2017 Sec 1 Green Book

seven (27%) of these patients had progression in at least one ear, and 2 patients had progression in both ears. Twenty-three of the 100 (23%) patients had ipsilateral progression, whereas 6 of 100 (6%) had contralateral pro- gression. As compared to patients with EVA and ipsilateral hearing loss (65 of 164 [39.6%]), patients with unilateral hearing loss without EVA had a significantly lower rate of progression (27 of 100 [27%]; P ¼ .037). There was no difference in the rate of progression in patients with normal hearing and EVA (3 of 37 [8.1%]) and patients with unilateral hearing loss without EVA (6 of 100 [6%]; P ¼ .9). Low-Frequency Hearing Loss Progression Of the 144 patients with EVA, 237 ears had pure tone audiometric data at 250 Hz (PT250); 194 of these ears had hearing loss at 250 Hz. PT250 strongly corre- lated with midpoint and operculum measurements (Spearman rho ¼ 0.43, P < .001 and 0.42, P < .0001, respectively). The PT250 also strongly correlated with the final PTA and HFPTA (Spearman rho ¼ 0.79, P < .0001 and 0.64; P < .0001, respectively). Controlling for temporal bone measurements, the PT250 was still highly correlated with the final PTA (Spearman rho ¼ 0.7; P < .0001). There was no association between the PT250 and a positive SLC26A4 test result. One hundred seventy-six patients met our study criteria for determining hearing loss progression. In these patients, 57 ears showed progression (median, 40 dB hearing loss at 250 Hz), and 119 ears showed no progres- sion (median, 25 dB hearing loss at 250 Hz; P ¼ .003). A mixed hearing loss at 250 Hz was seen in 117 ears. There was a significantly higher rate of progression in ears with a hearing loss at 250 Hz than in ears with normal hearing thresholds (46 of 117 [39.3%] vs. 11 of 59 [18.6%], respec- tively; P ¼ .0003). Among all ears that had PT250 values and were an- alyzed for progression (n ¼ 176 ears) using GEE to account for clustered data by ear, the odds for progres- sion increased with increasing PT250 (Table IV). This relationship weakened when midpoint measurements and initial PTA were controlled for in the analysis. Both the hearing level at 250 Hz and the initial PTA were strongly correlated with the likelihood of progression (Table IV).

TABLE V. Genetic Test Results.

Unilateral EVA, n ¼ 74

Bilateral EVA, n ¼ 70

P

Number of patients who received genetic testing GJB2

51 (68.9%)

50 (71.4%)

.74

4 (5.4%)

5 (7.1%)

.74*

GJB6

39 (52.7%)

46 (65.7%)

.11

SLC26A4

4 (5.4%)

3 (4.3%)

1.0*

MTRNR1

Positive results among those tested GJB2

3 (5.9%)

3 (6.0%) 1 (20%)

1.0* 1.0*

0

GJB6

4 (10.3%)

20 (43.5%)

0.0007

SLC26A4

0

0

—

MTRNR1

*Fisher exact test. EVA ¼ enlarged vestibular aqueduct.

Genetics A summary of genetic test results is shown in Tables V and VI. SLC26A4 testing was positive for a sig- nificantly higher number of patients with bilateral EVA than with unilateral EVA (43.5% vs. 10.3%; P ¼ .007). Of patients with positive SLC26A4 results, 7 of 24 (29%) had biallelic mutations (i.e., Pendred syndrome), and 17 of 24 (71%) had a single mutation. No unilateral EVA patients had biallelic mutations compatible with Pen- dred syndrome. Very few patients had mutations in the GJB2 , GJB6 , or MTRNR1 genes. Only 1 patient had biallelic GJB2 mutations. Overall, the rate of hearing loss progression in patients with SLC26A4 mutations was similar to the rate in patients without SLC26A4 mutations (Table VII). Analysis of hearing loss phenotypes indicated that the rate of progression was significantly related to positive results in ears with hearing loss in patients with bilat- eral EVA (Table VIII). Additionally, of patients with positive genetic test results and progressive hearing loss, significantly more had bilateral EVA (14 of 35 [40%]) than unilateral EVA (3 of 30 [10%]; P ¼ .006). DISCUSSION Although unilateral EVA is not an uncommon otologic finding, its audiometric and temporal bone

TABLE VI. SLC26A4 Genotypes.

TABLE IV. Risk Analysis of Hearing Loss Progression.

3 –2 A > G

682–698del17

L445W

Variable

Odds Ratio

95% CI

P

M1T

N322D (2)

1614 þ 1 G > A

PTT @ 250 Hz PTT @ 250 Hz † PTT @ 250 Hz ‡

1.10* 1.08* 1.04* 1.12* 1.10*

1.03-1.19 0.996-1.17 0.93-1.16 1.04-1.20 1.02-1.19

.009

P10T (2) L50R (2)

N324Y F335L F335S

Y530H L597S L729P G740S G740V

.06

.5

G209V T410M V138F

Initial PTA4 Initial PTA4 §

.003 .018

1001 þ 1 G > A (2)

T416P (3)

*For every 5-dB increase in initial value. † Controlling for midpoint. ‡ Controlling for initial PTA4 value. § Controlling for midpoint. CI ¼ confidence interval; PTA ¼ pure tone average; PTT ¼ pure tone threshold.

L236P (2)

L441P

Amino acid changes shown for missense mutations. Numbers in parentheses denote the number of alleles found.

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