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Luciana Pinto Brito
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Tamaya Castro Ribeiro
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Madson Q Almeida Unidade de Endocrinologia do Desenvolvimento, Unidade de Suprarrenal, Unidade de Endocrinologia Genética LIM/25, Divisão de Anatomia Patológica do Hospital das Clínicas LIM/14, Laboratorio de Hormonios e Genetica Molecular LIM/42, Faculdade de Medicina da Universidade de Sao Paulo, Avenida Dr Enéas de Carvalho Aguiar, No. 155 PAMB, 2° Andar, Bloco 6, Sao Paulo CEP 05403-900, Brazil

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Alexander Augusto de Lima Jorge Unidade de Endocrinologia do Desenvolvimento, Unidade de Suprarrenal, Unidade de Endocrinologia Genética LIM/25, Divisão de Anatomia Patológica do Hospital das Clínicas LIM/14, Laboratorio de Hormonios e Genetica Molecular LIM/42, Faculdade de Medicina da Universidade de Sao Paulo, Avenida Dr Enéas de Carvalho Aguiar, No. 155 PAMB, 2° Andar, Bloco 6, Sao Paulo CEP 05403-900, Brazil

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Iberê Cauduro Soares Unidade de Endocrinologia do Desenvolvimento, Unidade de Suprarrenal, Unidade de Endocrinologia Genética LIM/25, Divisão de Anatomia Patológica do Hospital das Clínicas LIM/14, Laboratorio de Hormonios e Genetica Molecular LIM/42, Faculdade de Medicina da Universidade de Sao Paulo, Avenida Dr Enéas de Carvalho Aguiar, No. 155 PAMB, 2° Andar, Bloco 6, Sao Paulo CEP 05403-900, Brazil

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Ana Claudia Latronico
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Berenice Bilharinho Mendonca
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Maria Candida Barisson Villares Fragoso Unidade de Endocrinologia do Desenvolvimento, Unidade de Suprarrenal, Unidade de Endocrinologia Genética LIM/25, Divisão de Anatomia Patológica do Hospital das Clínicas LIM/14, Laboratorio de Hormonios e Genetica Molecular LIM/42, Faculdade de Medicina da Universidade de Sao Paulo, Avenida Dr Enéas de Carvalho Aguiar, No. 155 PAMB, 2° Andar, Bloco 6, Sao Paulo CEP 05403-900, Brazil

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Antonio Marcondes Lerario Unidade de Endocrinologia do Desenvolvimento, Unidade de Suprarrenal, Unidade de Endocrinologia Genética LIM/25, Divisão de Anatomia Patológica do Hospital das Clínicas LIM/14, Laboratorio de Hormonios e Genetica Molecular LIM/42, Faculdade de Medicina da Universidade de Sao Paulo, Avenida Dr Enéas de Carvalho Aguiar, No. 155 PAMB, 2° Andar, Bloco 6, Sao Paulo CEP 05403-900, Brazil

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Fabio R Faucz Section on Endocrinology & Genetics, Program on Developmental Endocrinology & Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, United States of America

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Anelia D Horvath Department of Pharmacology and Physiology, School of Medicine and Health Sciences, The George Washington University, Washington, District of Columbia, United States of America

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Guillaume Assié Université Paris Cité, CNRS UMR8104, INSERM U1016, Institut Cochin, Paris, France
Endocrine Department, Center for Rare Adrenal Diseases, AP-HP, Hôpital Cochin, Paris, France

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Madson Q Almeida Section on Endocrinology & Genetics, Program on Developmental Endocrinology & Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, United States of America
Adrenal Unit, Laboratory of Molecular and Cellular Endocrinology LIM/25, Division of Endocrinology and Metabolism, University of Sao Paulo Medical School, São Paulo, Brasil

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Eva Szarek Section on Endocrinology & Genetics, Program on Developmental Endocrinology & Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, United States of America

