4.6 Article

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

Journal

JOURNAL OF CLINICAL IMMUNOLOGY
Volume 42, Issue 8, Pages 1748-1765

Publisher

SPRINGER/PLENUM PUBLISHERS
DOI: 10.1007/s10875-022-01312-7

Keywords

CXCR4; myelokathexis; warts; autoimmunity; neutropenia; lymphopenia

Categories

Funding

  1. National Institutes of Health [R01AI100887-05, R24AI 049393]
  2. Robert A. Good Endowment, University of South Florida
  3. Jeffrey Modell Foundation
  4. X4 Pharmaceuticals, Inc.
  5. National Institute of Allergy and Infectious Diseases of the National Institutes of Health [K23AI163350]

Ask authors/readers for more resources

The study describes a cohort of 66 WHIM syndrome patients, including 57 previously unreported cases, with diverse clinical phenotypes. Mutations in the same region of the CXCR4 gene lead to hyperactive signaling. The age of diagnosis and onset of clinical manifestations of WHIM syndrome vary, with earlier detection and treatment leading to better outcomes, especially in patients with a family history of the syndrome.
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.

Authors

I am an author on this paper
Click your name to claim this paper and add it to your profile.

Reviews

Primary Rating

4.6
Not enough ratings

Secondary Ratings

Novelty
-
Significance
-
Scientific rigor
-
Rate this paper

Recommended

No Data Available
No Data Available