Final Diagnosis -- Double Heterozygote for Hemoglobin E and Beta Thalassemia



Contributor's Note:

Hemoglobin E (Hb E) is the second most common hemoglobin variant in the world after Hb S. The variant is virtually limited to people of Southeast Asian origin where malaria is endemic. It is estimated that the prevalence of Hb E in Southeast Asian immigrants to the United States is about 10%.

The Hb E variant is a result of a single amino acid substitution at the 26th position of the beta globin chain, where lysine is substituted for glutamic acid.

Hb E trait (heterozygous Hb E, Hb AE) is an asymptomatic benign condition associated with microcytosis (average MCV 72 fl) but no anemia. On electrophoresis, Hb A always predominates over Hb E. The amount of Hb E averages 30%, and is always less than 45%. There are no bone marrow abnormalities.

Hb E disease (homozygous Hb E, Hb EE) is also a benign disorder with a mild microcytic anemia (average MCV 62 fl, Hgb 12 g/dl). The reticulocyte count is normal and red blood cell morphology shows numerous target forms (up to 75% RBCs). Hemoglobin electrophoresis demonstrates 98% Hb E, with 2% Hb F and no Hb A. The bone marrow frequently shows mild erythroid hyperplasia.

Patients with combined Hb E/beta thalassemia (double heterozygotes) present with the most clinically severe Hb E syndromes, with clinical pictures indistinguishable from that of thalassemia intermedia or major. Patients present with a moderate to severe microcytic anemia (average MCV 70 fl, Hgb 6 g/dl) and an increased reticulocyte count. Peripheral blood smear demonstrates the target cells characteristic of Hb E and the basophilic stippling characteristic of beta thalassemia. Hemoglobin electrophoresis shows a predominance of Hb E (40-75%), with increased Hb F (7-40%) and variable Hb A (1-30%). The percentage of Hb F is always elevated. The bone marrow shows erythrocyte hyperplasia.

A Hb E syndrome should always be considered in a Southeast Asian patient with microcytosis, with or without anemia. The most common method used to identify variant hemoglobins is hemoglobin electrophoresis. Hb E co-migrates with the Group C hemoglobins (Hb C, E, A2, O Arab) on cellulose acetate pH 8.4-8.6. Hb E can be further distinguished by electrophoreses on citrate agar, pH 6.0-6.2, where it migrates with Hb A. In addition, Hb E can usually be distinguished from Hb C and Hb O Arab on a clinical basis, since Hb C and Hb O Arab are seen almost exclusively in people of African descent.

There has been much hypothesis as to whether the Hb E variant confers an increased resistance to malaria, similar to thalassemias. The studies to date have been inconclusive.

In summary, this three year-old child was incidentally found to have a severe microcytic anemia while undergoing work-up for ITP. The etiology of this patient's anemia is most likely due to double heterozygosity for Hb E and beta thalassemia. Unfortunately, by the time these conclusions had been reached, the patient and her parents had returned to Canada, and confirmatory hemoglobin electrophoresis on the parents could not be performed.


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    Contributed by Melissa Halpern, MD


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