Abstract
IMPORTANCE: Meniere disease (MD) is a heterogenous disorder whose underlying etiologies remain poorly understood. A subtype of MD characterized by endolymphatic sac (ES) underdevelopment (ES hypoplasia), frequent bilateral disease, and male predominance-termed MD-hp-has emerged as a promising model for genetic investigation. OBJECTIVE: To test whether the PHEX gene underlies the association of XLH with MD-hp. DESIGN, SETTING, AND PARTICIPANTS: This prospective, cross-sectional, study was conducted at tertiary academic centers in the US (Boston, Massachusetts) and Switzerland (Zurich) from January 2021 to August 2024. Participants aged 18 years and older with XLH were recruited. Data were analyzed from October 2024 to August 2025. EXPOSURE: Diagnosis of XLH. MAIN OUTCOMES AND MEASURES: The primary outcome was co-occurrence of XLH and MD-hp as compared with population prevalences. MD-hp assessment included pure-tone audiometry and speech-intelligibility testing, vestibular function testing via caloric and video head-impulse testing, symptom history indicating definite MD criteria, high-resolution computed tomography assessment of ES hypoplasia (angular trajectory of the vestibular aqueduct ≥140°), delayed 3-dimensional fluid-attenuated inversion recovery magnetic resonance imaging for detection of endolymphatic hydrops, and PHEX pathway gene sequencing. RESULTS: Given population prevalences of XLH (approximately 0.005%), MD (approximately 0.2%), and MD-hp (approximately 30% of MD), random co-occurrence would be approximately 1 in 33 million. In this cohort of 33 patients (10 male; mean [SD] age, 53.1 [13.0] years and 23 female; mean [SD] age, 46.2 [17.6] years), 6 (18.2%) met bilateral MD-hp criteria (approximately 1 in 5.5 patients)-a more than 6 million-fold enrichment. All 6 case patients were hemizygous males (including 2 males with fluctuating-progressive sensorineural hearing loss but no vertigo). Two additional hemizygous males younger than 40 years displayed bilateral ES hypoplasia without clinical MD, and 2 males with mosaic or hypomorphic PHEX variants showed normal ES anatomy and no audiovestibular symptoms. No female carriers met MD-hp criteria; instead, 5 females exhibited mild to moderate, low- to mid-frequency sensorineural hearing loss without vertigo, and 2 females 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, and MD) enables early risk stratification and personalized surveillance and paves the way for targeted therapies in patients with XLH.