Congenital hemolytic anemias represent a genetically and clinically heterogeneous group of disorders that broadly fall into three categories: disorders of the red blood cell membrane, enzyme deficiencies, and hemoglobinopathies. The predominant conditions within these categories are hereditary spherocytosis (HS), glucose-6-phosphate dehydrogenase (G6PD) deficiency, and thalassemia, respectively. Despite their distinct pathogenic mechanisms, these disorders share overlapping clinical manifestations including anemia, jaundice, splenomegaly, and reticulocytosis, which can create significant diagnostic challenges, particularly when multiple conditions coexist.
Hereditary spherocytosis is the most common inherited red blood cell membrane disorder, characterized by the presence of spherocytes in the peripheral blood smear resulting from defects in membrane proteins that compromise structural integrity and deformability of erythrocytes. Thalassemia, on the other hand, is one of the most common monogenic hereditary diseases worldwide, caused by defective synthesis of one or more globin chains of hemoglobin. The co-occurrence of HS and thalassemia-related genetic variations is extremely rare and presents a unique clinical scenario that can complicate diagnosis and management. This case report describes a 2-year-old Chinese boy who presented with a complex hematological picture involving both hereditary spherocytosis and α-globin gene triplication. The child's initial disease manifestation was bilateral cataracts requiring surgical correction at age 5, followed by emergence of neuromuscular symptoms in adolescence including postural hand tremors at age 15 and progressive lower limb weakness at age 16.
However, the hematological manifestations were the most prominent feature, with a history of longstanding hemolytic disease characterized by recurrent acute episodes of anemia, with the lowest hemoglobin concentration reaching 78 g/L, accompanied by recurrent abdominal pain and jaundice, typically triggered by upper respiratory infections. Abdominal ultrasound revealed splenomegaly, and magnetic resonance imaging demonstrated cholecystolithiasis, findings consistent with chronic hemolytic disease. Although no family history of hemolytic anemia was reported and no typical spherocytes were observed on peripheral blood smear, the classic triad of anemia, jaundice, and splenomegaly strongly suggested the possibility of hemolytic anemia. Additional laboratory support came from heightened osmotic fragility of red blood cells and elevated reticulocyte count, both characteristic findings in hereditary spherocytosis.
The genetic investigation proved instrumental in establishing the definitive diagnosis. Mutation analysis identified a de novo heterozygous mutation in the SPTB gene: c.149-1G>A, a novel splicing mutation that was not detected in either parent, confirming its de novo origin. The SPTB gene, located at chromosome 14q23.3, encodes β-spectrin, a critical structural component of the erythrocyte cytoskeleton that plays an essential role in maintaining the biconcave shape, mechanical stability, and deformability of red blood cells. Mutations in SPTB are a well-established cause of hereditary spherocytosis, accounting for approximately 45% of HS cases in the Chinese population. The novel c.149-1G>A mutation identified in this patient affects the consensus splice acceptor site at the intron-exon boundary, and is predicted to disrupt proper pre-mRNA splicing of β-spectrin, leading to aberrant transcript processing and potentially a truncated or dysfunctional protein product.
This pathogenic variant has not been previously reported in the literature, expanding the known mutational spectrum of SPTB-related hereditary spherocytosis. The classification of this mutation as pathogenic is supported by its location at a critical splice site, its de novo occurrence in a patient with a consistent clinical phenotype, and absence of the variant in both unaffected parents. In addition to the SPTB mutation, genetic analysis revealed that the child carries α-globin gene triplication (αααanti4.2), a relatively rare numerical variation of the α-globin gene cluster on chromosome 16. α-globin gene triplication arises from unequal crossing over between misaligned homologous segments during meiosis, resulting in a chromosome containing three α-globin structural loci instead of the normal two. In southern China, the prevalence of α-globin gene triplication has been estimated at 0.9% for the αααanti3.7 variant and 0.3% for the αααanti4.2 variant, with carrier rates varying across different provinces.
While carriers of α-globin gene triplication typically exhibit a normal hematological phenotype in the absence of β-thalassemia, the triplication can exacerbate the imbalance in globin chain synthesis in the context of β-thalassemia, potentially leading to more severe anemia. In this patient, who carried the α-globin gene triplication without β-thalassemia, the clinical presentation was more severe than typically expected for hereditary spherocytosis alone, raising the possibility that the α-globin gene triplication may have contributed to phenotypic severity, although the exact mechanism remains unclear and requires further investigation. The co-occurrence of hereditary spherocytosis and α-globin gene triplication in this patient highlights the complexity involved in diagnosing hemolytic anemias, particularly when multiple genetic factors contribute to the clinical phenotype.
DOI:10.1007/s11684-026-1226-y