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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 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