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Characterization of the Clinical and Immunologic Phenotype and Management of 157 Individuals With 56 Distinct Heterozygous Nfkb1 Mutations Publisher



Lorenzini T1, 2 ; Fliegauf M1, 3 ; Klammer N1 ; Frede N1 ; Proietti M1 ; Bulashevska A1 ; Camachoordonez N1 ; Varjosalo M4 ; Kinnunen M4 ; De Vries E5 ; Van Der Meer JWM6 ; Ameratunga R7 ; Roifman CM8 ; Schejter YD8 Show All Authors
Authors
  1. Lorenzini T1, 2
  2. Fliegauf M1, 3
  3. Klammer N1
  4. Frede N1
  5. Proietti M1
  6. Bulashevska A1
  7. Camachoordonez N1
  8. Varjosalo M4
  9. Kinnunen M4
  10. De Vries E5
  11. Van Der Meer JWM6
  12. Ameratunga R7
  13. Roifman CM8
  14. Schejter YD8
  15. Kobbe R9
  16. Hautala T10
  17. Atschekzei F11, 12
  18. Schmidt RE11, 12
  19. Schroder C11
  20. Stepensky P13
  21. Shadur B13, 14
  22. Pedroza LA15, 16
  23. Van Der Flier M17
  24. Martinezgallo M18, 19
  25. Gonzalezgranado LI20
  26. Allende LM21
  27. Shcherbina A22
  28. Kuzmenko N22
  29. Zakharova V23
  30. Neves JF24
  31. Svec P25
  32. Fischer U26
  33. Ip W27
  34. Bartsch O28
  35. Baris S29
  36. Klein C30
  37. Geha R31
  38. Chou J31
  39. Alosaimi M31
  40. Weintraub L32
  41. Boztug K33
  42. Hirschmugl T33
  43. Dos Santos Vilela MM34
  44. Holzinger D35
  45. Seidl M36
  46. Lougaris V2
  47. Plebani A2
  48. Alsina L37
  49. Piquergibert M37
  50. Deyamartinez A37
  51. Slade CA38
  52. Aghamohammadi A39
  53. Abolhassani H39, 40
  54. Hammarstrom L40
  55. Kuismin O41
  56. Helminen M42
  57. Allen HL43, 44
  58. Thaventhiran JE45
  59. Freeman AF46
  60. Cook M47, 48
  61. Bakhtiar S49
  62. Christiansen M50
  63. Cunninghamrundles C51
  64. Patel NC52
  65. Rae W53
  66. Niehues T54
  67. Brauer N54
  68. Syrjanen J55
  69. Seppanen MRJ56
  70. Burns SO57
  71. Tuijnenburg P58
  72. Kuijpers TW58
  73. Warnatz K1, 61
  74. Grimbacher B1, 3, 12, 59, 60, 61
Show Affiliations
Authors Affiliations
  1. 1. Institute for Immunodeficiency, Center for Chronic Immunodeficiency, Medical Center University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
  2. 2. 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
  3. 3. CIBSS (Centre for Integrative Biological Signalling Studies), University of Freiburg, Freiburg, Germany
  4. 4. Institute of Biotechnology, University of Helsinki, Helsinki, Finland
  5. 5. Laboratory for Medical Microbiology and Immunology, Elisabeth Tweesteden Hospital, Department of Tranzo, Tilburg University, Tilburg, The Netherlands, Netherlands
  6. 6. Department of Internal Medicine, Radboud University Medical Centre, Nijmegen, The Netherlands, Netherlands
  7. 7. Department of Virology and Immunology and the Department of Clinical Immunology, Auckland City Hospital, Auckland, New Zealand
  8. 8. 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, ON, Canada
  9. 9. Department of Pediatrics, University Medical Centre Hamburg, Hamburg, Germany
  10. 10. Department of Internal Medicine, Oulu University Hospital, Oulu, Finland
  11. 11. Division of Immunology and Rheumatology, Hannover Medical University, Hannover, Germany
  12. 12. RESIST – Cluster of Excellence 2155 to Hanover Medical School, Satellite Center Freiburg, Freiburg, Germany
  13. 13. Bone Marrow Transplantation Department, Hadassah-Hebrew University Medical Center, Jerusalem, Israel
  14. 14. Department of Immunology, Garvan Institute of Medical Research, University of New South Wales, Graduate Research School, Sydney, Australia
  15. 15. Colegio de ciencias de la salud-Hospital de los Valles and Instituto de Microbiologia, Universidad San Francisco de Quito, Quito, Ecuador
  16. 16. Department of Pediatrics, Section of Immunology, Allergy, and Rheumatology, Baylor College of Medicine, Houston, Tex, United States
  17. 17. Department of Pediatric Infectious Diseases & Immunology and Nijmegen Institute for Infection, Immunity and Inflammation, Radboud University Medical Centre, Nijmegen, The Netherlands, Netherlands
  18. 18. 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
  19. 19. Jeffrey Model Foundation Excellence Center, Barcelona, Spain
  20. 20. Primary Immunodeficiencies Unit, Pediatrics, School of Medicine, Complutense University, 12 de Octubre Health Research Institute (imas12), Madrid, Spain
  21. 21. Immunology Department, Hospital Universitario 12 de Octubre, Madrid, Spain
  22. 22. Department of Clinical Immunology, Dmitry Rogachev Federal Research and Clinical Center of Pediatric Hematology, Oncology and Immunology, Moscow, Russian Federation
  23. 23. Department of Hematopoietic Stem Cell Transplantation, Dmitry Rogachev National Medical and Research Center of Pediatric Hematology, Oncology and Immunology, Moscow, Russian Federation
  24. 24. Primary Immunodeficiencies Unit, Hospital Dona Estefania, Centro Hospitalar de Lisboa Central, Lisbon, Portugal
  25. 25. Department of Paediatric Haematology and Oncology, Haematopoietic Stem Cell Transplantation Unit, Comenius University Children's Hospital, Bratislava, Slovakia
