Coinheritance of Alpha^-3.7 Deletion and Hb Questembert [¹³¹alpha-2 Tct > CCT](Ser131>Pro)] in an African American Patient Results in an Alpha Thalassemia Phenotype

Patients with Hemoglobin Questembert carry a Ser131Pro mutation in one of their alpha globin chains encoded by a TCT-CCT mutation of one of their alpha 2 globin gene. This mutation usually results in an unstable hemoglobin variant with mild anemia that is rarely symptomatic. Rarely these patients may show increased extravascular hemolysis during stress, due to oxidative membrane damage. Our patient is a 7 year old African American girl that came to medical attention due to severe anemia, reticulocytosis, absent haptoglobin levels, persistent jaundice and hyperbilirubinemia. Over a period of several years the patient progressed to develop marked splenomegaly with progressive anemia. Isoelectric focusing in this patient revealed Hb A, A2 and a variant "S" band which was less than 1% and thus not detectable by HPLC. We speculate that in the presence of limited alpha globin synthesis, due to a deletion of one α-2 gene and in the presence of a highly unstable alpha-2 variant, synthesis of wild-type alpha globin from the remaining alpa-1 gene is not sufficient to allow for normal alpha-globin/ beta-globin assembly. Furthermore the assembly of the alpha-globin Questembert into the hemoglobin tetramer is favored resulting in an extravascular hemolytic disorder.