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Angelica Malinoc Departments of, Nephrology and General Medicine, Pathology, Department of Pathology and Neuropathology, Department of Urology, Institute of Pathology, Department of Urology, Division of Clinical Chemistry, Otolaryngology, Genomic Medicine Institute, Taussig Cancer Institute, University Medical Center, Albert‐Ludwigs‐University, Freiburg, Germany

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Maren Sullivan Departments of, Nephrology and General Medicine, Pathology, Department of Pathology and Neuropathology, Department of Urology, Institute of Pathology, Department of Urology, Division of Clinical Chemistry, Otolaryngology, Genomic Medicine Institute, Taussig Cancer Institute, University Medical Center, Albert‐Ludwigs‐University, Freiburg, Germany

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Thorsten Wiech Departments of, Nephrology and General Medicine, Pathology, Department of Pathology and Neuropathology, Department of Urology, Institute of Pathology, Department of Urology, Division of Clinical Chemistry, Otolaryngology, Genomic Medicine Institute, Taussig Cancer Institute, University Medical Center, Albert‐Ludwigs‐University, Freiburg, Germany

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Kurt Werner Schmid Departments of, Nephrology and General Medicine, Pathology, Department of Pathology and Neuropathology, Department of Urology, Institute of Pathology, Department of Urology, Division of Clinical Chemistry, Otolaryngology, Genomic Medicine Institute, Taussig Cancer Institute, University Medical Center, Albert‐Ludwigs‐University, Freiburg, Germany

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Cordula Jilg Departments of, Nephrology and General Medicine, Pathology, Department of Pathology and Neuropathology, Department of Urology, Institute of Pathology, Department of Urology, Division of Clinical Chemistry, Otolaryngology, Genomic Medicine Institute, Taussig Cancer Institute, University Medical Center, Albert‐Ludwigs‐University, Freiburg, Germany

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Joern Straeter Departments of, Nephrology and General Medicine, Pathology, Department of Pathology and Neuropathology, Department of Urology, Institute of Pathology, Department of Urology, Division of Clinical Chemistry, Otolaryngology, Genomic Medicine Institute, Taussig Cancer Institute, University Medical Center, Albert‐Ludwigs‐University, Freiburg, Germany

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Serdar Deger Departments of, Nephrology and General Medicine, Pathology, Department of Pathology and Neuropathology, Department of Urology, Institute of Pathology, Department of Urology, Division of Clinical Chemistry, Otolaryngology, Genomic Medicine Institute, Taussig Cancer Institute, University Medical Center, Albert‐Ludwigs‐University, Freiburg, Germany

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Michael M Hoffmann Departments of, Nephrology and General Medicine, Pathology, Department of Pathology and Neuropathology, Department of Urology, Institute of Pathology, Department of Urology, Division of Clinical Chemistry, Otolaryngology, Genomic Medicine Institute, Taussig Cancer Institute, University Medical Center, Albert‐Ludwigs‐University, Freiburg, Germany

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Alexander Bosse Departments of, Nephrology and General Medicine, Pathology, Department of Pathology and Neuropathology, Department of Urology, Institute of Pathology, Department of Urology, Division of Clinical Chemistry, Otolaryngology, Genomic Medicine Institute, Taussig Cancer Institute, University Medical Center, Albert‐Ludwigs‐University, Freiburg, Germany

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Gerd Rasp Departments of, Nephrology and General Medicine, Pathology, Department of Pathology and Neuropathology, Department of Urology, Institute of Pathology, Department of Urology, Division of Clinical Chemistry, Otolaryngology, Genomic Medicine Institute, Taussig Cancer Institute, University Medical Center, Albert‐Ludwigs‐University, Freiburg, Germany

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Charis Eng Departments of, Nephrology and General Medicine, Pathology, Department of Pathology and Neuropathology, Department of Urology, Institute of Pathology, Department of Urology, Division of Clinical Chemistry, Otolaryngology, Genomic Medicine Institute, Taussig Cancer Institute, University Medical Center, Albert‐Ludwigs‐University, Freiburg, Germany
Departments of, Nephrology and General Medicine, Pathology, Department of Pathology and Neuropathology, Department of Urology, Institute of Pathology, Department of Urology, Division of Clinical Chemistry, Otolaryngology, Genomic Medicine Institute, Taussig Cancer Institute, University Medical Center, Albert‐Ludwigs‐University, Freiburg, Germany
Departments of, Nephrology and General Medicine, Pathology, Department of Pathology and Neuropathology, Department of Urology, Institute of Pathology, Department of Urology, Division of Clinical Chemistry, Otolaryngology, Genomic Medicine Institute, Taussig Cancer Institute, University Medical Center, Albert‐Ludwigs‐University, Freiburg, Germany