  26. 26. Department of Paediatric Oncology, Hematology and Clinical Immunology, Center for Child and Adolescent Health, Medical Faculty, Heinrich Heine University, Dusseldorf, Germany
  27. 27. 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
  28. 28. Institute of Human Genetics, Medical Centre of the Johannes Gutenberg University, Mainz, Germany
  29. 29. Department of Pediatrics, Division of Allergy and Immunology, Marmara University School of Medicine, Istanbul, Turkey
  30. 30. Department of Pediatrics, Dr von Hauner Children's Hospital, University Hospital, LMU Munich, Munich, Germany
  31. 31. Division of Immunology, Boston Children's Hospital and Department of Pediatrics, Harvard Medical School, Boston, MA, United States
  32. 32. Divisions of Pediatric Hematology/Oncology, Albany Medical Center, Albany, NY, United States
  33. 33. 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
  34. 34. Laboratory of Pediatric Immunology, Center for Investigation in Pediatrics, Faculty of Medical Sciences, University of Campinas - UNICAMP, Campinas, Brazil
  35. 35. Department of Pediatric Hematology-Oncology, University of Duisburg-Essen, Essen, Germany
  36. 36. Center for Chronic Immunodeficiency and Molecular Pathology, Department of Pathology, University Medical Center, University of Freiburg, Freiburg, Germany
  37. 37. Pediatric Allergy and Clinical Immunology Department and Institut de Recerca, Hospital Sant Joan de Deu, Universitat de Barcelona, Barcelona, Spain
  38. 38. Department of Clinical Immunology and Allergy, Royal Melbourne Hospital, Melbourne, Australia
  39. 39. Research Center for Immunodeficiencies, Pediatrics Center of Excellence, Children's Medical Center, Tehran University of Medical Science, Tehran, Iran
  40. 40. Division of Clinical Immunology, Department of Laboratory Medicine, Karolinska Institute at Karolinska University Hospital Huddinge, Stockholm, Sweden
  41. 41. PEDEGO Research Unit, Medical Research Center Oulu, University of Oulu and Department of Clinical Genetics, Oulu University Hospital, Oulu, Finland
  42. 42. Tampere Center for Child Health Research, University of Tampere and Tampere University Hospital, Tampere, Finland
  43. 43. Department of Haematology, University of Cambridge, Cambridge, United Kingdom
  44. 44. NHS Blood and Transplant Cambridge, Cambridge Biomedical Campus, Cambridge, United Kingdom
  45. 45. Department of Medicine, University of Cambridge, Cambridge, United Kingdom
  46. 46. Laboratory of Clinical Immunology and Microbiology, NIAID, National Institutes of Health, Bethesda, Md, United States
  47. 47. Australian National University Medical School and John Curtin School of Medical Research, Australian National University, Acton, Australia
  48. 48. Department of Immunology, Canberra Hospital, Canberra, Australia
  49. 49. Division for Pediatric Stem-Cell Transplantation and Immunology, University Hospital Frankfurt, Frankfurt/Main, Germany
  50. 50. International Center for Immunodeficiency Diseases and Department of Clinical Immunology, Aarhus University Hospital Skejby, Aarhus, Denmark
  51. 51. Division of Clinical Immunology, Icahn School of Medicine at Mount Sinai, New York, NY, United States
  52. 52. Department of Pediatrics, Section of Infectious Disease and Immunology, Levine Children's Hospital, Atrium Health, Charlotte, NC, United States
  53. 53. 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
  54. 54. Department of Pediatric Hematology and Oncology, Helios Klinikum Krefeld, Krefeld, Germany
  55. 55. Department of Internal Medicine, Tampere University Hospital, Tampere, Finland
  56. 56. Rare Disease Center, New Children's Hospital and Adult immunodeficiency Unit, Inflammation Center, University of Helsinki and Helsinki University Hospital, Helsinki, Finland
  57. 57. Department of Immunology, Royal Free London NHS Foundation Trust, University College London Institute of Immunity and Transplantation, London, United Kingdom
  58. 58. Emma Children's Hospital, Amsterdam UMC, University of Amsterdam, Department of Pediatric Immunology, Rheumatology and Infectious diseases, Meibergdreef 9, Amsterdam, The Netherlands, Netherlands
  59. 59. Institute of Immunology and Transplantation, Royal Free Hospital and University College London, London, United Kingdom
  60. 60. DZIF (German Center for Infection Research) Satellite Center Freiburg, Freiburg, Germany
  61. 61. Rheumatology and Clinical Immunology, Center for Chronic Immunodeficiency, Medical Center University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
  62. 62. NIHR BioResource, Cambridge University Hospitals, Cambridge Biomedical Campus, Cambridge, United Kingdom

Source: Journal of Allergy and Clinical Immunology Published:2020


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. © 2020
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