PHEX Gene Dosage Drives Meniere′s Disease and Related Audiovestibular Phenotypes in X-Linked Hypophosphatemia

Importance: A subset of Meniere′s disease (MD) patients—defined by endolymphatic sac underdevelopment (ES hypoplasia), frequent bilateral disease, and strong male predominance—termed ″MD-hp″, has emerged as a promising model for genetic investigation. We observed a striking enrichment of X-linked hypophosphatemia (XLH) caused by PHEX mutations among MD-hp patients, suggesting a shared genetic driver and immediate opportunities for biomarker discovery and targeted therapy development. Objective: To test whether XLH and MD-hp share a causal, PHEX gene-driven relationship. Design: Prospective, cross-sectional observational study. Setting: Two tertiary academic centers. Participants: Thirty-three adult XLH patients. Main Outcome Measures: Pure-tone audiometry and speech-intelligibility testing; vestibular function via caloric and video head-impulse testing; symptom history fulfilling definite MD criteria; high-resolution CT assessment of ES hypoplasia (ATVA ≥ 140°) to define MD-hp; delayed 3D-FLAIR MRI detection of endolymphatic hydrops; and PHEX/pathway gene sequencing. Results: Given population prevalences (XLH ≈ 0.005%; MD ≈ 0.2%; MD-hp ~30% of MD), random co-occurrence would be ~1 in 33 million. In our cohort, 6 of 33 met bilateral MD-hp criteria (XLH+MD-hp ≈ 18.2%; 1 in 5.5)—a > 6 million-fold enrichment—all hemizygous males (including two with fluctuating progressive sensorineural hearing loss (SNHL) but no vertigo). Two additional hemizygous males < 40 years of age displayed bilateral ES hypoplasia without clinical MD, and two males with mosaic or hypomorphic PHEX variants showed normal ES anatomy and no audiovestibular symptoms. No female carriers met MD-hp criteria; instead, five exhibited mild-to-moderate low-to-mid frequency sensorineural hearing loss without vertigo, and two had isolated conductive hearing loss. Conclusions and Relevance: These findings support an inner ear–specific PHEX gene-dosage threshold model for MD-hp penetrance: complete loss-of-function in hemizygous males leads to bilateral ES hypoplasia and MD, whereas mosaic or partial loss variants in males—and heterozygosity in females—permit residual PHEX activity, resulting in milder or absent audiovestibular phenotypes. This genotype–endotype–phenotype linkage (complete PHEX loss → ES hypoplasia → MD) enables early risk stratification, personalized surveillance, and paves the way for targeted therapies in XLH patients.