Atypical X‐Linked Severe Combined Immunodeficiency in a Patient With Early‐Onset Inflammatory Bowel Disease

ABSTRACT

Primary immunodeficiency disorders may present with gastrointestinal inflammation resembling inflammatory bowel disease (IBD), particularly in patients with pediatric or very‐early‐onset disease. We report a 24‐year‐old male with lifelong immune dysregulation and early‐onset IBD who was ultimately found to carry a hemizygous intronic IL2RG variant (c.270‐14C>G). Despite extensive infectious complications, lymphoproliferative disease, and chronic lung pathology, his Crohn's‐like intestinal inflammation had been managed successfully with azathioprine. Genome sequencing followed by RNA analysis demonstrated that the IL2RG variant introduced a cryptic splice acceptor site, causing aberrant splicing, intron retention, and a premature stop codon, confirming a diagnosis of atypical or hypomorphic X‐linked severe combined immunodeficiency (X‐SCID). This case expands the phenotypic spectrum of X‐SCID to include chronic IBD‐like enterocolitis and underscores the diagnostic utility of comprehensive genomic and transcriptomic testing in patients with complex, unexplained immune and gastrointestinal disease. Recognition of atypical presentations of X‐SCID has implications for surveillance, prognosis, and consideration of definitive therapies.