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

Christoph B Geier; Maryssa Ellison; Rachel Cruz; Sumit Pawar; Alexander Leiss-Piller; Katarina Zmajkovicova; Shannon M McNulty; Melis Yilmaz; Martin Oman Evans, 2nd; Sumai Gordon; Boglarka Ujhazi; Ivana Wiest; Hassan Abolhassani; Asghar Aghamohammadi; Sara Barmettler; Saleh Bhar; Anastasia Bondarenko; Audrey Anna Bolyard; David Buchbinder; Michaela Cada; Mirta Cavieres; James A Connelly; David C Dale; Ekaterina Deordieva; Morna J Dorsey; Simon B Drysdale; Stephan Ehl; Reem Elfeky; Francesca Fioredda; Frank Firkin; Elizabeth Förster-Waldl; Bob Geng; Vera Goda; Luis Gonzalez-Granado; Eyal Grunebaum; Elzbieta Grzesk; Sarah E Henrickson; Anna Hilfanova; Mitsuteru Hiwatari; Chihaya Imai; Winnie Ip; Soma Jyonouchi; Hirokazu Kanegane; Yuta Kawahara; Amer M Khojah; Vy Hong-Diep Kim; Marina Kojić; Sylwia Kołtan; Gergely Krivan; Daman Langguth; Yu-Lung Lau; Daniel Leung; Maurizio Miano; Irina Mersyanova; Talal Mousallem; Mica Muskat; Flavio A Naoum; Suzie A Noronha; Monia Ouederni; Shuichi Ozono; G Wendell Richmond; Inga Sakovich; Ulrich Salzer; Catharina Schuetz; Filiz Odabasi Seeborg; Svetlana O Sharapova; Katja Sockel; Alla Volokha; Malte von Bonin; Klaus Warnatz; Oliver Wegehaupt; Geoffrey A Weinberg; Ke-Juin Wong; Austen Worth; Huang Yu; Yulia Zharankova; Xiaodong Zhao; Lisa Devlin; Adriana Badarau; Krisztian Csomos; Marton Keszei; Joao Pereira; Arthur G Taveras; Sarah L Beaussant-Cohen; Mei-Sing Ong; Anna Shcherbina; Jolan E Walter

doi:10.1007/s10875-022-01312-7

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

Journal article

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

Christoph B Geier, Maryssa Ellison, Rachel Cruz, Sumit Pawar, Alexander Leiss-Piller, Katarina Zmajkovicova, Shannon M McNulty, Melis Yilmaz, Martin Oman Evans, 2nd, Sumai Gordon, …

Journal of clinical immunology, Vol.42(8), pp.1748-1765

01/11/2022

DOI: https://doi.org/10.1007/s10875-022-01312-7

PMID: 35947323

Abstract

Agammaglobulinemia - genetics

Disease Progression

Humans

Immunologic Deficiency Syndromes - diagnosis

Immunologic Deficiency Syndromes - epidemiology

Immunologic Deficiency Syndromes - genetics

Lymphopenia - complications

Neutropenia - genetics

Receptors, CXCR4 - genetics

Warts - diagnosis

Warts - epidemiology

Warts - genetics

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.

