Alternative titles; symbols
ORPHA: 90042; DO: 0060652;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 9p24.1 | Erythrocytosis, somatic | 133100 | 3 | JAK2 | 147796 | |
| 12q24.12 | Erythrocytosis, somatic | 133100 | 3 | SH2B3 | 605093 | |
| 19p13.2 | [Erythrocytosis, familial, 1] | 133100 | Autosomal dominant | 3 | EPOR | 133171 |
A number sign (#) is used with this entry because familial erythrocytosis-1 (ECYT1) is caused by heterozygous mutation in the gene encoding the erythropoietin receptor (EPOR; 133171) on chromosome 19p13.
Familial erythrocytosis-1 (ECYT1) is an autosomal dominant disorder characterized by increased serum red blood cell mass and hemoglobin concentration, hypersensitivity of erythroid progenitors to EPO (133170), and low serum levels of EPO. There is no increase in platelets or leukocytes and the disorder does not progress to leukemia (Kralovics et al., 1998).
Genetic Heterogeneity of Familial Erythrocytosis
See also ECYT2 (263400), caused by mutation in the VHL gene (608537) on chromosome 3p25; ECYT3 (609820), caused by mutation in the EGLN1 gene (606425) on chromosome 1q42; ECYT4 (611783), caused by mutation in the EPAS1 gene (603349) on chromosome 2p21; ECYT5 (617907), caused by mutation in the EPO gene (133170) on chromosome 7q22; ECYT6 (617980), caused by mutation in the HBB gene (141900) on chromosome 11q15; ECYT7 (617981), caused by mutation in the HBA genes (141800; 141850) on chromosome 16p13; and ECYT8 (222800), caused by mutation in the BPGM gene (613896) on chromosome 7q33.
Stamatoyannopoulos (1972) reviewed causes of familial erythrocytosis and noted that the disorder may result from defects in the regulation of 2,3-diphosphoglycerate (see 613896 and 222800).
Erythrocytosis may also be caused by somatic mutation in the JAK2 (147796) or the SH2B3 (605093) gene on chromosome 9p24 and 12q24, respectively.
For a review of the genetics of congenital erythrocytosis, see Bento et al. (2014).
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 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.
Erythrocytosis can be classified as primary or secondary. Primary erythrocytosis is due to an intrinsic inherited or somatic defect in erythroid progenitor cells resulting in an enhanced response to circulating cytokines. In primary erythrocytosis, the red cell compartment expands independently of extrinsic influences. Familial erythrocytosis-1 is a primary erythrocytosis due to a defect in the EPOR gene that results in enhanced response of erythroid progenitors to physiologic or low levels of erythropoietin. Polycythemia vera is also considered to be a primary erythrocytosis because it is due to a defect in the JAK2 gene within erythroid progenitor cells resulting in constitutive intracellular signaling and clonal proliferation. In contrast, secondary erythrocytosis is driven by hormonal factors extrinsic to the erythroid compartment, such as hypoxia due to lung disease or increased EPO from an EPO-secreting tumor (Prchal, 2005; Cario, 2005; Gregg and Prchal, 2005).
Engelking (1920) and Wieland (1932) separately reported a family in which 11 members of 3 generations had erythrocytosis. In some, the abnormality was noted in childhood. A patient reported by Auerback et al. (1958) was again reported by Cassileth and Hyman (1966) with family study.
Prchal et al. (1985) reported a family with autosomal dominant inheritance of erythrocytosis. Affected members had increased serum red blood cell mass, increased hemoglobin, and decreased EPO levels. Arterial oxygen levels and blood oxygen affinity were normal. In vitro erythroid colony forming units showed significantly increased stimulation by low levels of EPO.
Queisser et al. (1988) described erythrocytosis in 7 members of a family in 4 generations with male-to-male transmission. The propositus was first diagnosed at age 26 years. He had headaches and marked plethora. Erythropoietin levels were not elevated. The disorder was characterized in middle age in other members of the family by hypertension, cardiovascular and thromboembolic phenomena, and abnormal bleeding. The proband was treated successfully with repeated venous phlebotomies.
Juvonen et al. (1991) reported a large Finnish family with autosomal dominant erythrocytosis. In vitro studies showed hypersensitivity of erythroid progenitors to EPO. The erythrocytosis had not had any obvious effect on the health or life span of the affected individuals. In fact, many reached an advanced age and 1 won several Olympic gold medals and world championships in endurance sports.
In the large Finnish kindred with familial erythrocytosis reported by Juvonen et al. (1991), de la Chapelle et al. (1993) demonstrated linkage to a highly informative, simple sequence repeat (SSR) polymorphism in the 5-prime region of the EPOR gene (lod score of 6.37).
The transmission pattern of ECYT1 in the family reported by Juvonen et al. (1991) was consistent with autosomal dominant inheritance.
In all 29 affected members of a large Finnish family with autosomal dominant erythrocytosis reported by Juvonen et al. (1991), de la Chapelle et al. (1993) identified a heterozygous mutation in the EPOR gene (133171.0001).
In 2 unrelated families with autosomal dominant erythrocytosis, Kralovics et al. (1997) identified 2 different heterozygous mutations in the EPOR gene (133171.0004; 133171.0005). The authors noted that most of the described EPOR mutations (6 of 8) associated with polycythemia resulted in an absence of the C-terminal negative regulatory domain of the receptor.
In 3 affected members of a family with familial erythrocytosis originally reported by Prchal et al. (1985), Kralovics et al. (1998) identified a heterozygous mutation in the EPOR gene (133171.0006).
Dainiak et al. (1979), Yonemitsu et al. (1973), and Distelhorst et al. (1981) attributed familial erythrocytosis to increased autonomous erythropoietin production.
Emanuel et al. (1992) reported studies of 3 extensively affected families with familial and congenital erythrocytosis. Although 13 affected individuals were identified in 4 generations in 1 family, there was no instance of male-to-male transmission; in the second family, however, there were 2 such instances. Another patient was an isolated case. In all 3 families, secondary causes of erythrocytosis were ruled out. Erythropoietin levels were normal or low, even after phlebotomy. No evidence of rearrangement or amplification of the EPOR gene could be demonstrated. Functional studies examining the number and binding affinity of the EPO receptor on erythroid progenitors from 3 of their patients demonstrated no abnormalities. Emanuel et al. (1992) suggested that the erythrocytosis in these families may not involve the EPOR itself, but may have resulted from alterations in postreceptor responses.
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