TY - JOUR
T1 - Characterization of the clinical and immunologic phenotype and management of 157 individuals with 56 distinct heterozygous NFKB1 mutations
AU - NIHR BioResource
AU - NIHR BioResource
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 - Bethune, Claire
N1 - Publisher Copyright:
© 2020
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.
KW - autosomal dominant
KW - common variable immunodeficiency
KW - NF-κB1-related phenotype
KW - NFKB1 mutation
KW - NFKB1 variant
KW - reduced penetrance
UR - https://www.scopus.com/pages/publications/85084240212
U2 - 10.1016/j.jaci.2019.11.051
DO - 10.1016/j.jaci.2019.11.051
M3 - Article
AN - SCOPUS:85084240212
SN - 0091-6749
VL - 146
SP - 901
EP - 911
JO - Journal of Allergy and Clinical Immunology
JF - Journal of Allergy and Clinical Immunology
IS - 4
ER -
SDG 3 Good Health and Well-being