Characterization of the clinical and immunologic phenotype and management of 157 individuals with 56 distinct heterozygous NFKB1 mutations - 06/05/20

Doi : 10.1016/j.jaci.2019.11.051

Tiziana Lorenzini, MD ^a,^b, Manfred Fliegauf, PhD ^a,^c, Nils Klammer ^a, Natalie Frede, MD ^a, Michele Proietti, MD, PhD ^a, Alla Bulashevska, PhD ^a, Nadezhda Camacho-Ordonez, MD ^a, Markku Varjosalo, PhD ^d, Matias Kinnunen, MSc ^d, Esther de Vries, MD, PhD ^e, Jos W.M. van der Meer, MD, PhD ^f, Rohan Ameratunga, PhD ^g, Chaim M. Roifman, MD ^h, Yael D. Schejter, MD ^h, Robin Kobbe, MD ⁱ, Timo Hautala, MD, PhD ^j, Faranaz Atschekzei, MD, PhD ^k,^l, Reinhold E. Schmidt, MD ^k,^l, Claudia Schröder, MSc ^k, Polina Stepensky, MD ^m, Bella Shadur, MBBS, BMedSci, FRACP ^m,ⁿ, Luis A. Pedroza, PhD ^o,^p, Michiel van der Flier, MD, PhD ^q, Mónica Martínez-Gallo, PhD ^r,^s, Luis Ignacio Gonzalez-Granado, MD ^t, Luis M. Allende, PhD ^u, Anna Shcherbina, MD, PhD ^v, Natalia Kuzmenko, MD, PhD ^v, Victoria Zakharova, PhD ^w, João Farela Neves, MD ^x, Peter Svec, MD ^y, Ute Fischer, PhD ^z, Winnie Ip, MD(Res), FRACP ^aa, Oliver Bartsch, MD, PhD ^bb, Safa Barış, MD ^cc, Christoph Klein, MD, PhD ^dd, Raif Geha, MD ^ee, Janet Chou, MD ^ee, Mohammed Alosaimi, MD ^ee, Lauren Weintraub, MD ^ff, Kaan Boztug, MD ^gg, Tatjana Hirschmugl, MSc ^gg, Maria Marluce Dos Santos Vilela, MD, PhD ^hh, Dirk Holzinger, MD ⁱⁱ, Maximilian Seidl, MD ^jj, Vassilios Lougaris, MD ^b, Alessandro Plebani, MD ^b, Laia Alsina, MD, PhD ^kk, Monica Piquer-Gibert, MD ^kk, Angela Deyà-Martínez, MD, PhD ^kk, Charlotte A. Slade, MBBS ^ll, Asghar Aghamohammadi, MD, PhD ^mm, Hassan Abolhassani, MD, PhD ^mm,ⁿⁿ, Lennart Hammarström, MD, PhD ⁿⁿ, Outi Kuismin, MD, PhD ^oo, Merja Helminen, MD, PhD ^pp, Hana Lango Allen, PhD ^qq,^rr, James E. Thaventhiran, MRCP, FRCPath, PhD ^ss, Alexandra F. Freeman, MD ^tt, Matthew Cook, MBBS, PhD, FRACP, FRCPA ^uu,^vv, Shahrzad Bakhtiar, MD ^ww, Mette Christiansen, PhD ^xx, Charlotte Cunningham-Rundles, MD, PhD ^yy, Niraj C. Patel, MD ^zz, William Rae, MRCP ^aaa, Tim Niehues, MD ^bbb, Nina Brauer, MD ^bbb, Jaana Syrjänen, MD, PhD ^ccc, Mikko R.J. Seppänen, MD, PhD ^ddd, Siobhan O. Burns, MRCP, PhD ^eee, Paul Tuijnenburg, MD ^fff, Taco W. Kuijpers, MD ^fff, on behalf of the
NIHR-BioResource – Rare Diseases Consortium^ggg
Klaus Warnatz, MD ^a,^jjj, Bodo Grimbacher, MD ^a,^c,^l,^hhh,^iii,^jjj,^⁎
^a Institute for Immunodeficiency, Center for Chronic Immunodeficiency, Medical Center University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
^b Pediatrics Clinic and Institute for Molecular Medicine A. Nocivelli, Department of Clinical and Experimental Sciences, University of Brescia and ASST- Spedali Civili of Brescia, Brescia, Italy
^c CIBSS (Centre for Integrative Biological Signalling Studies), University of Freiburg, Freiburg, Germany
^d Institute of Biotechnology, University of Helsinki, Helsinki, Finland
^e Laboratory for Medical Microbiology and Immunology, Elisabeth Tweesteden Hospital, and Department of Tranzo, Tilburg University, Tilburg, The Netherlands
^f Department of Internal Medicine, Radboud University Medical Centre, Nijmegen, The Netherlands
^g Department of Virology and Immunology and the Department of Clinical Immunology, Auckland City Hospital, Auckland, New Zealand
^h Canadian Centre for Primary Immunodeficiency, Immunogenomic Laboratory, Division of Immunology and Allergy, Department of Pediatrics, The Hospital for Sick Children and the University of Toronto, Toronto, Ontario, Canada
ⁱ Department of Pediatrics, University Medical Centre Hamburg, Hamburg, Germany
^j Department of Internal Medicine, Oulu University Hospital, Oulu, Finland
^k Division of Immunology and Rheumatology, Hannover Medical University, Hannover, Germany
^l RESIST – Cluster of Excellence 2155 to Hanover Medical School, Satellite Center Freiburg, Freiburg, Germany
^m Bone Marrow Transplantation Department, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
ⁿ Department of Immunology, Garvan Institute of Medical Research, and University of New South Wales, Graduate Research School, Sydney, Australia
^o Colegio de ciencias de la salud-Hospital de los Valles and Instituto de Microbiología, Universidad San Francisco de Quito, Quito, Ecuador
^p Department of Pediatrics, Section of Immunology, Allergy, and Rheumatology, Baylor College of Medicine, Houston, Tex
^q Department of Pediatric Infectious Diseases & Immunology and Nijmegen Institute for Infection, Immunity and Inflammation, Radboud University Medical Centre, Nijmegen, The Netherlands
^r Immunology Division, Hospital Universitari Vall d’Hebron (HUVH), Vall d’Hebron Research Institute (VHIR), Department of Cell Biology, Physiology and Immunology, Autonomous University of Barcelona (UAB), Barcelona, Spain
^s Jeffrey Model Foundation Excellence Center, Barcelona, Spain
^t Primary Immunodeficiencies Unit, Pediatrics, School of Medicine, Complutense University, 12 de Octubre Health Research Institute (imas12), Madrid, Spain
^u Immunology Department, Hospital Universitario 12 de Octubre, Madrid, Spain
^v Department of Clinical Immunology, Dmitry Rogachev Federal Research and Clinical Center of Pediatric Hematology, Oncology and Immunology, Moscow, Russia
