Phenotypic Spectrum of Heterozygous NFKB1 Variants in Four Unrelated Families from Argentina

Introduction Nuclear factor-kappa B (NF-κB) is a pivotal transcription factor involved in immune regulation, inflammation, and cell survival. Initially identified as a key regulator in B cell development and function, mutations in NFKB1 have been increasingly recognized as a cause of inborn errors of immunity (IEIs), particularly common variable immunodeficiency (CVID). NF-κB also mediates inflammatory responses across various cell types, contributing to a wide array of clinical phenotypes. Variants in NFKB1 exhibit incomplete penetrance and variable expressivity, leading to diverse immunological and autoinflammatory conditions. Objective To characterize the clinical, immunological, and genetic features of patients harboring heterozygous NFKB1 variants from four unrelated Argentine families. Methods This retrospective study analyzed clinical data, laboratory results, and genetic findings from patients seen at the Bezrodnik Immunology Centre and Hospital El Cruce. Results A total of nine patients from four unrelated families carrying heterozygous NFKB1 variants were included. All variants were classified as likely pathogenic, according to the American College of Medical Genetics and Genomics/ClinGen guidelines. Two novel variants were identified: c.202G>A (p.Gly68Ser) and c.936_937del (p.Val313Fs). Sex distribution: four females and five males, median-age 26 years (range 6–75). Clinically, 55% experienced recurrent respiratory infections, 33% had lymphoproliferative features such as adenopathy and splenomegaly, and 22% presented with autoimmune cytopenias. Other manifestations: chronic diarrhea (11%) and onychomycosis (11%). Immunologically, hypogammaglobulinemia was observed in 66%, and reduced switched memory B cells in the same proportion. One exhibited CD21low 21%. Treatment approaches: 55% received immunoglobulin replacement therapy, three patients were on immunosuppressants (mycophenolate mofetil and systemic steroids), and one with rituximab. Interestingly, two asymptomatic carriers were identified, highlighting incomplete penetrance. Conclusion Heterozygous NFKB1 variants are associated with a broad spectrum of clinical phenotypes, including antibody deficiencies, lymphoproliferation, and autoinflammatory features. Further research into the mechanisms of phenotypic variability will enhance our understanding of NF-κB pathway disorders and inform future therapeutic approaches.