WHIM syndrome is predominantly caused by an autosomal dominant pathogenic variant in the CXCR4 gene.1

Currently, ~40 variants are classified as pathogenic or likely pathogenic for WHIM syndrome.2

Mechanism of Disease: CXCR4 Pathway Dysregulation Pathological Feature: Myelokathexis

Pathogenic variants of the CXCR4 gene can result in the retention of white blood cells in the bone marrow.1

WHIM MOA Graphic

Myelokathexis, the abnormal retention of neutrophils in the bone marrow, is a hallmark feature of WHIM syndrome, present in ~100% of cases. It is detected by bone marrow biopsy but can be challenging to identify and may be missed on initial biopsy evaluation.1,4-7

Bone Marrow Aspirates of WHIM Syndrome Patients Showing Key Pathological Features of Myelokathexis*,†,3,7

WHIM Myelokathexis Biopsy Image

Did You Know?

The understanding of CXCR4 variants continues to evolve.

Since 2019, 27 CXCR4 variants have been newly classified as pathogenic or likely pathogenic for WHIM syndrome.2,4 The continued emergence of new pathogenic variants may warrant genetic testing in patients suspected of having WHIM syndrome, even if genetic testing was previously completed.

Next Section: Diagnosis & Management

  1. Geier CB, Ellison M, Cruz R, et al. Disease progression of WHIM syndrome in an international cohort of 66 pediatric and adult patients. J Clin Immunol. 2022;42(8):1748-1765. doi:10.1007/s10875-022-01312-7
  2. Zmajkovicova K, Nykamp K, Blair G, Yilmaz M, Walter JE. Expanding CXCR4 variant landscape in WHIM syndrome: integrating clinical and functional data for variant interpretation. Front Immunol. 2024;15:1411141. doi:10.3389/fimmu.2024.1411141
  3. Beaussant Cohen S, Fenneteau O, Plouvier E, et al. Description and outcome of a cohort of 8 patients with WHIM syndrome from the French Severe Chronic Neutropenia Registry. Orphanet J Rare Dis. 2012;7:71. doi:10.1186/1750-1172-7-71
  4. Heusinkveld LE, Majumdar S, Gao JL, McDermott DH, Murphy PM. WHIM syndrome: from pathogenesis towards personalized medicine and cure. J Clin Immunol. 2019;39(6):532-556. doi:10.1007/s10875-019-00665-w
  5. Badolato R, Donadieu J; WHIM Research Group. How I treat warts, hypogammaglobulinemia, infections, and myelokathexis syndrome. Blood. 2017;130(23):2491-2498. doi:10.1182/blood-2017-02-708552
  6. McDermott DH, Murphy PM. WHIM syndrome: immunopathogenesis, treatment and cure strategies. Immunol Rev. 2019;287(1):91-102. doi:10.1111/imr.12719
  7. Al Ustwani O, Kurzrock R, Wetzler M. Genetics on a WHIM. Br J Haematol. 2014;164(1):15-23. doi:10.1111/bjh.12574