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Sosipatros Boikos Section on Endocrinology & Genetics, Program on Developmental Endocrinology & Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, United States of America

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Anna Angelousi Section on Endocrinology & Genetics, Program on Developmental Endocrinology & Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, United States of America

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Isaac Levy Section on Endocrinology & Genetics, Program on Developmental Endocrinology & Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, United States of America

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Andrea G Maria Section on Endocrinology & Genetics, Program on Developmental Endocrinology & Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, United States of America

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Ajay Chitnis Laboratory of Molecular Genetics, Section on Neural Developmental Dynamics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, United States of America

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Cristina R Antonescu Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, New York, United States of America

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Rainer Claus Hematology and Oncology, Medical Faculty, University of Augsburg, Augsburg, Germany

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Jérôme Bertherat Université Paris Cité, CNRS UMR8104, INSERM U1016, Institut Cochin, Paris, France
Endocrine Department, Center for Rare Adrenal Diseases, AP-HP, Hôpital Cochin, Paris, France

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Christoph Plass Division of Cancer Epigenomics, German Cancer Research Center, Heidelberg, Germany

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Charis Eng Genomic Medicine Institute, Lerner Research Institute, and Taussig Cancer Institute, Cleveland Clinic, Cleveland, Ohio, United States of America

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Constantine A Stratakis Section on Endocrinology & Genetics, Program on Developmental Endocrinology & Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland, United States of America
Human Genetics & Precision Medicine, IMBB, Foundation for Research & Technology Hellas, Heraklion, Crete, Greece
Research Institute, ELPEN, Pikermi, Athens, Greece

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Gastrointestinal stromal tumors (GISTs) are mesenchymal neoplasms, believed to originate from the interstitial cells of Cajal (ICC), often caused by overexpression of tyrosine kinase receptors (TKR) KIT or PDGFRA. Here, we present evidence that the embryonic stem cell factor FOXD3, first identified as ‘Genesis’ and involved in both gastrointestinal and neural crest cell development, is implicated in GIST pathogenesis; its involvement is investigated both in vitro and in zebrafish and a mouse model of FOXD3 deficiency. Samples from a total of 58 patients with wild-type GISTs were used for molecular analyses, including Sanger sequencing, comparative genomic hybridization, and methylation analysis. Immunohistochemistry and western blot evaluation were used to assess FOXD3 expression. Additionally, we conducted in vitro functional studies in tissue samples and in transfected cells to confirm the pathogenicity of the identified genetic variants. Germline partially inactivating FOXD3 sequence variants (p.R54H and p.Ala88_Gly91del) were found in patients with isolated GISTs. Chromosome 1p loss was the most frequent chromosomal abnormality identified in tumors. In vitro experiments demonstrate the impairment of FOXD3 in the presence of those variants. Animal studies showed disruption of the GI neural network and changes in the number and distribution in the ICC. FOXD3 suppresses KIT expression in human cells; its inactivation led to an increase in ICC in zebrafish, as well as mice, providing evidence for a functional link between FOXD3 defects and KIT overexpression leading to GIST formation.

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Marcela Rassi-Cruz Unidade de Suprarrenal, Laboratório de Hormônios e Genética Molecular LIM/42, Serviço de Endocrinologia e Metabologia, Hospital das Clínicas, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil

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Andrea G Maria Section on Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health, Bethesda, Maryland, USA

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Fabio R Faucz Section on Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health, Bethesda, Maryland, USA

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Edra London Section on Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health, Bethesda, Maryland, USA

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Leticia A P Vilela Unidade de Suprarrenal, Laboratório de Hormônios e Genética Molecular LIM/42, Serviço de Endocrinologia e Metabologia, Hospital das Clínicas, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil

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Lucas S Santana Unidade de Suprarrenal, Laboratório de Hormônios e Genética Molecular LIM/42, Serviço de Endocrinologia e Metabologia, Hospital das Clínicas, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil

