WHIM syndrome, a primary immunodeficiency disorder, is characterized by a unique set of clinical symptoms: Warts, Hypogammaglobulinemia, Infections, and Myelokathexis. The disorder is primarily driven by enhanced CXCR4 signaling, which disrupts immune cell function. CXCR4, a chemokine receptor found on immune and non-immune cells, interacts with its ligand CXCL12 to influence cell differentiation, migration, and proliferation through pathways like MAP kinase activation. Recent studies using human, animal models, and ex vivo cellular and molecular approaches have elucidated the pathogenesis of WHIM syndrome, leading to the development of targeted therapies focusing on the CXCR4 signaling pathway. As therapeutic options expand, the importance of recognizing and diagnosing WHIM syndrome grows. Advances in genetic testing have made it feasible to identify novel CXCR4 variants, revealing a broader clinical phenotype even within families. Moreover, patients with WHIM-like features have been found to have other genetic mutations or affected protein signaling pathways, highlighting the complexity of CXCR4 dysregulation. Despite these advances, there remains a need for further research to fully understand the syndrome's pathogenesis and improve patient outcomes.

This research topic aims to spotlight the clinical, translational, and basic science advancements that have deepened our understanding of WHIM syndrome over the past decade. The primary objectives include exploring the molecular signaling of CXCR4, understanding the variable clinical features of WHIM, examining population science insights from WHIM cohorts, and identifying new biomarkers. By addressing these areas, the research seeks to answer critical questions about the pathogenesis, clinical variability, and potential therapeutic strategies for WHIM syndrome.

To gather further insights into the complexities of WHIM syndrome, we welcome articles addressing, but not limited to, the following themes:
- Research advances in CXCR4 molecular signaling and disease pathogenesis.
- Clinical features and their variable penetrance in WHIM syndrome.
- Insights from retrospective and prospective WHIM cohorts.
- New information on biomarkers of WHIM.
- The role of CXCR4 in normal hematopoiesis versus WHIM syndrome.
- The impact of CXCR4 antagonism and HPV vaccination as therapeutic strategies.
- Genotype-phenotype correlations and global experiences in WHIM management.
- Quality of life outcomes from clinical trials targeting WHIM syndrome

Topic Editor Prof. Teresa K. Tarrant has grant funding with X4 Pharmaceuticals, which makes Mavoriaxafor and is in clinical trials to treat WHIM. She also receives consulting fees from X4. The other Topic Editors declare no competing interests with regard to the Research Topic subjecther Topic Editors declare no competing interests with regard to the Research Topic subject.

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Frontiers in Immunology

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