Erythrocytosis, Familial, 2

A number sign (#) is used with this entry because of evidence that familial erythrocytosis-2 (ECYT2) is caused by homozygous or compound heterozygous mutation in the VHL gene (608537) on chromosome 3p25.

Chuvash polycythemia, endemic in the Chuvash Republic of the Russian Federation, is associated with a specific mutation in the VHL gene (608537.0019). The VHL gene is also mutated in von Hippel-Lindau syndrome (193300).

For a general phenotypic description and a discussion of genetic heterogeneity of familial erythrocytosis, see ECYT1 (133100).

Description

Familial erythrocytosis-2 is an autosomal recessive disorder characterized by increased red blood cell mass, increased serum levels of erythropoietin (EPO; 133170), and normal oxygen affinity. Patients with ECYT2 carry a high risk for peripheral thrombosis and cerebrovascular events (Cario, 2005). Familial erythrocytosis-2 has features of both primary and secondary erythrocytosis. In addition to increased circulating levels of EPO, consistent with a secondary, extrinsic process, erythroid progenitors are also hypersensitive to EPO, consistent with a primary, intrinsic process (Prchal, 2005).

Nomenclature

The term 'polycythemia' (Greek: 'many cells in the blood') is used interchangeably with 'erythrocytosis,' although the latter term more specifically refers to an increase in the number of circulating differentiated red blood cells (Prchal, 2005; Cario, 2005). 'Erythrocytosis' is the preferred term used here in order to distinguish inherited disorders characterized by increased circulating red blood cells from 'polycythemia vera' (PV; 263300), which is a clonal myeloproliferative disorder associated with somatic mutations in the JAK2 gene (147796). Familial erythrocytosis is also distinct from erythroleukemia (133180), which is considered to be a subtype of acute myelogenous leukemia (AML; 601626) characterized by immature erythroid cells in the bone marrow and peripheral blood.

Clinical Features

Nadler and Cohn (1939) described a family in which 4 of 11 children showed polycythemia. The mother stated that these 4 children had red faces from the time of birth. Auerbach et al. (1958) reported 3 families. In 1 family, 2 brothers and a sister were affected, and in a second, the proband and an aunt. The parents were normal. Unlike patients with polycythemia vera, the subjects demonstrated no increase in white count, platelets, or uric acid, and the process was benign. Davey et al. (1968) and Stamatoyannopoulos (1972) noted autosomal recessive inheritance of erythrocytosis.

Yonemitsu et al. (1973) described 2 affected sons of parents related as half first cousins. Both had a marked increase in erythropoietin concentration in plasma and urine. Adamson et al. (1973) studied 2 families with recessive erythrocytosis and found increased erythropoietin production uninfluenced by alterations in the oxygen-carrying capacity of the blood when the hematocrit was lowered by phlebotomy. Hemoglobin and red cell function and renal vasculature were normal. A genetic defect in regulation of erythropoietin production was postulated. Greenberg and Golde (1977) studied 2 brothers, aged 26 and 28, whose erythrocytosis had been discovered incidentally. The parents were hematologically normal. Studies showed increased serum erythropoietin resulting in an expansion of the erythroid precursor pool.

Whitcomb et al. (1980) studied 3 cases of congenital erythrocytosis and found an absolute or relative elevation of erythropoietin. Urinary excretion of erythropoietin was more than doubled by phlebotomy. The authors postulated an inherited defect 'likely residing in the renal sensor responsible for the production of erythropoietin.'

Polyakova (1974) described familial erythrocytosis in the Chuvash population, an ethnic isolate in the mid-Volga river region of Russia of Asian descent (Prchal, 2005).

Sergeyeva et al. (1997) studied the autosomal recessive form of congenital erythrocytosis common in the Chuvash population. They stated that hundreds of individuals appeared to be affected in an autosomal recessive pattern. They studied 6 polycythemic Chuvash patients less than 20 years of age from unrelated families and 12 first-degree family members. Hemoglobins were markedly elevated in the index subjects (22.6 +/- 1.4 g/dl) and serum erythropoietin concentrations were elevated. Platelet and white blood cell counts were normal. Southern blot analysis of the Bgl2 erythropoietin gene polymorphism showed that one affected individual was a heterozygote, suggesting absence of linkage of polycythemia with the EPO gene. There was no evidence of linkage to the erythropoietin receptor gene (EPOR; 133171).

