Heterozygous Beta Thalassaemia of Unusual Severity

S ummary . The proband of each of three families of Northern European or Italian extraction had an unusual form of heterozygous β‐thalassaemia, confirmed by haem‐atological, genetic and peripheral blood globin synthesis studies. The unusual severity of this disorder was indicated by chronic haemolysis leading to splenectomy and cholecystectomy, by numerous nucleated red cells and reticulocytes in the peripheral blood, and by leg ulcers in one family. The diversity of clinical expression in many family members with heterozygous β‐thalassaemia was striking. Bone marrow examination in the probands showed numerous large inclusion bodies of the type usually found only in thalassaemia major. In addition, there was unbalanced globin synthesis in the bone marrow, in contrast to the more balanced synthesis found in asymptomatic β‐thalassaemia trait. The amount of newly synthesized α‐chain found in the free δ‐chain pool was markedly elevated. The unbalanced globin synthesis and δ‐chain inclusions in the bone marrow cells suggest that the severity of the disorder in these patients may be due to the inability of their red cell precursors to fully compensate for the thalassaemic defect or to remove excess δ‐chains. The diversity of clinical expression suggests the influence of undefined acquired or genetic factors on the expression of β‐thalassaemia in these families.