Deletion of IRF2BP2 Presenting as Late-Onset Common Variable Immunodeficiency with Bronchiectasis

Interferon regulatory factor-2-binding protein-2 (IRF2BP2) is a transcriptional regulator affecting diverse cellular functions, including cell differentiation and apoptosis. It plays an important role in lymphocyte and macrophage activation, positioning IRF2BP2 as a key regulator of the immune response. IRF2BP2 haploinsufficiency typically presents with common variable immunodeficiency (CVID) complicated by gastrointestinal and autoimmune features starting at a young age. Herein, we describe a case of late-onset CVID complicated by bronchiectasis associated with a heterozygous deletion in the IRF2BP2 gene.A 67-year-old White female had an unremarkable childhood and early adult medical history presented to the National Institutes of Health (NIH) (NCT00001355). At age 58 years, she was found to have an elevated C-reactive protein (CRP) level without an identifiable etiology. At age 65 years, she had an episode of laryngitis with dyspnea, and chest imaging revealed bronchiectasis. She reported no prior history of invasive or opportunistic infections, gastrointestinal or autoimmune disorders. Her family history was notable for immune-mediated disorders: a brother with CVID and Crohn’s disease, a nephew with CVID and Crohn’s disease, and a niece with Crohn’s disease. Further workup revealed pan-hypogammaglobulinemia (IgG 355, IgA 57, and IgM 11 mg/dL) with reduced class-switched memory B cells and an inadequate antibody response to pneumococcal polysaccharide vaccine, supporting a diagnosis of CVID. Whole-genome sequencing with chromosomal microarray analysis identified a heterozygous ∼0.003 Mb deletion within 1q42.3 involving the entire sequence of IRF2BP2. Her clinical, immunologic, and genetic findings are compatible with autosomal-dominant CVID due to IRF2BP2 haploinsufficiency. She was started on immunoglobulin replacement therapy, but CRP levels have remained mildly elevated without other symptoms. This case highlights the variable expressivity of CVID caused by IRF2BP2 haploinsufficiency, even within the same family, and shows that disease onset may occur later in life.DisclaimerThis research was supported by the Intramural Research Program of the NIH. The contributions of the NIH author(s) were made as part of their official duties as NIH federal employees, are in compliance with agency policy requirements, and are considered Works of the United States Government. The findings presented are those of the author(s).