In selected cases, variants in CXCR2 have been reported while other cases are unresolved since no genetic abnormalities were found yet the patients presented clinically with WHIM syndrome. WHIM syndrome (warts, hypogammaglobulinemia, infections, myelokathexis) is a rare multi-system combined immunodeficiency most often caused by autosomal dominant pathogenic variants in the CXCR4 gene region coding for the C-terminus of the C-X-C chemokine receptor type 4. Early-onset bacterial infections with severe neutropenia and/or lymphopenia should prompt genetic testing for WHIM syndrome, even in the absence of warts. The variable expressivity of WHIM syndrome in pediatric patients delays their diagnosis and therapy. Only one patient died death was attributed to complications of hematopoietic stem cell transplantation. This observation reinforces previous reports that early treatment for WHIM syndrome improves outcomes. Patients with a family history of WHIM syndrome also received earlier treatment, experienced less hospitalization, and had less end-organ damage. 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). However, we report greater prevalence and variety of autoimmune complications of WHIM syndrome (21.2%) than reported previously. 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. 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. All variants affect the same CXCR4 region and impair CXCR4 internalization resulting in hyperactive signaling. Of 17 distinct CXCR4 genetic variants within our cohort, 11 were novel pathogenic variants affecting 15 individuals (23%). We characterize a unique international cohort of 66 patients, including 57 (86%) cases previously unreported, with variable clinical phenotypes. 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.
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