A novel EPAS1/HIF2A germline mutation in a congenital polycythemia with paraganglioma

J Mol Med (Berl). 2013 Apr;91(4):507-12. doi: 10.1007/s00109-012-0967-z. Epub 2012 Oct 23.


Congenital polycythemias have diverse etiologies, including mutations in the hypoxia sensing pathway. These include HIF2A at exon 12, VHL gene (Chuvash polycythemia), and PHD2 mutations, which in one family was also associated with recurrent pheochromocytoma/paraganglioma (PHEO/PGL). Over the past two decades, we have studied seven unrelated patients with sporadic congenital polycythemia who subsequently developed PHEO/PGL with, until now, no discernible molecular basis. We now report a polycythemic patient with a novel germline HIF2A (F374Y) (exon 9) mutation, inherited from his mother, who developed PHEO/PGL. We show that this is a gain-of-function mutation and demonstrate no loss-of-heterozygosity or additional somatic mutation of HIF2A in the tumor, indicating HIF2A (F374Y) may be predisposing rather than causative of PHEO/PGL. This report, in view of two other concomitantly reported PHEO/PGL patients with somatic mutations of HIF2A and polycythemia, underscores the PHEO/PGL-promoting potential of mutations of HIF2A that alone are not sufficient for PHEO/PGL development.

Publication types

  • Case Reports
  • Research Support, N.I.H., Extramural
  • Research Support, N.I.H., Intramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Aged, 80 and over
  • Amino Acid Sequence
  • Base Sequence
  • Basic Helix-Loop-Helix Transcription Factors / chemistry
  • Basic Helix-Loop-Helix Transcription Factors / genetics*
  • Female
  • Germ-Line Mutation*
  • Humans
  • Male
  • Middle Aged
  • Models, Molecular
  • Molecular Sequence Data
  • Paraganglioma / complications*
  • Paraganglioma / genetics*
  • Polycythemia / complications*
  • Polycythemia / congenital
  • Polycythemia / genetics*
  • Protein Conformation
  • Sequence Alignment


  • Basic Helix-Loop-Helix Transcription Factors
  • endothelial PAS domain-containing protein 1