4.7 Article

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

期刊

JOURNAL OF ALLERGY AND CLINICAL IMMUNOLOGY
卷 146, 期 4, 页码 901-911

出版社

MOSBY-ELSEVIER
DOI: 10.1016/j.jaci.2019.11.051

关键词

NFKB1 variant; NFKB1 mutation; common variable immunodeficiency; reduced penetrance; NF-kappa B1-related phenotype; autosomal dominant

资金

  1. German Research Foundation (DFG) [SFB1160]
  2. Germany's Excellence Strategy [EXC-2189, 390939984, EXC 2155, 39087428]
  3. E-rare program of the European Union [GR1617/14-1]
  4. Netzwerke Seltener Erkrankungen of the German Ministry of Education and Research (BMBF) [GAIN_ 01GM1910A]
  5. German Ministry of Education and Research (BMBF) [01E01303, 01ZX1306F]
  6. MRC [MR/L006197/1, MR/K020919/1] Funding Source: UKRI

向作者/读者索取更多资源

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-kappa B) 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-kappa B1-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-kappa B1-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-kappa B1 pathway-targeted therapeutic strategies should be considered in the future.

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