In a matched cohort study, Gordeuk et al. (2004) found that patients with Chuvash polycythemia had increased frequency of vertebral hemangiomas, varicose veins, lower blood pressures, and elevated serum VEGF (192240) concentrations (p less than 0.0005), as well as premature mortality related to cerebrovascular events and peripheral thrombosis. Spinocerebellar hemangioblastomas, renal carcinomas, and pheochromocytomas typical of classic VHL syndrome were not found, suggesting that overexpression of the alpha subunit of hypoxia-inducible factor-1 (HIF1A; 603348) and VEGF is not sufficient for tumorigenesis. Although hemoglobin-adjusted serum erythropoietin concentrations were approximately 10-fold higher in patients compared to controls, erythropoietin response to hypoxia was identical. Gordeuk et al. (2004) concluded that Chuvash polycythemia is a distinct syndrome manifested by thrombosis, vascular abnormalities, and intact hypoxic regulation despite increased basal expression of hypoxia-regulated genes.

Mapping

Vasserman et al. (1999) studied the autosomal recessive benign erythrocytosis that has a high incidence in Chuvashia in the Russian Federation. They studied 12 unrelated families and excluded the erythropoietin gene and the erythropoietin receptor gene as candidates by linkage analysis. Using genomewide searching, they demonstrated linkage of the disorder between markers D11S4142 and D11S1356 on 11q23 (maximum lod = 6.61).

Ang et al. (2002) found that in a genomewide screen, the Chuvash polycythemia locus mapped not to 11q23 but to 3p, in a region containing the VHL gene.

Molecular Genetics

In patients with Chuvash polycythemia, Ang et al. (2002) identified a homozygous mutation in the VHL gene (R200W; 608537.0019). The VHL protein downregulates HIF1A (603348), the main regulator of adaptation to hypoxia, by targeting the protein for degradation. Ang et al. (2002, 2002) suggested that in this scenario, disruption of function of the VHL protein causes a failure to degrade HIF1-alpha resulting in its accumulation, upregulation of downstream target genes such as EPO, and the clinical manifestations of polycythemia. Chuvash polycythemia is thus a congenital disorder of oxygen homeostasis.

Pastore et al. (2003) presented evidence that homozygous or compound heterozygous mutations in the VHL gene are the most frequent cause of congenital erythrocytosis, present in up to half of the patients they examined.

Pathogenesis

Russell et al. (2011) presented evidence suggesting 2 main molecular mechanisms by which the R200W and H191D (608537.0024) VHL mutations result in polycythemia. In vitro studies showed that the R200W mutation attenuated formation of the E3 ubiquitin ligase and attenuated binding of HIF1 (603348). In patients, this would lead to overproduction of the HIF-target erythropoietin (EPO; 133170) and thus secondary polycythemia. In addition, VHL mutations cause conformational changes causing increased binding to SOCS1 (603597), which inhibits binding and degradation of phosphorylated JAK2 (147796). The resulting pJAK2 stabilization promotes hyperactivation of the JAK2-STAT5 (601511) pathway in erythroid progenitors, causing hypersensitivity to erythropoietin and thereby to primary polycythemia. Treatment of R200W-homozygous transgenic mice with a JAK2 inhibitor resulted in decreased hematocrit, smaller spleen, and decreased sensitivity to EPO compared to untreated transgenic mice.

Population Genetics

By haplotype analysis of 101 ethnically diverse individuals with the common R200W mutation in the VHL gene, including 72 Chuvash individuals, Liu et al. (2004) determined that the R200W mutation is due to a founder effect that originated from 14,000 to 62,000 years ago.

Cario et al. (2005) reported a Turkish patient who was homozygous for the R200W mutation. Haplotype analysis showed a different haplotype than that associated with the Chuvash population, indicating that the mutation arose independently and is not geographically restricted.

Perrotta et al. (2006) found that the R200W mutation is more frequent on the island of Ischia in the Bay of Naples (0.070) than it is in Chuvashia (0.057). The haplotype of all patients in Ischia matched that identified in the Chuvash cluster, thus supporting the single-founder hypothesis. Perrotta et al. (2006) also found that unaffected heterozygotes had increased HIF1-alpha activity, which might confer a biochemical advantage for mutation maintenance. They suggested that this form of familial polycythemia may be endemic in other regions of the world, a hypothesis supported by the reports of Percy et al. (2002, 2003). Because this disorder is not strictly confined to Chuvashia and not solely a result of the 598C-T mutation, Perrotta et al. (2006) suggested that a more accurate designation would be 'VHL-dependent polycythemia.'

Animal Model

Hickey et al. (2007) found that mice homozygous for the R200W mutation developed polycythemia similar to the human disease. Although bone marrow cellularity and morphology was similar to controls, spleens from the mutant mice showed increased numbers of erythroid progenitors and megakaryocytes, as well as erythroid differentiation of splenic cells in vitro. Further analysis showed upregulation of HIF2A (603349) and of key target genes, including EPO (133170), VEGF (192240), GLUT1 (138140), and PAI1 (173360), that contribute to polycythemia.