Digenic Inheritance of Hereditary Spherocytosis Type III and X-linked Agammaglobulinemia: Coexistence of Two Distinct Recessive Disorders in a Male Child

Hereditary spherocytosis (HS) is a common inherited hemolytic disease caused by mutations in genes encoding proteins crucial to the red blood cell (RBC) membrane, leading to a change in RBC shape from biconcave to spherical. There are five distinct types of hereditary spherocytosis, with types III and V being autosomal recessive and types I, II, and IV autosomal dominant. X-linked agammaglobulinemia (XLA) is a common inborn error of immunity that impairs B cell maturation and differentiation. We report a case of a two-year-old Saudi boy with persistent anemia, recurrent chest infections, and a subgaleal abscess. A whole exome sequencing study revealed digenic inheritance of hereditary spherocytosis type III and XLA. Despite a variant of uncertain significance in the Bruton's tyrosine kinase (BTK) gene, the patient's clinical and biochemical profile strongly indicated XLA. This case highlights how digenic inheritance can manifest as a complex phenotype, illustrating the challenges in diagnosing and managing patients with multigenic diseases.