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. Severa