Family Studies of Whim Syndrome

Background: WHIM syndrome (warts, hypogammaglobulinemia, immunodeficiency, myelokathexis) is a very rare autosomal dominant immunodeficiency disorder attributable to mutations in CXCR4. Neutropenia, lymphocytopenia and monocytopenia occur because the CXCR4 mutation impairs normal leukocyte trafficking. This disease is of special interest with the finding that CXCR4 antagonists can increase blood leukocytes and may be a therapeutic option for these patients. (Dale DC et al EHA abstract, Jun 16, 2018; McDermott DH et al., N Engl J Med 2019; 380: 163).

Methods: Through the Severe Chronic Neutropenia International Registry (SCNIR) we identified 9 WHIM families in the US with 24 affected members: 13 female, 11 male, median age 31.9 years, mean 35.2 +/- 21.6 SEM (range 0.4 to 82), with mutations p.R334x (16), p.E343x (3), p.fs344x (3), or p.fs365x (2). As expected, family members had the same CXCR4 mutation. In these families, the diagnosis of WHIM syndrome usually followed from a patient seeing a physician because of recurrent fevers and infections and having a CBC revealing a very low WBC.

Findings: We investigated the diversity of clinical manifestations and outcomes in these patients. Immunoglobulin levels were low but not extremely low, e.g., IgG mean of 683 mg/dL +/- 53.1, median 668 mg/dL, range 443-1188 mg/dL, and only 2 patients were treated with long-term IVIG treatment. There was no apparent difference in outcomes. Most patients have received routine vaccinations and appear to mount normal or near normal IgG responses to tetanus, rubella, rubeola and H. influenza type B, based on serial observations in 6 patients. By contrast, response to human papilloma virus vaccine in these same patients appeared to be much weaker and unsustained.

Off all therapies and absent infection, profound leukopenia (WBC mean 1.83 x 109/L +/- 0.21, median 1.48 x 10⁹/L, range 0.30 - 7.90 x 10⁹/L, neutropenia mean 0.42 x 10⁹/L +/- 0.08, median 0.21 x 10⁹/L, range 0.00 - 6.48 x 10⁹/L, lymphocytopenia mean 1.18 x 10⁹/L +/- 0.20, median 0.84, range 0.04 - 4.14) was a consistent finding across ages and mutations. Fifteen patients received low dose G-CSF (median dose 1.56 mcg/kilogram/day) most intermittently but one patient was on G-CSF for 28 years. G-CSF elevated neutrophils but did not increase other leukocyte counts. Intermittent bacterial or presumed bacterial infections (otitis, sinusitis, pharyngitis, bronchitis, skin abscesses and cellulitis) were relatively common. Several patients were known to have hearing loss secondary to repeated episodes of otitis media. Serious infections requiring hospitalizations were rare, estimate at less than one per year.

Warts were also quite variable within families living in the same household. There was no apparent genotype/phenotype association of warts but they did tend to accumulate with age and did not regress spontaneously. In this cohort, 4 patients developed malignancies: 1 AML (death age 12.3 years), 2 HPV-associated cervical cancer (death ages 46 and 73), and 1 lymphoma (death age 48). Cervical dysplasia is a frequent problem and concern.

Conclusions: Leukopenia, neutropenia and lymphocytopenia are the most consistent features of WHIM syndrome. Hearing loss, disfiguring and disabling warts and HPV associated malignancies are its most serious complications. The variability of warts, respiratory and skin infections may be due to environmental factors. The promise of novel therapies should lead to more frequent diagnosis and early treatment to prevent the numerous serious complications of this syndrome.