Primary Immune Regulatory Disorder with Features of Behçet’s Disease: The Role of Persistent CMV Viremia in Inflammatory Bowel Disease Pathogenesis

Background Behçet’s disease is a multisystem inflammatory disorder whose diagnosis can be challenging due to overlapping features with other inflammatory conditions and primary immunodeficiencies (1). In patients with immune dysregulation, the role of cytomegalovirus (CMV) in the development of inflammatory bowel disease remains poorly understood. We present a case of a patient initially diagnosed with Behçet’s disease who subsequently developed Crohn’s colitis in the setting of persistent CMV viremia and combined immunodeficiency. Case Presentation A 37-year-old woman was referred to our immunology service for recurrent sinopulmonary infections, hypogammaglobulinemia, and persistent CMV viremia. Her history included childhood varicella-zoster virus reactivation, chronic cytopenia, lymphadenopathy, hepatomegaly, and hypogammaglobulinemia. In 2017, she developed inflammatory arthralgias, oral ulcers, and biopsy-proven leukocytoclastic vasculitis, leading to a diagnosis of Behçet’s disease. Her course was complicated by severe thrombocytopenia requiring rituximab and Pneumocystis jirovecii pneumonia, followed by neuro-Behçet’s. In 2022, she developed COVID-19 pneumonia, followed by CMV viremia. In 2024, she presented with chronic diarrhea, weight loss, and rising CMV viral loads. Immunologic evaluation demonstrated CD4+ lymphopenia, persistently low B cell counts, and absent CMV-specific T cell responses (supplementary table 1). Colonoscopy confirmed Crohn’s colitis with superimposed CMV colitis. A close temporal relationship was observed between gastrointestinal symptoms and CMV viral burden, with C-reactive protein (CRP) peaking at 226.90 mg/L, coinciding with CMV detection, improving following viral suppression (11.90 mg/L), and rebounding (73.20 mg/L) directly with CMV recurrence (supplementary table 2). Whole-exome sequencing identified a heterozygous likely pathogenic variant in the SLC46A1 gene (supplementary table 3). Discussion This case emphasizes the complex interplay between genetic predisposition, immune dysregulation, and viral triggers in the pathogenesis of inflammatory disease. Comprehensive immunological evaluation and serial viral monitoring may be critical in patients with atypical presentations of rheumatologic diseases, particularly when accompanied by recurrent infections or unusual laboratory findings. Conclusion Further investigation into the role of persistent viral infections and folate pathway abnormalities in immune dysregulation may provide insights into novel therapeutic approaches for patients with complex immune-mediated inflammatory disorders. Tabular data are included as downloadable supplement files.