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Hartmut P H Neumann Departments of, Nephrology and General Medicine, Pathology, Department of Pathology and Neuropathology, Department of Urology, Institute of Pathology, Department of Urology, Division of Clinical Chemistry, Otolaryngology, Genomic Medicine Institute, Taussig Cancer Institute, University Medical Center, Albert‐Ludwigs‐University, Freiburg, Germany

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Ringel MD Eng C 2012 Germline SDHx variants modify breast and thyroid cancer risks in Cowden and Cowden-like syndrome via FAD/NAD-dependant destabilization of p53 . Human Molecular Genetics 21 300 – 310 . doi:10.1093/hmg/ddr459 . Pavlovich

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Jean-Pierre Bayley Department of Human Genetics, Leiden University Medical Center, Leiden, the Netherlands

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Peter Devilee Department of Human Genetics, Leiden University Medical Center, Leiden, the Netherlands
Department of Pathology, Leiden University Medical Center, Leiden, the Netherlands

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-density genotyping arrays, FISH or karyotype In an SDHx-derived model The cell line should show low or absent SDHB protein expression ( SDHA, B , C & D mutated) or SDHA (in case of SDHA mutation) Establish the identity of proliferating cells

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Jared S Rosenblum Neuro-Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States

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Herui Wang Neuro-Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States

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Matthew A Nazari Eunice Kennedy Shriver National Institute of Child Health and Development, Bethesda, Maryland, United States

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Zhengping Zhuang Neuro-Oncology Branch, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States

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Karel Pacak Eunice Kennedy Shriver National Institute of Child Health and Development, Bethesda, Maryland, United States

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the time, defects in genes putatively related to hypoxia signaling pathways such as VHL (von Hippel–Lindau), EGLN1 , and SDHx (succinate dehydrogenase complex genes) had been associated with neural crest tumors prior to our discovery ( Neumann

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Vanessa D'Antongiovanni Department of Experimental and Clinical Biomedical Sciences University of Florence, Florence, Italy

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Serena Martinelli Department of Experimental and Clinical Biomedical Sciences University of Florence, Florence, Italy

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Susan Richter Institute of Clinical Chemistry and Laboratory Medicine University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany

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Letizia Canu Department of Experimental and Clinical Biomedical Sciences University of Florence, Florence, Italy

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Daniele Guasti Department of Experimental and Clinical Medicine University of Florence, Florence, Italy

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Tommaso Mello Department of Experimental and Clinical Biomedical Sciences University of Florence, Florence, Italy

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Paolo Romagnoli Department of Experimental and Clinical Medicine University of Florence, Florence, Italy

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Karel Pacak Eunice Kennedy Shriver National Institute of Child Health and Human Development National Institutes of Health, Bethesda, Maryland, USA

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Graeme Eisenhofer Institute of Clinical Chemistry and Laboratory Medicine University Hospital Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany

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Massimo Mannelli Department of Experimental and Clinical Biomedical Sciences University of Florence, Florence, Italy

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Elena Rapizzi Department of Experimental and Clinical Medicine University of Florence, Florence, Italy

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SDHB -silenced cells, resembling those found in human SDHx mutated Pheos/PGLs, whereas in 2D cultures, SDHB -silenced cell mitochondria did not differ from the ones in control cells ( Fig. 3 ). The use of spheroids does not just mean using a system

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Cristina Capatina Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford OX3 7LE, UK

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Georgia Ntali Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford OX3 7LE, UK

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Niki Karavitaki Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford OX3 7LE, UK

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Ashley B Grossman Oxford Centre for Diabetes, Endocrinology and Metabolism, University of Oxford, Oxford OX3 7LE, UK

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screening of paraganglioma and pheochromocytoma in SDHx mutation carriers: a multicenter prospective study from the PGL.EVA Investigators . Journal of Clinical Endocrinology and Metabolism 98 E162 – E173 . ( doi:10.1210/jc.2012-2975 ). Gjuric M

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Hartmut P Neumann Section for Preventive Medicine, University Medical Center, Albert-Ludwigs-University, Freiburg, Germany

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William F Young Jr Division of Endocrinology, Diabetes, Metabolism, and Nutrition, Mayo Clinic, Rochester, New York, USA

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Tobias Krauss Department of Radiology, Medical Center – University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany

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Jean-Pierre Bayley Department of Human Genetics, Leiden University Medical Center, Leiden, The Netherlands

