Clinical manifestations of WHIM syndrome can be heterogeneous, nonspecific, and variable over time, contributing to potential diagnostic delays.1,2

Clinical manifestations of WHIM syndrome can be heterogeneous, nonspecific, and variable over time, contributing to potential diagnostic delays.1,2

What are the most frequent manifestations of WHIM?

WHIM syndrome is a rare, combined primary immunodeficiency disorder and a chronic neutropenic disorder, named for the manifestations of 3:

Warts | Hypogammaglobulinemia | Infections | Myelokathexis


However, many patients will not present with each of these features.2

Neutropenia is the most frequent laboratory finding of WHIM syndrome. Neutropenia alone or with lymphopenia, monocytopenia, or both could indicate WHIM.2,4

WHIM Syndrome Symptom Map

Combined immunodeficiencies are defined by impaired cellular and humoral immunity, which are part of the adaptive immune system, and lead to increased susceptibility to bacterial, viral, and opportunistic infections, disorders of immune regulation, and malignancies.6

WHIM syndrome presentation varies from patient to patient and can range from manageable to severe symptoms, including complications that may require hospitalization.2,7

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Why is early diagnosis essential?

Left undiagnosed, people with WHIM syndrome may suffer from debilitating and life-threatening complications, including2,7:

  • Increased cancer risk§
    • 30% estimated overall risk of cancer by age 405
    • Includes HPV- and EBV-associated malignancies2,5,7
  • Irreversible end-organ damage¶,2
    • Observed in ~20% of patients
    • May include bronchiectasis and bronchiolectasis due to recurrent pneumonias and hearing loss due to recurrent otitis
  • Sepsis resulting from bacterial meningitis and bacteremia2
    • Cumulative lifetime prevalence of 13%

§ Based on analysis of n=60 patients, as described in Beaussant Cohen et al. Variable rates of cancer risk and prevalence in patients with WHIM are reported in the literature.
Based on analysis of n=66 patients, as described in Geier et al.

How can a WHIM diagnosis impact patient outcomes?

An early diagnosis may help reduce the risk of end-organ damage

WHIM syndrome management is aimed at controlling infections and reducing the risk of potential long-term complications.2,3

  • Patients in a retrospective analysis who were diagnosed early due to family history (FH) and/or newborn screening (NBS) compared to patients diagnosed by clinical signs2:
    • Experienced fewer hospitalizations (69% vs. 87%)
    • Deferred inpatient treatment until a later age (7 years of age vs. 2 years of age)
    • Had a lower incidence of end-organ damage

Incidence of End-Organ Damage Based on Diagnostic Delay#,2

End-organ Damage Incididence Chart
End-organ Damage Incididence Chart

# Diagnostic delay defined as the time from first date of recorded neutropenia to final molecular diagnosis of WHIM syndrome.

A diagnosis may help identify at-risk family members

WHIM syndrome is most often caused by autosomal dominant pathogenic variants in the CXCR4 gene, and genetic testing may help identify relatives of patients who share a pathogenic variant.2

WHIM Syndrome is Autosomal Dominant
WHIM Syndrome is Autosomal Dominant

Additionally, a definitive diagnosis and an explanation of their symptoms can give patients a sense of relief.

  1. 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
  2. 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
  3. Dale DC, Firkin F, Bolyard AA, et al. Results of a phase 2 trial of an oral CXCR4 antagonist, mavorixafor, for treatment of WHIM syndrome. Blood. 2020;136(26):2994-3003. doi:10.1182/blood.2020007197
  4. 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
  5. 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
  6. Speckmann C, Doerken S, Aiuti A, et al. A prospective study on the natural history of patients with profound combined immunodeficiency: An interim analysis. J Allergy Clin Immunol. 2017;139(4):1302-1310.e4. doi:10.1016/j.jaci.2016.07.040
  7. Kawai T, Malech HL. WHIM syndrome: congenital immune deficiency disease. Curr Opin Hematol. 2009;16(1):20-26. doi:10.1097/MOH.0b013e32831ac557
  8. National Cancer Institute Dictionary of Cancer Terms. Accessed August 21, 2023.