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Title: Disease Progression of WHIM Syndrome in an International Cohort of 66 Pediatric and Adult Patients
Creators - without role: Christoph B Geier - University of Freiburg
Maryssa Ellison - University of South Florida St. Petersburg
Rachel Cruz - University of South Florida St. Petersburg
Sumit Pawar - X4 Pharmaceuticals (Austria) GmbH, Vienna, Austria
Alexander Leiss-Piller - Immunology Outpatient Clinic, Vienna, Austria
Katarina Zmajkovicova - X4 Pharmaceuticals (Austria) GmbH, Vienna, Austria
Shannon M McNulty - University of North Carolina at Chapel Hill
Melis Yilmaz - University of South Florida St. Petersburg
Martin Oman Evans, 2nd - Blanchfield Army Community Hospital
Sumai Gordon - University of South Florida St. Petersburg
Boglarka Ujhazi - University of South Florida St. Petersburg
Ivana Wiest - X4 Pharmaceuticals (Austria) GmbH, Vienna, Austria
Hassan Abolhassani - Tehran University of Medical Sciences
Asghar Aghamohammadi - Children's Medical Center
Sara Barmettler - Massachusetts General Hospital
Saleh Bhar - Texas Children's Hospital
Anastasia Bondarenko - Shupyk National Healthcare University of Ukraine
Audrey Anna Bolyard - Seattle University
David Buchbinder - Children's Hospital of Orange County
Michaela Cada - Hospital for Sick Children
Mirta Cavieres - Hospital Luis Calvo Mackenna
James A Connelly - Vanderbilt University Medical Center
David C Dale - University of Washington
Ekaterina Deordieva - Dmitry Rogachev National Research Center of Pediatric Hematology, Oncology and Immunology
Morna J Dorsey - UCSF Benioff Children's Hospital
Simon B Drysdale - St George’s University Hospitals NHS Foundation Trust
Stephan Ehl - University of Freiburg
Reem Elfeky - The Royal Free Hospital
Francesca Fioredda - Istituto Giannina Gaslini
Frank Firkin - St Vincent's Hospital
Elizabeth Förster-Waldl - Medical University of Vienna
Bob Geng - University of California, San Diego
Vera Goda - STEM
Luis Gonzalez-Granado - Research Institute Hospital 12 de Octubre
Eyal Grunebaum - Hospital for Sick Children
Elzbieta Grzesk - Nicolaus Copernicus University
Sarah E Henrickson - Children's Hospital of Philadelphia
Anna Hilfanova - Shupyk National Healthcare University of Ukraine
Mitsuteru Hiwatari - The University of Tokyo
Chihaya Imai - Niigata University
Winnie Ip - Great Ormond Street Hospital
Soma Jyonouchi - Children's Hospital of Philadelphia
Hirokazu Kanegane - Tokyo Medical and Dental University
Yuta Kawahara - Jichi Medical University
Amer M Khojah - Northwestern University
Vy Hong-Diep Kim - University of Toronto
Marina Kojić - Medical University of Vienna
Sylwia Kołtan - Nicolaus Copernicus University
Gergely Krivan - STEM
Daman Langguth - Sullivan Nicolaides Pathology
Yu-Lung Lau - University of Hong Kong
Daniel Leung - University of Hong Kong
Maurizio Miano - Istituto Giannina Gaslini
Irina Mersyanova - Dmitry Rogachev National Research Center of Pediatric Hematology, Oncology and Immunology
Talal Mousallem - Duke University Hospital
Mica Muskat - University of California, San Francisco
Flavio A Naoum - Faculdade de Medicina de São José do Rio Preto
Suzie A Noronha - University of Rochester Medical Center
Monia Ouederni - Tunis El Manar University
Shuichi Ozono - Kurume University
G Wendell Richmond - Rush University Medical Center
Inga Sakovich - Belarusian Research Center For Pediatric Oncology and Hematology
Ulrich Salzer - University Medical Center Freiburg
Catharina Schuetz - University Hospital Carl Gustav Carus
Filiz Odabasi Seeborg - Texas Children's Hospital
Svetlana O Sharapova - Belarusian Research Center For Pediatric Oncology and Hematology
Katja Sockel - University Hospital Carl Gustav Carus
Alla Volokha - Shupyk National Healthcare University of Ukraine
Malte von Bonin - Medizinische Klinik und Poliklinik I, Universitätsklinikum Dresden, Dresden, Germany
Klaus Warnatz - University Medical Center Freiburg
Oliver Wegehaupt - University of Freiburg
Geoffrey A Weinberg - Golisano Children's Hospital
Ke-Juin Wong - Sabah Women and Children’s Hospital, Sabah, Malaysia
Austen Worth - Great Ormond Street Hospital
Huang Yu - Children's Hospital of Chongqing Medical University
Yulia Zharankova - Belarusian Research Center For Pediatric Oncology and Hematology
Xiaodong Zhao - Children's Hospital of Chongqing Medical University
Lisa Devlin - Belfast Health and Social Care Trust
Adriana Badarau - X4 Pharmaceuticals (Austria) GmbH, Vienna, Austria
Krisztian Csomos - University of South Florida St. Petersburg
Marton Keszei - Karolinska Institutet
Joao Pereira - Yale University
Arthur G Taveras - X4 Pharmaceuticals, Inc, Cambridge, USA
Sarah L Beaussant-Cohen - X4 Pharmaceuticals, Inc, Cambridge, USA
Mei-Sing Ong - Harvard Pilgrim Health Care
Anna Shcherbina - Dmitry Rogachev National Research Center of Pediatric Hematology, Oncology and Immunology
Jolan E Walter - University of South Florida St. Petersburg
Publication Details: Journal of clinical immunology, Vol.42(8), pp.1748-1765
Grant note: R24 AI049393 / NIAID NIH HHS K23 AI163350 / NIAID NIH HHS R01 AI100887 / NIAID NIH HHS
Identifiers: 9931730208331
Academic Unit: Umm Al Qura University
Language: English
Resource Type: Journal article