Advancing Research, Clinical Recognition, and Targeted Therapies for WHIM Syndrome

WHIM syndrome is a primary immunodeficiency disorder known for the constellation of clinical symptoms for which it is named – Warts, Hypogammaglobulinemia, Infections, and Myelokathexis. WHIM is also known for its predominant pathogenic mechanism of enhanced CXCR4 signaling that alters immune cell function. Specifically, CXCR4 is a chemokine receptor present on the surface of all immune cells and most non-immune cells that when bound to its cognate chemokine ligand CXCL12, can affect cell differentiation, migration, and proliferation through MAP kinase activation and other downstream signalling pathways.

Human, animal models, and ex vivo cellular and molecular studies have helped to clarify disease pathogenesis in WHIM and have led to targeted therapies aimed at the CXCR4 signaling pathway. With more therapeutic alternatives that could improve short- and long-term outcomes for patients, the recognition and diagnosis of WHIM syndrome is increasingly relevant. Genetic testing is more economically and technically feasible in the clinic such that novel CXCR4 variants are being identified, which has revealed an expanding clinical phenotype even among family members. Additionally, patients with overlapping features to WHIM have been identified with other genetic mutations or protein signalling pathways that are affected in relationship with the dysregulation of CXCR4 signaling pathway.

Thus, the goals of this Research Topic are to highlight clinical, translational, and basic science advances that have expanded our understanding of WHIM syndrome over the last decade.

Four educational goals are identified below for this themed submission on WHIM syndrome. This Research Topic will accept Original Research and Review articles. Each bullet point under the individual goals would be a separate topic request to invited authors to provide the recent advances for this area of WHIM syndrome:

- Highlight the research advances in CXCR4 molecular signalling and/or disease pathogenesis as it pertains to WHIM syndrome with the following invited topic submissions:

1. WHIM-receptor mutant mice and mechanisms of disease pathogenesis in WHIM.
2. WHIM genetic variants (novel variants identified within the CXCR4 gene and/or alternative genes of
interest that have been identified in WHIM-like patients (ex. GRK3 or CXCR2) and how this expands our
understanding of WHIM pathogenesis including cell migration.
3. Downstream signalling pathways and cellular functional responses activated by CXCR4 wildtype and
WHIM mutant receptors.
4. Neutrophil biology and chemokine receptors in WHIM.
5. Human papillomavirus (HPV) pathogenesis as it pertains to CXCR4 function in WHIM patients and what
can be extrapolated from it to host cell immune and non-immune responses.

-Highlight clinical features while addressing their variable penetrance in WHIM syndrome with the following invited topic submissions:

1. Pathogenesis of gynecologic malignancy in WHIM and discussion of CXCR4 antagonism/HPV vaccination
as future therapeutic strategies compared to other standard of care.
2. Leukopenia variability in WHIM (neutropenia vs. lymphopenia).
3. CXCR4 as it pertains to normal hematopoiesis vs. in WHIM syndrome.
4. Hypogammaglobulinemia and/or B cell function in WHIM.
5. Glioma as rare complication in WHIM.

- Highlight the information being learned from population science looking at retrospective and prospective WHIM cohorts with the following invited submissions:

1. Genotype-Phenotype updates in WHIM.
2. European experience in WHIM syndrome (iPOPI) and/or WHIM worldwide with focus on disease
identification, management, and long-term prognosis.
3. Phase 3 quality of life (QOL) Mavorixafor Trial in WHIM.
4. Summarize current knowledge on CXCR4 antagonism as a pharmacologic target for WHIM as an invited
review.

- Highlight new information in biomarkers of WHIM with the following submissions:

1. Precursor B cells as a biomarker in WHIM.

2. Clarifying the definition of myelokathexis and what findings in the bone marrow are (or are not)
pathognomonic of WHIM.
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.