Hemoglobin Chapel Hill masquerading as hemoglobin S in newborn sickle cell screening: A case study

Newborn screening for hemoglobinopathies is an effective tool for the early detection of clinically significant conditions, such as sickle cell disease. High-performance liquid chromatography (HPLC) is broadly used as it enables high-throughput automation and detection of clinically significant variants using minimal sample volumes. However, it may misidentify hemoglobin variants due to overlapping retention times.

Abnormal sickle cell screening results in a newborn female, including a peak in the hemoglobin S window, prompted hemoglobinopathy investigation. Capillary electrophoresis results suggested a possible alpha chain variant. Genetic testing revealed four distinct alterations, including a hemizygous HBA2 c.224A > G (p.Asp75Gly) variant, known as Hb Chapel Hill, and a 3.7 kb alpha-globin gene deletion consistent with an alpha-thalassemia silent carrier state.

This case represents the first documented occurrence of Hb Chapel Hill in an infant. Gamma globin production alongside Hb Chapel Hill results in a HbS zone peak on both HPLC and capillary electrophoresis, posing an interpretive challenge. Considering the complete pattern of peaks observed in hemoglobin fractionation methods can help distinguish clinically relevant conditions from likely benign profiles. Molecular analysis in complex cases is essential for confirmation of the suspected diagnosis.