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

Tiziana Lorenzini; Manfred Fliegauf; Nils Klammer; Natalie Frede; Michele Proietti; Alla Bulashevska; Nadezhda Camacho-Ordonez; Markku Varjosalo; Matias Kinnunen; Esther de Vries; Jos W M van der Meer; Rohan Ameratunga; Chaim M Roifman; Yael D Schejter; Robin Kobbe; Timo Hautala; Faranaz Atschekzei; Reinhold E Schmidt; Claudia Schröder; Polina Stepensky; Bella Shadur; Luis A Pedroza; Michiel van der Flier; Mónica Martínez-Gallo; Luis Ignacio Gonzalez-Granado; Luis M Allende; Anna Shcherbina; Natalia Kuzmenko; Victoria Zakharova; João Farela Neves; Peter Svec; Ute Fischer; Winnie Ip; Oliver Bartsch; Safa Barış; Christoph Klein; Raif Geha; Janet Chou; Mohammed Alosaimi; Lauren Weintraub; Kaan Boztug; Tatjana Hirschmugl; Maria Marluce Dos Santos Vilela; Dirk Holzinger; Maximilian Seidl; Vassilios Lougaris; Alessandro Plebani; Laia Alsina; Monica Piquer-Gibert; Angela Deyà-Martínez; Charlotte A Slade; Asghar Aghamohammadi; Hassan Abolhassani; Lennart Hammarström; Outi Kuismin; Merja Helminen; Hana Lango Allen; James E Thaventhiran; Alexandra F Freeman; Matthew Cook; Shahrzad Bakhtiar; Mette Christiansen; Charlotte Cunningham-Rundles; Niraj C Patel; William Rae; Tim Niehues; Nina Brauer; Jaana Syrjänen; Mikko R J Seppänen; Siobhan O Burns; Paul Tuijnenburg; Taco W Kuijpers; Klaus Warnatz; Bodo Grimbacher; NIHR BioResource

doi:10.1016/j.jaci.2019.11.051

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

Journal article

Peer reviewed

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

Tiziana Lorenzini, Manfred Fliegauf, Nils Klammer, Natalie Frede, Michele Proietti, Alla Bulashevska, Nadezhda Camacho-Ordonez, Markku Varjosalo, Matias Kinnunen, Esther de Vries, …

Journal of allergy and clinical immunology, Vol.146(4), pp.901-911

01/10/2020

DOI: https://doi.org/10.1016/j.jaci.2019.11.051

PMCID: 8246418

PMID: 32278790

Abstract

Adult

Aged

Autoimmunity - genetics

Biological Variation, Population

Biomarkers

Disease Management

Female

Fluorescent Antibody Technique

Genetic Association Studies - methods

Genetic Predisposition to Disease

Heterozygote

Humans

Immunohistochemistry

Kaplan-Meier Estimate

Magnetic Resonance Imaging

Male

Middle Aged

Mutation

NF-kappa B p50 Subunit - genetics

Phenotype

Prognosis

Tomography, X-Ray Computed

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.

