Pitfalls in the Diagnosis of beta-Thalassemia Intermedia

We present case histories of three patients who had beta-thalassemia (beta-thal) trait with 'unusual severity' managed as beta-thal intermedia (beta-TI) where the basis of disease severity could not be explained with routine hematological and genetic investigations. The clinical diagnosis of 'thalassemia intermedia' was justifiable as they had a beta-thal mutation and disease severity that did not fit in with either beta-thal trait or with beta-thal major (beta-TM). As mutations of alpha, beta, and gamma genes could not explain the unusual severity of the disease, further analysis with next-generation sequencing (NGS) for red cell diseases was carried out, which led to the diagnosis of coexisting membranopathies. This case series highlights the inherent difficulty in the diagnosis of beta-TI with certainty in some patients where the genetic basis is not clear-cut.