Congenital polycythemias have diverse etiologies, including mutations in the hypoxia sensing pathway. These include
HIF2A
at exon 12,
VHL
gene (Chuvash polycythemia), and
PHD2
mutations, which in one ...family was also associated with recurrent pheochromocytoma/paraganglioma (PHEO/PGL). Over the past two decades, we have studied seven unrelated patients with sporadic congenital polycythemia who subsequently developed PHEO/PGL with, until now, no discernible molecular basis. We now report a polycythemic patient with a novel germline
HIF2A
F374Y
(exon 9) mutation, inherited from his mother, who developed PHEO/PGL. We show that this is a gain-of-function mutation and demonstrate no loss-of-heterozygosity or additional somatic mutation of
HIF2A
in the tumor, indicating
HIF2A
F374Y
may be predisposing rather than causative of PHEO/PGL. This report, in view of two other concomitantly reported PHEO/PGL patients with somatic mutations of
HIF2A
and polycythemia, underscores the PHEO/PGL-promoting potential of mutations of
HIF2A
that alone are not sufficient for PHEO/PGL development.
Objectives
Erythrocytosis is characterized by the expansion of erythrocyte compartment including elevated red blood cell number, hematocrit, and hemoglobin content. Familial erythrocytosis (FE) is a ...congenital disorder with different genetic background. Type 1 FE is primary FE caused by mutation in erythropoietin receptor gene (EPOR). Type 2‐5 FE are secondary FEs caused by mutations of genes involved in oxygen sensing pathway important for erythropoietin (EPO) regulation. In the present study, we summarized associations between EPOR and EPO gene variations with development of FE and searched for genetic variants located within regulatory regions.
Methods
Publications reporting EPOR and EPO sequence variants associated with FE or clinical features of erythrocytosis were retrieved from PubMed and WoS. In silico, sequence reanalysis was performed using Ensembl genomic browser, release 89 to screen for variants located within regulatory regions.
Results
To date, 28 variants of the EPOR and seven variants of the EPO gene have been associated with erythrocytosis or upper hematocrit. Sequence variants were also found to be present within regulatory regions.
Conclusions
Role of variants in regulatory regions of the EPO gene should be further investigated.
Familial erythrocytosis (FE) is a congenital disorder, defined by elevated red blood cell number, hemoglobin, and hematocrit. Among eight types of FE, type 4 is caused by variants in the EPAS1 gene. ...Two other hypoxia‐inducible factor alpha (HIFA) subunits, HIF1A and HIF3A, have not yet been associated with medical history of FE, but have potential role in the development of erythrocytosis. To improve diagnosis, it is crucial to identify new variants in genes involved in erythrocyte production. Published literature and data from genome browsers were used to obtain HIFA sequence variants associated with erythrocytosis and to locate them on protein sequence and regulatory sites. We retrieved 24 variants from the literature: 2 in HIF1A, 20 in EPAS1 and 2 in HIF3A gene. Sixteen out of 20 variants in the EPAS1 gene are positioned in a conserved region of 13 amino acids within exon 12, next to regulatory post‐translational modification and binding sites, suggesting that EPAS1 has an important role in erythropoiesis. The role of HIF1A and HIF3A in the development of erythrocytosis should be further investigated.
The discovery in 2005 of the
V617F gain-of-function mutation in myeloproliferative neoplasms and more particularly in polycythemia vera has deeply changed the diagnostic and therapeutic approaches to ...polycythemia. More recently, the use of NGS in routine practice has revealed a large number of variants, although it is not always possible to classify them as pathogenic. This is notably the case for the
E846D variant for which for which questions remain unanswered. In a large French national cohort of 650 patients with well-characterized erythrocytosis, an isolated germline heterozygous
E846D substitution was observed in only two cases. For one of the patients, a family study could be performed, without segregation of the variant with the erythrocytosis phenotype. On the other hand, based on the large UK Biobank resource cohort including more than half a million UK participants, the
E846D variant was found in 760 individuals, associated with a moderate increase in hemoglobin and hematocrit values, but with no significant difference to the mean values of the rest of the studied population. Altogether, our data as well as UK Biobank cohort analyses suggest that the occurrence of an absolute polycythemia cannot be attributed to the sole demonstration of an isolated
E846D variant. However, it must be accompanied by other stimuli or favoring factors in order to generate absolute erythrocytosis.
Idiopathic erythrocytosis (IE) is an absolute erythrocytosis with no known cause, diagnosed by exclusion of primary and secondary erythrocytosis. Familial erythrocytosis (FE) is a rare disease and as ...the rare patients with JAK2-wild-type polycythemia vera (PV) may be misdiagnosed as IE. We compared 78 patients with IE, 21 with FE and 136 with PV in the effort to identify simple features capable of discriminating between them. FE patients were younger at diagnosis either than IE and PV (
p
< 0.001); IE and FE had lower WBC, platelet counts and higher serum EPO levels, and had splenomegaly and thrombotic events less frequently than PV patients. Phlebotomies to obtain a haematocrit lower than 45 % induce platelet count increase in 70 % of PV but not in IE. Mainly in men, normal spleen, normal platelet counts and no history of thrombosis at diagnosis argue against PV; diagnosis of IE could be supported by means of a cycle of venesection to see how it affects their platelet count. No simple data capable of distinguishing between IE and FE were identified; therefore, a case of sporadic erythrocytosis in a young patient should be investigated as a possible genetic cause.
Abstract We present a case of a mother and daughter who were initially diagnosed with polycythaemia vera and treated with venesectio. As JAK2 V6217F/exon 12 mutation analyses became available, these ...were performed and turned out negative. Haemoglobin electrophoresis was performed and the patients were found to have high oxygen affinity haemoglobin Ypsilanti. It is important and relevant to look for high oxygen affinity variants of haemoglobin when there is a family history of erythrocytosis, in young persons and when there is no apparent reason or clonal marker present.
Dominant mutations in the erythropoietin receptor (EPOR) gene account for only about 15% of cases of primary congenital erythrocytosis. To search for molecular alterations in patients with this ...disorder. Sixteen patients with Epo <10 mU/mL were studied, 3 were related. Analyses included EPOR and JAK2 gene sequencing, quantitative PRV-1 RT-PCR, and erythroid colony assays. A novel sporadic EPOR 1453G->A (Trp439Stop) mutation was detected. All familial cases, varied in phenotype, presented the EPOR 1414C->G (Tyr426Stop) mutation. JAK2 mutations are not involved in the pathogenesis of primary congenital erythrocytosis.
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