title: First report of bilateral pheochromocytoma in the clinical spectrum of HIF2A-related polycythemia-paraganglioma syndrome.
abstract: BACKGROUND
  Molecular genetic research has so far resulted in the identification of 10 well-characterized susceptibility genes for hereditary pheochromocytoma (PHEO) or paraganglioma (PGL). Recently, a new syndrome characterized by multiple PGLs and somatostatinomas associated with congenital polycythemia due to somatic mutations in HIF2A has been reported.
  
  
  OBJECTIVE
  The aim of the study was to define the genetic defect in a new case of bilateral PHEO and multiple PGLs associated with congenital polycythemia.
  
  
  METHODS
  A female patient presented with neonatal polycythemia (treated by phlebotomies, 1 session approximately every 4 mo), mildly enlarged cerebral ventricles, and bilateral PHEO and multiple PGLs. There was no family history of any neuroendocrine tumor or polycythemia. Surgical removal of the tumors only temporarily normalized plasma erythropoietin (Epo) levels and discontinued phlebotomies. No germline mutations were initially detected in the SDHB, SDHC, SDHD, VHL, and PHD2 genes, known to be associated with polycythemia. The PHEOs presented with a typical noradrenergic biochemical phenotype.
  
  
  RESULTS
  A heterozygous missense mutation (c.1589C>T) was identified in exon 12 of HIF2A, resulting in an alanine 530 substitution in the HIF-2α protein with valine (A530V). This somatic mutation was detected in the tissue from 1 PHEO and 1 PGL, with no HIF2A germline mutation found. This mutation led to stabilization of HIF-2α and hence a gain-of-function phenotype, as in previously published studies.
  
  
  CONCLUSIONS
  This case represents the first association of a somatic HIF2A gain-of-function mutation with PHEO and congenital polycythemia, and it alerts physicians to perform proper genetic screening in patients presenting with multiple norepinephrine-producing PHEOs and polycythemia. This report also extends the previous findings of a new syndrome of only multiple PGLs, somatostatinomas, and polycythemia to multiple PHEOs.
authors.affiliation: Department of Nuclear Medicine, La Timone University Hospital, Centre Européen de Recherche en Imagerie Médicale, Aix-Marseille University, 13005 Marseille, France.
authors.forename: David
authors.initials: D
authors.lastname: Taïeb
authors.forename: Chunzhang
authors.initials: C
authors.lastname: Yang
authors.forename: Blandine
authors.initials: B
authors.lastname: Delenne
authors.forename: Zhengping
authors.initials: Z
authors.lastname: Zhuang
authors.forename: Anne
authors.initials: A
authors.lastname: Barlier
authors.forename: Fréderic
authors.initials: F
authors.lastname: Sebag
authors.forename: Karel
authors.initials: K
authors.lastname: Pacak
mesh_terms: D000310:Adrenal Gland Neoplasms / Q000209:etiology* / Q000473:pathology / Q000503:physiopathology / Q000601:surgery; D000328:Adult; D019943:Amino Acid Substitution; D051792:Basic Helix-Loop-Helix Proteins / Q000235:genetics / Q000378:metabolism*; D005091:Exons; D005260:Female; D006579:Heterozygote; D006801:Humans; D020125:Mutation, Missense; D010235:Paraganglioma / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology* / Q000601:surgery; D010673:Pheochromocytoma / Q000209:etiology* / Q000473:pathology / Q000503:physiopathology / Q000601:surgery; D011086:Polycythemia / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology* / Q000601:surgery; D012720:Severity of Illness Index; D013577:Syndrome; D047368:Tumor Burden; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D000099162:Endothelial PAS Domain-Containing Protein 1
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