FGF23 Deficiency Leads to Mixed Hearing Loss and Middle Ear Malformation in Mice

Fibroblast growth factor 23 (FGF23) is a circulating hormone important in phosphate homeostasis. Abnormal serum levels of FGF23 result in systemic pathologies in humans and mice, including renal phosphate wasting diseases and hyperphosphatemia. We sought to uncover the role FGF23 plays in the auditory system due to shared molecular mechanisms and genetic pathways between ear and kidney development, the critical roles multiple FGFs play in auditory development and the known hearing phenotype in mice deficient in klotho (KL), a critical co-factor for FGF23 signaling. Using functional assessments of hearing, we demonstrate that Fgf mice are profoundly deaf. Fgf mice have moderate hearing loss above 20 kHz, consistent with mixed conductive and sensorineural pathology of both middle and inner ear origin. Histology and high-voltage X-ray computed tomography of Fgf mice demonstrate dysplastic bulla and ossicles; Fgf mice have near-normal morphology. The cochleae of mutant mice appear nearly normal on gross and microscopic inspection. In wild type mice, FGF23 is ubiquitously expressed throughout the cochlea. Measurements from Fgf mice do not match the auditory phenotype of Kl−/− mice, suggesting that loss of FGF23 activity impacts the auditory system via mechanisms at least partially independent of KL. Given the extensive middle ear malformations and the overlap of initiation of FGF23 activity and Eustachian tube development, this work suggests a possible role for FGF23 in otitis media

Auditory measurements from <i>Fgf</i> mutant mice.

<p>(A) ABR and (B) DPOAE thresholds demonstrate profound hearing loss at all frequencies in <i>Fgf</i> mice, and moderate hearing loss at high frequencies in <i>Fgf</i> mice. (C) ABR wave I amplitudes appear slightly depressed in <i>Fgf</i> mice but are not statistically differentiable (except at 32 kHz where threshold differences impact magnitude ). ABR amplitudes in <i>Fgf</i> mice are significantly reduced compared to the other genotypes . (D) Threshold adjusted ABR wave I latency measurements demonstrate significant increases in latency in both <i>Fgf</i> and <i>Fgf</i> genotypes when compared to <i>Fgf</i> littermates . Error bars present standard error of the mean.</p

Mid-modiolar cochlear sections from <i>Fgf</i> (left column) and <i>Fgf</i> mice (right column).

<p>(A) Neural populations and gross anatomical structure appear normal in <i>Fgf</i> mice. (B) The stria vascularis (StVas), spiral ligament (SpLig), spiral limbus (SpLim), tectorial membrane (TM) and Reissner's membrane (RM) are similar to <i>Fgf</i> mice. (C) Inner hair cells (IHC), Outer hair cells (OHC), supporting cells (SC) and basilar membrane (BM) are morphologically normal. Sections were embedded in araldite and osmium stained.</p

Morphological and histological comparisons of the middle and inner ears.

<p>(A) The bullae of <i>Fgf</i> mice (bottom row) appear white and cloudy with less structural refinement than both <i>Fgf</i> (top row) and <i>Fgf</i> mice (middle row), indicating incomplete ossification. (B) The auditory ossicles are dysplastic in <i>Fgf</i> mice. (C) H&E stained, paraffin sections demonstrate increased vascularization of the bony labyrinth in <i>Fgf</i> mice (arrowheads). (D) The highly-organized laminar structure of the otic capsule, bordering the spiral ligament, is lost in the <i>Fgf</i> genotype. Lines in A and B are orienting lines from the microscope objective.</p

Morphological comparisons of the otic capsule from (A) <i>Fgf</i>, (B) <i>Fgf</i> and (C) <i>Fgf</i> mice.

<p>All genotypes appear similar but the <i>Fgf</i> cochlea is slightly smaller and whiter. Black lines are orienting lines from the microscope objective.</p

2D and 3D CT reconstructions of bullae from <i>Fgf</i> and <i>Fgf</i> mice.

<p>Each row contains reconstructions from one ear (top row: <i>Fgf</i>, bottom row: <i>Fgf</i>). (A) The otic capsule and bulla show loss of structural refinement and decreased density (arrowheads). (B) In <i>Fgf</i> mice the footplate of the stapes demonstrate thickening (arrowheads). (C) The incus and incudomalleal joint are dysplastic (arrowheads) and the mastoid is under-pneumatized (asterisks). (D) The borders of 3D reconstructed <i>Fgf</i> ossicles are sharp and well-defined while those of <i>Fgf</i> ossicles are blurry due to poor contrast with surroundings, resulting from decreased bone density in the mutant. <i>Fgf</i> ossicles demonstrate reduced structural refinement, particularly in the malleus and incus.</p

Super-resolution Diffusion Tensor Imaging for Delineating the Facial Nerve in Patients with Vestibular Schwannoma

Objectives  Predicting the course of cranial nerves (CNs) VII and VIII in the cerebellopontine angle on preoperative imaging for vestibular schwannoma (VS) may help guide surgical resection and reduce complications. Diffusion magnetic resonance imaging dMRI is commonly used for this purpose, but is limited by its resolution. We investigate the use of super-resolution reconstruction (SRR), where several different dMRIs are combined into one dataset. We hypothesize that SRR improves the visualization of the CN VII and VIII. Design  Retrospective case review. Setting  Tertiary referral center. SRR was performed on the basis of axial and parasagittal single-shot epiplanar diffusion tensor imaging on a 3.0-tesla MRI scanner. Participants  Seventeen adult patients with suspected neoplasms of the lateral skull base. Main Outcome Measures  We assessed separability of the two distinct nerves on fractional anisotropy (FA) maps, the tractography of the nerves through the cerebrospinal fluid (CSF), and FA in the CSF as a measure of noise. Results  SRR increases separability of the CN VII and VIII (16/17 vs. 0/17, p  = 0.008). Mean FA of CSF surrounding the nerves is significantly lower in SRRs (0.07 ± 0.02 vs. 0.13 ± 0.03 [axial images]/0.14 ± 0.05 [parasagittal images], p  = 0.00003/ p  = 0.00005). Combined scanning times (parasagittal and axial) used for SRR were shorter (8 minute 25 seconds) than a comparable high-resolution scan (15 minute 17 seconds). Conclusion  SRR improves the resolution of CN VII and VIII. The technique can be readily applied in the clinical setting, improving surgical counseling and planning in patients with VS