Alternative titles; symbols
DO: 0111631;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 16p13.3 | Erythrocytosis, familial, 7 | 617981 | Autosomal dominant | 3 | HBA2 | 141850 |
| 16p13.3 | Erythrocytosis, familial, 7 | 617981 | Autosomal dominant | 3 | HBA1 | 141800 |
A number sign (#) is used with this entry because autosomal dominant erythrocytosis-7 (ECYT7) is caused by heterozygous mutations in the alpha-globin genes (HBA1, 141800 or HBA2, 141850) that result in a high oxygen affinity hemoglobin.
Familial erythrocytosis-7 (ECYT7) is characterized by an increased oxygen affinity of hemoglobin (Hb), which results in decreased delivery of oxygen into the peripheral tissues and compensatory polycythemia. Patients are generally asymptomatic, as compensatory polycythemia assures normal oxygen tissue delivery. Patients have normal red cell morphology (summary by Kralovics and Prchal, 2000). Wajcman and Galacteros (2005) noted that although high oxygen affinity hemoglobins are usually well tolerated in young patients, they can lead to thrombotic complications in older patients or when they are associated with another cause that increases thrombotic risk. Wajcman and Galacteros (2005) also noted that the effect of increased oxygen affinity of Hb caused by an alpha chain variant is usually milder than that caused by a beta chain variant (see 617980).
Charache et al. (1966) were the first to report a case of erythrocytosis due to the presence of an abnormal Hb. They described an 81-year-old patient with mild angina pectoris who had a Hb level of 19.9 g/dL and an abnormal Hb band on electrophoresis. The oxygen equilibrium curve of the patient's blood was significantly shifted to the left. A family study revealed 15 other members with both erythrocytosis and the abnormal Hb, which was isolated and confirmed to have a marked increased oxygen affinity.
Erythrocytosis caused by high oxygen affinity Hb variants is inherited in an autosomal dominant manner (Wajcman and Galacteros, 2005).
Because some high oxygen affinity hemoglobins are electrophoretically silent, the determination of hemoglobin oxygen dissociation kinetics is the best initial screening laboratory test for suspected congenital secondary polycythemia. A decreased P(50) indicates mutant hemoglobin or, even rarer, 2,3-bisphosphoglycerate deficiency (summary by Kralovics and Prchal, 2000).
The hemoglobin tetramer oscillates between the R (relaxed; fully oxygenated hemoglobin) and T (tense; fully deoxygenated hemoglobin) state of the quaternary protein conformation, requiring the cooperative interaction of globin subunits. Mutations affecting the equilibrium between R and T states result in a change of oxygen affinity. Most of these mutations occur in the alpha1/beta2 interface of the tetramer, but some interfere with the 2,3-bisphosphate binding site, and others occur at the C terminus of one of the globin subunits and interfere with binding of heme (summary by Kralovics and Prchal, 2000).
In affected members of a family with erythrocytosis, Charache et al. (1966) identified a heterozygous mutation in the HBA1 gene (Hb Chesapeake; 141800.0018).
Erythrocytosis is a feature of several variants in the alpha globin genes; see, e.g., hemoglobins Nonobiki (141800.0109), Sassari (141800.0126), Inkster (141850.0015), Columbia-Missouri (141850.0016), and Hanamaki (141850.0023).
Gonzalez Fernandez et al. (2009) noted that 89 Hb variants that show high affinity for oxygen had been described: 18 in the alpha chain and 71 in the beta chain. Two thirds of them are not accompanied by erythrocytosis either because the affinity increase is slight or moderate and only found during in vitro studies or when molecular instability is also present, determining a concomitant hemolysis; or if the mutating gene expression is low, as occurs in the alpha chain variations, or is reduced, as in Hb Crete (141900.0058).
Charache, S., Weatherall, D. J., Clegg, J. B. Polycythemia associated with a hemoglobinopathy. J. Clin. Invest. 45: 813-822, 1966. [PubMed: 5913291] [Full Text: https://doi.org/10.1172/JCI105397]
Gonzalez Fernandez, F. A., Villegas, A., Ropero, P., Carreno, M. D., Anguita, E., Polo, M., Pascual, A., Henandez, A. Haemoglobinopathies with high oxygen affinity: experience of erythropathology Cooperative Spanish Group. Ann. Hemat. 88: 235-238, 2009. [PubMed: 18818920] [Full Text: https://doi.org/10.1007/s00277-008-0581-x]
Kralovics, R., Prchal, J. T. Congenital and inherited polycythemia. Curr. Opin. Pediat. 12: 29-34, 2000. [PubMed: 10676771] [Full Text: https://doi.org/10.1097/00008480-200002000-00006]
Wajcman, H., Galacteros, F. Hemoglobins with high oxygen affinity leading to erythrocytosis: new variants and new concepts. Hemoglobin 29: 91-106, 2005. [PubMed: 15921161]