Interaction of an alpha(+)-thalassemia deletion with either a highly unstable alpha-globin variant (alpha 2, codon 59, G(G)under-barC -> G(A)under-barC) or a nondeletional alpha-thalassemia mutation (AATAA(A)under-bar -> AATAA(G)under-bar): Comparison of phenotypes illustrating "dominant" alpha-thalassemia

Thalassemia syndromes and unstable hemoglobins traditionally represent two phenotypically separate disorders of hemoglobin synthesis. Highly unstable hemoglobin variants, however, often have phenotypic characteristics associa ted with both ineffective erythropoiesis (thalassemias) and peripheral hemo lysis (unstable hemoglobins). Many highly unstable beta chain variants caus e a dominant thalassemia-like phenotype, in which simple heterozygotes for such mutations have a clinical expression similar to thalassemia intermedia . The phenotypic expression of highly unstable alpha-globin variants is usu ally less severe, due mainly to a gene dosage effect, and they are often on ly characterized on interaction with other alpha-thalassemia mutations, whe nce they are classified as nondeletional alpha-thalassemia determinants. Th is study reports the clinical and hematological findings in five cases with rare alpha-thalassemia genotypes: a single patient with the thalassemic al pha 2-globin gene codon 59 Gly-->Asp hemoglobin variant in trans to an alph a(+)-thalassemia deletion, and four compound heterozygotes for the nondelet ional alpha-thalassemia polyadenylation mutation (alpha 2 gene AATAAA-->AAT AAG or alpha(T-Saudi)alpha/-alpha) and an alpha(+)-thalassemia deletion. Ev aluation of the clinical and hematological features in these two analogous genotypes clearly demonstrates the more severe clinical expression associat ed with the alpha-thalassemic unstable hemoglobin variant. In addition, the case in this study with the codon 59 alpha chain variant provides a furthe r example illustrating the spectrum of phenotypes associated with the alpha -thalassemic hemoglobinopathies.