Distinct Phenotypic Expression Associated with a New Hyperunstable Alpha Globin Variant (Hb Heraklion, α1cd37(C2)Pro>0): Comparison to Other α-Thalassemic Hemoglobinopathies

Clinical phenotypes associated with abnormal globin chain biosynthesis may result in thalassemia (deficient quantity) or hemolytic anemia (abnormal hemoglobins). However, the phenotypic expression of hyperunstable hemoglobin variants often includes features of thalasssemia, along with variable peripheral hemolysis. Hemoglobinopathies caused by highly unstable β-chain variants have a dominant thalassemia-like phenotype, in which carriers have a clinical expression of thalassemia intermedia, but highly unstable α-globin variants are usually only phenotypically apparent when they interact with other α-thalassemia mutations. In a child with clinical and hematological features consistent with β-thalassemia intermedia, DNA analysis excluded any β-globin gene mutations but characterized a novel deletion cd37(C2)Pro>0 (Hb Heraklion) in the α1 globin gene, in trans to a common Mediterranean nondeletion α-thalassemia mutation (αHphα). The deletion of proline at α37(C2) is predicted to result in severe instability of the variant hemoglobin, which on interaction with a synthesis-deficient α-thalassemia mutation causes a relatively severe dyserythropoietic anemia, representing an alternative phenotype associated with highly unstable α-chain variants. Hb Heraklion is the fourth highly unstable α-globin variant that we have observed in patients from Greece and Albania. Two variants involve the α2-globin gene: Hb Agrinio (α29(B10)Leu>Pro) and Hb Adana (α59(E8)Gly>Asp), and two the α1-gene: Hb Aghia Sophia (α62(E11)Val>0) and (Hb Heraklion a37(C2)Pro>0). Each has been observed on interaction with a different α-thalassemia mutation and the phenotypes associated with these highly unstable α-variants are presented.