Congenital
erythrocytoses represent a heterogenous group of rare defects of erythropoiesis characterized by elevated erythrocyte mass. We performed molecular-genetic analysis of 21 Czech patients with
congenital erythrocytosis and assessed the mutual link between chronic erythrocyte overproduction and
iron homoeostasis. Causative mutations in
erythropoietin receptor (EPOR),
hypoxia-inducible factor 2 alpha (HIF2A) or Von Hippel-Lindau (VHL) genes were detected in nine patients, including a novel p.A421Cfs*4 EPOR and a homozygous intronic c.340+770T>C VHL mutation. The association and possible cooperation of five identified missense germline EPOR or
Janus kinase 2 (JAK2) variants with other genetic/non-genetic factors in
erythrocytosis manifestation may involve variants of Piezo-type mechanosensitive
ion channel component 1 (PIEZO1) or Ten-eleven translocation 2 (TET2), but this requires further research. In two families,
hepcidin levels appeared to prevent or promote phenotypic expression of the disease. No major contribution of heterozygous
haemochromatosis gene (HFE) mutations to the erythrocytic phenotype or
hepcidin levels was observed in our cohort. VHL- and HIF2A-mutant
erythrocytosis showed increased erythroferrone and suppressed
hepcidin, whereas no overproduction of erythroferrone was detected in other patients regardless of molecular defect, age or
therapy. Understanding the interplay between
iron metabolism and erythropoiesis in different subgroups of
congenital erythrocytosis may improve current treatment options.