• Alexandre Buffet, Sarra Smati, Ludovic Mansuy, Mélanie Ménara, Maëlle Lebras, Marie-Françoise Heymann, Christophe Simian, Judith Favier, Arnaud Murat, Bertrand Cariou, and Anne-Paule Gimenez-Roqueplo.
• Assistance Publique-Hôpitaux de Paris (A.B., C.S., A-P.G.-R.), Hôpital Européen Georges Pompidou (HEGP), Service de Génétique, 75908 Paris, France; Clinique d'Endocrinologie (S.S., M.L., A.M., B.C.), l'Institut du Thorax, Centre Hospitalier Universitaire (CHU) de Nantes, 44007 Nantes, France; Département d'Oncologie et d'Hématologie Pédiatriques et de Thérapie Cellulaire (L.M.), CHU de Nancy, Hôpital d'Enfants, 54500 Vandœuvre-lès-Nancy, France; Inserm (M.M., J.F., A.-P.G.-R.), Unité Mixte de Recherche 970, Centre de recherche cardiovasculaire de l'HEGP, 75015 Paris, France; Service d'Anatomopathologie (M.-F.H.), CHU de Nantes, 44007 Nantes, France; INSERM (M.-F.H.), UMR957, Faculté de Médecine, 44035 Nantes, France; and Université Paris Descartes (J.F., A.-P.G.-R.), Faculté de Médecine, 75006 Paris Cité Sorbonne, France.
• J. Clin. Endocrinol. Metab. 2014 Feb 1; 99 (2): E369-73.

ContextHIF2A germline mutations were known to cause congenital polycythemia. Recently, HIF2A somatic mutations were found in several patients with polycythemia and paraganglioma, pheochromocytoma, or somatostatinoma, suggesting the occurrence of a de novo postzygotic HIF2A mutation that has not been demonstrated clearly.PatientsPatient 1 is a woman suffering from polycythemia diagnosed at the age of 16 years. She was operated on for a pheochromocytoma at 45 years and for two abdominal paragangliomas at 59 years. She was also diagnosed with somatostatinoma. Patient 2 is a young boy who suffered from polycythemia since infancy. He underwent surgery for a nonfunctional adrenal paraganglioma at the age of 9 years.MethodsWe sequenced by Sanger and next-generation sequencing the HIF2A gene in DNA extracted from tumors, leukocytes, and buccal cells.ResultsIn patient 1, we identified a somatic HIF2A mutation (c.1586T>C; p.Leu529Pro) in DNA extracted from both paragangliomas. The mutation was detected as a somatic mosaic in DNA extracted from somatostatinoma and was absent from germline DNA. In patient 2, we found an HIF2A heterozygous mutation (c.1625T>C; p.Leu542Pro) in the paraganglioma, but the mutation was also present as a mosaic in leukocyte DNA and in DNA extracted from buccal cells (3.3 and 8.96% of sequencing reads, respectively). Both mutations disrupt the hydroxylation domain of the HIF2α protein.ConclusionsOur study shows that HIF2A-related tumors are caused by postzygotic mutations occurring in early developmental stages. Potential germline mosaicism should be considered during the familial genetic counseling when an individual has been diagnosed with HIF2A-related polycythemia-paraganglioma syndrome.

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