Alternative titles; symbols
SNOMEDCT: 716682000; ORPHA: 231226, 848; DO: 0080770;
Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
Gene/Locus |
Gene/Locus MIM number |
---|---|---|---|---|---|---|
11p15.4 | Thalassemia-beta, dominant inclusion-body | 603902 | Autosomal dominant | 3 | HBB | 141900 |
A number sign (#) is used with this entry because of evidence that dominantly inherited inclusion body beta-thalassemia is caused by mutation in the beta-globin gene (HBB; 141900).
Dominantly inherited inclusion body beta-thalassemia is characterized by the presence of inclusion bodies in red blood cell precursors, moderately severe anemia, jaundice, and splenomegaly (summary by Ropero et al., 2005).
Weatherall et al. (1973) observed what appeared to be a hitherto unreported type of congenital anemia in 6 members of an Irish family. Inherited as an autosomal dominant, it was characterized by moderate anemia, lifelong jaundice, cholelithiasis and splenomegaly, marked morphologic changes in the red cells (which were, however, well hemoglobinized), erythroid hyperplasia of the bone marrow with increased numbers of multinucleate red cell precursors, and the presence of large inclusion bodies in the normoblasts, both in the marrow and in the peripheral blood after splenectomy. There was an imbalance in globin chain synthesis with an excess of alpha-chain over beta-chain by a factor of 2 to 1. The authors postulated either an 'overproduction abnormality' of alpha-globin chain synthesis or a defect in cell division leading to an excess of genetic material per cell. The disorder appears to fall into the general category of congenital dyserythropoietic anemia. Subsequently, this kindred and 3 similarly affected ones, all of Anglo-Saxon origin, were considered by the Weatherall group to have a dominantly inherited inclusion body beta-thalassemia.
Stamatoyannopoulos et al. (1974) described this disorder in beta-thalassemia heterozygotes of a Swiss-French family and suggested that this condition be designated inclusion body beta-thalassemia.
Thein et al. (1990) studied the molecular basis of the dominantly inherited beta-thalassemia in the 4 families reported by Weatherall et al. (1973). They suggested that the phenotypic difference between this condition and the more common recessive form of beta-thalassemia lies mainly in the length and stability of the abnormal translation products that are synthesized and particularly in whether they are capable of binding heme and producing aggregations that are relatively resistant to proteolytic degradation.
Thein et al. (1990) provided a revised pedigree of the Irish family reported by Weatherall et al. (1973) and stated that all affected members had moderate anemia with splenomegaly, increased levels of Hb A2 and Hb F, and increased alpha/beta chain synthesis ratios. Two family members had undergone splenectomy. One individual had died and at autopsy was found to have extensive extramedullary hemopoiesis with marked erythroid hyperplasia of the bone marrow. There was also extensive hemosiderosis of the pancreas, kidneys, lymph nodes, ovaries, thyroid, and bronchus. The distribution of iron in this case occurred mainly in parenchymal tissues, which is typical of overload derived from excessive iron absorption rather than from transfusion. This pattern of iron overload together with the extensive extramedullary hemopoiesis was typical of a hematologic disorder characterized by ineffective hemopoiesis.
Ropero et al. (2005) described inclusion body beta-thalassemia in a 51-year-old Spanish man who had been diagnosed with beta-thalassemia with marked siderosis (serum ferritin 2,005 ng/ml) in adulthood. He presented with microcytic anemia, mild hemolysis, subclinical jaundice, painful splenomegaly on palpation, and hepatomegaly. The levels of hemoglobin A2 and hemoglobin F were increased (5% and 4% respectively), and inclusion bodies were present in peripheral red blood cells.
The transmission pattern of inclusion body beta-thalassemia in the families reported by Weatherall et al. (1973) and Stamatoyannopoulos et al. (1974) was consistent with autosomal dominant inheritance.
In affected members of the Swiss-French family reported by Stamatoyannopoulos et al. (1974), Fei et al. (1989) identified a glu121-to-ter mutation in the HBB gene (E121X; 141900.0314). The E121X mutation was also identified in a sporadic patient of Greek-Polish descent (Kazazian et al., 1986) and in the 3 British families reported by Thein et al. (1990). Thein et al. (1990) found that the Irish family reported by Weatherall et al. (1973) had a complex rearrangement in the third exon of the HBB gene (141900.0520), the site of the E121X mutation.
Ropero et al. (2005) identified an 11-basepair deletion in exon 3 of the beta-globin gene (141900.0540) in a 51-year-old Spanish man who had been diagnosed with beta-thalassemia as an adult. The deletion was predicted to result in frameshift and synthesis of an abnormal and likely unstable beta-chain variant.
Fei, Y. J., Stoming, T. A., Kutlar, A., Huisman, T. H. J., Stamatoyannopoul os, G. One form of inclusion body beta-thalassemia is due to a GAA-to-TAA mutation at codon 121 of the beta chain. Blood 73: 1075-1077, 1989. [PubMed: 2563949]
Kazazian, H. H., Jr., Orkin, S. H., Boehm, C. D., Goff, S. C., Wong, C., Dowling, C. E., Newburger, P. E., Knowlton, P. G., Brown, V., Donis-Keller, H. Characterization of a spontaneous mutation to a beta-thalassemia allele. Am. J. Hum. Genet. 38: 860-867, 1986. [PubMed: 3014870]
Ropero, P., Villegas, A., Martinez, M., Ataulfo Gonzalez Fernandez, F., Benavente, C., Mateo, M. A deletion of 11 bp (CD 131-134) in exon 3 of the beta-globin gene produces the phenotype of inclusion body beta-thalassemia. Ann. Hemat. 84: 584-587, 2005. [PubMed: 15977037] [Full Text: https://doi.org/10.1007/s00277-004-0992-2]
Stamatoyannopoulos, G., Woodson, R., Papayannopoulou, T., Heywood, D., Kurachi, S. Inclusion-body beta-thalassemia trait: a form of beta-thalassemia producing clinical manifestations in simple heterozygotes. New Eng. J. Med. 290: 939-943, 1974. [PubMed: 4361439] [Full Text: https://doi.org/10.1056/NEJM197404252901705]
Thein, S. L., Hesketh, C., Taylor, P., Temperley, I. J., Hutchinson, R. M., Old, J. M., Wood, W. G., Clegg, J. B., Weatherall, D. J. Molecular basis for dominantly inherited inclusion body beta-thalassemia. Proc. Nat. Acad. Sci. 87: 3924-3928, 1990. [PubMed: 1971109] [Full Text: https://doi.org/10.1073/pnas.87.10.3924]
Weatherall, D. J., Clegg, J. B., Knox-Macaulay, H. H. M., Bunch, C., Hopkins, C. R., Temperley, I. J. A genetically determined disorder with features both of thalassaemia and congenital dyserythropoietic anaemia. Brit. J. Haemat. 24: 681-702, 1973. [PubMed: 4351905] [Full Text: https://doi.org/10.1111/j.1365-2141.1973.tb01696.x]