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EVA and proposed that EVA was a congenital malforma-

tion of the temporal bone that predisposes affected

individuals to the early onset of hearing loss and vestibu-

lar disturbance. Valvassori and Clemis, as well as other

authors, maintained that enlargement of the endolym-

phatic sac and duct is the underlying process causing the

bony change of the vestibular aqueduct.

7–9

Spiegel and

Lalwani proposed that the underlying pathophysiology of

EVA is similar to that of endolymphatic hydrops.

EVA was initially defined as a vestibular aqueduct

1.5 mm at the midpoint.

This measurement was based

on polytomographic studies, which are somewhat crude in

comparison to our current technology. Although early

generation CT scans allowed for a clearer view of the

vestibular aqueduct, the advent of high-resolution CT per-

mitted more accurate and quantifiable aqueduct

assessment; this enabled researchers to distinguish

between normal and enlarged aqueducts. In view of this

technological advancement, Vijayasekaran et al. were able

to specifically define EVA.

Using a standardized measure-

ment algorithm, they studied 73 children with normal

hearing and determined a normal vestibular aqueduct mid-

point to be at 0.9 mm and a normal vestibular aqueduct

operculum to be 1.9 mm. These measurements have since

been used as the radiographic standard for defining EVA.

The otologic phenotype of EVA is exceedingly vari-

able. This phenotype can be associated with fluctuating

and progressive hearing loss

12,13

as well as disequili-

brium and vertigo.

The age at diagnosis of the hearing

loss ranges from infancy to adulthood. The reported se-

verity of hearing loss ranges from normal hearing (rare)

to profound hearing loss, which is usually bilateral.

15,16

Although unilateral hearing loss in patients with EVA

has been reported,

12,17,18

it is not well described. Pre-

ciado et al.

found that the diagnostic yield of imaging

studies in children with EVA was significantly higher in

those with unilateral vs. bilateral SNHL. In patients

with bilateral SNHL, there was a statistically significant

trend toward a higher prevalence of EVA with increasing

severity of the hearing loss. No specific analysis was per-

formed on patients with unilateral EVA in this study.

A conductive component of the hearing loss has been

observed at 250 Hz, despite a clinically normal middle ear

and tympanogram.

9,12,20

The prevalence of an accompanying

low-frequency conductive or mixed hearing loss ranges from

28% to 80% of ears with EVA.

7,12,20

Although the clinical sig-

nificance of the conductive component is unknown, some

investigators have proposed that it may represent the audio-

logic effect of a third inner ear window.

Others have

suggested that it may represent an inherent increased stiff-

ness of the ossicles due to the inner ear fluid disturbance.

5,20

The prevalence of progressive SNHL in patients with

EVA varies from 12% to 65%.

9,12,13,16,21

Hearing loss pro-

gression can occur in a stepwise fashion over a prolonged

period of time, or suddenly, after minor head trauma, baro-

trauma, or in idiopathic SNHL. In a seminal study, Boston

et al.

found a linear relationship between the size of the

aqueduct and the likelihood of hearing loss progression.

Additionally, these authors found that the presence of a

low-frequency conductive hearing loss was associated with

an increased risk of hearing loss progression.

The most common genetic etiology for EVA is muta-

tions in the

SLC26A4

gene (also known as

PDS

This

gene produces a protein called pendrin, which is responsi-

ble for iodine and chloride ion transport in the inner ear

and thyroid gland. Biallelic mutations in

SLC26A4

cause

Pendred syndrome and are present in 10% to 20% of

patients with EVA.

23,24

Patients with this syndrome typi-

cally have severe to profound hearing loss and inner ear

anomalies such as EVA; they can also develop a thyroid

goiter and hypothyroidism. Single

SLC26A4

mutations

have been found in 15% to 20% of patients with EVA.

These patients typically have a less severe hearing pheno-

type than patients with Pendred syndrome, have less

severe abnormalities of the vestibular aqueduct, and have

no thyroid dysfunction. It has been proposed that

sequence changes in other gene(s) interact with the single

mutations in

SLC26A4

23–25

Recently, mutations have

been identified in

FOXI1

, which reduce the transcription

SLC26A4

, resulting in an EVA phenotype.

Mutations

in the

KCNJ10

gene have also been implicated in EVA

when present in combination with

SLC26A4

heterozy-

gotes.

Additionally, EVA has been associated with

disorders such as CHARGE syndrome,

Waardenburg

syndrome,

and branchio-otorenal syndrome.

Children with bilateral EVA and any

SLC26A4

muta-

tions are more likely to have greater aqueduct enlargement

and are more likely to experience progression of hearing

loss.

Data pertaining to the prevalence of

SLC26A4

muta-

tions in patients with unilateral EVA is scant. Berrettini

et al.

reported on two patients with unilateral EVA who

did not have mutations in

SLC26A4

. Consistent with this

finding, Madden et al.

observed a lower prevalence of

these mutations in a clinical population of patients with

unilateral EVA than in those with bilateral EVA.

In a review of studies investigating patients with

EVA, Zalzal et al.

found that reported prevalence rates

of unilateral EVA ranged from 6% to 40%.

7,31

Although

unilateral EVA is not uncommon, its audiometric and

temporal bone phenotype, natural history, and genetic

etiology are not well understood. This gap in knowledge

creates several problematic clinical questions: 1) How

should families be counseled in regard to their child’s

hearing loss and imaging findings?; 2) How should

patients be monitored in regard to their hearing loss

and the potential risk of disease progression?; and 3)

What is the positive predictive value of genetic testing?

In light of these issues, the purpose of the current

study was to describe the clinical phenotype of patients

with unilateral EVA and then to compare the findings to

two clinically related phenotypes: bilateral EVA and

unilateral hearing loss without EVA. Taking into account

our clinical observations and the aforementioned data, we

hypothesized that patients with unilateral EVA would

have a much higher rate of contralateral hearing loss

than patients with unilateral hearing loss without EVA.

MATERIALS AND METHODS

Enlarged Vestibular Aqueduct Population

We performed a database search of all children seen at

our center who were diagnosed with EVA or unilateral hearing

Laryngoscope 123: June 2013

Greinwald et al.: Unilateral Enlarged Vestibular Aqueduct

133