Modification of Hemoglobin H Disease by Sickle Trait

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Abstract

The rarity of hemoglobin (Hb) H disease in combination with sickle trait may be due in part to the absence of actual Hb H in individuals who, nonetheless, have inherited the deletion of three α-globin genes. We describe here a boy with persistent microcytic, hypochromic anemia despite adequate iron stores, who exhibited splenomegaly with a normal reticulocyte count and only rare inclusions in circulating erythrocytes. Starch gel electrophoresis and isoelectric focusing at age 5 yr showed 21% Hb S, persistent Hb Bart's, but no Hb H. Recticulocyte α/non-α globin chain synthesis ratio was 0.58 at age 5. The mother (Asian) had laboratory evidence of α-thalassemia trait and the father (Black) had sickle trait. The nature of α-thalassemia in this patient was investigated both by liquid hybridization and by the Southern method of gene mapping, in which DNA is digested with restriction endonucleases and the DNA fragments that contained the α-globin structural gene identified by hybridization with complementary DNA. The patient had only one α-globin structural gene, located in a DNA fragment shorter than that found in normal or α-thalassemia trait individuals, but similar to that present 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 hemoglobin. The lack of demonstrable Hb H may be the result of both diminished amounts of βA available for Hb H formation (since one β-globin gene is βS) and the greater affinity of α-chains for βA than βS-globin chains leading to the formation of relatively more Hb A than Hb S. The presence of a βS gene may thus modify the usual clinical expression of Hb H disease.

Authors

Katherine K. Matthay, William C. Mentzer Jr., Andree M. Dozy, Yuet Wai Kan, Dorothy F. Bainton