Genetic basis of congenital erythrocytosis

Congenital Erythrocytosis (CE) represents a rare and heterogeneous clinical entity. It is caused by deregulated erythropoiesis where red blood cell overproduction results in elevated hemoglobin and hematocrit levels. CE may either be primary or secondary to elevated erythropoietin concentrations. The only known form of primary CE is caused by mutations in the EPOR gene. Secondary CE can be a consequence of tissue hypoxia, being caused by congenital defects such as hemoglobin variants with increased oxygen affinity, due to mutations in the α- or β-globin genes (HBB, HBA2, HBA1), or due to mutations in the BPGM gene. Secondary CE can also result from defects in the components of the oxygen-sensing pathway (PHD2, HIF2α and VHL).

The family history and the quantification of serum EPO are mandatory to define the best diagnostic strategy regarding molecular studies. Based upon the serum EPO level, P50 and familial data, it is possible to establish a diagnostic algorithm.

Despite recent important discoveries in the molecular pathogenesis of CE, in about 70% of the patients the genetic causes remain to be identified. Clinical data on patients suffering from CE are sparse. This fact is conditional upon the effective way to predict the disease evolution, the establishment of the best management and the genetic counselling.

The number and phenotypic variability of patients that remain without an identified etiology suggest that other genes have to be implicated. Studies by next generation sequencing methodologies are already being performed and it is expected the identification of other genes involved in the pathophysiology of the CE.