No abstract

4 Laryngoscope, 128:S1-S13, 2018.

Sensorineural hearing loss is a common and currently irreversible disorder, because mammalian hair cells (HCs) do not regenerate and current stem cell and gene delivery protocols result only in immature HC-like cells. Importantly, although the transcriptional regulators of embryonic HC development have been described, little is known about the postnatal regulators of maturating HCs. Here we apply a cell type-specific functional genomic analysis to the transcriptomes of auditory and vestibular sensory epithelia from early postnatal mice. We identify RFX transcription factors as essential and evolutionarily conserved regulators of the HC-specific transcriptomes, and detect Rfx1,2,3,5 and 7 in the developing HCs. To understand the role of RFX in hearing, we generate Rfx1/3 conditional knockout mice. We show that these mice are deaf secondary to rapid loss of initially well-formed outer HCs. These data identify an essential role for RFX in hearing and survival of the terminally differentiating outer HCs.

Cellular heterogeneity hinders the extraction of functionally significant results and inference of regulatory networks from wide-scale expression profiles of complex mammalian organs. The mammalian inner ear consists of the auditory and vestibular systems that are each composed of hair cells, supporting cells, neurons, mesenchymal cells, other epithelial cells, and blood vessels. We developed a novel protocol to sort auditory and vestibular tissues of newborn mouse inner ears into their major cellular components. Transcriptome profiling of the sorted cells identified cell type–specific expression clusters. Computational analysis detected transcription factors and microRNAs that play key roles in determining cell identity in the inner ear. Specifically, our analysis revealed the role of the Zeb1/miR-200b pathway in establishing epithelial and mesenchymal identity in the inner ear. Furthermore, we detected a misregulation of the ZEB1 pathway in the inner ear of Twirler mice, which manifest, among other phenotypes, malformations of the auditory and vestibular labyrinth. The association of misregulation of the ZEB1/miR-200b pathway with auditory and vestibular defects in the Twirler mutant mice uncovers a novel mechanism underlying deafness and balance disorders. Our approach can be employed to decipher additional complex regulatory networks underlying other hearing and balance mouse mutants.

Objectives/Hypothesis Identify correlations among SLC26A4 genotype, cochlear structural anomalies, and hearing loss associated with enlargement of the vestibular aqueduct (EVA). Study Design Prospective cohort survey, National Institutes of Health, Clinical Center, a federal biomedical research facility. Methods 83 individuals, 11 months to 59 years of age, with EVA in at least one ear. Correlations among pure-tone hearing thresholds, number of mutant SLC26A4 alleles, and the presence of cochlear anomalies detected by computed tomography or magnetic resonance imaging. Results Linear mixed-effect model indicates significantly poorer hearing in ears with EVA from individuals with two mutant alleles of SLC26A4 than in those with EVA and a single mutant allele (p = .012) or no mutant alleles (p = .007) in this gene. There was no detectable relationship between degree of hearing loss and the presence of structural cochlear anomalies. Conclusions The number of mutant alleles of SLC26A4, but not the presence of cochlear anomalies, has a significant association with severity of hearing loss in ears with EVA. This information will be useful for prognostic counseling of patients and families with EVA.

No abstract

Sigmoid sinus diverticulum and dehiscence is a surgically treatable cause of PST, with a high rate of success. The radiographic diagnosis may be subtle and easily overlooked. Complications of surgery can be serious, and vigilance must be maintained to ensure prompt diagnosis and treatment.

Children with radiographic cochlear malformations benefit from cochlear implantation with multichannel devices. They ultimately perform as well as their matched counterparts with normal cochleae, although they may improve more slowly over time.