Volumetry improves the assessment of the vestibular aqueduct size in inner ear malformation.

OBJECTIVES: Enlarged vestibular aqueduct (EVA) is a common finding associated with inner ear malformations (IEM). However, uniform radiologic definitions for EVA are missing and various 2D-measurement methods to define EVA have been reported. This study evaluates VA volume in different types of IEM and compares 3D-reconstructed VA volume to 2D-measurements. METHODS: A total of 98 high-resolution CT (HRCT) data sets from temporal bones were analyzed (56 with IEM; [cochlear hypoplasia (CH; n = 18), incomplete partition type I (IPI; n = 12) and type II (IPII; n = 11) and EVA (n = 15)]; 42 controls). VA diameter was measured in axial images. VA volume was analyzed by software-based, semi-automatic segmentation and 3D-reconstruction. Differences in VA volume between the groups and associations between VA volume and VA diameter were assessed. Inter-rater-reliability (IRR) was assessed using the intra-class-correlation-coefficient (ICC). RESULTS: Larger VA volumes were found in IEM compared to controls. Significant differences in VA volume between patients with EVA and controls (p < 0.001) as well as between IPII and controls (p < 0.001) were found. VA diameter at the midpoint (VA midpoint) and at the operculum (VA operculum) correlated to VA volume in IPI (VA midpoint: r = 0.78, VA operculum: r = 0.91), in CH (VA midpoint: r = 0.59, VA operculum: r = 0.61), in EVA (VA midpoint: r = 0.55, VA operculum: r = 0.66) and in controls (VA midpoint: r = 0.36, VA operculum: r = 0.42). The highest IRR was found for VA volume (ICC = 0.90). CONCLUSIONS: The VA diameter may be an insufficient estimate of VA volume, since (1) measurement of VA diameter does not reliably correlate with VA volume and (2) VA diameter shows a lower IRR than VA volume. 3D-reconstruction and VA volumetry may add information in diagnosing EVA in cases with or without additional IEM.

Molecular epidemiology and functional assessment of novel allelic variants of SLC26A4 in non-syndromic hearing loss patients with enlarged vestibular aqueduct in China.

BACKGROUND: Mutations in SLC26A4, which encodes pendrin, are a common cause of deafness. SLC26A4 mutations are responsible for Pendred syndrome and non-syndromic enlarged vestibular aqueduct (EVA). The mutation spectrum of SLC26A4 varies widely among ethnic groups. To investigate the incidence of EVA in Chinese population and to provide appropriate genetic testing and counseling to patients with SLC26A4 variants, we conducted a large-scale molecular epidemiological survey of SLC26A4. METHODS: A total of 2352 unrelated non-syndromic hearing loss patients from 27 different regions of China were included. Hot spot regions of SLC26A4, exons 8, 10 and 19 were sequenced. For patients with one allelic variant in the hot spot regions, the other exons were sequenced one by one until two mutant alleles had been identified. Patients with SLC26A4 variants were then examined by temporal bone computed tomography scan for radiological diagnosis of EVA. Ten SLC26A4 variants were cloned for functional study. Confocal microscopy and radioisotope techniques were used to examine the membrane expression of pendrin and transporter function. RESULTS: Of the 86 types of variants found, 47 have never been reported. The ratio of EVA in the Chinese deaf population was at least 11%, and that in patients of Han ethnicity reached at least 13%. The mutational spectrum and mutation detection rate of SLC26A4 are distinct among both ethnicities and regions of Mainland China. Most of the variants caused retention of pendrin in the intracellular region. All the mutant pendrins showed significantly reduced transport capability. CONCLUSION: An overall description of the molecular epidemiological findings of SLC26A4 in China is provided. The functional assessment procedure can be applied to identification of pathogenicity of variants. These findings are valuable for genetic diagnosis, genetic counseling, prenatal testing and pre-implantation diagnosis in EVA families.

Functional assessment of allelic variants in the SLC26A4 gene involved in Pendred syndrome and nonsyndromic EVA.

