Beta-Thalassemia, Dominant Inclusion Body Type
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).
Clinical FeaturesWeatherall 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.
Molecular GeneticsIn 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.