Heterozygous IRF2BP2 Variant Associated with Immune Dysregulation and Recurrent Infections

Introduction IRF2BP2 encodes interferon regulatory factor 2 binding protein 2, a transcriptional co-repressor involved in modulating multiple immune pathways and maintenance of immune tolerance. Heterozygous IRF2BP2 variants have been linked to immune dysregulation, autoimmunity, and susceptibility to infections. Case Presentation We evaluated a family in which the index case, an adult, presented a benign lesion in the floor of the cavernous sinus showing lymphocytosis. He also suffered recurrent respiratory infections, chronic active hepatitis, and febrile episodes without infectious triggers. Immunological workup: hypergammaglobulinemia with elevated IgG and IgA, normal IgM levels, and persistent lymphocytosis characterized by an expansion of double-negative T cells. His 55-year-old sister presents arthritis, sicca, and Raynaud with altered capiloroscopy and C3 consumption, atopy, and lymphoproliferation. Whole exome sequencing (WES) identified a heterozygous missense variant in IRF2BP2 (c.1502G>T, p.Ser501Ile), located within a conserved domain critical for its repressor function. The same variant was confirmed by Sanger sequencing in his symptomatic sister. Sanger sequencing is pending in another sister who has severe arthritis and his niece, with recurrent Staphylococcus infections and prominent lymphadenopathy, and other family members with autoimmunity. Type I interferon-stimulated gene (ISG) profiling showed an elevated interferon signature in the proband and his sister. These findings are consistent with a possible autosomal dominant inheritance pattern with full penetrance but variable expressivity. Discussion Functional impairment of IRF2BP2 likely disrupts immune homeostasis by altering the transcriptional repression of pro-inflammatory pathways and regulatory T cell function, contributing to the development of autoimmunity and recurrent infections. Lymphoproliferation, including the expansion of unconventional T cell subsets, supports the presence of immune dysregulation. Conclusion IRF2BP2 variants should be considered in patients with unexplained immune dysregulation, overlapping features of autoimmunity, lymphoproliferation, and recurrent infections. Genetic testing facilitates early diagnosis and supports targeted management strategies, including immunosuppressive therapy and family counseling.