DIFFERENT HEMATOLOGICAL PHENOTYPES CAUSED BY THE INTERACTION OF TRIPLICATED ALPHA-GLOBIN GENES AND HETEROZYGOUS BETA-THALASSEMIA

The pathophysiology and clinical severity of beta-thalassemia are rela ted to the degree of alpha/non-alpha-chain imbalance. A triplicated al pha-globin gene locus can exacerbate effects of excess alpha-chains ca used by a defective beta-globin gene, although this is not observed in all cases. Extensive studies on this condition are lacking. We report a group of 17 patients who are heterozygous for both the alpha alpha alpha(anti-3.7) allele and a mutation in the beta-globin gene cluster. Their clinical phenotypes varied: six had mild anemia with microcytos is and hypochromia, while 11 had more severe anemia with splenomegaly requiring splenectomy (three cases) and blood transfusions (four cases ), Different phenotypes were also evident in the presence of the same beta-thalassemia mutation: in one family, two individuals had the same alpha- and beta-globin genotypes but presented with different hematol ogic phenotypes. In addition, the complex interaction involving a trip licated alpha-globin gene, beta(39)- and delta(+27)-thalassemia mutati ons is studied in a family with two siblings presenting with hemolytic anemia, normal Hb A(2) and increased Hb F. Analysis of this series of patients suggests that additional genetic determinants play a role in modulating phenotypic expression in individuals with identical alpha- and beta-globin genotypes. Interaction with a triplicated alpha-gene can play a role in the clinical presentation of patients with defectiv e beta-globin gene expression and should be considered in the diagnosi s of atypical cases. (C) 1997 Wiley-Liss, Inc.