Background An increasing number of NFKB1 variants are being identified in patients with heterogeneous immunological phenotypes. Objective We set out to characterize the clinical and cellular phenotype as well as the management of patients with heterozygous NFKB1 mutations. Methods In a world-wide collaborative effort, we evaluated 231 individuals harboring 105 distinct heterozygous NFKB1 variants. To provide evidence for pathogenicity, each variant was assessed in silico; additionally, 32 variants were assessed by functional in vitro testing of NF-κB signaling. Results We classified 56 of the 105 distinct NFKB1 variants in 157 individuals from 68 unrelated families as pathogenic. Incomplete clinical penetrance (70%) and age-dependent severity of NFKB1-related phenotypes were observed. The phenotype included hypogammaglobulinemia (88·9%), reduced switched memory B cells (60·3%), and respiratory (83%) and gastrointestinal (28·6%) infections, thus characterizing the disorder as primary immunodeficiency. However, the high frequency of autoimmunity (57·4%), lymphoproliferation (52·4%), non-infectious enteropathy (23·1%), opportunistic infections (15·7%), autoinflammation (29·6%), and malignancy (16·8%) identified NF-κB1-related disease as an inborn error of immunity with immune dysregulation, rather than a mere primary immunodeficiency. Current treatment includes immunoglobulin replacement and immunosuppressive agents. Conclusion We present a comprehensive clinical overview of the NF-κB1-related phenotype, which includes immunodeficiency, autoimmunity, autoinflammation, and cancer. Due to its multi-system involvement, clinicians from each and every medical discipline need to be made aware of this autosomal-dominant disease. Hematopoietic stem cell transplantation and NF-κB1 pathway-targeted therapeutic strategies should be considered in the future.
- 1184 Genetiikka, kehitysbiologia, fysiologia
- 3111 Biolääketieteet