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Impact of Screening Kindreds for SDHD p.Cys11X as a Common Mutation Associated with Paraganglioma Syndrome Type 1

Mariola Pczkowska, Zoran Erlic, Michael M. Hoffmann, Mariusz Furmanek, Jarosaw wika, Agata Kubaszek, Aleksander Prejbisz, Zbigniew Szutkowski, Andrzej Kawecki, Krzysztof Chojnowski, Anna Lewczuk, Mieczysaw Litwin, Witold Szyfter, Martin A. Walter, Maren Sullivan, Charis Eng, Andrzej Januszewicz and Hartmut P. H. Neumann

Department of Hypertension (M.P., A.Ku., A.P., A.J.), Institute of Cardiology, 04-628 Warsaw, Poland; Departments of Nephrology and Hypertension (Z.E., M.S., H.P.H.N.) and Laboratory Medicine (M.M.H.), Albert-Ludwigs-University, D-79106 Freiburg, Germany; Department of Radiology and Diagnostic Imaging at the Medical Center for Postgraduate Education (M.F., J.C.), 02-813 Warsaw, Poland; Department of Head and Neck Cancer (Z.S., A.Ka.), Skodowska-Curie Memorial Institute of Oncology, 02-781 Warsaw, Poland; Department of Endocrinology (K.C.), Medical University of Warsaw, 02-091Warsaw, Poland; Department of Internal Medicine (A.L.), Endocrinology and Haemostatic Disorders, Medical University of Gdansk, 80-952 Gdansk, Poland; Department of Nephrology and Hypertension (M.L.), the Children’s Memorial Health Institute, 04-730 Warsaw, Poland; Department of Otolaryngology and Laryngological Oncology (W.S.), Karol Marcinkowski University of Medical Sciences, 61-701, Pozna, Poland; Department of Endocrinology and Nuclear Medicine (M.A.W.), University of Basel, CH-4051 Basel, Switzerland; and Genomic Medicine Institute (C.E.), Lerner Research Institute and Taussig Cancer Institute, Cleveland Clinic Foundation, Cleveland, Ohio 44195

Address all correspondence and requests for reprints to: Prof. Dr. Hartmut P. H. Neumann, Department of Nephrology and General Medicine, University Medical Center, Albert-Ludwigs-University, Hugstetter Strasse 55, D-79106 Freiburg, Germany. E-mail: hartmut.neumann{at}uniklinik-freiburg.de.

Context and Objective: Germline mutations of the genes SDHB, SDHC, and SDHD predispose to paraganglioma syndromes. Mutation-specific counseling, risk assessment, and management recommendations ideally should be performed. Here, we provide data for a single common mutation of the SDHD gene.

Methods: The European-American Pheochromocytoma-Paraganglioma Registry served as the source for unrelated index cases affected by pheochromocytoma or paraganglioma. Patients with the SDHD c.33 CA (p.Cys11X) germline mutations were reinvestigated by whole-body magnetic resonance imaging and 24-h urinary catecholamine assay. First-degree relatives underwent genetic testing and those testing positive had same clinical investigations. Microsatellite analyses were used to test the hypothesis that all index cases were related and the mutation is a founding one.

Results: Sixteen index cases with the mutation SDHD p.Cys11X are registered. After testing their relatives, there were a total of 25 mutation carriers. We excluded seven subjects who inherited the mutation from the mother because of maternal imprinting. Thus, 18 mutation carriers were clinically affected. Among these 16 (89%) had head and neck paragangliomas, six (33%) thoracic tumors, six (33%) extraadrenal retroperitoneal, and five (28%) intraadrenal. Of note, 16 (89%) had multiple tumors at first diagnosis, and one (5%) had signs of malignancy during follow-up. Overall penetrance was 100% at age 54. Haplotype analyses revealed evidence for a founder effect.

Conclusions: The SDHD p.Cys11X mutation is a founding mutation associated with a high penetrance for paraganglial tumors of the skull base, neck, thorax, and retroperitoneum in the first four decades of life and, rarely, with malignancy.

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