^w Department of Hematopoietic Stem Cell Transplantation, Dmitry Rogachev National Medical and Research Center of Pediatric Hematology, Oncology and Immunology, Moscow, Russia
^x Primary Immunodeficiencies Unit, Hospital Dona Estefania, Centro Hospitalar de Lisboa Central, Lisbon, Portugal
^y Department of Paediatric Haematology and Oncology, Haematopoietic Stem Cell Transplantation Unit, Comenius University Children’s Hospital, Bratislava, Slovakia
^z Department of Paediatric Oncology, Hematology and Clinical Immunology, Center for Child and Adolescent Health, Medical Faculty, Heinrich Heine University, Düsseldorf, Germany
^aa Department of Immunology and Molecular and Cellular Immunology Unit, Great Ormond Street Hospital & University College London (UCL), Great Ormond Street Institute of Child Health, London, United Kingdom
^bb Institute of Human Genetics, Medical Centre of the Johannes Gutenberg University, Mainz, Germany
^cc Department of Pediatrics, Division of Allergy and Immunology, Marmara University School of Medicine, Istanbul, Turkey
^dd Department of Pediatrics, Dr von Hauner Children’s Hospital, University Hospital, LMU Munich, Munich, Germany
^ee Division of Immunology, Boston Children’s Hospital and Department of Pediatrics, Harvard Medical School, Boston, Mass
^ff Divisions of Pediatric Hematology/Oncology, Albany Medical Center, Albany, NY
^gg CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases, Department of Pediatrics and Adolescent Medicine and St Anna Kinderspital and Children’s Cancer Research Institute, Department of Pediatrics, Medical University of Vienna, Vienna, Austria
^hh Laboratory of Pediatric Immunology, Center for Investigation in Pediatrics, Faculty of Medical Sciences, University of Campinas - UNICAMP, Campinas, Brazil
ⁱⁱ Department of Pediatric Hematology-Oncology, University of Duisburg-Essen, Essen, Germany
^jj Center for Chronic Immunodeficiency and Molecular Pathology, Department of Pathology, University Medical Center, University of Freiburg, Freiburg, Germany
^kk Pediatric Allergy and Clinical Immunology Department and Institut de Recerca, Hospital Sant Joan de Déu, Universitat de Barcelona, Barcelona, Spain
^ll Department of Clinical Immunology and Allergy, Royal Melbourne Hospital, Melbourne, Australia
^mm Research Center for Immunodeficiencies, Pediatrics Center of Excellence, Children’s Medical Center, Tehran University of Medical Science, Tehran, Iran
ⁿⁿ Division of Clinical Immunology, Department of Laboratory Medicine, Karolinska Institute at Karolinska University Hospital Huddinge, Stockholm, Sweden
^oo PEDEGO Research Unit, Medical Research Center Oulu, and University of Oulu and Department of Clinical Genetics, Oulu University Hospital, Oulu, Finland
^pp Tampere Center for Child Health Research, University of Tampere and Tampere University Hospital, Tampere, Finland
^qq Department of Haematology, University of Cambridge, Cambridge, United Kingdom
^rr NHS Blood and Transplant Cambridge, Cambridge Biomedical Campus, Cambridge, United Kingdom
^ss Department of Medicine, University of Cambridge, Cambridge, United Kingdom
^tt Laboratory of Clinical Immunology and Microbiology, NIAID, National Institutes of Health, Bethesda, Md
^uu Australian National University Medical School and John Curtin School of Medical Research, Australian National University, Acton, Australia
^vv Department of Immunology, Canberra Hospital, Canberra, Australia
^ww Division for Pediatric Stem-Cell Transplantation and Immunology, University Hospital Frankfurt, Frankfurt/Main, Germany
^xx International Center for Immunodeficiency Diseases and Department of Clinical Immunology, Aarhus University Hospital Skejby, Aarhus, Denmark
^yy Division of Clinical Immunology, Icahn School of Medicine at Mount Sinai, New York, NY
^zz Department of Pediatrics, Section of Infectious Disease and Immunology, Levine Children’s Hospital, Atrium Health, Charlotte, NC
^aaa Southampton NIHR Wellcome Trust Clinical Research Facility and NIHR Biomedical Research Centre, University Hospital Southampton NHS Foundation Trust, Department of Allergy, Asthma and Clinical Immunology, University Hospital Southampton, Southampton, United Kingdom
^bbb Department of Pediatric Hematology and Oncology, Helios Klinikum Krefeld, Krefeld, Germany
^ccc Department of Internal Medicine, Tampere University Hospital, Tampere, Finland
^ddd Rare Disease Center, New Children’s Hospital and Adult immunodeficiency Unit, Inflammation Center, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
^eee Department of Immunology, Royal Free London NHS Foundation Trust, University College London Institute of Immunity and Transplantation, London, United Kingdom
^fff Emma Children’s Hospital, Amsterdam UMC, University of Amsterdam, Department of Pediatric Immunology, Rheumatology and Infectious diseases, Meibergdreef 9, Amsterdam, The Netherlands
^ggg NIHR BioResource, Cambridge University Hospitals, Cambridge Biomedical Campus, Cambridge, United Kingdom
^hhh Institute of Immunology and Transplantation, Royal Free Hospital and University College London, London, United Kingdom
ⁱⁱⁱ DZIF (German Center for Infection Research) Satellite Center Freiburg, Freiburg, Germany
^jjj Rheumatology and Clinical Immunology, Center for Chronic Immunodeficiency, Medical Center University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany

