Identification of Two Novel EPOR Gene Variants in Primary Familial Polycythemia: Case Report and Literature Review

Abstract

Primary familial and congenital polycythemia is a rare disease characterized by an increase in red cell mass that may be due to pathogenic variants in the EPO receptor (EPOR) gene. To date, 33 genetic variants have been reported to be associated. We analyzed the presence of EPOR variants in two patients with polycythemia in whom JAK2 pathogenic variants had been previously discarded. Molecular analysis of the EPOR gene was performed by Sanger sequencing of the coding regions and exon/intron boundaries of exon 8. We performed in vitro culture of erythroid progenitor cells. Segregation studies were done whenever possible. The two patients studied showed hypersensitivity to EPO in in vitro cultures. Analysis of the EPOR gene unveiled two novel pathogenic variants. Genetic testing of asymptomatic relatives could guarantee surveillance and proper management.

Benefit of phlebotomy and low-dose aspirin in the prevention of vascular events in patients with <i>EPOR</i> primary familial polycythemia on the island of New Caledonia

“…According to ACMG/AMP guidelines, among the 35 EPOR variants reported to be associated with PFCP to date, 4 are classified as benign or likely benign, 3 are variants of uncertain significance, and 28 are pathogenic or likely pathogenic 6 .…”

“…Surprisingly, to date, no study has been carried out to investigate possible complications, particularly vascular ones, in patients with an EPOR mutation: at most, some case reports described possible complications, but these reports involved very few patients, and data on treatment were not always provided. To the best of our knowledge, 130 cases had been reported in the literature so far, 25 with information on the presence or absence of thrombotic events, and 18 with information on treatment, mainly phlebotomy but without a clear benefit on thrombosis [5][6][7] . Most of the reported cases had not been treated using low-dose aspirin, mainly due to the fact that EPORrelated polycythemia was considered benign, as opposed to polycythemia vera, for which the prevention of thrombotic risk by low-dose aspirin has long been demonstrated.…”

“…Most of the reported cases had not been treated using low-dose aspirin, mainly due to the fact that EPORrelated polycythemia was considered benign, as opposed to polycythemia vera, for which the prevention of thrombotic risk by low-dose aspirin has long been demonstrated. Only two cases reported treatment with a combination of phlebotomy and aspirin, with no thrombosis observed 6 (supplemental table 1).…”

“… 5 According to guidelines from the American College of Medical Genetics and Genomics and the Association of Molecular Pathologists, among the 35 EPOR variants reported to be associated with primary familial and congenital polycythemia to date, four are classified as benign or likely benign, three are variants of uncertain significance, and 28 are pathogenic or likely pathogenic. 6 Mutations in EPOR are relatively rare among patients with JAK2 -negative erythrocytosis, and are found in only approximately 1% of cases. 7 …”

“… 5-7 Most of the reported cases had not been treated using low-dose aspirin, mainly because EPOR -related polycythemia was considered benign, as opposed to polycythemia vera, for which low-dose aspirin has long been demonstrated to lower the risk of thrombosis. Only two cases have been reported to have been treated with a combination of phlebotomy and aspirin, with no thrombosis observed 6 ( Online Supplementary Table S1 ). The benefit of phlebotomy in congenital erythrocytosis is debated, particularly because it is ineffective, or even harmful, in Chuvash polycythemia: in a large cohort of such patients, a history of previous phlebotomy was associated with a higher risk of thrombosis.…”