Fibroblast growth factor receptor 3 (Fgfr3) is a tyrosine kinase receptor expressed in developing bone, cochlea, brain and spinal cord. Achondroplasia, the most common genetic form of dwarfism, is caused by mutations in FGFR3. Here we show that mice homozygous for a targeted disruption of Fgfr3 exhibit skeletal and inner ear defects. Skeletal defects include kyphosis, scoliosis, crooked tails and curvature and overgrowth of long bones and vertebrae. Contrasts between the skeletal phenotype and achondroplasia suggest that activation of FGFR3 causes achondroplasia. Inner ear defects include failure of pillar cell differentiation and tunnel of Corti formation and result in profound deafness. Our results demonstrate that Fgfr3 is essential for normal endochondral ossification and inner ear development.

This study extended the ®ndings of Ketten et al. [Ann. Otol. Rhinol. Laryngol. Suppl. 175:1±16 (1998)] by estimating the three-dimensional (3D) cochlear lengths, electrode array intracochlear insertion depths, and characteristic frequency ranges for 13 more Nucleus-22 implant recipients based on in vivo computed tomography (CT) scans. Array insertion depths were correlated with NU-6 word scores (obtained one year after SPEAK strategy use) by these patients and the 13 who used the SPEAK strategy from the Ketten et al. study. For these 26 patients, the range of cochlear lengths was 29.1±37.4 mm. Array insertion depth range was 11.9±25.9 mm, and array insertion depth estimated from the surgeon's report was 1.14 mm longer than CT-based estimates. Given the assumption that the human hearing range is ®xed (20± 20,000 Hz) regardless of cochlear length, characteristic frequencies at the most apical electrode (estimated with Greenwood's equation [Greenwood DD (1990) A cochlcar frequency ± position function of several species ± 29 years later. J Acoust. Soc. Am. 33: 1344±1356] and a patient-speci®c constant a s ) ranged from 308 to 3674 Hz. Patients' NU-6 word scores were signi®cantly correlated with insertion depth as a percentage of total cochlear length (R = 0.452; r 2 = 0.204; p = 0.020), suggesting that part of the variability in word recognition across implant recipients can be accounted for by the position of the electrode array in the cochlea. However, NU-6 scores ranged from 4% to 81% correct for patients with array insertion depths between 4% and 68% of total cochlear length. Lower scores appeared related to low spiral ganglion cell survival (e.g., lues), aberrant current paths that produced facial nerve stimulation by apical electrodes (i.e., otosclerosis), central auditory processing dif®culty, below-average verbal abilities, and early Alzheimer's disease. Higher scores appeared related to patients' highaverage to above-average verbal abilities. Because most patients' scores increased with SPEAK use, it is hypothesized that they accommodated to the shift in frequency of incoming sound to a higher pitch percept with the implant than would normally be perceived acoustically.

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