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Anna Flavia F Benedetti Unidade de Suprarrenal, Laboratório de Hormônios e Genética Molecular LIM/42, Serviço de Endocrinologia e Metabologia, Hospital das Clínicas, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil

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Tatiana S Goldbaum Unidade de Suprarrenal, Laboratório de Hormônios e Genética Molecular LIM/42, Serviço de Endocrinologia e Metabologia, Hospital das Clínicas, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil

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Fabio Y Tanno Serviço de Urologia, Hospital das Clínicas, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil

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Vitor Srougi Serviço de Urologia, Hospital das Clínicas, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil

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Jose L Chambo Serviço de Urologia, Hospital das Clínicas, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil

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Maria Adelaide A Pereira Unidade de Suprarrenal, Laboratório de Hormônios e Genética Molecular LIM/42, Serviço de Endocrinologia e Metabologia, Hospital das Clínicas, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil

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Aline C B S Cavalcante Instituto de Radiologia InRad, Hospital das Clínicas, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil

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Francisco C Carnevale Instituto de Radiologia InRad, Hospital das Clínicas, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil

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Bruna Pilan Instituto de Radiologia InRad, Hospital das Clínicas, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil

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Luiz A Bortolotto Unidade de Hipertensão, Instituto do Coração (InCor), Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil

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Luciano F Drager Unidade de Hipertensão, Instituto do Coração (InCor), Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil
Unidade de Hipertensão, Disciplina de Nefrologia, Hospital das Clínicas, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil

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Antonio M Lerario Unidade de Suprarrenal, Laboratório de Hormônios e Genética Molecular LIM/42, Serviço de Endocrinologia e Metabologia, Hospital das Clínicas, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil
Endocrinology, Metabolism and Diabetes, University of Michigan, Ann Arbor, Michigan, USA

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Ana Claudia Latronico Unidade de Suprarrenal, Laboratório de Hormônios e Genética Molecular LIM/42, Serviço de Endocrinologia e Metabologia, Hospital das Clínicas, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil

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Maria Candida B V Fragoso Unidade de Suprarrenal, Laboratório de Hormônios e Genética Molecular LIM/42, Serviço de Endocrinologia e Metabologia, Hospital das Clínicas, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil
Servico de Endocrinologia, Instituto do Câncer do Estado de São Paulo (ICESP), Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil

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Berenice B Mendonca Unidade de Suprarrenal, Laboratório de Hormônios e Genética Molecular LIM/42, Serviço de Endocrinologia e Metabologia, Hospital das Clínicas, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil

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Maria Claudia N Zerbini Divisão de Anatomia Patológica, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil

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

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Madson Q Almeida Unidade de Suprarrenal, Laboratório de Hormônios e Genética Molecular LIM/42, Serviço de Endocrinologia e Metabologia, Hospital das Clínicas, Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil
Servico de Endocrinologia, Instituto do Câncer do Estado de São Paulo (ICESP), Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil

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Abstract

Familial primary aldosteronism (PA) is rare and mostly diagnosed in early-onset hypertension (HT). However, ‘sporadic’ bilateral adrenal hyperplasia (BAH) is the most frequent cause of PA and remains without genetic etiology in most cases. Our aim was to investigate new genetic defects associated with BAH and PA. We performed whole-exome sequencing (paired blood and adrenal tissue) in six patients with PA caused by BAH that underwent unilateral adrenalectomy. Additionally, we conducted functional studies in adrenal hyperplastic tissue and transfected cells to confirm the pathogenicity of the identified genetic variants. Rare germline variants in phosphodiesterase 2A (PDE2A) and 3B (PDE3B) genes were identified in three patients. The PDE2A heterozygous variant (p.Ile629Val) was identified in a patient with BAH and early-onset HT at 13 years of age. Two PDE3B heterozygous variants (p.Arg217Gln and p.Gly392Val) were identified in patients with BAH and HT diagnosed at 18 and 33 years of age, respectively. A strong PDE2A staining was found in all cases of BAH in zona glomerulosa and/or micronodules (that were also positive for CYP11B2). PKA activity in frozen tissue was significantly higher in BAH from patients harboring PDE2A and PDE3B variants. PDE2A and PDE3B variants significantly reduced protein expression in mutant transfected cells compared to WT. Interestingly, PDE2A and PDE3B variants increased SGK1 and SCNN1G/ENaCg at mRNA or protein levels. In conclusion, PDE2A and PDE3B variants were associated with PA caused by BAH. These novel genetic findings expand the spectrum of genetic etiologies of PA.

