A 27 years old primigravida hailing from Assam, a north-eastern state of India presented to the hospital for routine antenatal check up. She was clinically asymptomatic and had never received any blood transfusions. Her family history was negative. On examination, she had no organomegaly.
Her hemogram showed minimal anemia of 103 g/L with relative erythrocytosis and hypochromic microcytosis (RBC count: 4.44 x 1012/L, Mean Corpuscular Volume: 69.1fl and Mean Corpuscular Hemoglobin: 17.4 pg). Reticulocyte count was 2.1%. Peripheral blood film examination showed microcytic hypochromic red cells with occasional target cells (Figure 1). Her serum iron profile was normal. High pressure liquid chromatography (HPLC, Bio-Rad Variant II) done as part of routine screening in antenatal women revealed a variant peak in HbA2 region of 87.5% with a HbF of 1.5%, and HbA0 of 3.8% (Figure 2). Cellulose acetate hemoglobin electrophoresis at alkaline pH (8.6) showed a prominent band in C/E/O/A2 region and no band in A0 region (Figure 3). HPLC of the mother revealed a variant peak (23.8%) in HbA2 region indicating a heterozygous state for HbE disease (Figure 4). Her husband’s HPLC revealed an HbA2 of 5.2% with HbF of 1.2% and HbA0 of 84.6% (Figure 5). The molecular genotyping for the beta gene mutation showed heterozygous IVS I-5 (G>C) in HBB gene (NM_000518.5: c.[92+5G>C]) which is commonly encountered pathogenic variant encountered in this region.
The couple were normal for the common deletional genotypes (alpha 3.7 and 4.2 deletions) common in India. The couple were then counseled that the fetus has a 50% chance of being affected by a double heterozygous HbE-beta thalassemia state which usually has a thalassemia intermedia phenotype which can range from requirement of regular blood transfusions to non-transfusion dependent thalassemia syndrome. The prenatal DNA test on the chorionic villous biopsy showed the fetus to be a carrier of HbE and the pregnancy was continued.
Learning points
1. HbE disease is a thalassemic hemoglobinopathy affecting the HBB gene (HBB:c.79G>A).
2. The beta globin chain is reduced as this mutation creates an alternative splice donor site and leads to abnormal splicing.
3. Geographically, it is prevalent in South-East Asia including India, Thailand, Myanmar, Malaysia, Vietnam, etc.
4. Both heterozygous and homozygous states are asymptomatic. However, double heterozygous states with beta thalassemia can give rise to a thalassemia intermedia phenotype of variable severity. Double heterozygosity of HbE with sickle cell disease can result in a mild sickling disorder.
5. Spousal HPLC is required in patients with HbE disease to rule out beta thalassemia trait as this might lead to an affected fetus.
6. On complete blood count, it has microcytic hypochromic indices in both heterozygous and homozygous states.
