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

An increasing number of NFKB1 variants are being identified in patients with heterogeneous immunologic phenotypes. To characterize the clinical and cellular phenotype as well as the management of patients with heterozygous NFKB1 mutations. In a worldwide collaborative effort, we evaluated 231 indivi...

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Published in:	Journal of allergy and clinical immunology Vol. 146; no. 4; pp. 901 - 911
Main Authors:	Lorenzini, Tiziana, Fliegauf, Manfred, Klammer, Nils, Proietti, Michele, Bulashevska, Alla, Schejter, Yael D., Atschekzei, Faranaz, Stepensky, Polina, Pedroza, Luis A., van der Flier, Michiel, Martínez-Gallo, Mónica, Svec, Peter, Fischer, Ute, Ip, Winnie, Geha, Raif, Chou, Janet, Alosaimi, Mohammed, Weintraub, Lauren, Dos Santos Vilela, Maria Marluce, Holzinger, Dirk, Seidl, Maximilian, Lougaris, Vassilios, Plebani, Alessandro, Abolhassani, Hassan, Thaventhiran, James E., Warnatz, Klaus, Grimbacher, Bodo, Ashford, Sofie, Bacchelli, Chiara, Batista, Joana, Bibi, Shahnaz, Boardman, Barbara, Booth, Claire, Breen, Gerome, Burns, Siobhan O., Burren, Oliver S., Carss, Keren, Chambers, John, Cooper, Nichola, Davies, E.G., Dempster, John, Dewhurst, Eleanor F., Drewe, Elizabeth, Duarte, Daniel, Edgar, J. David M., Egner, William, El-Shanawany, Tariq, Erwood, Marie, Fox, James, Frontini, Mattia, Furnell, Abigail, Gaspar, H. Bobby, Gleadall, Nicholas S., Grigoriadou, Sofia, Hackett, Scott, Hague, Rosie, Haimel, Matthias, Hayman, Grant, Hu, Fengyuan, Huissoon, Aarnoud P., Jolles, Stephen, Kasanicki, Mary A., Kelleher, Peter, Klein, Nigel, Kreuzhuber, Roman, Kuijpers, Taco W., Kumararatne, Dinakantha, Allen, Hana Lango, Linger, Rachel, Lorenzo, Lorena E., Maimaris, Jesmeen, Martin, Jennifer, McDermott, Elizabeth M., Meacham, Stuart, Morrisson, Valerie, Nasir, Iman, Nejentsev, Sergey, Papadia, Sofia, Ponsford, Mark J., Quinn, Ellen, Quinti, Isabella, Rayner-Matthews, Paula J., Samani, Nilesh, Sanchis-Juan, Alba, Savic, Sinisa, Simpson, Michael A., Smith, Kenneth G.C., Tilly, Tobias, Titterton, Catherine, Tuna, Salih, Urniaz, Rafal, von Ziegenweidt, Julie, Watt, Christopher, Welch, Steven B., Whitehorn, Deborah, Wood, Yvette, Workman, Sarita, Worth, Austen, Young, Timothy
Format:	Journal Article
Language:	English
Published:	United States Elsevier Inc 01-10-2020
Subjects:	Adult Aged Autoimmunity - genetics autosomal dominant Biological Variation, Population Biomarkers common variable immunodeficiency Disease Management Female Fluorescent Antibody Technique Genetic Association Studies - methods Genetic Predisposition to Disease Heterozygote Humans Immunohistochemistry Kaplan-Meier Estimate Magnetic Resonance Imaging Male Medicin och hälsovetenskap Middle Aged Mutation NF-kappa B p50 Subunit - genetics NF-κB1-related phenotype NFKB1 mutation NFKB1 variant Phenotype Prognosis reduced penetrance Tomography, X-Ray Computed GFP CVID NF-κB OR reduced penetrance NFKB1 mutation common variable immunodeficiency autosomal dominant NFKB1 variant WT NF-κB1-related phenotype
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Summary:	An increasing number of NFKB1 variants are being identified in patients with heterogeneous immunologic phenotypes. To characterize the clinical and cellular phenotype as well as the management of patients with heterozygous NFKB1 mutations. 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. 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. 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. [Display omitted]
Bibliography:	ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 For a list of NIHR BioResource authors, please see the acknowledgments at the end of the article.
ISSN:	0091-6749 1097-6825 1097-6825
DOI:	10.1016/j.jaci.2019.11.051