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Francesca Schiavi Familial Cancer Clinic and Oncoendocrinology, Veneto Institute of Oncology, IRCCS, Padova, Italy

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Giuseppe Opocher Familial Cancer Clinic and Oncoendocrinology, Veneto Institute of Oncology, IRCCS, Padova, Italy

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Carsten C Boedeker Department of Otorhinolaryngology, HELIOS Hanseklinikum Stralsund, Stralsund, Germany

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Amit Tirosh Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel

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Frederic Castinetti Department of Endocrinology, Aix-Marseille Université, Institut National de la Santé et de la Recherche Médicale (INSERM), U1251, Marseille Medical Genetics (MMG), Marseille, France
Assistance Publique – Hôpitaux de Marseille (AP-HM), Hôpital de la Conception, Centre de Référence des Maladies Rares Hypophysaires HYPO, Marseille, France

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Juri Ruf Department of Nuclear Medicine, Faculty of Medicine, Albert-Ludwigs-University, Freiburg, Germany

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Dmitry Beltsevich Department of Surgery, Endocrinology Research Center, Moscow, Russia

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Martin Walz Department of Surgery and Center of Minimally-Invasive Surgery, Kliniken Essen-Mitte, Essen, Germany

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Harald-Thomas Groeben Department of Anesthesiology, Kliniken Essen-Mitte, Essen, Germany

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Ernst von Dobschuetz Section of Endocrine Surgery, Clinic of General, Visceral and Thoracic Surgery, Krankenhaus Reinbek, Academic Teaching Hospital University of Hamburg, Reinbek, Germany

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Oliver Gimm Department of Clinical and Experimental Medicine, Faculty of Health Sciences, Linköping University, Linköping, Sweden
Department of Surgery, Region Östergötland, Linköping, Sweden

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Nelson Wohllk Endocrine Section, Universidad de Chile, Hospital del Salvador, Santiago de Chile, Chile

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Marija Pfeifer Department of Endocrinology, University Medical Center Ljubljana, Ljubljana, Slovenia

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Delmar M Lourenço Jr Endocrine Genetics Unit, Endocrinology Division, Hospital das Clínicas, University of São Paulo School of Medicine (FMUSP), Endocrine Oncology Division, Institute of Cancer of the State of São Paulo, FMUSP, São Paulo, Brazil

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Mariola Peczkowska Department of Hypertension, Institute of Cardiology, Warsaw, Poland

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Attila Patocs HSA-SE ‘Lendület’ Hereditary Endocrine Tumor Research Group, Hungarian Academy of Sciences and Semmelweis University, Budapest, Hungary

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Joanne Ngeow Lee Kong Chian School of Medicine, Nanyang Technological University Singapore and Cancer Genetics Service, National Cancer Centre Singapore, Singapore, Singapore

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Özer Makay Division of Endocrine Surgery, Department of General Surgery, Ege University, Izmir, Turkey

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Nalini S Shah Department of Endocrinology, Seth G S Medical College, K.E.M. Hospital, Parel, Mumbai, India

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Arthur Tischler Department of Pathology and Laboratory Medicine, Tufts Medical Center and Tufts University School of Medicine, Boston, Massachusetts, USA

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Helena Leijon Department of Pathology, University of Helsinki, and HUSLAB, Helsinki University Hospital, Helsinki, Finland

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Gianmaria Pennelli Department of Medicine (DIMED), Surgical Pathology Unit, University of Padua, Padua, Italy

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Karina Villar Gómez de las Heras Central Services, Servicio de Salud de Castilla-La Mancha (SESCAM), Toledo, Spain

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Thera P Links Department of Endocrinology, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands

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Birke Bausch Department of Medicine II, Medical Center – University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany

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Charis Eng Genomic Medicine Institute, Lerner Research Institute and Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio, USA

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that retroperitoneal, pelvic and thoracic paraganglial tumors also showed germline mutations of any of the SDH genes ( SDHx ). Germline mutations in one of the SDH genes, especially the SDHD and SDHB gene, are found in 8–10% of hereditary

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Catherine Goudie Division of Hematology-Oncology, Department of Pediatrics, The Hospital for Sick Children, Toronto, Canada

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Fady Hannah-Shmouni Section on Endocrinology and Genetics The Eunice Kennedy Shriver Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, USA

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Mahmure Kavak Department of Pharmacology and Toxicology, University of Toronto, Toronto, Canada

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Constantine A Stratakis Section on Endocrinology and Genetics The Eunice Kennedy Shriver Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, USA

