Rare thalassemic syndrome caused by interaction of Hb Questembert (α1 codon 131, TCT>CCT, Ser>Pro) with an α-thalassemia-2 deletion: implications for diagnosis and management

Abnormal globin chain biosynthesis may result in deficient quantity (thalassemia) or structural variation (abnormal hemoglobins) and traditionally, they represent two phenotypically distinct groups of disorders. However, the phenotypic expression of unstable hemoglobin variants often combine features of thalassemia together with variable peripheral hemolysis. To achieve definitive diagnosis in a child presenting with hemolytic anemia along with features associated with thalassemia intermedia, we evaluated clinical, hematological, biochemical, globin biosynthetic and molecular data. Definitive diagnosis was achieved by DNA analysis which characterized the proband to be a compound heterozygote for a common α-thalassemia-2 deletion (3.7kb) and Hb Questembert (α131[H14] Ser>Pro) caused by a C>T mutation in codon 131 of the α1 globin gene in trans. The phenotype of thalassemia intermedia with marked dyserythropoiesis, found in patients inheriting α-thalassemia mutations along with unstable α-globin variants (i.e., α-thalassemic hemoglobinopathies), represents a distinct type of thalassemic syndrome. The proband in this study additionally had variable peripheral hemolysis, presumably related to characteristics of the unstable Hb Questembert. There is minimal experience for the management of such atypical cases and this case illustrates that it is probably insufficient to monitor clinical status in patients with such hemoglobinopathies based only on the levels of hemoglobin.