Clinical, Immunological, and Genetic Features in Patients with NFKB1 and NFKB2 Mutations: a Systematic Review

Inborn errors of immunity (IEIs) encompass various diseases with diverse clinical and immunological symptoms. Determining the genotype–phenotype of different variants in IEI entity precisely is challenging, as manifestations can be heterogeneous even in patients with the same mutated gene.

In the present study, we conducted a systematic review of patients recorded with NFKB1 and NFKB2 mutations, two of the most frequent monogenic IEIs.

The search for relevant literature was conducted in databases including Web of Science, PubMed, and Scopus. Information encompassing demographic, clinical, immunological, and genetic data was extracted from cases reported with mutations in NFKB1 and NFKB2. The comprehensive features of manifestations in patients were described, and a comparative analysis of primary characteristics was conducted between individuals with NFKB1 loss of function (LOF) and NFKB2 (p52-LOF/IκBδ-gain of function (GOF)) variants.

A total of 397 patients were included in this study, 257 had NFKB1 mutations and 140 had NFKB2 mutations. There were 175 LOF cases in NFKB1 and 122 p52^LOF/IκBδ^GOF cases in NFKB2 pivotal groups with confirmed functional implications. NFKB1LOF and p52^LOF/IκBδ^GOF predominant cases (81.8% and 62.5% respectively) initially presented with a CVID-like phenotype. Patients with NFKB1LOF variants often experienced hematologic autoimmune disorders, whereas p52^LOF/IκBδ^GOF patients were more susceptible to other autoimmune diseases. Viral infections were markedly higher in p52^LOF/IκBδ^GOF cases compared to NFKB1LOF (P-value < 0.001). NFKB2 (p52^LOF/IκBδ^GOF) patients exhibited a greater prevalence of ectodermal dysplasia and pituitary gland involvement than NFKB1LOF patients. Most NFKB1LOF and p52^LOF/IκBδ^GOF cases showed low CD19 + B cells, with p52^LOF/IκBδ^GOF having more cases of this type. Low memory B cells were more common in p52^LOF/IκBδ^GOF patients.

Patients with NFKB2 mutations, particularly p52^LOF/IκBδ^GOF, are at higher risk of viral infections, pituitary gland involvement, and ectodermal dysplasia compared to patients with NFKB1LOF mutations. Genetic testing is essential to resolve the initial complexity and confusion surrounding clinical and immunological features. Emphasizing the significance of functional assays in determining the probability of correlations between mutations and immunological and clinical characteristics of patients is crucial.