WHIM syndrome: from mechanism to targeted therapy - advances shaping clinical care

Warts, hypogammaglobulinemia, infections, and myelokathexis (WHIM) syndrome is an autosomal dominant combined immunodeficiency (CID), often caused by increased CXCR4 pathway signaling. Against early-onset hallmark of neutropenia, diagnosis is delayed due to lack of awareness, incomplete penetrance, and requirement for specialized bone marrow evaluation to detect myelokathexis.

Some infants with WHIM are identified via newborn screening for low thymic emigrant T cells. Early pediatric diagnosis is associated with improved outcomes. The genetic spectrum of CXCR4 expands beyond the canonical C-terminal hotspot, with N-terminal p.D84H variant. Recent trials of oral CXCR4 antagonist demonstrated increased circulating mature neutrophils and lymphocytes, reduced infection burden, and, in some cases, wart regression. Mechanistic studies in human and murine models contribute to the understanding of the combined immunodeficiency phenotype and highlight how CXCR4 hyperactivation impairs hematopoietic stem/progenitor cell egress, leukocyte trafficking and disrupts stromal niches critical for lymphocyte development and survival.

Increased awareness, opportunities for screening at birth, improved pathological and genetic diagnostics, and 2024 FDA approval of the first oral CXCR4 antagonist create practical advance in targeting WHIM syndrome. As a CID with lifetime risk for humoral deficiency, impaired antiviral defense and malignancy, WHIM warrants long-term monitoring and further investigation into broader applications of CXCR4 antagonism.