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

TY - JOUR

T1 - Characterization of the clinical and immunologic phenotype and management of 157 individuals with 56 distinct heterozygous NFKB1 mutations

AU - Lorenzini, Tiziana

AU - Fliegauf, Manfred

AU - Klammer, Nils

AU - Frede, Natalie

AU - Proietti, Michele

AU - Bulashevska, Alla

AU - Camacho-Ordonez, Nadezhda

AU - Varjosalo, Markku

AU - Kinnunen, Matias

AU - de Vries, Esther

AU - van der Meer, Jos W M

AU - Ameratunga, Rohan

AU - Roifman, Chaim M

AU - Schejter, Yael D

AU - Kobbe, Robin

AU - Hautala, Timo

AU - Atschekzei, Faranaz

AU - Schmidt, Reinhold E

AU - Schröder, Claudia

AU - Stepensky, Polina

AU - Shadur, Bella

AU - Pedroza, Luis A

AU - van der Flier, Michiel

AU - Martínez-Gallo, Mónica

AU - Gonzalez-Granado, Luis Ignacio

AU - Allende, Luis M

AU - Shcherbina, Anna

AU - Kuzmenko, Natalia

AU - Zakharova, Victoria

AU - Neves, João Farela

AU - Svec, Peter

AU - Fischer, Ute

AU - Ip, Winnie

AU - Bartsch, Oliver

AU - Barış, Safa

AU - Klein, Christoph

AU - Geha, Raif

AU - Chou, Janet

AU - Alosaimi, Mohammed

AU - Weintraub, Lauren

AU - Boztug, Kaan

AU - Hirschmugl, Tatjana

AU - Dos Santos Vilela, Maria Marluce

AU - Holzinger, Dirk

AU - Seidl, Maximilian

AU - Lougaris, Vassilios

AU - Plebani, Alessandro

AU - Alsina, Laia

AU - Piquer-Gibert, Monica

AU - Deyà-Martínez, Angela

AU - Slade, Charlotte A

AU - Aghamohammadi, Asghar

AU - Abolhassani, Hassan

AU - Hammarström, Lennart

AU - Kuismin, Outi

AU - Helminen, Merja

AU - Allen, Hana Lango

AU - Thaventhiran, James E

AU - Freeman, Alexandra F

AU - Cook, Matthew

AU - Bakhtiar, Shahrzad

AU - Christiansen, Mette

AU - Cunningham-Rundles, Charlotte

AU - Patel, Niraj C

AU - Rae, William

AU - Niehues, Tim

AU - Brauer, Nina

AU - Syrjänen, Jaana

AU - Seppänen, Mikko R J

AU - Burns, Siobhan O

AU - Tuijnenburg, Paul

AU - Kuijpers, Taco W

AU - Warnatz, Klaus

AU - Grimbacher, Bodo

AU - NIHR BioResource

N1 - Copyright © 2020. Published by Elsevier Inc.

PY - 2020/10

Y1 - 2020/10

N2 - 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.

AB - 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.

U2 - 10.1016/j.jaci.2019.11.051

DO - 10.1016/j.jaci.2019.11.051

M3 - SCORING: Journal article

C2 - 32278790

VL - 146

SP - 901

EP - 911

JO - J ALLERGY CLIN IMMUN

JF - J ALLERGY CLIN IMMUN

SN - 0091-6749

IS - 4

ER -