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Title: Characterization of the clinical and immunologic phenotype and management of 157 individuals with 56 distinct heterozygous NFKB1 mutations
Creators - without role: Tiziana Lorenzini - University of Freiburg
Manfred Fliegauf - University of Freiburg
Nils Klammer - University of Freiburg
Natalie Frede - University of Freiburg
Michele Proietti - University of Freiburg
Alla Bulashevska - University of Freiburg
Nadezhda Camacho-Ordonez - University of Freiburg
Markku Varjosalo - University of Helsinki
Matias Kinnunen - University of Helsinki
Esther de Vries - Elisabeth-TweeSteden Ziekenhuis
Jos W M van der Meer - Radboud University Medical Center
Rohan Ameratunga - Auckland City Hospital
Chaim M Roifman - University of Toronto
Yael D Schejter - University of Toronto
Robin Kobbe - Department of Pediatrics, University Medical Centre Hamburg, Hamburg, Germany
Timo Hautala - Oulu University Hospital
Faranaz Atschekzei - Medizinische Hochschule Hannover
Reinhold E Schmidt - Medizinische Hochschule Hannover
Claudia Schröder - Medizinische Hochschule Hannover
Polina Stepensky - Hadassah Medical Center
Bella Shadur - Garvan Institute of Medical Research
Luis A Pedroza - Universidad San Francisco de Quito
Michiel van der Flier - Department of Pediatric Infectious Diseases & Immunology and Nijmegen Institute for Infection, Immunity and Inflammation, Radboud University Medical Centre, Nijmegen, The Netherlands
Mónica Martínez-Gallo - Vall d'Hebron Institut de Recerca
Luis Ignacio Gonzalez-Granado - Research Institute Hospital 12 de Octubre
Luis M Allende - Hospital Universitario 12 De Octubre
Anna Shcherbina - Dmitry Rogachev National Research Center of Pediatric Hematology, Oncology and Immunology
Natalia Kuzmenko - Dmitry Rogachev National Research Center of Pediatric Hematology, Oncology and Immunology
Victoria Zakharova - Dmitry Rogachev National Research Center of Pediatric Hematology, Oncology and Immunology
João Farela Neves - Hospital de Dona Estefânia
Peter Svec - Comenius University Bratislava
Ute Fischer - Heinrich Heine University Düsseldorf
Winnie Ip - Great Ormond Street Hospital
Oliver Bartsch - University Medical Center of the Johannes Gutenberg University Mainz
Safa Barış - Marmara University
Christoph Klein - Department of Pediatrics, Dr von Hauner Children's Hospital, University Hospital, LMU Munich, Munich, Germany
Raif Geha - Boston Children's Hospital
Janet Chou - Boston Children's Hospital
Mohammed Alosaimi - Boston Children's Hospital
Lauren Weintraub - Albany Medical Center Hospital
Kaan Boztug - CeMM Research Center for Molecular Medicine
Tatjana Hirschmugl - Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases
Maria Marluce Dos Santos Vilela - Universidade Estadual de Campinas (UNICAMP)
Dirk Holzinger - University of Duisburg-Essen
Maximilian Seidl - University Medical Center Freiburg
Vassilios Lougaris - University of Brescia
Alessandro Plebani - University of Brescia
Laia Alsina - Hospital Sant Joan de Déu Barcelona
Monica Piquer-Gibert - Hospital Sant Joan de Déu Barcelona
Angela Deyà-Martínez - Hospital Sant Joan de Déu Barcelona
Charlotte A Slade - Royal Melbourne Hospital
Asghar Aghamohammadi - Children's Medical Center
Hassan Abolhassani - Children's Medical Center
Lennart Hammarström - Karolinska University Hospital
Outi Kuismin - Oulu University Hospital
Merja Helminen - Tampere University Hospital
Hana Lango Allen - University of Cambridge
James E Thaventhiran - University of Cambridge
Alexandra F Freeman - National Institute of Allergy and Infectious Diseases
Matthew Cook - Australian National University
Shahrzad Bakhtiar - University Hospital Frankfurt
Mette Christiansen - Aarhus University Hospital
Charlotte Cunningham-Rundles - Icahn School of Medicine at Mount Sinai
Niraj C Patel - Levine Children's Hospital
William Rae - University Hospital Southampton NHS Foundation Trust
Tim Niehues - Helios Klinikum Krefeld
Nina Brauer - Helios Klinikum Krefeld
Jaana Syrjänen - Tampere University Hospital
Mikko R J Seppänen - Helsinki University Hospital
Siobhan O Burns - Royal Free London NHS Foundation Trust
Paul Tuijnenburg - University of Amsterdam
Taco W Kuijpers - University of Amsterdam
Klaus Warnatz - University Medical Center Freiburg
Bodo Grimbacher - University of Freiburg
NIHR BioResource
Publication Details: Journal of allergy and clinical immunology, Vol.146(4), pp.901-911
Grant note: MR/L006197/1 / Medical Research Council MR/K020919/1 / Medical Research Council MC_PC_18030 / Medical Research Council U24 AI086037 / NIAID NIH HHS P01 AI061093 / NIAID NIH HHS
Identifiers: 9947907808331
Academic Unit: King Saud University
Language: English
Resource Type: Journal article