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American Journal of Otolaryngology – Head and Neck Medicine and Surgery 26 (2005) 363 – 371
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Original contributions
Large vestibular aqueduct syndrome: audiological, radiological,
clinical, and genetic features
Stefano Berrettini, MDa,T, Francesca Forli, MDa, Fausto Bogazzib, Emanuele Neri, MDc,
Luca Salvatori, MDc, Augusto Pietro Casani, MDa, Stefano Sellari Franceschini, MDa
a
ENT Unit, Neuroscience Department, University of Pisa, 56126 Pisa, Italy
Department of Endocrinology and Metabolism, University of Pisa, 56126 Pisa, Italy
c
Division of Diagnostic and Interventional Radiology, Department of Oncology, Transplants, and Advanced Technologies in Medicine,
University of Pisa, 56126 Pisa, Italy
Revised 8 December 2004
b
Abstract
Purpose: The aim of this study was to analyze the clinical, audiological, radiological, and genetic
features of a group of patients affected with large vestibular aqueduct syndrome.
Materials and methods: Seventeen patients affected with large vestibular aqueduct syndrome
(LVAS), diagnosed by means of high-resolution magnetic resonance imaging of the inner ear, with
3-dimensional reconstructions of the labyrinth and by high-resolution spiral computed tomography
of the temporal bone, performed only on the oldest patients, have been submitted to a complete
audiological evaluation, a thyroid functional and ultrasonographic study, and a molecular study of
the PDS gene.
Results: The clinical presentation of LVAS was very variable in our group of patients. The enlarged
vestibular aqueduct was bilateral in 15 cases and unilateral in 2; it was the only malformation of the
labyrinth in 12 patients, whereas it was associated with other inner ear anomalies in the other 5. The
hearing loss was very variable in degree (from mild to profound), age at onset, and progression.
Moreover, among the 17 patients, 10 were clinically affected by Pendred’s syndrome (PS), 3 by
distal renal tubular acidosis associated with large vestibular aqueduct, whereas in 3 patients the large
vestibular aqueduct was not syndromal. Finally, we identified mutations in the PDS gene in 5 of
10 patients with PS.
Conclusions: Our data underscore the frequent role of the large vestibular aqueduct syndrome in the
pathogenesis of sensorineural hearing loss and the overall wide variability in its audiological
features. It is also highlighted that LVAS is often part of some syndromal diseases, most of which are
PS, which is often misdiagnosed because of the varying degree of thyroid symptoms. This study also
underscores the possible role of hydro-electrolyte and acid-base endolymphatic fluid disorders in the
pathogenesis of enlarged vestibular aqueduct syndrome.
D 2005 Elsevier Inc. All rights reserved.
1. Introduction
The large vestibular aqueduct syndrome (LVAS) is
characterized by the presence of an abnormally large
vestibular aqueduct (LVA) generally associated with fluctuating, progressive sensorineural hearing loss (SNHL), often
T Corresponding author. ENT Unit, Neuroscience Department, University of Pisa, 56126 Pisa, Italy. Tel.: +39 50 992625; fax: +39 50 550307.
E-mail address: [email protected] (S. Berrettini).
0196-0709/$ – see front matter D 2005 Elsevier Inc. All rights reserved.
doi:10.1016/j.amjoto.2005.02.013
with sudden, stepwise onset or progression secondary to
activities involving minor head trauma, large sudden shifts of
barometric pressure, the Valsalva maneuver, and so forth
[1-11]. Large vestibular aqueduct syndrome is considered to
be the most frequent morphogenetic cause of hearing loss in
children [12], although its frequency is probably underestimated [3,12,13]. It is often associated with other
congenital inner ear anomalies, the most common being an
abnormally large vestibule, an enlarged semicircular canal, or
a hypoplastic cochlea [9,14,15], although according to some
364
S. Berrettini et al. / American Journal of Otolaryngology – Head and Neck Medicine and Surgery 26 (2005) 363 – 371
Fig. 1. Volume rendering of the labyrinth showing the enlarged
endolymphatic duct/sac complex (arrow), together with the cochlea,
vestibule, and semicircular canals.
S.F., m, 12 yrs (case 9)
dB HL
authors, SNHL associated with LVA as the only radiographically detectable inner ear anomaly constitutes a separate
clinical entity [1,15].
Large vestibular aqueduct syndrome may be associated
with nonsyndromic [16] as well as syndromic forms of
SNHL, such as the Pendred’s syndrome (PS) [17-21] and
the branchiootorenal syndrome [22]. Moreover, we have
recently reported on 3 consecutive, unrelated pediatric
patients in whom LVAS was associated with SNHL and
distal renal tubular acidosis (dRTA) [23].
