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

Research output: Contribution to journalResearch articleContributedpeer-review

Contributors

  • University of Freiburg
  • University of South Florida
  • X4 Pharmaceuticals
  • Immunology Outpatient Clinic Vienna
  • University of North Carolina at Chapel Hill
  • United States Army
  • Tehran University of Medical Sciences
  • Karolinska Institutet
  • Harvard University
  • Baylor College of Medicine
  • Shupyk National Medical Academy of Postgraduate Education
  • University of Washington
  • University of California at Irvine
  • University of Toronto
  • Dr Luis Calvo Mackenna Children’s Hospital
  • Vanderbilt University
  • Oncology and Immunology
  • University of California at San Francisco
  • St George's University Hospitals NHS Foundation Trust
  • Royal Free London NHS Foundation Trust
  • IRCCS Istituto Giannina Gaslini - Genova
  • University of Melbourne
  • St. Vincent's Hospital Melbourne
  • Medical University of Vienna
  • University of California at San Diego
  • Central Hospital of Southern Pest
  • Complutense University
  • Nicolaus Copernicus University in Toruń
  • University of Pennsylvania
  • The University of Tokyo
  • Niigata University
  • Great Ormond Street Hospital for Children NHS Trust
  • Tokyo Medical and Dental University
  • Jichi Medical University
  • Northwestern University

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.

Details

Original languageEnglish
Pages (from-to)1748-1765
Number of pages18
JournalJournal of clinical immunology
Volume42
Issue number8
Publication statusPublished - Nov 2022
Peer-reviewedYes

External IDs

PubMed 35947323
ORCID /0009-0003-6519-0482/work/149439120

Keywords

ASJC Scopus subject areas

Keywords

  • autoimmunity, CXCR4, lymphopenia, myelokathexis, neutropenia, warts

Library keywords