The Audiologic and Otolaryngologic Phenotype in WHIM Syndrome

OBJECTIVE: WHIM syndrome (warts, hypogammaglobulinemia, infections, and myelokathexis syndrome) is an ultra-rare primary immunodeficiency disease caused by autosomal dominant hyperfunctional mutations in the chemokine receptor CXCR4. Otolaryngologists are frequently consulted to evaluate WHIM patients because of recurrent acute ear and sinus infections, particularly in early childhood; however, a systematic assessment of otolaryngologic and audiometric phenotypes is lacking. This study comprehensively describes the auditory and otolaryngology phenotype of WHIM syndrome. STUDY DESIGN: Prospective observational case-series. SETTING: Quaternary Care Research Facility. METHODS: We report qualitative and quantitative otolaryngologic and audiometric assessments for 44 WHIM patients followed at the National Institutes of Health Clinical Center (NIH CC) for up to 17 years. RESULTS: Thirty-five patients gave a history of recurrent otitis media and 29 had a history of chronic or recurrent sinusitis. Hearing loss, usually bilateral and ranging from mild to profound, was identified in 43% (n = 18) of patients. Two previously unreported otolaryngologic phenotypes were also identified: maxillary sinus hypoplasia (n = 19, 51%) and defective olfaction (n = 22, 73%), including 6 patients (27%) with anosmia. Neither impaired olfaction nor maxillary sinus hypoplasia was associated with upper respiratory infection frequency or severity. Two patients were diagnosed with human papillomavirus head and neck squamous cell carcinoma (HNSCC). CONCLUSION: The results reveal a possible noninfectious direct effect of hyperfunctional CXCR4 on paranasal sinus development and odorant sensing and demonstrate a high risk of hearing loss. Further, the results emphasize the importance of baseline assessment and careful follow-up of WHIM patients by otolaryngologists and audiologists. CLINICALTRIALS: gov NCT02231879 and NCT00128973.