A Novel Case of IRF2BP2 Deficiency Presenting as a CVID-Like Disorder With Prominent Autoinflammatory Features and Dyslipidaemia

Background Interferon regulatory factor-2–binding protein-2 (IRF2BP2) is a nuclear transcriptional co-regulator originally characterised as a co-repressor of IRF2 but now recognised to exert broader functions as both a co-repressor and co-activator of additional transcription factors, including NFAT1, KLF2, and others. IRF2BP2 plays a pivotal role across innate and adaptive immune systems: it constrains CD4+ T cell activation by repressing IL-2–induced JAK-STAT5 signalling and activation markers (CD25 and CD69), promotes B cell maturation and immunoglobulin class switching, and attenuates NF-κB–mediated pro-inflammatory cytokine production. Beyond immunity, IRF2BP2 contributes to cholesterol homeostasis by facilitating cholesterol efflux in macrophages. Pathogenic variants in the IRF2BP2 gene have recently been identified as a monogenic cause of inborn errors of immunity, typically presenting with hypogammaglobulinaemia, poor vaccine responses, and pronounced immune dysregulation. Mouse models further implicate IRF2BP2 deficiency as a cause of accelerated cholesterol accumulation in macrophages, leading to macrophage-driven inflammation and early atherosclerosis. While case series have begun to define its phenotypic spectrum, single case reports remain valuable for highlighting clinical heterogeneity and expanding genotype–phenotype correlations. Case Presentation We report a 23-year-old male who presented with recurrent pyogenic skin and deep-seated abscesses, sinopulmonary infections, seronegative symmetric inflammatory polyarthritis affecting large joints (knees, wrists, ankles), radiologically confirmed bronchiectasis, and significant dyslipidaemia. Immunological evaluation demonstrated pan-hypogammaglobulinaemia, markedly reduced switched memory B cells, and impaired responses to both protein and polysaccharide vaccines, fulfilling criteria for common variable immunodeficiency (CVID). Genetic testing identified a heterozygous nonsense variant, c.1665C>A (p.Cys555*), in exon 2 of the IRF2BP2 gene, resulting in a premature stop codon and predicted truncation of the protein. The patient is the proband with no family history of immunodeficiency or autoimmunity. Although functional validation was not performed, the variant’s predicted loss-of-function effect and the congruent clinical phenotype strongly support pathogenicity. Conclusion This case adds to the expanding body of evidence implicating IRF2BP2 deficiency as an inborn error of immunity presenting with humoral immunodeficiency, autoinflammatory manifestations, and metabolic derangement. Recognition of this emerging genotype–phenotype association has important implications for diagnosis, genetic counselling, and the future development of targeted immunomodulatory therapies.