MODIFICATION OF HEMOGLOBIN-H DISEASE BY SICKLE TRAIT

The rarity of Hb H disease in combination with sickle trait may be due in part to the absence of actual Hb H in individuals who inherited the deletion of 3 .alpha.-globin genes. A boy with persistent microcytic, hypochromic anemia despite adequate Fe stores, who exhibited splenomegaly with a normal reticulocyte count and only rare inclusions in circulating erythrocytes was described. Starch gel electrophoresis and isoelectric focusing at age 5 yr showed 21% Hb S, persistent Hb Bart''s, but no Hb H. Reticulocyte .alpha./non-.alpha. globin chain synthesis ratio was 0.58 at age 5. The mother (Asian) had laboratory evidence of .alpha.-thalassemia trait and the father (Black) had sickle trait. The nature of .alpha.-thalassemia in this patient was investigated by liquid hybridization and by the Southern method of gene mapping, in which DNA was digested with restriction endonucleases and the DNA fragments that contained the .alpha.-globin structural gene identified by hybridization with complementary DNA. The patient had only 1 .alpha.-globin structural gene, located in a DNA fragment shorter than in normal or .alpha.-thalassemia trait individuals, but similar to that in other patients with Hb H disease. Morphologic studies of bone marrow by light and electron microscopy revealed erythroid hyperplasia with inclusions in polychromatic and orthochromatic erythroblasts, suggesting early precipitation of an unstable Hb. The lack of demonstrable Hb H may be the result of diminished amounts of .beta.A available for Hb H formation (since 1 .beta.-globulin gene was .beta.S) and the greater affinity of .alpha.-chains for .beta.A than .beta.S-globin chains leading to the formation of relatively more Hb A than Hb S. The presence of a .beta.S gene may thus modify the usual clinical expression of Hb H disease.