revealed a dilated stomach with obstruction at the pylorus, consistent with PA. Tense, and often haemorrhagic, blisters and erosions on the trunk and extremities appeared and recurred at sites of mechanical trauma (Fig. 1A). Similar bullous lesions were noted in the oral mucosa. Creatine kinase (CK) was found 1,468 U/l (normal range < 350 U/l) on the 5 th day of life. On the 6 th day of life, laparotomy revealed PA type 2 (pyloric canal replaced by a solid cord of tissue) and gastroduodenostomy was performed. Feeding was started approximately 1 week after surgery, was well tolerated, and hence gradually increased to full enteral nutrition. A renal ultrasound at day 8 showed mild hydronephrosis. Skin lesions continued to recur, and healing occurred without scarring, accompanied by mild atrophy. A skin biopsy was taken for immunofluorescence mapping, using a panel of antibodies to components of the dermo–epidermal junction and showed intraepidermal blisters and strongly reduced staining with 2 antibodies against plectin (Fig. 1B, 2 left panels). All other markers stained similarly to control skin. These findings were consistent with the diagnosis of EBS due to PLEC mutations. A custom-designed panel of EB-related genes was analysed by the Depart- ment of Medical Genetics in Warsaw, Poland, using Fig. 1. Clinical picture of the patient and diagnostics compatible with the diagnosis of epidermolysis bullosa simpelx due to PLEC mutations. (a) Abdominal X-ray after birth showed a large gastric air bubble with no gas distally. Small blisters and erosions were present over the whole integument. (b) Immunofluorescence mapping reveals intraepidermal blisters (white stars in plectin, integrin β4 (clone 3Ε1) and cytokeratin 5 (clone D5/16 B4) staining) and strongly reduced plectin expression with 2 different antibodies, whereas integrin a6 shows a staining pattern comparable to control skin. Scale: 100 μm. Immunoblot with the 2 plectin antibodies (31 recognizing the C-terminus and 10F6 for the rod domain) reveals residual presence of full-length plectin in lysates from patient keratinocytes, although a slightly shorter fragment cannot be fully excluded. Plectin expression appears to be comparably strongly reduced, regardless of the epitope recognized by the 2 plectin antibodies. (c) At the age of 2 years the skin phenotype has improved with mostly acral blisters and thickened dystrophic nails. This is an open access article under the CC BY-NC license. www.medicaljournals.se/acta Journal Compilation © 2019 Acta Dermato-Venereologica. doi: 10.2340/00015555-3317 Acta Derm Venereol 2019; 99: 1309–1310