Congenital erythrocytosis

Abstract

Erythrocytosis, or increased red cell mass, may be labeled as primary or secondary, depending on whether the molecular defect is intrinsic to the red blood cells/their precursors or extrinsic to them, the latter being typically associated with elevated erythropoietin (EPO) levels. Inherited/congenital erythrocytosis (CE) of both primary and secondary types is increasingly recognized as the cause in many patients in whom acquired, especially neoplastic causes have been excluded. During the past two decades, the underlying molecular mechanisms of CE are increasingly getting unraveled. Gain‐in‐function mutations in the erythropoietin receptor gene were among the first to be characterized in a disorder termed primary familial and congenital polycythemia. Another set of mutations affect the components of the oxygen‐sensing pathway. Under normoxic conditions, the hypoxia‐inducible factor (HIF), upon hydroxylation by the prolyl‐4‐hydroxylase domain protein 2 (PHD2) enzyme, is degraded by the von Hippel‐Lindau protein. In hypoxic conditions, failure of prolyl hydroxylation leads to stabilization of HIF and activation of the EPO gene. CE has been found to be caused by loss‐of‐function mutations in VHL and PHD2/EGLN1 as well as gain‐of‐function mutations in HIF‐2α (EPAS1), all resulting in constitutive activation of EPO signaling. Apart from these, globin gene mutations leading to formation of high oxygen affinity hemoglobins also cause CE. Rarely, bisphosphoglycerate mutate mutations, affecting the 2,3‐bisphosphoglycerate levels, can increase the oxygen affinity of hemoglobin and cause CE. This narrative review examines the current mutational spectrum of CE and the distinctive pathogenetic mechanisms that give rise to this increasingly recognized condition in various parts of the world.

A Screening Approach for Inherited Erythrocytosis due to the VHL:c.598C > T Mutation (Chuvash Polycythemia)

“…Erythrocytosis, after excluding spurious causes, can be classified as secondary to increased Epo levels, or primary, i.e., erythropoietin (Epo)-independent disease [ 1 – 3 ]. Either type may be inherited or acquired [ 2 ].…”

“…Homozygosity for a hypomorphic VHL : c.598C > T; p.R200W mutation leads to the rare autosomal-recessive Chuvash polycythemia. Initially described in the Chuvash Republic of Russia and in Italy, this disorder (with features of secondary as well as primary erythrocytosis) has been reported from India, Afghanistan, Turkey, Bangladesh and Pakistan [ 1 , 8 – 11 ].…”

“…Genetic diagnosis of erythrocytosis requires an algorithmic testing approach that may be too resource-intensive for developing countries [ 12 ]. Next-generation testing (NGS) has, in recent years, enabled one-shot testing of all implicated genes, however, the work-up remains technically-complex and expensive [ 1 , 13 ]. A prior study revealed a very high prevalence (61%) of Chuvash polycythemia among north Indian patients [ 10 ].…”

Ultra-rare Hb Regina (HBB:c.289C>G) with coinherited β-thalassaemia trait: solving the puzzle for extreme erythrocytosis

“…Clinical laboratories that lack facilities for oxygen-saturation curve analysis may calculate the p50 mathematically using venous blood gas analysis parameters 3. Genetic confirmation is often also straightforward using direct DNA sequencing of the relatively small globin genes by Sanger’s method 1 4 5…”

“…High oxygen-affinity Hb’s are uncommon causes of congenital erythrocytosis 1 4–6. A prior Indian study found that 3 out of 18 patients with congenital erythrocytosis (including two brothers) had high oxygen affinity variants—Hb McKees Rocks and Hb Rainier 4.…”