Revisiting hemoglobin constant spring: molecular insights, pathophysiological mechanisms, and clinical perspectives

Abstract

Background: Hemoglobin Constant Spring (Hb CS) is an α-globin variant predominantly found in Southeast Asian populations. Compound heterozygosity of Hb CS with α-thalassemia results in a spectrum of chronic hemolytic anemia. Recent advances in cellular therapy, particularly gene editing approaches currently under in-vitro investigation, offer potential new avenues for treatment in patients with severe phenotypes. Main body: This review discusses the molecular basis, pathophysiology, clinical manifestations, and current management strategies of Hb CS. The condition arises from a point mutation in the termination codon of the HBA2 gene (HBA2:c.427T > C; p.Ter143Gln), leading to unstable mRNA, defective hemoglobin synthesis, and red blood cell membrane abnormalities. The clinical presentation of Hb H/Constant Spring disease and related genotypes ranges from mild anemia to severe hemolysis. In cases of homozygous Hb Constant Spring, affected fetuses may present with hydrops fetalis and severe intrauterine anemia; however, clinical improvement is typically observed after birth, with anemia often stabilizing to a milder form during infancy or early childhood. Management strategies vary from observation in mild cases to regular blood transfusions in more severe cases. Emerging gene editing techniques, including prime editing, represent promising therapeutic modalities under preclinical investigation. Conclusion: Hb CS is characterized by complex molecular mechanisms and a broad clinical spectrum. This review aims to provide a comprehensive overview to support improved clinical management of affected individuals and to explore future directions in therapeutic development.