Concerning the genetics of LVAS, it has been postulated
to be inherited as an autosomal recessive trait [5,24].
Recently, the locus for nonsyndromic SNHL associated
with LVAS has been mapped to the same chromosomal
region as the PS locus, 7q31 [25,26], and it has been
reported that the gene responsible for the PS, the PDS, is
also mutated in patients with LVA associated with nonsyndromic SNHL [16,21,27,28].
In this paper, we describe the clinical, audiological,
radiological, and genetic features of a group of 17 patients
affected with LVA, studied by means of high-resolution
magnetic resonance imaging (HR-MRI) of the inner ear with
3-dimensional (3D) reconstructions of the labyrinth and by
high-resolution computed tomography (HR-CT) of the
petrous bone, performed only on the oldest patients.
patients over 6 years of age, or conditioned audiometry
for patients between 1 and 6 years. The hearing loss was
considered progressive when a deterioration of more than
15 dB in the PTA (average between 500-1000-2000 Hz) was
recorded within a 10-year period [29].
Vestibular function was studied only in the oldest
patients (15/17) through evaluation of spontaneous, positional, and head-shaking nystagmus, and by the caloric
stimulation test, following the procedures of Fitzgerald and
Hallpike [30], with video-nystagmograph recording.
The diagnosis of LVA was made by means of HR-MRI at
high field strength (Signa 1.5 T; GE/Medical Systems,
Milwaukee, Wis), with 3D reconstructions of the labyrinth
(Figs. 1 and 2), performed on each patient and confirmed via
spiral HR-CT of the temporal bone in the oldest patients
(15/17 patients). High-resolution MRI was performed with a
Signa 1.5 T machine (GE/Medical Systems). An acquisition
was performed on each ear using a 3-in circular surface coil
for signal reception, with a 3D, T2-weighted, fast spinecho sequence in the axial plane (TR 5000, TE 275, echo
train length 64, partition thickness 0.5 mm, 72 partitions,
field of view 12 cm, matrix 512 512). A single excitation
was acquired and the imaging time was 7 minutes and
22 seconds [31].
Images were transferred to a high-end graphics
workstation (Dextroscope; Volume Interactions/Bracco,
Singapore), and volume analysis was performed with a
dedicated software.
The software embedded with the workstation allows a
rapid segmentation and provides a fast and intuitive method
to generate 3D models with a volume rendering algorithm.
The 3D models of the membranous labyrinth were
displayed with a stereoscopic view. Using hand-tracking
devices, it was possible to isolate the vestibular duct and sac
from the membranous labyrinth.
A volume is calculated by counting bvisibleQ voxels and
multiplying them by the voxel dimensions as obtained from
the DICOM (Digital Imaging and Communication in
Medicine) 3.0 data source.
The user needs to specify a rectangular box that
completely includes the volume of interest and a voxel
2. Material and methods
We report on 17 patients, 9 males and 8 females, affected
by LVAS, with a mean age of 24.7 years, ranging from 4 to
50 years.
Each patient underwent a complete audiological and
clinical evaluation: apart from family and clinical history
evaluation and an otomicroscopic examination, the tests
included impedance audiometry, the stapedius reflex threshold test, and brainstem auditory-evoked potentials, for all,
and pure-tone audiometry (PTA, 0.5-1-2-4-8 kHz) for
-20
-10
0
10
20
30
40
50
60
70
80
90
100
110
120
250
500
1000
2000
4000
8000
Hz
Fig. 2. Pure tone audiogram of patient 9, showing the presence of an airbone gap bilaterally.
S. Berrettini et al. / American Journal of Otolaryngology – Head and Neck Medicine and Surgery 26 (2005) 363 –371
threshold value. Voxels inside the volume of interest, and
voxel values above the specified threshold, will be counted
toward the final volume value.
High-resolution CT was performed with a 4-row CT
(Light Speed Plus; GE Medical Systems) with a collimation
of 1.25 mm, section thickness 0.63 mm, pitch 3, 0.8 s
rotation tube, 120 kVp, 200 mAs, in the axial and coronal
planes. Images were reconstructed at 0.63-mm interval with
a bone algorithm [32].
The diameters of the vestibular aqueduct (VA) and the
endolymphatic duct (ED) and sac (ES) were measured by
axial CT and axial MRI scans, respectively. A VA was
considered to be enlarged if its caliber, measured midway
between the common crus and external aperture, was greater
than or equal to 1.5 mm [15].