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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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Alfonso Massimiliano Ferrara Familial Cancer Clinic and Oncoendocrinology, Veneto Institute of Oncology IOV- IRCCS, Padua, Italy

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

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Ulrich Wellner Department of Surgery, University of Luebeck, Luebeck, Germany

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Irina Bancos Division of Endocrinology, Diabetes, Metabolism, and Nutrition, Mayo Clinic, Rochester, USA

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Andrey Kvachenyuk Institute of Endocrinology and Metabolism, NAMS of Ukraine, Kiev, Ukraine

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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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Marina Y Yukina Department of Surgery, Endocrinology Research Center, Moscow, Russia

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Roman Petrov Department of Surgery, Bakhrushin Brothers Moscow City Hospital, Moscow, Russia

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Garrett Bullivant Princess Margaret Cancer Center, University Health Network, Toronto, Ontario, Canada

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Laura von Duecker Department of Medicine IV, Faculty of Medicine, Albert-Ludwigs-University, Freiburg, Germany

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Swati Jadhav Department of Endocrinology, KEM Hospital, Mumbai, India

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Ursula Ploeckinger Interdisciplinary Center of Metabolism: Endocrinology, Diabetes and Metabolism, Charité-University Medicine Berlin, Campus Virchow-Klinikum, Berlin, Germany

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Staffan Welin Department of Endocrine Oncology, Uppsala University Hospital, Uppsala, Sweden

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Camilla Schalin-Jäntti Endocrinology, Abdominal Center, University of Helsinki and Helsinki University Hospital, Helsinki, Finland

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Oliver Gimm Department of Clinical and Experimental Medicine, Department of Surgery, University of Linköping, Linköping, Sweden

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

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Joanne Ngeow Cancer Genetics Service, Division of Medical Oncology, National Cancer Center Singapore and Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore

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Kornelia Hasse-Lazar Department of Endocrine Oncology and Nuclear Medicine, Center of Oncology, MSC Memorial Institute, Gliwice, Poland

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Gabriela Sansó Centro de Investigaciones Endocrinológicas “Dr Cesar Bergada” (CEDIE), Hospital de Niños Ricardo Gutiérrez, CABA, Buenos Aires, Argentina

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Xiaoping Qi Department of Oncologic and Urologic Surgery, the 117th PLA Hospital, Wenzhou Medical University, Hangzhou, Peoples Republic of China

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M Umit Ugurlu Department of General Surgery, Breast and Endocrine Surgery Unit, Marmara University School of Medicine, Istanbul, Turkey

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Rene E Diaz Endocrine Section, Hospital del Salvador, Santiago de Chile, Chile

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Nelson Wohllk Department of Medicine, Endocrine Section, Hospital del Salvador, University of Chile, Santiago de Chile, Chile

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

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Jens Aberle 3rd Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

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Delmar M Lourenço Jr Serviço de Endocrinologia, Hospital das Clínicas (HCFMUSP) and Instituto do Cancer do Estado de São Paulo (ICESP), Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil

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Maria A A Pereira Serviço de Endocrinologia, Hospital das Clinicas (HCFMUSP), Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil

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Maria C B V Fragoso Serviço de Endocrinologia, Hospital das Clínicas (HCFMUSP) and Instituto do Cancer do Estado de São Paulo (ICESP), Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil

