Longstanding Microcytosis with a Thalassaemia-Like Phenotype and Inconclusive Molecular Testing: A Case Report

Persistent microcytosis in adults with normal or only mildly reduced haemoglobin usually prompts investigation for iron deficiency or thalassaemia trait. In some patients, however, the cause remains uncertain despite haemoglobin fractionation and targeted molecular testing.

An asymptomatic adult male had longstanding microcytosis, with haemoglobin of 13.6 g/dL, a red blood cell count of 5.67 × 10⁶/µL, and a mean corpuscular volume of 72 fL. Serum iron was low, but ferritin remained within the reference range at 100.5 ng/mL. Haemoglobin fractionation showed HbA₂ of 2.4% and HbF below 1%, without an abnormal fraction. Multiplex PCR, sequencing of HBA2, HBA1, and HBB, and MLPA of the alpha-globin gene cluster identified no causative deletion, sequence variant, or copy-number change within the scope of testing. Rare or untested mechanisms remained possible. Empirical iron treatment was not initiated.

The longstanding microcytosis, relatively preserved red blood cell count, normal HbA₂ and HbF, and preserved ferritin were consistent with a thalassaemia-like phenotype. Classical raised-HbA₂ beta-thalassaemia trait was considered less likely. An inherited alpha-globin abnormality or another disorder of haemoglobin synthesis remained possible, although it could not be confirmed. The preserved ferritin made absolute iron deficiency less likely, but iron-restricted erythropoiesis could not be excluded because additional iron studies were unavailable.

This case highlights the difficulty of interpreting a stable microcytic phenotype when molecular testing does not establish a causative abnormality. Molecular findings should be considered alongside the longitudinal haematological pattern and interpreted within the analytical scope of the methods used. Iron treatment should be reserved for patients in whom iron deficiency has been demonstrated by appropriate testing.