Polycythemia and Paraganglioma With a Novel Somatic HIF2A Mutation in a Male

Abstract

Recently, a new syndrome of paraganglioma, somatostatinoma, and polycythemia has been discovered (known as Pacak-Zhuang syndrome). This new syndrome, with somatic HIF2A gain-of-function mutations, has never been reported in male patients. We describe a male patient with Pacak-Zhuang syndrome who carries a newly discovered HIF2A mutation. Congenital polycythemias have diverse etiologies, including germline mutations in the oxygen-sensing pathway. These include von Hippel-Lindau (Chuvash polycythemia), prolyl hydroxylase domain-containing protein-2, and hypoxia-inducible factor-2a (HIF2a). Somatic gain-of-function mutations in the gene encoding HIF-2a were reported in patients with paraganglioma and polycythemia and have been found exclusively in female patients. Through sequencing of the HIF2A using DNA from paraganglioma in 15-year-old male patient, we identified a novel mutation of HIF2A: a heterozygous C to A substitution at base 1589 in exon 12 of HIF2A. The mutation was not found in germline DNA from leukocytes. The C1589A mutations resulted in substitution of alanine 530 in the HIF-2a protein with glutamic acid. This mutation is undoubtedly associated with increased HIF-2a activity and increased protein half-life, because it affects the vicinity of the prolyl hydroxylase target residue, proline 531. To our knowledge, this is the first report describing Pacak-Zhuang syndrome with somatic gain-of-function mutation in HIF2A in a male patient. Congenital polycythemia of unknown origin should raise suspicion for the novel disorder Pacak-Zhuang syndrome, even in male patients. Pediatrics 2014;133:e1787-e1791

Novel insights into the polycythemia–paraganglioma–somatostatinoma syndrome

“…2013; Buffet et al . 2014; Toyoda et al . 2014), as well as in one patient with familial polycythemia and PGL (Lorenzo et al .…”

Hypoxia Pathway Mutations in Pheochromocytomas and Paragangliomas

“…The recent discovery of EPAS1/HIF2A activating mutations in a particular set of patients harboring PCC/PGL, somatostatinomas, and polycythemia in a familial context, resulted in the proposal of a new syndrome, termed PacakZhuang syndrome [Toyoda et al, 2014]. This opens new perspectives on cancer genetics, in particular the hypothesis that other tumors, especially those of neuroendocrine origin, have gain-of-function EPAS1/HIF2A mutations [Zhuang et al, 2012;Pacak et al, 2013]; the precise mechanism by which EPAS1/HIF2A mutations contribute to tumorigenesis also warrants additional studies [Pacak et al, 2013;Taieb et al, 2013].…”

“…These recent discoveries also underline the necessity of clarifying whether patients presenting with polycythemia should be screened for the presence of neuroendocrine tumors, and whether patients with PGL or somatostatinomas need to be screened for EPAS1/ HIF2A mutations [Zhuang et al, 2012;Pacak et al, 2013]. Considering the female preponderance in this syndrome, it is also important to determine if unique female-related molecular mechanisms, such as hormone and gender-dependent copy number variations and signaling pathways, play a role in HIF2α signaling and tumorigenesis [Taieb et al, 2013;Toyoda et al, 2014].…”

“…While germline EPAS1 mutations in exon 12 were previously described in patients with hereditary polycythemia, the recent identification of patients carrying EPAS1 mutations occurring at an early developmental stage, who develop PGL and somatostatinomas in a context of previously settled polycythemia, has led to the proposal of the Pacak-Zhuang syndrome [Toyoda et al, 2014].…”

“…Recently, Toyoda et al [2014] described the PacakZhuang syndrome in a male patient who presented with polycythemia since infancy and, at the age of 15, developed multiple PGL; the EPAS1 mutation at the A530 residue was found in the PGL tumor tissue. This is the first report of the Pacak-Zhuang syndrome in a male patient [Toyoda et al, 2014].…”