The HR-MR investigations of the inner ear were repeated
in 6 patients some years after the diagnosis of LVAS (range
4–10 years, mean 5.6 years) to assess any variations in the
volume of the ED and ES; 4 of 6 patients presented a bilateral
LVA, whereas 2 of 6 patients presented a unilateral LVA.
The MRI data sets of those patients were coregistered,
and the volume of the vestibular aqueduct was then
calculated by using a 3D workstation (Dextroscope; Volume
Interactions/Bracco), to see whether the volume had
changed over time.
Image coregistration was performed with a semiautomatic registration method (multipoint plus freehand fusion).
Three anatomical landmarks were visually identified by the
radiologist in the MRI 3D images corresponding respectively to the middle tract of the superior and lateral
semicircular canals, and the initial part of the basal turn of
the cochlea. A marker was manually placed on each of the
identified points. Once the markers were placed in both
datasets the software produced a preliminary combined
coregistered 3D model. The 3D model was then displayed
as a fused 3D image incorporating the magnetic resonance
data. An assessment was made by the radiologist by visually
inspecting the fused 3D images to determine the accuracy of
image coregistration. In the case of incorrect superimposition of labyrinth components, a manual adjustment of the
data was made. By using the volume rendering of the MRI
data, the membranous tract of the vestibular aqueduct
acquired at different time intervals was isolated and
displayed both in the same 3D model. The radiological
study of all the patients, both HR-CT and HR-MR
investigations, has been performed and evaluated by the
same radiologist, expert in the imaging study of the petrous
bone. Also, the measurements of the diameters, the 3D
reconstructions, and the analysis of the volumes of the ED/
ES complexes have been performed by the same radiologist.
Each patient also underwent a functional and ultrasonograph evaluation of the thyroid and a perchlorate (KClO4)
discharge test to reveal the presence of the PS, as previously
described [33], apart from 2 patients: 1 patient was not
submitted to perchlorate discharge test, because she was too
young (4 years old) and 1 patient, previously submitted to
365
thyroidectomy, was not submitted to the evaluation of
thyroid function nor to perchlorate discharge test.
Finally, each patient underwent mutation analysis of the
PDS gene, as described in previous studies [33].
3. Results
A summary description of each patient’s case is provided
in Tables 1 and 2. An enlargement of the membranous ED/
ES complex was disclosed by HR-MR bilaterally in 15 cases
(30 ears) and unilaterally in the other 2 (right-sided in both).
In the patients who underwent HR-CT, it confirmed the
presence of an enlargement of the bony VA in every ear in
which HR-MR had revealed an enlarged ED and ES.
The mean volume of ED and ES complex, measured on
3D reconstructions of the membranous labyrinth as described, was 0.67 mL, ranging from 0.09 to 1.78 mL.
In 12 patients, LVA was the only radiographically
detectable inner ear anomaly, whereas in 5 patients it was
accompanied by other inner ear abnormalities: bilateral
dilatation of the vestibule, the apical turn of the cochlea, and
the lateral semicircular canal in patient 9, bilateral dilatation
of the vestibule in patients 10 and 17, and bilateral classical
Mondini deformity in patients 12 and 13.
The volume of the ED/ES complex remained stable in
the 6 patients who underwent serial HR-MR of the inner ear,
and particularly the 2 cases of these 6 with unilateral LVA
also exhibited unilateral LVA upon the second HR-MR.
The degree of SNHL in the affected ears (32 ears with
LVA) ranged from moderate to profound, with a PTA from
47 to 113 dB HL and a downsloping (29 ears) or U-shaped
(3 ears) hearing threshold curve; only 2 ears (patients 1 and
6) presented a moderate hearing deficit, 4 ears (patients 1, 2,
10, and 17) exhibited a severe hearing deficit, whereas in the
remaining 26 ears the deficit was profound. A conductive
component was present in 10 of our patients, 19 ears (cases
1– 3, 5, 8 –11, 16 and 17), whereas in 1 patient it was not
tested (case 7: the patient was too young). The average of
the air-bone gap was calculated between the frequencies of
500-1000-2000 Hz and ranged between 3 and 26.6 dB HL,
with a mean value of 15.2 dB HL. Two of our patients
(cases 3 and 4) received a cochlear implant in adult life
without intraoperative perilymph gusher and with good
postoperative outcomes, 14 patients are traditional hearingaid users, and 1 patient (case 6), with a unilateral moderate
hearing deficit, does not use hearing aids.
We did not find a clear correspondence between volumes
of ED/ES complex and the degree of the hearing deficit; we
only found that all the patients with ED/ES complex volume
greater than 1 mL exhibited a profound hearing loss.
