Object: Von Hippel-Lindau (VHL) disease is a hereditary multiple-neoplasia syndrome mapping to chromosome 3p25-26. Endolymphatic sac (ELS) tumors have been identified as a neoplastic manifestation of VHL disease. The purpose of this study was to evaluate comprehensively the natural history of inner ear disease in a large population of patients with confirmed or suspected VHL disease and to correlate the clinical features with the VHL genotype.
Methods: The authors collated and analyzed clinical and genotypic data obtained in patients enrolled in an Institutional Review Board-approved protocol in which families and individuals affected by VHL disease were studied. These data included results from multidisciplinary history workups and physical examinations, imaging studies, and a battery of audiological tests. One hundred seventy-five patients were enrolled in the study, 129 with confirmed VHL disease and 46 of their family members in whom test results for VHL disease were negative and who served as controls. Twenty-one patients had ELS tumors that were evident on magnetic resonance images; three of them had bilateral ELS lesions. Hearing loss, often sudden in onset and severe to profound in nature, vestibulopathy, aural fullness, and tinnitus represented the primary symptoms of ELS tumor. Distinct patterns of auditory and vestibular dysfunction occurred at different stages of the disease. Phenotypic data showed that 17 of 21 patients with ELS tumors did not have pheochromocytomas, whereas all had VHL disease affecting the kidney, all but two had VHL disease affecting the central nervous system, and all but one had disease affecting the pancreas. Genotyping revealed 10 rearrangements (partial deletions), eight single bp substitutions, and one 3-bp insertion. Although there was no difference in the incidence of hearing loss between populations, symptoms of imbalance and aural fullness were more common in patients with VHL disease but without imaging evidence of ELS tumor than they were in family members who did not have VHL disease (p < 0.01).
Conclusions: Endolymphatic sac tumors are frequently associated with VHL disease. Symptoms of disequilibrium or aural fullness in patients with VHL disease may be an early indication of endolymphatic dysfunction. Patients with VHL disease provide a unique opportunity to examine the effects of specific gene mutations and a discrete neoplastic process on the human inner ear. The study of ELS tumors in this group also provides a pathological model of ELS function and supplies evidence for a role of the ELS in clinical Ménière-like disease(s).