Pendred syndrome is an autosomal recessive disorder characterized by sensorineural hearing loss, with malformations of the inner ear, ranging from enlarged vestibular aqueduct (EVA) to Mondini malformation, and deficient iodide organification in the thyroid gland. Nonsyndromic EVA (ns-EVA) is a separate type of sensorineural hearing loss showing normal thyroid function. Both Pendred syndrome and ns-EVA seem to be linked to the malfunction of pendrin (SLC26A4), a membrane transporter able to exchange anions between the cytosol and extracellular fluid. In the past, the pathogenicity of SLC26A4 missense mutations were assumed if the mutations fulfilled two criteria: low incidence of the mutation in the control population and substitution of evolutionary conserved amino acids. Here we show that these criteria are insufficient to make meaningful predictions about the effect of these SLC26A4 variants on the pendrin-induced ion transport. Furthermore, we functionally characterized 10 missense mutations within the SLC26A4 ORF, and consistently found that on the protein level, an addition or omission of a proline or a charged amino acid in the SLC26A4 sequence is detrimental to its function. These types of changes may be adequate for predicting SLC26A4 functionality in the absence of direct functional tests.

Changes in quality of life and the cost-utility associated with cochlear implantation in patients with large vestibular aqueduct syndrome.

OBJECTIVE: A group of 20 patients with large vestibular aqueduct syndrome was identified at the Indiana University School of Medicine. The major objective of this study was to explore the improvements in quality of life associated with cochlear implantation in patients with large vestibular aqueduct syndrome, as well as the cost-utility of cochlear implantation in this group. SETTING: A total of 70 patients were identified with large vestibular aqueduct syndrome through analysis of thin-section computed tomography of the temporal bone over the past 6 years at this medical center. Data collected from the medical records for each patient included demographic data, hearing-related statistics, implantation data, and audiometric data. Sixteen children and adults with large vestibular aqueduct syndrome had undergone cochlear implantation before the beginning of this study, and the remaining 54 children and adults were identified as undergoing treatment of progressive or fluctuant sensorineural hearing loss. Health utility indexes used in this analysis were taken through the use of the Ontario Health Utility Index, Mark III. The range of costs used for cost-utility analysis was derived from the costs of cochlear implantation at this medical center, as well as from costs associated with implantation published in the medical literature. METHODS: Participants were selected from the total population of patients with large vestibular aqueduct syndrome at this center who were postlingually deafened and who currently had severe hearing loss. Two groups were formed. These groups comprised either cochlear implant patients with large vestibular aqueduct syndrome or patients with large vestibular aqueduct syndrome currently using hearing aids. Ten of the 16 cochlear implant patients and 10 of the remaining 54 patients with large vestibular aqueduct syndrome met these criteria. Mark III health utility indexes were distributed to patients in each group and scored. Those health utility indexes not completed by the patients were scored by proxy, using the audiologist at this center who was the most familiar with the patient. Changes in quality of life associated with cochlear implantation were derived by comparison of the health utility index results of the two groups. Cost-utility measures were then made using discounted costs per quality-of-life years (QALYs) (5%), and a sensitivity analysis was performed that evaluated changes in scoring done by proxy. The cost-utility results were then compared with the cost-utilities derived from similar studies and associated with other disease states. RESULTS: Although both groups of patients had significant hearing loss, the hearing aid group had a better mean pure-tone average. The mean pure-tone average for the hearing aid group was 70.8 dB (SD 24.4), and the mean pure-tone average for the cochlear implant group was 107.0 dB (SD 21.7). Seven of the 20 health utility indexes were scored by proxy. Results from the base case indicate a 0.20 gain in health utility from cochlear implantation (hearing aid = 0.62, cochlear implant = 0.82, p = 0.037), resulting in a discounted cost per QALY of $12,774. Sensitivity analysis of the proxy scoring indicated that decreasing the hearing score one level on the health utility index resulted in a gain in health utility with cochlear implantation of 0.15, resulting in a discounted cost per QALY of $17,832. A decrease of the hearing score by two levels on the health utility survey resulted in no significant gain in quality of life with cochlear implantation. CONCLUSION: This study found an improvement in quality of life associated with cochlear implantation in postlingually deafened patients with large vestibular aqueduct syndrome. By weighing this improvement in quality of life against the significant difference noted between the pure-tone averages of each group, further strength can be given to this conclusion. This gain in quality of life, as well as the results derived for the cost-utility of cochlear implantation, was similar to that in previous published studies of cochlear implantation in all types of patients. These results also indicate a favorable cost-utility when compared with published data about other disease states. As patients with large vestibular aqueduct syndrome progress to profound levels of hearing loss, these results indicate that cochlear implantation can be offered as a beneficial, life-improving therapy.