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Editor’s note: Hypoxia-inducible factor-1α (HIF-1α) and HIF-2α regulate several key aspects of cellular adaptation to hypoxia, with control of hundreds of genes involved in cell metabolism, cell growth, angiogenesis, and matrix remodeling, among other things. HIF are degraded via ubiquitination by the von Hipple–Lindau (VHL) E-3 ubiquitin ligase. Chuvash polycythemia (CP) is a rare disorder caused by a germline hypomorphic allele of VHL, leading to increased expression and activity of HIF in cells. The disease is characterized by erythrocytosis, hyperventilation, arterial hypocapnia, and pulmonary hypertension. The present authors compared the clinical presentation of two genetic diseases associated with altered HIF signaling: classic VHL disease, with a heterozygous mutation in the VHL gene, and gain of function mutations in the HIF-2α gene.