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

Journal Article (Journal Article)

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.

Full Text

Duke Authors

Cited 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, JWM; Ameratunga, R; Roifman, CM; Schejter, YD; Kobbe, R; Hautala, T; Atschekzei, F; Schmidt, RE; Schröder, C; Stepensky, P; Shadur, B; Pedroza, LA; van der Flier, M; Martínez-Gallo, M; Gonzalez-Granado, LI; Allende, LM; Shcherbina, A; Kuzmenko, N; Zakharova, V; Neves, JF; Svec, P; Fischer, U; Ip, W; Bartsch, O; Barış, S; Klein, C; Geha, R; Chou, J; Alosaimi, M; Weintraub, L; Boztug, K; Hirschmugl, T; Dos Santos Vilela, MM; Holzinger, D; Seidl, M; Lougaris, V; Plebani, A; Alsina, L; Piquer-Gibert, M; Deyà-Martínez, A; Slade, CA; Aghamohammadi, A; Abolhassani, H; Hammarström, L; Kuismin, O; Helminen, M; Allen, HL; Thaventhiran, JE; Freeman, AF; Cook, M; Bakhtiar, S; Christiansen, M; Cunningham-Rundles, C; Patel, NC; Rae, W; Niehues, T; Brauer, N; Syrjänen, J; Seppänen, MRJ; Burns, SO; Tuijnenburg, P; Kuijpers, TW; Warnatz, K; Grimbacher, B; Adhya, Z; Alachkar, H; Anantharachagan, A; Antrobus, R; Arumugakani, G; Ashford, S; Astle, WJ; Attwood, A; Bacchelli, C; Batista, J; Baxendale, HE; Bethune, C; Bibi, S; Bleda, M; Boardman, B; Booth, C; Bradley, JR; Breen, G; Brown, M; Browning, MJ; Brownlie, M; Buckland, MS; Burren, OS; Carss, K; Chambers, J; Chandra, A

Published Date

  • October 1, 2020

Published In

Volume / Issue

  • 146 / 4

Start / End Page

  • 901 - 911

Electronic International Standard Serial Number (EISSN)

  • 1097-6825

International Standard Serial Number (ISSN)

  • 0091-6749

Digital Object Identifier (DOI)

  • 10.1016/j.jaci.2019.11.051

Citation Source

  • Scopus