Familial Cohort with Novel IRF2BP2 Variant and Autoimmunity

We present a 16-month-old previous term male with recurrent infections starting at 3 months of age. Parents reported recurrent infections, including 2 episodes of RSV and 8 episodes of otitis media by 6 months of age, requiring tympanostomy tubes—with persistent drainage for months afterward. He was up-to-date with vaccines. Family history was significant for autoimmunity. Mother and great maternal aunt have systemic lupus erythematosus diagnosed in adulthood. The mother also has Sjögren’s disease and had recurrent otitis media during childhood. The maternal grandmother has hypothyroidism, rheumatoid arthritis, Raynaud's, lichen planopilaris, irritable bowel syndrome, monoclonal gammopathy of undetermined significance, and breast cancer. She was also diagnosed with common variable immunodeficiency (CVID) at age 50. Initial immune evaluation was unremarkable with normal T, B, and NK cell counts, B cell subpopulations, immunoglobulin levels, and protective titers to diphtheria and tetanus. Genetic testing via commercial genetic panel for inborn errors of immunity revealed a missense variant of uncertain significance in IRF2BP2 in exon 1 c.794C>T (p.Ala265Val). The gnomAD database (v4.1) shows a population frequency of 0.00001799 for the variant. The variant has an AlphaMissense score of 0.08059, categorizing it as likely benign, and a CADD score of 14.7. Other variants in the vicinity of this variant have been categorized as likely benign or of uncertain significance in ClinVar. Parental testing revealed that the variant was maternally inherited. Extended investigation confirmed that the variant is present in the maternal grandmother. Because impaired regulatory T cell function has been reported in IRF2BP2 deficiency, Foxp3 expression in T cells was tested in the patient and was normal. Increased type 1 interferon signature has also been described; type 1 interferon activity was normal in this patient. IRF2BP2 mutations have also been associated with STAT1 hyperactivity; however, STAT1 functional testing was normal for our patient. IRF2BP2 was initially associated with CVID with the phenotype expanding further to include autoimmunity and immune dysregulation. Our patient does not currently have features of CVID or autoimmunity; however, the family history is significant for both. He will require careful lifetime monitoring for both of these conditions.