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Ana O Hoff Serviço de Endocrinologia, Hospital das Clínicas (HCFMUSP) and Instituto do Cancer do Estado de São Paulo (ICESP), Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil

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Madson Q Almeida Serviço de Endocrinologia, Hospital das Clínicas (HCFMUSP) and Instituto do Cancer do Estado de São Paulo (ICESP), Faculdade de Medicina da Universidade de São Paulo, São Paulo, Brazil

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Alice H D Violante Department of Internal Medicine-Endocrinology, Faculty of medicine-Hospital Universitario Clementino Fraga Filho, Federal University of Rio de Janeiro, Rio de Janeiro, Brazil

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Ana R P Quidute Department of Physiology and Pharmacology, Drug Research and Development Center (NPDM), Faculty of Medicine, Federal University of Ceará (UFC), Fortaleza, Brazil

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Zhewei Zhang Department of Urology, 2nd Hospital of Zhejiang University, School of Medicine, Hangzhou, China

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Mònica Recasens Hospital Universitari de Girona, Gerencia Territorial Girona, Institut Català de la Salut, Girona, Spain

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Luis Robles Díaz Unidad de Tumores Digestivos, Servicio de Oncología Médica, Hospital Universitario 12 de Octubre, Madrid, Spain

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Tada Kunavisarut Division of Endocrinology and metabolism, Siriraj Hospital, Mahidol University, Bangkok, Thailand

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Taweesak Wannachalee Division of Endocrinology and metabolism, Siriraj Hospital, Mahidol University, Bangkok, Thailand

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Sirinart Sirinvaravong Division of Endocrinology and metabolism, Siriraj Hospital, Mahidol University, Bangkok, Thailand

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Eric Jonasch Department of Genitourinary Medical Oncology, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA

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Simona Grozinsky-Glasberg Neuroendocrine Tumor Division, Endocrinology & Metabolism Service, Department of Medicine, Hadassah-Hebrew University Medical Center, Jerusalem, Israel

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Merav Fraenkel Neuroendocrine Tumor Division, Endocrinology & Metabolism Service, Department of Medicine, Hadassah-Hebrew University Medical Center, Jerusalem, Israel

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

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Viacheslav I Egorov Department of Surgery, Bakhrushin Brothers Moscow City Hospital, Moscow, Russia

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Dirk Bausch Department of Surgery, University of Luebeck, Luebeck, Germany

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Matthias Schott Department of Endocrinology, Heinrich-Heine-University, Düsseldorf, Germany

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Nikolaus Tiling Interdisciplinary Center of Metabolism: Endocrinology, Diabetes and Metabolism, Charité-University Medicine Berlin, Campus Virchow-Klinikum, Berlin, Germany

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

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Stefan Zschiedrich Department of Medicine IV, Faculty of Medicine, Albert-Ludwigs-University, Freiburg, Germany

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Roland Därr Department of Medicine IV, Faculty of Medicine, Albert-Ludwigs-University, Freiburg, Germany
Department of Cardiology and Angiology I, Heart Center Freiburg University, Faculty of Medicine, University of Freiburg, Freiburg, Germany

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

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Timm Denecke Department of Radiology, Campus Virchow-Klinikum, Charité – Universitätsmedizin Berlin, Berlin, Germany

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Karl-Heinrich Link Department of Surgery, Asklepios-Paulinen Klinik, Wiesbaden, Germany

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Stefania Zovato Familial Cancer Clinic and Oncoendocrinology, Veneto Institute of Oncology IOV- IRCCS, Padua, Italy

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Ernst von Dobschuetz Section of Endocrine Surgery, Reinbek Hospital, Academic Teaching Hospital University of Hamburg, Reinbek, Germany

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Svetlana Yaremchuk Institute of Endocrinology and Metabolism, NAMS of Ukraine, Kiev, Ukraine

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Holger Amthauer Department of Clinical Nuclear Medicine, Charité – Universitätsmedizin Berlin, Berlin, Germany

