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phenotype, natural history, and genetic etiology remain unclear. The underlying goal of the present study was to shed light on these areas of uncertainty and to deter- mine the clinical significance of unilateral EVA in pediatric patients. Overall, the patients in this study demonstrated an extremely heterogeneous audiometric phenotype. Patients with unilateral EVA as well as those with bilat- eral EVA had unilateral and bilateral hearing loss and varying levels of hearing loss severity. Interestingly, we found no difference in hearing loss severity between the unilateral and bilateral EVA cohorts. This finding implies that the inner ear dysfunction in patients with bilateral EVA is not necessarily more severe than the dysfunction in patients with unilateral EVA. In patients with unilateral EVA, there was no corre- lation between the side of the hearing loss and the side of the EVA, as > 50% of patients with unilateral EVA had contralateral hearing loss. Furthermore, these patients showed no difference in hearing loss severity between the contralateral and ipsilateral ears. These findings suggest that unilateral EVA may be a phenotypic expression of bilateral alterations in the membranous labyrinth and that unilateral EVA is likely not a unilateral disease pro- cess. The latter conclusion can perhaps be explained by events that occur during embryogenesis. Specifically, per- turbation of the inner ear labyrinth, which causes endolymphatic duct dilatation, can occur after embryonic temporal bone mesenchyme condenses into bone; hence, imaging would not reveal enlargement of the vestibular aqueduct. Alternatively, if endolymphatic duct dilatation occurs earlier in embryogenesis, imaging studies would reveal the enlargement of the vestibular aqueduct. Data pertaining to temporal bone phenotypes show a correlation between the final PTA and midpoint and oper- culum measurements and the HFPTA and midpoint and operculum measurements. This correlation has not been previously established. Studies conducted by Zalzal et al. 12 and Colvin et al. 21 reported no relationship between the absolute level of hearing or hearing loss progression and temporal bone measurements; however, both studies used more restrictive criteria for EVA (i.e., a midpoint measure- ment 1.5 mm) and had small study populations. TABLE VII. Rate of Progression Based on Audiometric Phenotype and SLC26A4 Testing Results by Patient. Progression in Unilateral EVA, n ¼ 54 Bilateral EVA, n ¼ 54 P Both ears 6 (11%) 11 (20.4%) .18 Only one ear 15 (27.8%) 19 (35.2%) No ears 33 (61.1%) 24 (44.4%)

TABLE VIII. Rate of Progression Based on Audiometric Phenotype and SLC26A4 Testing Results by Ears.

SLC26A4 Positive

SLC26A4 Negative

P

Ears with HL

14/27 (51.9%)

26/73 (35.6%) 20/59 (33.9%) 10/24 (41.7%)

.14 .08

Ears with HL þ EVA 14/26 (53.9%)

Ears with HL

0/2

.51*

þ unilateral EVA þ bilateral EVA

Ears with HL

14/24 (58.3%)

10/35 (28.6%)

.02

*Fisher exact test. EVA ¼ enlarged vestibular aqueduct; HL ¼ hearing loss.

Reporting on 77 patients, Madden et al. 5 found a relation- ship between the midpoint and operculum measurements and the rate of progression, but not with the initial PTA. The disparity between historical findings and the present study may be attributed to our use of a final PTA measure- ment, which may have been affected by the presence of progressive hearing loss. Patients with unilateral EVA had slightly better hearing compared to those with bilateral EVA, although this difference was not statistically significant. The difference may be related to the relatively high preva- lence of isolated high-frequency hearing loss in patients with unilateral EVA. Overall, a comparison of temporal bone measurements in patients with unilateral and bilateral EVA revealed no critical differences. Neverthe- less, subtle differences were evident. Specifically, although operculum measurements were larger in patients with unilateral EVA, there was no difference in midpoint measurements between patients with unilat- eral and bilateral EVA. Also, patients with unilateral EVA and ipsilateral hearing loss had larger vestibular aqueduct measurements than patients with bilateral EVA, suggesting the possibility of a different underlying etiology between the two groups. Hearing loss progression was seen both in patients with unilateral EVA and in patients with bilateral EVA. Although it was more commonly seen in patients with bilateral EVA, this difference was not statistically signifi- cant. This lack of significance remained constant when analyzing ears with unilateral and bilateral hearing loss. Interestingly, patients with unilateral EVA had a similar rate of progression in both the ipsilateral and contralateral ears. When compared to the ears in patients with unilateral hearing loss without EVA, the ears of patients with unilateral EVA had a higher likeli- hood of progression. In patients with unilateral hearing loss without EVA, only 6% had involvement of the con- tralateral ear. In sharp contrast, 55% of patients with unilateral EVA had involvement of the contralateral ear. Collectively, these data support our study hypothesis that patients with unilateral EVA would have a much higher rate of contralateral hearing loss than patients with unilateral hearing loss without EVA. In patients with EVA, hearing loss at 250 Hz is strongly correlated with the severity of the PTA and the likelihood of progression. Additionally, the hearing loss

SLC26A4 Positive

SLC26A4 Negative

Rate of Progression

All patients with EVA

10/17 (58.8%) 22/48 (45.8%) .36

Patients with unilateral EVA 0/3

13/27 (48.2%) .24* 9/21 (42.9%) .10

Patients with bilateral EVA 10/14 (71.4%)

*Fisher exact test. EVA ¼ enlarged vestibular aqueduct.

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