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William D Foulkes Department of Human Genetics, Research Institute of the McGill University Health Centre, and Lady Davis Institute, Jewish General Hospital, McGill University, Montreal, Canada

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dominant syndrome due to germline pathogenic variants in SDHA, SDHB , SDHC or SDHD (collectively referred to as SDHx) that predisposes to gastrointestinal tumours (GISTs), paragangliomas and adrenocortical tumours ( Carney & Stratakis 2002 ). These

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Minghao Li Department of Medicine III, University Hospital Carl Gustav Carus, Technische Universität Dresden, Fetscherstrasse, Dresden, Germany
Department of Urology, Xiangya Hospital, Central South University, Changsha, China

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Susan Richter Institute for Clinical Chemistry and Laboratory Medicine, University Hospital Carl Gustav Carus, Medical Faculty Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany

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Hermine Mohr Institute for Diabetes and Cancer, Helmholtz Centre Munich, Neuherberg, Germany

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Stephan Drukewitz Institute of Human Genetics, University of Leipzig Medical Center, Leipzig, Germany
Core Unit for Molecular Tumor Diagnostics (CMTD), National Center for Tumor Diseases (NCT), Partner Site Dresden, Dresden, Germany

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Isabel Poser Institute for Clinical Chemistry and Laboratory Medicine, University Hospital Carl Gustav Carus, Medical Faculty Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany

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Daniela Stanke Institute for Clinical Chemistry and Laboratory Medicine, University Hospital Carl Gustav Carus, Medical Faculty Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany

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Bruna Calsina Hereditary Endocrine Cancer Group, Spanish National Cancer Research Center and Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain

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Angel M Martinez-Montes Hereditary Endocrine Cancer Group, Spanish National Cancer Research Center and Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain

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Marcus Quinkler Endocrinology in Charlottenburg, Berlin, Germany

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Henri J L M Timmers Department of Internal Medicine, Radboud University Medical Center, Nijmegen, The Netherlands

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Svenja Nölting Medizinische Klinik Und Poliklinik IV, Klinikum der Ludwig-Maximilians-Universität München, Munich, Germany
Department of Endocrinology, Diabetology and Clinical Nutrition, Universitätsspital Zürich (USZ) and University of Zurich (UZH), Zurich, Switzerland

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Felix Beuschlein Medizinische Klinik Und Poliklinik IV, Klinikum der Ludwig-Maximilians-Universität München, Munich, Germany
Department of Endocrinology, Diabetology and Clinical Nutrition, Universitätsspital Zürich (USZ) and University of Zurich (UZH), Zurich, Switzerland

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Hanna Remde Division of Endocrinology and Diabetes, Department of Internal Medicine I, University Hospital of Würzburg, Würzburg, Germany

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Giuseppe Opocher Department of Medicine, University of Padua, Padua, Italy

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Elena Rapizzi Department of Experimental and Clinical Medicine, University of Florence, Italy

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Karel Pacak Section on Medical Neuroendocrinology, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, United States

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Christina Pamporaki Department of Medicine III, University Hospital Carl Gustav Carus, Technische Universität Dresden, Fetscherstrasse, Dresden, Germany

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Mercedes Robledo Hereditary Endocrine Cancer Group, Spanish National Cancer Research Center and Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Madrid, Spain

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Longfei Liu Department of Urology, Xiangya Hospital, Central South University, Changsha, China

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Jingjing Jiang Department of Endocrinology and Metabolism, Zhongshan Hospital, Fudan University, Shanghai, China

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Stefan R Bornstein Department of Medicine III, University Hospital Carl Gustav Carus, Technische Universität Dresden, Fetscherstrasse, Dresden, Germany

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Graeme Eisenhofer Department of Medicine III, University Hospital Carl Gustav Carus, Technische Universität Dresden, Fetscherstrasse, Dresden, Germany

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Stephanie M J Fliedner University Cancer Center Schleswig-Holstein, University Medical Center Schleswig-Holsten, Lübeck, Germany

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Nicole Bechmann Institute for Clinical Chemistry and Laboratory Medicine, University Hospital Carl Gustav Carus, Medical Faculty Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany

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succinate dehydrogenase subunits A–D ( SDHx ), fumarate hydratase ( FH ), von Hippel-Lindau ( VHL ) tumor suppressor, endothelial PAS domain protein 1 ( EPAS1 or HIF2α ), prolyl hydroxylase domain-containing proteins 1/2 ( PHD1/2 ) and isocitrate

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Margo Dona Department of Internal Medicine, Radboud University Medical Center, Nijmegen, the Netherlands

