Clinical Heterogeneity in NFKB1 Deficiency: Report of Two Cases
Year: 2025
Type: article
Study design: Case Report
Abstract: Introduction Heterozygous pathogenic variants in NFKB1, encoding the p105/p50 subunit of the NF-κB complex, are among the most frequent monogenic causes of combined immunodeficiency with immune dysregulation. Clinical manifestations are highly variable and may include autoimmunity, susceptibility to infections, autoinflammation, and even malignancy. Recent findings also suggest a role in hyperinflammatory responses due to impaired autophagy and enhanced type I interferon signaling. Case Presentation Case 1: A 34-year-old male, previously healthy, presented at age 32 with genital verrucous lesions, dysphagia, weight loss, and oral candidiasis. He was diagnosed with HPV infection, ulcerative esophagitis, and later developed a Buschke–Löwenstein tumor and soft tissue infections. Laboratory findings showed IgG in 660 mg/dL, normal IgA and IgM, leukopenia, neutropenia, and lymphopenia. Genetic analysis revealed a heterozygous pathogenic variant in NFKB1: c.904dup (p.Ser302Phefs*7). Case 2: A 21-year-old female began at age of 5 with idiopathic thrombocytopenic purpura, followed by autoimmune hemolytic anemia. She experienced recurrent pneumonias and an episode of septic shock. At her last admission, she had fungal otitis externa, lymphopenia, neutropenia, and hypogammaglobulinemia. Immunophenotyping showed reduced T (CD4+, CD8+), B (CD20+), and natural killer cell counts. She carried the heterozygous pathogenic variant in NFKB1 c.909dup (p.Thr304Hisfs*5). Discussion These cases illustrate the broad clinical spectrum of NFKB1 deficiency, from early-onset autoimmunity to severe infections. Both frameshift variants result in premature protein truncation and support a loss-of-function mechanism. Recognition of this heterogeneity is key for timely diagnosis. Genetic testing should be considered in patients with overlapping features of autoimmunity and immunodeficiency to guide appropriate management.
Source: Journal of Human Immunity
Institutions: Hospital Civil de Guadalajara, Universidad de Guadalajara
Language: English
Subfield: Immunology
Field: Immunology and Microbiology
Domain: Life Sciences
Open Access status: diamond
OpenAlex ID: W7116793874
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