Indian Journal of Hematology and Blood Transfusion | 2021
Extreme Genotype/Phenotype Heterogeneity of Double Heterozygous Sickle β-Thalassemia in a Family: Implications in Antenatal Diagnosis
Abstract
Dear Sir, A 12-year-old boy from North India with transfusiondependent anemia for 3 years presented with recurrent episodes of chest and abdominal pain. Examination revealed mild pallor, icterus, and splenomegaly (12 cm below costal margin). No positive family history was found. On investigation, hemoglobin (Hb) was 83 g/L with reticulocytosis (8.0%). Peripheral blood film revealed hypochromic microcytosis with few target cells and drepanocytes. Cation-exchange high-performance liquid chromatography (CE-HPLC, Variant II instrument, Beta Thal Short program, BioRad Laboratories, USA) revealed a double heterozygous state for HbS ? b-thalassemia with HbS (61.2%), HbF (31%) with HbA2 (4.8%), and near absence of HbA0. Hemoglobin electrophoresis (pH-8.4) showed slow-migrating bands of HbF and HbS. Laboratory findings are summarized in Table 1. Hb-HPLCs of his father and two sisters showed b-thalassemia trait (Table 1, Fig. 1), while his mother’s Hb-HPLC also showed double heterozygous HbS ? b-thalassemia (HbS 62.1%, HbF 8.3%, HbA2 6.5%) but with 20.1% HbA0. The asymptomatic mother was 8 weeks pregnant and had mild pallor. In a detailed and leading history she denied any prior anemia, blood transfusions (including her three prior pregnancies), jaundice, chronic/episodic pain, leg ulcers or chronic medication use. Physical examination did not reveal organomegaly. Since both the mother and son showed double heterozygous HbS ? b-thalassemia but with completely divergent phenotypes, genetic studies were undertaken. Both were heterozygous for the sickle cell mutation [HBB:c.20A[T] by PCR–RFLP with DdeI. Amplification-refractory mutation system PCR testing in the patient and his father revealed heterozygosity for HBB:c.126_129delCTTT [Fr 41/42 (–CTTT)]. The mother was heterozygous for HBB:c.-138C[T [-88(C[T)]. Multiplex GAP PCR for a-globin gene deletions [-a, -a, –, –, –, –, – and –(a) ] and gene triplications aaa and aaa were negative in the mother and son. Xmn-1c polymorphism by PCR– RFLP displayed a ?/pattern in both. Subsequently, chorionic villus biopsy, revealed that the fetus was compound heterozygous for severe b Fr 41/42 (–CTTT) and mild b -88(C[T) mutation. The family was counseled about a likely transfusion-dependant thalassemia phenotype in the fetus and termination of the pregnancy. Sickle-beta thalassemia, despite its monogenic origins, can display genotype–phenotype heterogeneity as shown by our cases. Major implicating factors are the type of HBB allele (b, bor b), the HbS haplotype, co-inheritance of alpha thalassemia (ameliorating) or alpha gene triplication (aggravating), and factors modulating HbF production (e.g., Xmn1c)[1]. In our mother-son duo, the co-inheritance of HbS, alpha-globin status, and Xmn1c status were identical. The clinical heterogeneity was attributable to the different HBB mutations which led to a significant difference in the production of HbA0. & Reena Das [email protected]