ESPE Abstracts (2018) 89 P-P1-179

Beckwith Wiedemann Syndrome: First International Consensus Regarding Diagnosis and Clinical Management

Frederic Brioudea, Jennifer M. Kalishb, Alessandro Mussac,d, Alison C. Fostere,f, Jet Bliekg, Giovanni B. Ferreroc, Susanne E. Boonenh, Robert Bakeri, Monica Bertolettij, Guido Cocchik, Carole Cozel, Maurizio De Pellegrinm, Khalid Hussainn, Malgorzata Krajewska-Walaseko, Christian P. Kratzp, Yves Le Bouca, Saskia M. Maasg, Katrin Ounapq, Licia Peruzzir, Sylvie Rossignols, Silvia Russot, Caroleen Shipsteru, Agata Skorkav, Katrina Tatton-Brownw, Jair Tenoriox,y, Chiara Tortoraz, Karen Gronskovaa, Irene Netchinea, Raoul C. Hennekambb, Dirk Prawittcc, Zeynep Tümeraa, Thomas Eggermanndd, Deborah J. G. Mackayee, Andrea Riccioff & Eamonn R. Mahergg

aSorbonne Université, INSERM UMR_S938 Centre de Recherche Saint-Antoine (CRSA), APHP Hôpital Trousseau, Paris, France; bDivision of Human Genetics, Children’s Hospital of Philadelphia and the Department of Pediatrics at the Perelman School of Medicine, University of Pennsylvania, Philadelphia, USA; cDepartment of Public Health and Pediatric Sciences, University of Torino, Torino, Italy; dNeonatal Intensive Care Unit, Department of Gynaecology and Obstetrics, Sant’Anna Hospita, Torino, Italy; eBirmingham Health Partners, West Midlands Regional Genetics Service, Birmingham Women’s and Children’s National Health Service (NHS) Foundation Trust, Birmingham, UK; fInstitute of Cancer and Genomic Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK; gDepartment of Clinical Genetics, Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands; hClinical Genetic Unit, Department of Pediatrics, Zealand University Hospital, Roskilde, Denmark; iBeckwith -- Wiedemann Support Group UK, Dorset, United Kingdom; jItalian Association of Beckwith -- Wiedemann syndrome (AIBWS), Vergiate, Italy; kAlma Mater Studiorum, Bologna University, Paediatric Department, Neonatology Unit, Bologna, Italy; lAix-Marseille Univ et Assistance Publique Hôpitaux de Marseille (APHM), Hôpital d’Enfants de La Timone, Marseille, France; mPediatric Orthopaedic Unit IRCCS Ospedale San Raffaele, Milan, Italy; nDepartment of Paediatric Medicine, Division of Endocrinology, Sidra Medical and Research Center, Doha, Qatar; oDepartment of Medical Genetics, The Children’s Memorial Health Institute, Warsaw, Poland; pPediatric Hematology and Oncology, Hannover Medical Schoo, Hannover, Germany; qDepartment of Clinical Genetics, United Laboratories, Tartu University Hospital and Department of Clinical Genetics, Institute of Clinical Medicine, University of Tartu, Tartu, Estonia; rEuropean Society for Paediatric Nephrology (ESPN), Inherited Kidney Disorders Working Group, Regina Margherita Children’s Hospital, Torino, Italy; sService de Pédiatrie, Hôpitaux Universitaires de Strasbourg, Laboratoire de Génétique Médicale, INSERM U1112, Strsbourg, France; tMedical Cytogenetics and Molecular Genetics Laboratory, Centro di Ricerche e Tecnologie Biomediche IRCCS, Istituto Auxologico Italiano, Milan, Italy; uGreat Ormond Street Hospital for Children National Health Service (NHS) Foundation Trust, Londn, UK; vDepartment of Pediatrics, The Medical University of Warsaw, Warsaw, Poland; wSouth West Thames Regional Genetics Service and St George’s University of London and Institute of Cancer Research, London, UK; xInstituto de Genética Médica y Molecular (INGEMM)-IdiPAZ, Hospital Universitario La Paz, Madrd, Spain; yCIBERER, Centro de Investigación Biomédica en Red de Enfermedades Raras, ISCIII, Madrid, Spain; zRegional Center for CLP, Smile House, San Paolo University Hospital, Milan, Italy; aaKennedy Center, Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet, Copenhagen, Denmark; bbDepartment of Pediatrics, Emma Children’s Hospital, Academic Medical Center, University of Amsterdam, Amsterdam, Netherlands; ccCenter for Pediatrics and Adolescent Medicine, Johannes Gutenberg University Medical Center, Mainz, Germany; ddInstitute of Human Genetics, University Hospital, Technical University of Aachen, Aachen, Germany; eeHuman Development and Health, Faculty of Medicine, University of Southampton, Southampton, UK; ffDepartment of Environmental, Biological, and Pharmaceutical Sciences and Technologies(DiSTABiF), University of Campania Luigi Vanvitelli, Caserta and Institute of Genetics and Biophysics A. ‘‘Buzzati-Traverso’’, Napoli, Italy; ggDepartment of Medical Genetics, University of Cambridge and National Institute for Health Research (NIHR) Cambridge Biomedical Research Centre and Cancer Research UK Cambridge Centre, Cambridge, UK

Beckwith Wiedemann syndrome (BWS) is a rare overgrowth disorder characterised by macroglossia, exomphalos, lateralised overgrowth, organomegaly, hyperinsulinism, and an increased risk of embryonic tumor during early life. In about 80% of BWS cases, molecular defects are identified at the imprinted 11p15.5 region which contains the IGF2 and the CDKN1C genes (most patients show methylation defects at either imprinting control region IC1 or IC2, or paternal uniparental isodisomy). Previously, many clinical scoring systems have been proposed to delineate BWS with variable sensitivity or specificity. Regarding clinical management, especially regarding tumor screening, no consensual approaches have hitherto been determined.

Aim: to establish recommendations regarding clinical and molecular diagnosis of BWS, and clinical management of patients with BWS.

Method: Based on a PubMed search, a comprehensive literature review was performed by a group of international experts to establish a draft consensus statement. A 3-day face-to-face meeting involving 35 participants took place in March 2017 to discuss, formulate and vote on 72 consensus recommendations.

Results: A new scoring system based on clinical symptoms (including cardinal and suggestive features) has been established to 1) indicate molecular testing and 2) define patients with a clinical diagnosis of BWS. The experts introduced the notion of “Beckwith Wiedemann spectrum” (BWSp) which includes patients with a molecular defect at 11p15.5 (irrespective of the clinical presentation) and those with a clinical diagnosis of BWS (irrespective of the results of the molecular investigations). Consensus recommendations are applicable to all BWSp patients. A diagnostic tree has been established to guide molecular testing in case of suspicion of BWSp, with first-line diagnosis based on methylation studies of the 11p15.5 imprinted region. Regarding clinical management, recommendations include those for growth, lateralised overgrowth, macroglossia, exomphalos, hypoglycaemia and hyperinsulinism, cardiac, renal and neurological complications. Regarding tumor screening, the experts agreed about a surveillance program stratified by the molecular subtype, with no tumor screening recommended for patients with BWSp due to an IC2 hypomethylation because of their lower tumor risk, and an abdominal ultrasound scan every 3 months until the age of 7 years for all other BWSp patients, including patients with a clinical diagnosis of BWS and no molecular defect.

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