Characterization of the clinical and immunologic phenotype and management of 157 individuals with 56 distinct heterozygous NFKB1 mutations

J Allergy Clin Immunol. 2020 Oct;146(4):901-911. doi: 10.1016/j.jaci.2019.11.051. Epub 2020 Apr 9.

Abstract

Background: An increasing number of NFKB1 variants are being identified in patients with heterogeneous immunologic phenotypes.

Objective: To characterize the clinical and cellular phenotype as well as the management of patients with heterozygous NFKB1 mutations.

Methods: In a worldwide collaborative effort, we evaluated 231 individuals harboring 105 distinct heterozygous NFKB1 variants. To provide evidence for pathogenicity, each variant was assessed in silico; in addition, 32 variants were assessed by functional in vitro testing of nuclear factor of kappa light polypeptide gene enhancer in B cells (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%), noninfectious 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.

Conclusions: We present a comprehensive clinical overview of the NF-κB1-related phenotype, which includes immunodeficiency, autoimmunity, autoinflammation, and cancer. Because of its multisystem 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.

Keywords: NF-κB1-related phenotype; NFKB1 mutation; NFKB1 variant; autosomal dominant; common variable immunodeficiency; reduced penetrance.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Autoimmunity / genetics
  • Biological Variation, Population
  • Biomarkers
  • Disease Management
  • Female
  • Fluorescent Antibody Technique
  • Genetic Association Studies* / methods
  • Genetic Predisposition to Disease*
  • Heterozygote*
  • Humans
  • Immunohistochemistry
  • Kaplan-Meier Estimate
  • Magnetic Resonance Imaging
  • Male
  • Middle Aged
  • Mutation*
  • NF-kappa B p50 Subunit / genetics*
  • Phenotype*
  • Prognosis
  • Tomography, X-Ray Computed

Substances

  • Biomarkers
  • NF-kappa B p50 Subunit
  • NFKB1 protein, human