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.This original article describes the disease progression and clinical spectrum of WHIM syndrome in an international cohort of 66 pediatric and adult patients. WHIM syndrome is a combined immunodeficiency caused by gain-of-function variants in CXCR4, leading to impaired receptor internalization and hyperactive CXCR4 signaling. The study includes 57 previously unreported cases and identifies 17 distinct CXCR4 variants, including 11 novel pathogenic variants. Infections, neutropenia, lymphopenia and warts showed variable age of onset, and autoimmune complications were more frequent and diverse than previously reported. Earlier diagnosis through family history was associated with earlier treatment, fewer hospitalizations and less end-organ damage, supporting early genetic testing for WHIM syndrome in patients with early-onset bacterial infections, severe neutropenia and/or lymphopenia, even in the absence of warts.