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 ... 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).
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 ... 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.
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. ... 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.
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 ... 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.'