^∗Corresponding author: Bodo Grimbacher, MD, CCI-Center for Chronic Immunodeficiency, Universitätsklinikum Freiburg, Breisacher Straße 115, 79106 Freiburg, Germany.CCI-Center for Chronic ImmunodeficiencyUniversitätsklinikum FreiburgBreisacher Straße 115Freiburg79106Germany

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Abstract

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.

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Graphical abstract

Le texte complet de cet article est disponible en PDF.

Key words : NFKB1 variant, NFKB1 mutation, common variable immunodeficiency, reduced penetrance, NF-κB1-related phenotype, autosomal dominant

Abbreviations used : CVID, GFP, NF-κB, OR, WT

Plan

Methods

Results

Genetic and functional assays

Patient characteristics

Respiratory involvement

Gastrointestinal involvement

Autoimmunity and immune dysregulation

Lymphoproliferation and malignancies

Types of infections

Immunologic assessment

Treatment

Discussion

This study was supported by the German Research Foundation (DFG) (SFB1160 – IMPATH to B.G.), and under Germany’s Excellence Strategy (CIBSS - EXC-2189 - Project ID 390939984 and RESIST - EXC 2155 - Project ID 39087428), by the E-rare program of the European Union, managed by the DFG, grant code GR1617/14-1/iPAD; by the “Netzwerke Seltener Erkrankungen” of the German Ministry of Education and Research (BMBF) (grant code: GAIN_ 01GM1910A); and by research funding from the German Ministry of Education and Research (BMBF, grant nos. 01E01303 and 01ZX1306F).

Disclosure of potential conflict of interest: All authors declare that they have no relevant conflicts of interest.