SPTA1-Related Hereditary Spherocytosis: Novel Compound Heterozygous Mutations With Severe Clinical Manifestation

Hereditary spherocytosis (HS) is a common hereditary hemolytic anemia in which red blood cells (RBCs) assume spherocytic morphology, predisposing to easy destruction in the spleen. Diagnosis is readily made when spherocytes are demonstrated in the blood film of patients presenting with anemia, jaundice, and splenomegaly. A positive osmotic fragility test (OFT) is also supportive. However, when classical features are not seen in either blood film or OFT, diagnosis might become complicated, particularly in resource-limited settings. We report a teenager who was transitioned to the adult medical outpatient department with a diagnosis of hemolytic anemia; the etiology, however, was never identified. He has required monthly transfusions since six months of life and has developed antibodies to RBCs, secondary hemochromatosis, and gallstones. Workup for thalassemia and autoimmune causes was negative. A barrage of negative investigations ultimately led to a genetic analysis, which revealed a heterozygous mutation for the c.2671C>T (p.Arg891*) variant in the SPTA1 gene and a novel mutation for SPTA1 c.7134+5G>A (intronic). He was formally diagnosed with HS and underwent splenectomy. Post procedure, his anemia improved, and transfusion requirements steadily reduced. His sister exhibits the same heterozygous mutation for SPTA1 c.7134+5G>A (intronic), but did not have any clinical or laboratory manifestation of the disease. We postulate that this novel mutation in SPTA1 c.7134+5G>A (intronic) might play a role in determining disease severity, particularly when associated with a pathogenic variant.