Clinical Information

Erythrocytosis (ie, increased RBC mass or polycythemia) may be primary, due to an intrinsic defect of bone marrow stem cells (ie, polycythemia vera, or secondary, in response to increased serum erythropoietin levels). Secondary erythrocytosis is associated with a number of disorders including chronic lung disease, chronic increase in carbon monoxide (due to smoking), cyanotic heart disease, high-altitude living, renal cysts and tumors, hepatoma, and other Epo-secreting tumors. When these common causes of secondary erythrocytosis are excluded, a heritable cause involving hemoglobin or erythrocyte regulatory mechanisms may be suspected.

Unlike polycythemia vera, hereditary erythrocytosis is not associated with the risk of clonal evolution and should present with isolated erythrocytosis that has been present since birth. A small subset of cases is associated with pheochromocytoma and paraganglioma formation. It is caused by mutations in several genes, including VHL, and may be inherited in either an autosomal dominant or autosomal recessive manner. A family history of erythrocytosis would be expected in these cases, although it is possible for new mutations to arise in an individual.

The genes coding for hemoglobin, hemoglobin-stabilization proteins (2,3 bisphosphoglycerate mutase: BPGM), the erythropoietin receptor (EPOR), and oxygen-sensing pathway enzymes (hypoxia-inducible factor: HIF/EPAS1, prolyl hydroxylase domain: PHD2/EGLN1, and VHL can result in hereditary erythrocytosis (see Table). High-oxygen-affinity hemoglobin variants and BPGM abnormalities result in a decreased p50 result, whereas those affecting EPOR, HIF, PHD, and VHL typically have normal p50 results. The true prevalence of hereditary erythrocytosis causing mutations is unknown.

Genes Associated with Hereditary Erythrocytosis

The oxygen-sensing pathway functions through an enzyme, hypoxia-inducible factor (HIF), which regulates RBC mass. A heterodimer protein comprised of alpha and beta subunits, HIF functions as a marker of depleted oxygen concentration. When present, oxygen becomes a substrate-mediating HIF-alpha subunit degradation. In the absence of oxygen, degradation does not take place and the alpha protein component is available to dimerize with a HIF-beta subunit. The heterodimer then induces transcription of many hypoxia response genes including EPO, VEGF, and GLUT1.

HIF-alpha is regulated by von Hippel-Lindau (VHL) protein-mediated ubiquitination and proteasomal degradation, which requires prolyl hydroxylation of HIF proline residues. Mutations resulting in altered VHL proteins can lead to familial erythrocytosis, type 2 (ECYT2; OMIM 263400). ECYT2 is a clinically heterogeneous disorder characterized by congenital erythrocytosis with or without high serum EPO levels, venous and arterial thrombosis, and pulmonary hypertension that can manifest as early as infancy but more typically into adulthood. An increased risk for tumors associated with von Hippel-Lindau syndrome, which is also caused by mutations in the VHL gene, has not been observed.