Publications Search

Search for publications by author
Search for publications by abstract keyword(s)

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


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-kappaB) 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-kappaB1-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-kappaB1-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-kappaB1 pathway-targeted therapeutic strategies should be considered in the future.

Type Journal
ISBN 1097-6825 (Electronic) 0091-6749 (Linking)
Authors Lorenzini, T.; Fliegauf, M.; Klammer, N.; Frede, N.; Proietti, M.; Bulashevska, A.; Camacho-Ordonez, N.; Varjosalo, M.; Kinnunen, M.; de Vries, E.; van der Meer, J. W. M.; Ameratunga, R.; Roifman, C. M.; Schejter, Y. D.; Kobbe, R.; Hautala, T.; Atschekzei, F.; Schmidt, R. E.; Schroder, C.; Stepensky, P.; Shadur, B.; Pedroza, L. A.; van der Flier, M.; Martinez-Gallo, M.; Gonzalez-Granado, L. I.; Allende, L. M.; Shcherbina, A.; Kuzmenko, N.; Zakharova, V.; Neves, J. F.; Svec, P.; Fischer, U.; Ip, W.; Bartsch, O.; Baris, S.; Klein, C.; Geha, R.; Chou, J.; Alosaimi, M.; Weintraub, L.; Boztug, K.; Hirschmugl, T.; Dos Santos Vilela, M. M.; Holzinger, D.; Seidl, M.; Lougaris, V.; Plebani, A.; Alsina, L.; Piquer-Gibert, M.; Deya-Martinez, A.; Slade, C. A.; Aghamohammadi, A.; Abolhassani, H.; Hammarstrom, L.; Kuismin, O.; Helminen, M.; Allen, H. L.; Thaventhiran, J. E.; Freeman, A. F.; Cook, M.; Bakhtiar, S.; Christiansen, M.; Cunningham-Rundles, C.; Patel, N. C.; Rae, W.; Niehues, T.; Brauer, N.; Syrjanen, J.; Seppanen, M. R. J.; Burns, S. O.; Tuijnenburg, P.; Kuijpers, T. W.; BioResource, Nihr; Warnatz, K.; Grimbacher, B.; BioResource, Nihr
Responsible Garvan Author Dr Bella Shadur
Published Date 2020-10-31
Published Volume 146
Published Issue 4
Published Pages 901-911
Status Published in-print
DOI 10.1016/j.jaci.2019.11.051
URL link to publisher's version