SNOMEDCT: 68913001; ICD10CM: D56.0; ICD9CM: 282.43; ORPHA: 846; DO: 1099;
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
|---|---|---|---|---|---|---|
| 16p13.3 | Thalassemia, alpha- | 604131 | 3 | HBA2 | 141850 | |
| 16p13.3 | Thalassemias, alpha- | 604131 | 3 | HBA1 | 141800 |
A number sign (#) is used with this entry because of evidence that alpha-thalassemia is caused by mutation in the alpha-globin genes (HBA1, 141800; HBA2, 141850).
Sequences 30 to 50 kb upstream from the alpha-globin gene cluster, referred to as the locus control region alpha (LCRA; 152422), have been found to be deleted in cases of alpha-thalassemia with structurally intact alpha-globin genes.
Alpha-thalassemia is one of the most common hemoglobin genetic abnormalities and is caused by the reduced or absent production of the alpha-globin chains. Four clinical conditions of increased severity are recognized: the silent carrier state (clinically and hematologically normal); thalassemia trait (microcytosis, hypochromia, and mild anemia); hemoglobin H (HbH) disease (613978; moderate to severe microcytic, hypochromic, hemolytic anemia, mild jaundice, moderate hepatosplenomegaly); and Hb Bart hydrops fetalis syndrome (severe anemia, generalized edema, ascites, marked hepatosplenomegaly, skeletal and cardiac malformations, usually death in utero) (summary by Galanello and Cao, 2011).
The alpha-thalassemia phenotype ranges from asymptomatic to lethal. The severity of the disorder is usually well correlated with the number of nonfunctional copies of the alpha-globin genes. On the basis of the number of alpha-globin genes lost by deletion or totally or partially inactivated by point mutations, the alpha-thalassemias are classified into 2 main subgroups: alpha(+)-thalassemia (formerly alpha-thalassemia-2), in which one pair of the genes is deleted or inactivated by a point mutation, and alpha(0)-thalassemia (formerly alpha-thalassemia-1), in which both pairs of alpha-globin genes on the same chromosome are deleted. The clinically relevant forms of alpha-thalassemia usually involve alpha(0)-thalassemia, either coinherited with alpha(+)-thalassemia and resulting in HbH disease, or inherited from both parents and resulting in hemoglobin Bart hydrops fetalis. Milder variants of alpha-thalassemia act as genetic modifiers of other inherited conditions, as illustrated by epistatic interactions (when one gene influences another) between alpha-thalassemia and beta-thalassemia or between alpha-thalassemia and hemoglobin S (sickle hemoglobin). Triplications and quadruplications of the alpha-globin gene have frequently been observed in many populations, and these can interact with beta-thalassemia variants to produce more severe phenotypes (summary by Piel and Weatherall, 2014).
Alpha-Thalassemia-Related Hydrops Fetalis
Hydrops fetalis related to alpha-thalassemia results from severe anemia (and thus hypoxia) and heart failure. Fetuses that have deletion of all 4 alpha-globin genes (homozygous alpha(0)-thalassemia) have 80 to 90% Hb Bart (gamma-4 tetramers). These fetuses almost always succumb in utero during the second or third trimester of gestation, or die within hours after birth. This is known as Hb Bart hydrops fetalis syndrome, which is by far the most common cause of hydrops in Southeast Asia (summary by Lorey et al., 2001). For a general phenotypic description of nonimmune hydrops fetalis, see 236750.
Reviews
The molecular and clinical aspects of the severe alpha-thalassemia syndromes were reviewed by Higgs (1993) and Chui and Waye (1998).
Weatherall (2001) reviewed phenotype-genotype relationships in monogenic diseases based on studies of the thalassemias. The remarkable phenotypic diversity of the beta-thalassemias reflects the heterogeneity of mutations at the HBB locus, the action of many secondary and tertiary modifiers, and a wide range of environmental factors. Weatherall (2001) stated that phenotype-genotype relations will likely be equally complex in many monogenic diseases. The findings reviewed by Weatherall (2001) highlighted the problems that might be encountered in defining the relationship between the genome and the environment in multifactorial disorders, in which the degree of heritability may be relatively low and several environmental agents are involved.
Alpha-thalassemia occurs at a high frequency across the tropical belt, almost reaching fixation (i.e., it has reached a frequency of 100%) in parts of southern Asia. It has been estimated that about 5% of the population worldwide carry an alpha-thalassemia variant (summary by Piel and Weatherall, 2014).
For a review of mutations in the HBA genes causing alpha-thalassemia, see 141800 and 141850.
Chui, D. H. K., Waye, J. S. Hydrops fetalis caused by alpha-thalassemia: an emerging health care problem. Blood 91: 2213-2222, 1998. [PubMed: 9516118]
Galanello, R., Cao, A. Alpha-thalassemia. Genet. Med. 13: 83-88, 2011. [PubMed: 21381239] [Full Text: https://doi.org/10.1097/GIM.0b013e3181fcb468]
Higgs, D. R. Alpha-thalassaemia. Baillieres Clin. Haemat. 6: 117-150, 1993. [PubMed: 8353312] [Full Text: https://doi.org/10.1016/s0950-3536(05)80068-x]
Lorey, F., Charoenkwan, P., Witkowska, H. E., Lafferty, J., Patterson, M., Eng, B., Waye, J. S., Finklestein, J. Z., Chui, D. H. K. Hb H hydrops fetalis syndrome: a case report and review of literature. Brit. J. Haemat. 115: 72-78, 2001. [PubMed: 11722414] [Full Text: https://doi.org/10.1046/j.1365-2141.2001.03080.x]
Piel, F. B., Weatherall, D. J. The alpha-thalassemias. New Eng. J. Med. 371: 1908-1916, 2014. [PubMed: 25390741] [Full Text: https://doi.org/10.1056/NEJMra1404415]
Weatherall, D. J. Phenotype-genotype relationships in monogenic disease: lessons from the thalassaemias. Nature Rev. Genet. 2: 245-255, 2001. [PubMed: 11283697] [Full Text: https://doi.org/10.1038/35066048]