Markedly elevated fetal hemoglobin in myeloid neoplasms: A potential diagnostic pitfall during hemoglobinopathy work-up

Objectives: Screening tests, including high-performance liquid chromatography (HPLC) for the diagnosis of thalassemia syndromes, are based primarily on the detection of markedly elevated levels of fetal hemoglobin (HbF). However, several uncommon acquired conditions can also occasionally raise HbF levels to those similar to hemoglobinopathies. Very high HbF levels in myeloid neoplasms may reflect an extreme form of stress erythropoiesis, i.e., a reversion to a fetal phenotype characterized by red cell macrocytosis, reduced HbA2, increased i antigen expression, an excess of G γ over A γ globin chains, and low carbonic anhydrase levels with a fetal-type isozyme pattern. This study aims to explore the diagnostic challenges of elevated HbF on HPLC and highlight the value of combining morphological assessment and parental studies to improve the accuracy of thalassemia diagnosis. Materials and Methods: Cases with elevated HbF on HPLC were identified from laboratory archives, and clinical data were retrieved from the case files. Inherited hemoglobinopathies were excluded by the absence of prior suggestive history and confirmed by parental HPLC studies. Results: We report five male patients with unusually high acquired HbF levels associated with acute myeloid leukemia (AML) with myelodysplasia-related changes (a 24-year-old with 46.1% HbF), acute erythroleukemia (a 3-year-old with 38.9% HbF), and three juvenile myelomonocytic leukemia (JMML) patients (3-year-old with 44.2% HbF, 3-year-old with 58.2% HbF, and 5-year-old with 38% HbF). Conclusions: Recognizing dysplasia and increased blasts in blood and marrow during HPLC interpretation helped prevent misdiagnosis of thalassemia syndrome and unnecessary work-ups. Blood film review and parental HPLCs should be essential steps in all suspected thalassemia cases.