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Disease Progression of WHIM Syndrome in an International Cohort of 66 Pediatric and Adult Patients

Geier CB 1 , Ellison M 2 , Cruz R 2 , Pawar S 3 , Leiss-Piller A 4 , Zmajkovicova K 3 Show all authors , McNulty SM 5 , Yilmaz M 2 , Evans MO 6 , Gordon S 2 , Ujhazi B 2 , Wiest I 3 , Abolhassani H 7 , Aghamohammadi A 7 , Barmettler S 8 , Bhar S 9 , Bondarenko A 10 , Bolyard AA 11 , Buchbinder D 12 , Cada M 13 , Cavieres M 14 , Connelly JA 15 , Dale DC 16 , Deordieva E 17 , Dorsey MJ 18 , Drysdale SB 19 , Ehl S 1 , Elfeky R 20 , Fioredda F 21 , Firkin F 22 , Förster-Waldl E 23 , Geng B 24 , Goda V 25 , Gonzalez-Granado L 26 , Grunebaum E 27 , Grzesk E 28 , Henrickson SE 29 , Hilfanova A 10 , Hiwatari M 30 , Imai C 31 , Ip W 32 , Jyonouchi S 33 , Kanegane H 34 , Kawahara Y 35 , Khojah AM 36 , Kim VH 27 , Kojić M 23 , Kołtan S 28 , Krivan G 25 , Langguth D 37 , Lau YL 38 , Leung D 38 , Miano M 21 , Mersyanova I 17 , Mousallem T 39 , Muskat M 40 , Naoum FA 41 , Noronha SA 42 , Ouederni M 43 , Ozono S 44 , Richmond GW 45 , Sakovich I 46 , Salzer U 47 , Schuetz C 48 , Seeborg FO 49 , Sharapova SO 46 , Sockel K 50 , Volokha A 10 , von Bonin M 51 , Warnatz K 1 , Wegehaupt O 1 , Weinberg GA 52 , Wong KJ 53 , Worth A 32 , Yu H 54 , Zharankova Y 46 , Zhao X 54 , Devlin L 55 , Badarau A 3 , Csomos K 2 , Keszei M 56 , Pereira J 57 , Taveras AG 58 , Beaussant-Cohen SL 58 , Ong MS 59 , Shcherbina A 17 , Walter JE 60

