Tehran University of Medical Sciences

Science Communicator Platform

Stay connected! Follow us on X network (Twitter):
Share this content! On (X network) By
Disease Progression of Whim Syndrome in an International Cohort of 66 Pediatric and Adult Patients Publisher Pubmed



Geier CB1, 2 ; Ellison M3 ; Cruz R3, 4 ; Pawar S5 ; Leisspiller A6 ; Zmajkovicova K5 ; Mcnulty SM7 ; Yilmaz M3 ; Gordon S3 ; Ujhazi B3 ; Wiest I5 ; Abolhassani H9, 10 ; Aghamohammadi A9 ; Barmettler S11 Show All Authors
Authors
  1. Geier CB1, 2
  2. Ellison M3
  3. Cruz R3, 4
  4. Pawar S5
  5. Leisspiller A6
  6. Zmajkovicova K5
  7. Mcnulty SM7
  8. Yilmaz M3
  9. Gordon S3
  10. Ujhazi B3
  11. Wiest I5
  12. Abolhassani H9, 10
  13. Aghamohammadi A9
  14. Barmettler S11
  15. Bhar S12
  16. Bondarenko A13
  17. Bolyard AA14
  18. Buchbinder D15
  19. Cada M16, 17
  20. Cavieres M18
  21. Connelly JA19
  22. Dale DC20
  23. Deordieva E21
  24. Dorsey MJ22
  25. Drysdale SB23
  26. Ehl S1
  27. Elfeky R24
  28. Fioredda F25
  29. Firkin F26, 27
  30. Forsterwaldl E29, 30
  31. Geng B31
  32. Goda V32
  33. Gonzalezgranado L33
  34. Grunebaum E17, 34
  35. Grzesk E35
  36. Henrickson SE36, 37, 38
  37. Hilfanova A13
  38. Hiwatari M39
  39. Imai C40, 41
  40. Ip W42
  41. Jyonouchi S43
  42. Kanegane H44
  43. Kawahara Y45
  44. Khojah AM46
  45. Kim VHD17, 34
  46. Kojic M28
  47. Koltan S35
  48. Krivan G32
  49. Langguth D47
  50. Lau YL48
  51. Leung D48
  52. Miano M25
  53. Mersyanova I21
  54. Mousallem T49
  55. Muskat M50
  56. Naoum FA51
  57. Noronha SA52
  58. Ouederni M53, 54
  59. Ozono S55
  60. Richmond GW56
  61. Sakovich I57
  62. Salzer U2
  63. Schuetz C58
  64. Seeborg FO59
  65. Sharapova SO57
  66. Sockel K60
  67. Volokha A13
  68. Von Bonin M61
  69. Warnatz K1, 2
  70. Wegehaupt O1, 62
  71. Weinberg GA63
  72. Wong KJ64
  73. Worth A42
  74. Yu H65
  75. Zharankova Y57
  76. Zhao X65
  77. Devlin L67
  78. Badarau A5
  79. Csomos K3
  80. Keszei M68
  81. Pereira J69
  82. Taveras AG70
  83. Beaussantcohen SL70
  84. Ong MS71
  85. Shcherbina A21
  86. Walter JE3, 72
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. Department of Rheumatology and Clinical Immunology, Center for Chronic Immunodeficiency, Medical Center University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
  3. 3. Division of Pediatric Allergy and Immunology, Department of Pediatrics, University of South Florida, St. Petersburg, FL, United States
  4. 4. Morsani College of Medicine, University of South Florida, Tampa, FL, United States
  5. 5. X4 Pharmaceuticals (Austria) GmbH, Vienna, Austria
  6. 6. Immunology Outpatient Clinic, Vienna, Austria
  7. 7. Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC, United States
  8. 8. Blanchfield Army Community Hospital, Fort Campbell, KY, United States
  9. 9. Research Center for Immunodeficiencies, Pediatrics Center of Excellence, Children’s Medical Center, Tehran University of Medical Sciences, Tehran, Iran
  10. 10. Division of Clinical Immunology, Department of Laboratory Medicine, Karolinska Institute at Karolinska University Hospital Huddinge, Stockholm, Sweden
  11. 11. Allergy and Clinical Immunology Unit, Division of Rheumatology, Allergy & Immunology, Massachusetts General Hospital, Boston, MA, United States
  12. 12. Department of Pediatrics, Section of Hematology/Oncology and Critical Care Medicine, Bone Marrow Transplantation, Baylor College of Medicine, Texas Children’s Hospital, Houston, TX, United States
  13. 13. Shupyk National Medical Academy of Postgraduate Education, Kyiv, Ukraine
  14. 14. Severe Chronic Neutropenia International Registry, University of Washington, Seattle, WA, United States
  15. 15. Division of Hematology, CHOC Children’s Hospital, Orange, CA, United States
  16. 16. Division of Hematology and Oncology, Hospital for Sick Children, Toronto, ON, Canada
  17. 17. Department of Pediatrics, University of Toronto, Toronto, ON, Canada
  18. 18. Hematology Unit, Dr Luis Calvo Mackenna Children’s Hospital, Santiago, Chile
  19. 19. Vanderbilt University Medical Center, Nashville, TN, United States
  20. 20. Department of Medicine, University of Washington, Seattle, WA, United States
  21. 21. Immunology, the Dmitry Rogachev National Medical Center of Pediatric Hematology, Oncology and Immunology, Moscow, Russian Federation
  22. 22. Division of Allergy, Immunology and Blood and Marrow Transplantation, Department of Pediatrics, UCSF Benioff Children’s Hospital, San Francisco, CA, United States
  23. 23. Paediatric Infectious Diseases Research Group, St George’s University Hospitals NHS Foundation Trust, London, United Kingdom
  24. 24. Department of Clinical Immunology, Royal Free Hospital, London, United Kingdom
  25. 25. Haematology Unit, IRCCS Istituto Giannina Gaslini, Genoa, Italy
  26. 26. Department of Medicine, St Vincent’s Hospital, University of Melbourne, Vic, Fitzroy, Australia
  27. 27. Department of Clinical Haematology, St Vincent’s Hospital, Vic, Fitzroy, Australia
  28. 28. Department of Pediatrics and Adolescent Medicine, Medical University of Vienna, Vienna, Austria
