F-thalassemia: A study of thirty-one families with simple heterozygotes and combinations of F-thalassemia with A 2-thalassemia

Abstract

Phenotypes of F-thalassemia are described, as revealed by a study of sixty-eight simple heterozygotes and twenty-one combinations with A 2-thalassemia. Simple heterozygotes present with typical hematologic stigmata of the thalassemia trait, elevated fetal hemoglobin levels and normal hemoglobin A 2. Double heterozygotes for F-thalassemia and A 2-thalassemia display heterogeneity in their clinical and hematologic picture, but when compared to homozygotes for A 2-thalassemia they are found to have milder clinical manifestations, less anemia and usually no transfusion requirement. Absence of hemoglobin A was observed in more than one third of double heterozygotes. Mean hemoglobin A 2 in simple heterozygotes was 50 per cent lower than in those with A 2-thalassemia trait. Elevation of fetal hemoglobin levels was observed in all but one simple heterozygote and was transmitted in a dominant pattern of inheritance. High intrafamilial similarities in the levels of hemoglobin F were documented. The data are analyzed in relation to the information on F-thalassemia thus far available. The over-all picture is that of a mutation causing defective red cell hemoglobinization, simultaneous suppression of β and δ hemoglobin chain synthesis in cis position and hereditarily determined elevation of fetal hemoglobin levels. The proposed molecular mechanisms are discussed. It is concluded that current hypotheses as to the pathogenesis of thalassemias and prevailing concepts of the regulation of hemoglobin genes cannot account for the findings in F-thalassemia.