Affiliations 

  • 1 Institute for Immunodeficiency, Center for Chronic Immunodeficiency, Medical Center University of Freiburg Faculty of Medicine, University of Freiburg, Freiburg, Germany
  • 2 Division of Pediatric Allergy and Immunology, Department of Pediatrics, University of South Florida, St. Petersburg, FL, USA
  • 3 X4 Pharmaceuticals (Austria) GmbH, Vienna, Austria
  • 4 Immunology Outpatient Clinic, Vienna, Austria
  • 5 Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
  • 6 Blanchfield Army Community Hospital, Fort Campbell, KY, USA
  • 7 Research Center for Immunodeficiencies, Pediatrics Center of Excellence, Children's Medical Center, Tehran University of Medical Sciences, Tehran, Iran
  • 8 Allergy and Clinical Immunology Unit, Division of Rheumatology, Allergy & Immunology, Massachusetts General Hospital, Boston, MA, USA
  • 9 Department of Pediatrics, Section of Hematology/Oncology and Critical Care Medicine, Bone Marrow Transplantation, Baylor College of Medicine, Texas Children's Hospital, Houston, TX, USA
  • 10 Shupyk National Medical Academy of Postgraduate Education, Kyiv, Ukraine
  • 11 Severe Chronic Neutropenia International Registry, University of Washington, Seattle, WA, USA
  • 12 Division of Hematology, CHOC Children's Hospital, Orange, CA, USA
  • 13 Division of Hematology and Oncology, Hospital for Sick Children, Toronto, Ontario, Canada
  • 14 Hematology Unit, Dr Luis Calvo Mackenna Children's Hospital, Santiago, Chile
  • 15 Vanderbilt University Medical Center, Nashville, TN, USA
  • 16 Department of Medicine, University of Washington, Seattle, WA, USA
  • 17 Immunology, the Dmitry Rogachev National Medical Center of Pediatric Hematology, Oncology and Immunology, Moscow, Russia
  • 18 Division of Allergy, Immunology and Blood and Marrow Transplantation, Department of Pediatrics, UCSF Benioff Children's Hospital, San Francisco, CA, USA
  • 19 Paediatric Infectious Diseases Research Group, St George's University Hospitals NHS Foundation Trust, London, UK
  • 20 Department of Clinical Immunology, Royal Free Hospital, London, UK
  • 21 Haematology Unit, IRCCS Istituto Giannina Gaslini, Genoa, Italy
  • 22 Department of Medicine, St Vincent's Hospital, University of Melbourne, Vic, Fitzroy, Australia
  • 23 Department of Pediatrics and Adolescent Medicine, Medical University of Vienna, Vienna, Austria
  • 24 Divisions of Adult and Pediatric Allergy and Immunology, University of California, San Diego, CA, USA
  • 25 Department for Pediatric Hematology and Hemopoietic Stem Cell Transplantation, Central Hospital of Southern Pest - National Institute of Hematology and Infectious Diseases, Budapest, Hungary
  • 26 Immunodeficiencies Unit, Department of Pediatrics, University Hospital 12 de Octubre, Research Institute Hospital 12 Octubre, Madrid, Spain
  • 27 Department of Pediatrics, University of Toronto, Toronto, Ontario, Canada
  • 28 Department of Pediatrics, Hematology and Oncology Collegium Medicum, Bydgoszcz Nicolaus Copernicus University, Torun, Poland
  • 29 Division of Allergy and Immunology, Children's Hospital of Philadelphia, Philadelphia, PA, USA
  • 30 Department of Pediatrics, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
  • 31 Department of Pediatrics, Niigata University Graduate School of Medical and Dental Sciences, Niigata, Japan
  • 32 Great Ormond Street Hospital for Children, London, UK
  • 33 Division of Allergy and Immunology, Department of Pediatrics, Children's Hospital of Philadelphia, University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA
  • 34 Department of Child Health and Development, Graduate School of Medical and Dental Sciences, Tokyo Medical and Dental University (TMDU), Tokyo, Japan
  • 35 Department of Pediatrics, Jichi Medical University School of Medicine, Tochigi, Japan
  • 36 Northwestern University Feinberg School of Medicine, Chicago, IL, USA
  • 37 Department of Immunology, Sullivan and Nicolaides Pathology, Brisbane, Australia
  • 38 Department of Paediatrics and Adolescent Medicine, University of Hong Kong, Hong Kong, China
  • 39 Department of Pediatrics, Division of Pediatric Allergy and Immunology, Duke University Medical Center, Durham, NC, USA
  • 40 Department of Pediatrics, University of California, San Francisco School of Medicine, San Francisco, CA, USA
  • 41 Academia de Ciência e Tecnologia, Sao Jose do Rio Preto, Brazil
  • 42 Department of Pediatrics, Division of Hematology-Oncology, University of Rochester Medical Center, Rochester, NY, USA
  • 43 Faculty of Médecine, University Tunis El Manar, Tunis, Tunisia
  • 44 Department of Pediatrics, Kurume University School of Medicine, 67 Asahi-machi, Kurume, Fukuoka, Japan
  • 45 Section of Allergy and Immunology, Rush University Medical Center, Chicago, IL, USA
  • 46 Research Department, Belarusian Research Center for Pediatric Oncology, Hematology and Immunology, Minsk, Belarus
  • 47 Department of Rheumatology and Clinical Immunology, Center for Chronic Immunodeficiency, Medical Center University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
  • 48 Department of Pediatrics, Medizinische Fakultät Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany
  • 49 Department of Pediatrics, Section of Immunology, Allergy and Rheumatology, Baylor College of Medicine and Texas Children's Hospital, Houston, TX, USA
  • 50 Department of Internal Medicine I, University Hospital Carl Gustav Carus, Dresden, Germany
  • 51 Medizinische Klinik und Poliklinik I, Universitätsklinikum Dresden, Dresden, Germany
  • 52 Department of Pediatrics, University of Rochester School of Medicine and Dentistry, University of Rochester Golisano Children's Hospital, Rochester, NY, USA
  • 53 Sabah Women and Children's Hospital, Sabah, Malaysia
  • 54 National Clinical Research Center for Child Health and disorders, Children Hospital of Chongqing Medical University, Chongqing, 400014, People's Republic of China
  • 55 Belfast Health and Social Care Trust, Belfast, Northern Ireland, UK
  • 56 Department of Microbiology, Tumor and Cell Biology, Karolinska Institute, Stockholm, Sweden
  • 57 Department of Immunobiology, Yale University School of Medicine, Yale University, New Haven, CT, USA
  • 58 X4 Pharmaceuticals, Inc, Cambridge, MA, USA
  • 59 Department of Population Medicine, Harvard Medical School and Harvard Pilgrim Health Care Institute, Boston, MA, USA
  • 60 Division of Pediatric Allergy and Immunology, Department of Pediatrics, University of South Florida, St. Petersburg, FL, USA. [email protected]
J Clin Immunol, 2022 Nov;42(8):1748-1765.
PMID: 35947323 DOI: 10.1007/s10875-022-01312-7

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.

* Title and MeSH Headings from MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.

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