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Ali S Alzahrani Department of Medicine, King Faisal Specialist Hospital & Research Centre, Riyadh, Saudi Arabia
Department of Molecular Oncology, King Faisal Specialist Hospital & Research Centre, Riyadh, Saudi Arabia

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Meshael Alswailem Department of Molecular Oncology, King Faisal Specialist Hospital & Research Centre, Riyadh, Saudi Arabia

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Alexandre Buffet Université Paris Cité, Inserm, Paris Centre de Recherche Cardiovasculaire (PARCC), Equipe Labellisée Ligue contre le Cancer, Paris, France
Département de Médecine Génomique des Tumeurs et des Cancers, Fédération de Génétique et de Médecine Génomique, Assistance Publique-Hôpitaux de Paris (AP-HP) Centre, Hôpital Européen Georges Pompidou, Paris, France

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Balgees Alghamdi Department of Molecular Oncology, King Faisal Specialist Hospital & Research Centre, Riyadh, Saudi Arabia

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Lulu Alobaid Department of Medicine, King Faisal Specialist Hospital & Research Centre, Riyadh, Saudi Arabia

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Osamah Alsagheir Department of Medicine, King Faisal Specialist Hospital & Research Centre, Riyadh, Saudi Arabia

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Hindi Al-Hindi Department of Pathology and Laboratory Medicine, King Faisal Specialist Hospital & Research Centre, Riyadh, Saudi Arabia

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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, USA

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In 2012, somatic EPAS1 pathogenic variants were found to cause a triad of pheochromocytoma/paragangliomas (PPGLs), polycythemia, and somatostatinoma. Since then, a limited number of studies on this subject have been reported, and data on the long-term outcome of metastatic disease are not available on this rare syndrome. We comprehensively reviewed EPAS1-related PPGL and describe an unusual patient who has been living with an EPAS1-related metastatic PPGL for 47 years. The results of this work show that EPAS1 pathogenic variants are rare, more in females and patients without pathogenic variants in other PPGL susceptibility genes. PPGLs are the most common manifestation followed by polycythemia and somatostatinoma. The EPAS1 pathogenic variants are often postzygotic, and the timing of their acquirement during embryonic development seems to correlate with the number and timing of development of the disease manifestations. Although recurrent and multifocal disease is common in EPAS1-related PPGL, distant metastases are uncommon and usually indolent. This is illustrated by a case of a man who was diagnosed at the age of 9 years and is currently 56 years old, alive, and well for 47 years with these metastases. He was found to have a somatic EPAS1 pathogenic variant (c.1592C>A, p.Pro531His) in bilateral pheochomocytoma and a pancreatic NET (somatostatinoma) but not in genomic DNA isolated from peripheral leukocytes. This and previous reports suggest that distant metastases are uncommon and less aggressive in EPAS1-related PPGLs compared to those found in other hereditary PPGLs.

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Francesca Branzoli Paris Brain Institute - Institut du Cerveau (ICM), Center for Neuroimaging Research (CENIR), Paris, France
Sorbonne University, UMR S 1127, Inserm U 1127, CNRS UMR 7225, ICM, Paris, France

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Betty Salgues Sorbonne University, nuclear medicine department, Pitié-Salpêtrière Hospital, Assistance -Publique Hôpitaux de Paris, Paris, France
Paris Cardiovascular Research Center (PARCC), Inserm, Paris, France

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Małgorzata Marjańska Center for Magnetic Resonance Research, Department of Radiology, University of Minnesota, Minneapolis, Minnesota, USA

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Marie Laloi-Michelin Endocrinology department, Lariboisière Hospital, Assistance -Publique Hôpitaux de Paris, Paris, France

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Philippe Herman ENT unit, Lariboisière Hospital, Assistance -Publique Hôpitaux de Paris, Paris-Cité University, INSERM U1141, Paris, France

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Lauriane Le Collen Inserm/CNRS UMR 1283/8199, Pasteur Institute of Lille, EGID, University of Lille, Lille, France
Department of Endocrinology Diabetology, University Hospital Center of Reims, Reims, France
Department of Genetic, University Hospital Center of Reims, Reims, France

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Brigitte Delemer Department of Endocrinology Diabetology, University Hospital Center of Reims, Reims, France
CRESTIC EA 3804, University of Reims Champagne Ardenne, UFR Sciences Exactes et Naturelles, Moulin de La Housse, BP 1039, Reims, France

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Julien Riancho AP-HP, Hôpital Européen Georges Pompidou, Hypertension Unit, and Reference centre for rare adrenal diseases, Paris, France

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Emmanuelle Kuhn Pituitary Unit, Pitié-Salpêtrière Hospital APHP, Sorbonne University, Paris, France

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Christel Jublanc Pituitary Unit, Pitié-Salpêtrière Hospital APHP, Sorbonne University, Paris, France

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Nelly Burnichon Département de médecine génomique des tumeurs et des cancers, AP-HP, Hôpital Européen Georges Pompidou, Paris, France
Université Paris Cité, Inserm, PARCC, Paris, France

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Laurence Amar AP-HP, Hôpital Européen Georges Pompidou, Hypertension Unit, and Reference centre for rare adrenal diseases, Paris, France
Université Paris Cité, Inserm, PARCC, Paris, France

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Judith Favier Université Paris Cité, Inserm, PARCC, Paris, France

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Anne-Paule Gimenez-Roqueplo Département de médecine génomique des tumeurs et des cancers, AP-HP, Hôpital Européen Georges Pompidou, Paris, France
Université Paris Cité, Inserm, PARCC, Paris, France

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Alexandre Buffet Département de médecine génomique des tumeurs et des cancers, AP-HP, Hôpital Européen Georges Pompidou, Paris, France
Université Paris Cité, Inserm, PARCC, Paris, France

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Charlotte Lussey-Lepoutre Sorbonne University, nuclear medicine department, Pitié-Salpêtrière Hospital, Assistance -Publique Hôpitaux de Paris, Paris, France
Paris Cardiovascular Research Center (PARCC), Inserm, Paris, France

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Germline mutations in genes encoding succinate dehydrogenase (SDH) are frequently involved in pheochromocytoma/paraganglioma (PPGL) development and were implicated in patients with the ‘3PAs’ syndrome (associating pituitary adenoma (PA) and PPGL) or isolated PA. However, the causality link between SDHx mutation and PA remains difficult to establish, and in vivo tools for detecting hallmarks of SDH deficiency are scarce. Proton magnetic resonance spectroscopy (1H-MRS) can detect succinate in vivo as a biomarker of SDHx mutations in PGL. The objective of this study was to demonstrate the causality link between PA and SDH deficiency in vivo using 1H-MRS as a novel noninvasive tool for succinate detection in PA. Three SDHx-mutated patients suffering from a PPGL and a macroprolactinoma and one patient with an apparently sporadic non-functioning pituitary macroadenoma underwent MRI examination at 3 T. An optimized 1H-MRS semi-LASER sequence (TR = 2500 ms, TE = 144 ms) was employed for the detection of succinate in vivo. Succinate and choline-containing compounds were identified in the MR spectra as single resonances at 2.44 and 3.2 ppm, respectively. Choline compounds were detected in all the tumors (three PGL and four PAs), while a succinate peak was only observed in the three macroprolactinomas and the three PGL of SDHx-mutated patients, demonstrating SDH deficiency in these tumors. In conclusion, the detection of succinate by 1H-MRS as a hallmark of SDH deficiency in vivo is feasible in PA, laying the groundwork for a better understanding of the biological link between SDHx mutations and the development of these tumors.

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