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

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Attila Patocs 2nd Department of Medicine and Molecular Medicine Research Group, Hungarian Academy of Sciences, Semmelweis-University, Budapest, Hungary

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Martin K Walz Department of Surgery, Huyssens Foundation Clinics, Essen, Germany

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Tobias B Huber 3rd Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

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Jochen Seufert Department of Medicine II, Faculty of Medicine, Medical Center – University of Freiburg, University of Freiburg, Freiburg, Germany

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Per Hellman Department of Surgical Sciences, Uppsala University, University Hospital, Uppsala, Sweden

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Raymond H Kim Department of Medicine, University of Toronto, University Healthy Network & Mount Sinai Hospital, The Fred A Litwin Family Center in Genetic Medicine, Toronto, Ontario, Canada

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Ekaterina Kuchinskaya Department of Clinical Genetics and Department of Clinical and Experimental Medicine, Linköping University, Linköping, Sweden

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Francesca Schiavi Familial Cancer Clinic and Oncoendocrinology, Veneto Institute of Oncology IOV- IRCCS, Padua, Italy

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Angelica Malinoc Department of Medicine IV, Faculty of Medicine, Albert-Ludwigs-University, Freiburg, Germany

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Nicole Reisch Department of Endocrinology, Ludwigs-Maximilians-University of Munich, Munich, Germany

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Barbara Jarzab Department of Endocrine Oncology and Nuclear Medicine, Center of Oncology, MSC Memorial Institute, Gliwice, Poland

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Marta Barontini Centro de Investigaciones Endocrinológicas “Dr Cesar Bergada” (CEDIE), Hospital de Niños Ricardo Gutiérrez, CABA, Buenos Aires, Argentina

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Andrzej Januszewicz Department of Hypertension, Institute of Cardiology, Warsaw, Poland

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Nalini Shah Department of Endocrinology, KEM Hospital, Mumbai, India

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

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Giuseppe Opocher Scientific Direction, Veneto Institute of Oncology IOV-IRCCS, Padua, Italy

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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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Hartmut P H Neumann Section for Preventive Medicine, Faculty of Medicine, Albert-Ludwigs-University, Freiburg, Germany

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

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Pancreatic neuroendocrine tumors (PanNETs) are rare in von Hippel–Lindau disease (VHL) but cause serious morbidity and mortality. Management guidelines for VHL-PanNETs continue to be based on limited evidence, and survival data to guide surgical management are lacking. We established the European-American-Asian-VHL-PanNET-Registry to assess data for risks for metastases, survival and long-term outcomes to provide best management recommendations. Of 2330 VHL patients, 273 had a total of 484 PanNETs. Median age at diagnosis of PanNET was 35 years (range 10–75). Fifty-five (20%) patients had metastatic PanNETs. Metastatic PanNETs were significantly larger (median size 5 vs 2 cm; P < 0.001) and tumor volume doubling time (TVDT) was faster (22 vs 126 months; P = 0.001). All metastatic tumors were ≥2.8 cm. Codons 161 and 167 were hotspots for VHL germline mutations with enhanced risk for metastatic PanNETs. Multivariate prediction modeling disclosed maximum tumor diameter and TVDT as significant predictors for metastatic disease (positive and negative predictive values of 51% and 100% for diameter cut-off ≥2.8 cm, 44% and 91% for TVDT cut-off of ≤24 months). In 117 of 273 patients, PanNETs >1.5 cm in diameter were operated. Ten-year survival was significantly longer in operated vs non-operated patients, in particular for PanNETs <2.8 cm vs ≥2.8 cm (94% vs 85% by 10 years; P = 0.020; 80% vs 50% at 10 years; P = 0.030). This study demonstrates that patients with PanNET approaching the cut-off diameter of 2.8 cm should be operated. Mutations in exon 3, especially of codons 161/167 are at enhanced risk for metastatic PanNETs. Survival is significantly longer in operated non-metastatic VHL-PanNETs.

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