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Selma Waaijers Department of Laboratory Medicine, Radboud University Medical Center, Nijmegen, the Netherlands

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Susan Richter Institute of Clinical Chemistry and Laboratory Medicine, University Hospital Carl Gustav Carus, Medical Faculty Carl Gustav Carus, Technische Universitat Dresden, Dresden, Germany

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Graeme Eisenhofer Institute of Clinical Chemistry and Laboratory Medicine, University Hospital Carl Gustav Carus, Medical Faculty Carl Gustav Carus, Technische Universitat Dresden, Dresden, Germany
Department of Medicine ΙΙΙ, University Hospital Dresden, Dresden, Germany

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Jeroen Korving Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences and University Medical Center Utrecht, Utrecht, the Netherlands

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Sarah M Kamel Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences and University Medical Center Utrecht, Utrecht, the Netherlands

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Jeroen Bakkers Hubrecht Institute, Royal Netherlands Academy of Arts and Sciences and University Medical Center Utrecht, Utrecht, the Netherlands
Division of Heart and Lungs, Department of Medical Physiology, UMC Utrecht, Utrecht, the Netherlands

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Elena Rapizzi Department of Biomedical, Experimental and Clinical Sciences ‘Mario Serio’, University of Florence, Firenze, Italy

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Richard J Rodenburg Department of Pediatrics, Radboud Center for Mitochondrial Medicine, Translational Metabolic Laboratory, Radboud University Medical Center, Nijmegen, the Netherlands

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Jan Zethof Department of Animal Ecology and Physiology, Institute for Water and Wetland Research, Radboud University, Nijmegen, the Netherlands

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Marnix Gorissen Department of Animal Ecology and Physiology, Institute for Water and Wetland Research, Radboud University, Nijmegen, the Netherlands

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Gert Flik Department of Animal Ecology and Physiology, Institute for Water and Wetland Research, Radboud University, Nijmegen, the Netherlands

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Peter M T Deen Radboud University, Nijmegen, the Netherlands

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Henri J L M Timmers Department of Internal Medicine, Radboud University Medical Center, Nijmegen, the Netherlands

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rescue of the phenotype by maternal mRNA contribution from the yolk ( Harvey et al. 2013 , Despic & Neugebauer 2018 ) or alternative splicing ( Smits et al. 2019 ). Decreased aspartate has also been described in SDHx mutated PPGL-tumors and in

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Rachel Pimenta Riechelmann Clinical Oncology Department, A.C. Camargo Cancer Center, São Paulo, Brazil

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Mauro Daniel Spina Donadio Clinical Oncology Department, A.C. Camargo Cancer Center, São Paulo, Brazil

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Victor Hugo Fonseca de Jesus Clinical Oncology Department, A.C. Camargo Cancer Center, São Paulo, Brazil

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Nathalia de Angelis de Carvalho Clinical and Functional Genomics Group, International Research Center/CIPE, A.C. Camargo Cancer Center, São Paulo, Brazil

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Karina Miranda Santiago Clinical and Functional Genomics Group, International Research Center/CIPE, A.C. Camargo Cancer Center, São Paulo, Brazil

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Milton J Barros Clinical Oncology Department, A.C. Camargo Cancer Center, São Paulo, Brazil

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Laura Lopes Department of Pathology, A.C. Camargo Cancer Center, São Paulo, Brazil

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Gabriel Oliveira dos Santos Department of Pathology, A.C. Camargo Cancer Center, São Paulo, Brazil

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Maria Nirvana Formiga Clinical Oncology Department, A.C. Camargo Cancer Center, São Paulo, Brazil
Department of Oncogenetics, A.C. Camargo Cancer Center, São Paulo, Brazil

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Dirce Maria Carraro Clinical and Functional Genomics Group, International Research Center/CIPE, A.C. Camargo Cancer Center, São Paulo, Brazil
National Institute of Science and Technology in Oncogenomics and Therapeutic Innovation (INCITO-INOTE), São Paulo, Brazil

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Giovana Tardin Torrezan Clinical and Functional Genomics Group, International Research Center/CIPE, A.C. Camargo Cancer Center, São Paulo, Brazil
National Institute of Science and Technology in Oncogenomics and Therapeutic Innovation (INCITO-INOTE), São Paulo, Brazil

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Baudin E Buffet A Burnichon N Clifton-Bligh RJ Dahia PLM , 2021 International consensus on initial screening and follow-up of asymptomatic SDHx mutation carriers . Nature Reviews. Endocrinology 17 435 – 444 . ( https://doi.org/10.1038/s41574

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