  29. 29. Division of Neonatology, Pediatric Intensive Care & Neuropediatrics, Department of Pediatrics and Adolescent Medicine, Medical University of Vienna, Vienna, Austria
  30. 30. Center for Congenital Immunodeficiencies, Medical University of Vienna & Jeffrey Modell Diagnostic and Research Center, Vienna, Austria
  31. 31. Divisions of Adult and Pediatric Allergy and Immunology, University of California, San Diego, CA, United States
  32. 32. Department for Pediatric Hematology and Hemopoietic Stem Cell Transplantation, Central Hospital of Southern Pest - National Institute of Hematology and Infectious Diseases, Budapest, Hungary
  33. 33. Immunodeficiencies Unit, Department of Pediatrics, University Hospital 12 de Octubre, Research Institute Hospital 12 Octubre, Madrid, Spain
  34. 34. Division of Immunology and Allergy, Hospital for Sick Children, Toronto, ON, Canada
  35. 35. Department of Pediatrics, Hematology and Oncology Collegium Medicum, Bydgoszcz Nicolaus Copernicus University, Torun, Poland
  36. 36. Division of Allergy and Immunology, Children’s Hospital of Philadelphia, Philadelphia, PA, United States
  37. 37. Department of Pediatrics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
  38. 38. Institute for Immunology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, United States
  39. 39. Department of Pediatrics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
  40. 40. Department of Pediatrics, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
  41. 41. Department of Pediatrics, Niigata University Medical and Dental Hospital, Niigata, Japan
  42. 42. Great Ormond Street Hospital for Children, London, United Kingdom
  43. 43. Division of Allergy and Immunology, Department of Pediatrics, Children’s Hospital of Philadelphia, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, United States
  44. 44. Department of Child Health and Development, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo, Japan
  45. 45. Department of Pediatrics, Jichi Medical University School of Medicine, Tochigi, Japan
  46. 46. Northwestern University Feinberg School of Medicine, Chicago, IL, United States
  47. 47. Department of Immunology, Sullivan and Nicolaides Pathology, Brisbane, Australia
  48. 48. Department of Paediatrics and Adolescent Medicine, University of Hong Kong, Hong Kong
  49. 49. Department of Pediatrics, Division of Pediatric Allergy and Immunology, Duke University Medical Center, Durham, NC, United States
  50. 50. Department of Pediatrics, University of California, San Francisco School of Medicine, San Francisco, CA, United States
  51. 51. Academia de Ciencia e Tecnologia, Sao Jose do Rio Preto, Brazil
  52. 52. Department of Pediatrics, Division of Hematology-Oncology, University of Rochester Medical Center, Rochester, NY, United States
  53. 53. Faculty of Medecine, University Tunis El Manar, Tunis, Tunisia
  54. 54. Department of Pediatrics: Immuno-Hematology and Stem Cell Transplantation, Bone Marrow Transplantation Center of Tunisia, Tunis, Tunisia
  55. 55. Department of Pediatrics, Kurume University School of Medicine, 67 Asahi-machi, Kurume, Fukuoka, Japan
  56. 56. Section of Allergy and Immunology, Rush University Medical Center, Chicago, IL, United States
  57. 57. Research Department, Belarusian Research Center for Pediatric Oncology, Hematology and Immunology, Minsk, Belarus
  58. 58. Department of Pediatrics, Medizinische Fakultat Carl Gustav Carus, Technische Universitat Dresden, Dresden, Germany
  59. 59. Department of Pediatrics, Section of Immunology, Allergy and Rheumatology, Baylor College of Medicine and Texas Children’s Hospital, Houston, TX, United States
  60. 60. Department of Internal Medicine I, University Hospital Carl Gustav Carus, Dresden, Germany
  61. 61. Medizinische Klinik und Poliklinik I, Universitatsklinikum Dresden, Dresden, Germany
  62. 62. Center for Pediatrics and Adolescent Medicine, Medical Center, Faculty of Medicine, University of Freiburg, Freiburg, Germany
  63. 63. Department of Pediatrics, University of Rochester School of Medicine and Dentistry, University of Rochester Golisano Children’s Hospital, Rochester, NY, United States
  64. 64. Sabah Women and Children’s Hospital, Sabah, Malaysia
  65. 65. National Clinical Research Center for Child Health and disorders, Children Hospital of Chongqing Medical University, Chongqing, 400014, China
  66. 66. Belfast Health and Social Care Trust, Belfast, United Kingdom
  67. 67. Regional Immunology Service, Belfast Health and Social Care Trust, Belfast, United Kingdom
  68. 68. Department of Microbiology, Tumor and Cell Biology, Karolinska Institute, Stockholm, Sweden
  69. 69. Department of Immunobiology, Yale University School of Medicine, Yale University, New Haven, CT, United States
  70. 70. X4 Pharmaceuticals, Inc, Cambridge, MA, United States
  71. 71. Department of Population Medicine, Harvard Medical School and Harvard Pilgrim Health Care Institute, Boston, MA, United States
  72. 72. Division of Allergy and Immunology, Massachusetts General Hospital for Children, Boston, MA, United States

