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

Abstract

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.

Keywords: CXCR4; autoimmunity; lymphopenia; myelokathexis; neutropenia; warts.

Fig. 1

Genetic characterization of 66 patients with WHIM syndrome. A CXCR4 full-length sequence of the native CXCR4 aligned with CXCR4 mutations in C-terminus identified in WHIM syndrome patients. Novel mutations are highlighted with a red dot. B Snake plot of the schematic structure of CXCR4 with mutations highlighted in red. Light pink … CXCL12 (SDF1A) binding domain, yellow … dimerization domain. C Phyre² three-dimensional model structure of the chemokine receptor CXCR4 residues 2–334, with conformational change of CXCR4 truncating mutations highlighted in red. D K562 cells transfected with WT CXCR4 and the indicated variants were stimulated with CXCL12 (vehicle, 1 nM, 10 nM, 100 nM) for 45 min and 4 h, respectively, and the surface expression of CXCR4 was measured by flow cytometry. Values are expressed as % remaining CXCR4 signal compared to vehicle-treated cells. Values represent mean ± SEM, n = 3–12)

Fig. 2

Analysis of WHIM syndrome-related clinical manifestation and laboratory findings. A Type of first WHIM syndrome-related clinical manifestation. B Cumulative percentage of patients suffering from their first WHIM syndrome-related clinical manifestation at a given age for all patients (black line, n = 66), and prospectively diagnosed patients based on positive family history and < 1 year of age (blue line, n = 9). C Lifetime prevalence of individual WHIM syndrome-related manifestations and laboratory findings (frequency as % total cases)

Fig. 3

Clinical and immunological disease progression of WHIM syndrome. A Cumulative percentage of WHIM syndrome-related manifestations at a given age in all WHIM syndrome patients (n = 66, left panel) and patients prospectively diagnosed patients based on positive family history and < 1 year of age (n = 9, right panel). B Longitudinal analysis of WBC, ANC, and ALC counts (n = 35). Black line represents median value at a given age, dots represent individual patient’s values at a given time point and dotted line is age matched reference values

Fig. 4

Treatment approaches and end-organ damage in WHIM syndrome. A Prevalence of individual treatment strategies. B Percent of patients with a treatment response that was scored using the following criteria: “non” = no clinical response or side effects were limiting, “partial” = clinical improvement but therapeutic escalation was required, or “full” = clinical improvement with no escalation. C Time from first record of neutropenia to final diagnosis of WHIM syndrome. All patients (black box plot), patients diagnosed by family history or newborn screening (FHS/NBS blue box plot) and patients diagnosed by clinical signs (Sx, red box plot). Whiskers-box plot represents (median ± quantile 0.1–0.9). D Time from first record of neutropenia to initiation of either GCSF or IgGRT. All patients (black box plot), patients diagnosed by family history or newborn screening (FHS/NBS blue box plot) and patients diagnosed by clinical signs (Sx, red box plot). Whiskers-box plot represents (median ± quantile 0.1–0.9). E Patients with end organ damage, including bronchiectasis and/or hearing loss of all patients (black bar), those diagnosed by clinical signs (red bar) and those diagnosed by family history (red bar). F Cumulative percentage of first hospital admission due to WHIM-related manifestation by age

Fig. 5

Autoimmunity and hyperinflammation in WHIM syndrome. A Prevalence of individual autoimmune (AI) and hyperinflammatory (HI) complications (frequency as % patients with subtype among all patients with AI or HI complications, n = 14). B Occurrence of autoimmune and hyperinflammatory complications in isolation or combination (frequency reported as above). C Prevalence of single- and multi-lineage cytopenias (frequency reported as above). D Platelet and hemoglobin nadir during flares (symbols representing individual values; median ± SEM shown). E Prevalence of individual treatment strategies used for ITP and AIHA. F Ratio of patients with a treatment response for first line (steroids ± IVIG) and second line (biologicals, immunosuppressives or splenectomy). Treatment response was scored using the following criteria: “non” = no clinical response or side effects were limiting, “partial” = clinical improvement but therapeutic escalation was required, or “full” = clinical improvement with no escalation