Three-Dimensional High-Resolution Temporal Bone Histopathology Identifies Areas of Vascular Vulnerability in the Inner Ear

<b><i>Objectives:</i></b> Hypothesized causes of vestibular neuritis/labyrinthitis include neuroinflammatory or vascular disorders, yet vascular disorders of the inner ear are poorly understood. Guided by known microvascular diseases of the retina, we developed 2 hypotheses: (1) there exist vascular vulnerabilities of artery channels in cases of hypothetical nerve swelling for the superior, inferior, and vestibulocochlear artery and (2) there are arteriovenous crossings that could compromise vascular flow in disease states. <b><i>Methods:</i></b> Two fully mounted and stained temporal bones were used to render three-dimensional reconstructions of the labyrinth blood supply. Using these maps, areas of potential vascular compression were quantified in 50 human temporal bones. <b><i>Results:</i></b> Although inner ear arteries and veins mostly travel within their own bony channels, they may be exposed (1) at the entrance into the otic capsule, and (2) where the superior vestibular vein crosses the inferior vestibular artery. At the entry into the otic capsule, the ratio of the soft tissue to total space for the superior vestibular artery was significantly greater than the inferior vestibular artery/cochleovestibular artery (median 44, interquartile range 34–55 vs. 14 [9–17], <i>p</i> &#x3c; 0.0001). <b><i>Conclusions:</i></b> Three-dimensional reconstruction of human temporal bone histopathology can guide vascular studies of the human inner ear. Studies of retinal microvascular disease helped identify areas of vascular vulnerability in cases of hypothetical nerve swelling at the entrance into the otic capsule and at an arteriovenous crossing near the saccular macula. These data may help explain patterns of clinical findings in peripheral vestibular lesions.

A pathogenic deletion in Forkhead Box L1 (FOXL1) identifies the first otosclerosis (OTSC) gene

Otosclerosis is a bone disorder of the otic capsule and common form of late-onset hearing impairment. Considered a complex disease, little is known about its pathogenesis. Over the past 20 years, ten autosomal dominant loci (OTSC1-10) have been mapped but no genes identified. Herein, we map a new OTSC locus to a 9.96 Mb region within the FOX gene cluster on 16q24.1 and identify a 15 bp coding deletion in Forkhead Box L1 co-segregating with otosclerosis in a Caucasian family. Pre-operative phenotype ranges from moderate to severe hearing loss to profound sensorineural loss requiring a cochlear implant. Mutant FOXL1 is both transcribed and translated and correctly locates to the cell nucleus. However, the deletion of 5 residues in the C-terminus of mutant FOXL1 causes a complete loss of transcriptional activity due to loss of secondary (alpha helix) structure. FOXL1 (rs764026385) was identified in a second unrelated case on a shared background. We conclude that FOXL1 (rs764026385) is pathogenic and causes autosomal dominant otosclerosis and propose a key inhibitory role for wildtype Foxl1 in bone remodelling in the otic capsule. New insights into the molecular pathology of otosclerosis from this study provide molecular targets for non-invasive therapeutic interventions.

A Pathogenic Deletion in Forkhead Box L1 (FOXL1) Identifies the First Otosclerosis (OTSC) Gene

Otosclerosis is a bone disorder of the otic capsule and common form of late-onset hearing impairment. Considered a complex disease, little is known about its pathogenesis. Over the past 20 years, ten autosomal dominant loci (OTSC1-10) have been mapped but no genes identified. Herein, we map a new OTSC locus to a 9.96 Mb region within the FOX gene cluster on 16q24.1 and identify a 15 bp coding deletion in Forkhead Box L1 co-segregating with otosclerosis in a Caucasian family. Phenotype ranges from moderate to severe hearing loss resolved by stapedectomy, to profound sensorineural loss requiring a cochlear implant. Mutant FOXL1 is both transcribed and translated and correctly locates to the cell nucleus. However, the deletion of 5 residues in the C-terminus of mutant FOXL1 causes a complete loss of transcriptional activity due to loss of secondary (alpha helix) structure. FOXL1 (rs764026385) was identified in a second unrelated case on a shared background. We conclude that FOXL1 (rs764026385) is pathogenic and causes autosomal dominant otosclerosis and propose a key inhibitory role for wildtype Foxl1 in bone remodelling in the otic capsule. New insights into the molecular pathology of otosclerosis from this study provide molecular targets for non-invasive therapeutic interventions.

Rapidly progressive labyrinthitis ossificans in an immunocompromised pediatric patient

In this report, we present a case of rapid otic capsule obliteration within an exceedingly short timeframe in the setting of Chronic Suppurative Otitis Media (CSOM) in an immunocompromised pediatric patient with Down Syndrome. Following maximal therapy for a right sided cholesteatoma, the patient developed a multi-drug resistant infection that cause CSOM, which within 6 weeks progressed to complete obliteration of the right cochlea and otic capsule. The possibility of congenital temporal bone microscopic dehiscence allowing infection propagation cannot be excluded. Nonetheless, this case highlights the importance of appreciating how quickly chronic middle ear disease can progress to involve the labyrinth and cause intracranial complications, even with adequate concurrent medical therapy in the form of antibiotics and surgical therapy. A greater awareness as physicians should be made on management of refractory chronic middle ear disease to better treat their potential complications, which is made apparent in this case report. Keywords: Otic capsule; Chronic suppurative otitis media; Otic capsule; Tympanomastoidectomy; Multi-drug resistance. Abbreviations: CSOM: Chronic Suppurative Otitis Media; MDR: Multi-Drug Resistant; CT: Computed Tomography; MRI: Magnetic Resonance Imaging; ID: Infectious Disease.

CCDC154 Mutant Caused Abnormal Remodeling of the Otic Capsule and Hearing Loss in Mice

Osteopetrosis is a rare inherited bone disease characterized by dysfunction of osteoclasts, causing impaired bone resorption and remodeling, which ultimately leads to increased bone mass and density. Hearing loss is one of the most common complications of osteopetrosis. However, the etiology and pathogenesis of auditory damage still need to be explored. In this study, we found that a spontaneous mutation of coiled-coil domain-containing 154 (CCDC154) gene, a new osteopetrosis-related gene, induced congenital deafness in mice. Homozygous mutant mice showed moderate to severe hearing loss, while heterozygous or wild-type (WT) littermates displayed normal hearing. Pathological observation showed that abnormal bony remodeling of the otic capsule, characterized by increased vascularization and multiple cavitary lesions, was found in homozygous mutant mice. Normal structure of the organ of Corti and no substantial hair cell or spiral ganglion neuron loss was observed in homozygous mutant mice. Our results indicate that mutation of the osteopetrosis-related gene CCDC154 can induce syndromic hereditary deafness in mice. Bony remodeling disorders of the auditory ossicles and otic capsule are involved in the hearing loss caused by CDCC154 mutation.