Source: Journal of Clinical Immunology Published:2022


Abstract

Warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) syndrome (WS) is a combined immunodeficiency caused by gain-of-function mutations in the C-X-C chemokine receptor type 4 (CXCR4) gene. We characterize a unique international cohort of 66 patients, including 57 (86%) cases previously unreported, with variable clinical phenotypes. Of 17 distinct CXCR4 genetic variants within our cohort, 11 were novel pathogenic variants affecting 15 individuals (23%). All variants affect the same CXCR4 region and impair CXCR4 internalization resulting in hyperactive signaling. The median age of diagnosis in our cohort (5.5 years) indicates WHIM syndrome can commonly present in childhood, although some patients are not diagnosed until adulthood. The prevalence and mean age of recognition and/or onset of clinical manifestations within our cohort were infections 88%/1.6 years, neutropenia 98%/3.8 years, lymphopenia 88%/5.0 years, and warts 40%/12.1 years. However, we report greater prevalence and variety of autoimmune complications of WHIM syndrome (21.2%) than reported previously. Patients with versus without family history of WHIM syndrome were diagnosed earlier (22%, average age 1.3 years versus 78%, average age 5 years, respectively). Patients with a family history of WHIM syndrome also received earlier treatment, experienced less hospitalization, and had less end-organ damage. This observation reinforces previous reports that early treatment for WHIM syndrome improves outcomes. Only one patient died; death was attributed to complications of hematopoietic stem cell transplantation. The variable expressivity of WHIM syndrome in pediatric patients delays their diagnosis and therapy. Early-onset bacterial infections with severe neutropenia and/or lymphopenia should prompt genetic testing for WHIM syndrome, even in the absence of warts. © 2022, The Author(s).
Other Related Docs
11. Congenital Neutropenia and Primary Immunodeficiency Diseases, Critical Reviews in Oncology/Hematology (2019)
14. Common Presentations and Diagnostic Approaches, Stiehm's Immune Deficiencies: Inborn Errors of Immunity (2020)