The age at which hearing loss was diagnosed varied
widely, although it was reached in childhood or adolescence
in all patients: from 7 months to 15 years, with a mean age
of 3.9 years. It should be underscored that in 8 (cases 7, 9,
10, 12 – 15, and 17) the hearing loss was probably congenital and diagnosed at different ages (13 months in case 7;
366
Case
Side
of LVA
1. SL (f, 50 y)
Bilateral 15 y left,
45 y right
Bilateral 5 y
Bilateral 3 y
Bilateral 6 y
Right
7y
2.
3.
4.
5.
BI (f, 17 y)
BM (f, 43 y)
EA (m, 30 y)
SG (m, 18 y)
6. PM (m, 8 y)
Right
Age of
PTA (dB HL)
hearing loss
onset/diagnosis
8y
7. MC (f, 4 y)
Bilateral 13 mo
(congenital?)
8. IM (f, 30 y)
Bilateral 5 y
9. SF (m, 12 y) Bilateral 7 mo
(congenital?)
10. DVS
Bilateral 2 y
(m, 21 y)
(congenital?)
11. SP (m, 22 y) Bilateral 3 y
12. DMA
Bilateral 2 y
(m, 35 y)
(congenital?)
13. DMB
Bilateral 2 y
(f, 33 y)
(congenital?)
14. PF (m, 27 y) Bilateral 18 mo
(congenital?)
15. PN (f, 30 y) Bilateral 18 mo
(congenital?)
16. KI (f, 22 y) Bilateral 4 y
17. DPF
(m, 18 y)
Bilateral 8 mo
(congenital?)
R: 47, L: 81
R:
R:
R:
R:
101, L:
105, L:
113, L:
103, L:
Conductive component Sudden hearing Fluctuations Progression Vestibular function
(average between 500impairment
of hearing
of hearing
1000-2000 Hz) (dB HL) (after triggers) function
loss
Syndromic aspects
+ (R: 6.6, L: 11.6)
Nonsyndromic LVA Absent
81 + (R: 25, L: 13.3)
108 + (R: 16.6, L:20)
108
48 + (R: 26.6)
+
+
R: 55, L:
normal hearing
98 (COR)
Not tested
R: 95, L: 100 + (R: 18.3, L: 23.3)
R: 103, L: 103 + (R: 15, L: 23.3)
R: 103, L: 91
+
Left hypofunction
+
+
+
+
+
Bilateral hypofunction
Right hypofunction
Bilateral hypofunction
Normal
+
+
+
+
+
+
+
+ (R: 5, L: 8.3)
R: 105, L: 100 + (R: 13.3, L: 18.3)
R: 105, L: 108
+
+
+
R: 103, L: 107
Mutations
of PDS gene
Nonsyndromic LVA
Nonsyndromic LVA
Pendred
Distal renal tubular
acidosis
Not executed
Distal renal tubular
acidosis
Not executed
Distal renal tubular
acidosis
Left hypofunction (16 y) Pendred syndrome
Bilateral hypofunction
Pendred syndrome
Absent
Absent
Absent
Absent
Bilateral hypofunction
Pendred syndrome
T410M/L465W
Bilateral areflexia
Bilateral areflexia
Pendred syndrome
Pendred syndrome
G497R/wt
T505N7glV1001 + 1A
Bilateral areflexia
Pendred syndrome
T505N7glV1001 + 1A
Absent
Absent
Absent
R409H/L465W
R: 103, L: 98
+
Bilateral hypofunction
Pendred syndrome
Absent
R: 100, L:95
+
Bilateral hypofunction
Pendred syndrome
Absent
+
Bilateral hypofunction
? (patient previously Not completed
submitted to
thyroidectomy)
Pendred syndrome
Not completed
R: 96, L: 98
+ (R: 18.3, L: 20)
R: 92, L: 95
+ (R: 3, L: 3.3)
+
Pure-tone audiometry average is 0.5-1-2 kHz. COR indicates conditioned-oriented responses. R, right; L, left; wt, wild type.
Normal
S. Berrettini et al. / American Journal of Otolaryngology – Head and Neck Medicine and Surgery 26 (2005) 363 – 371
Table 1
Audiological, clinical, and genetic features of our group of patients
S. Berrettini et al. / American Journal of Otolaryngology – Head and Neck Medicine and Surgery 26 (2005) 363 –371
367
Table 2
Radiological findings in our group of patients and correlations with hearing loss
Case
Endolimphatic duct/sac complex volume (mL)
PTA (dB HL)
Association with other inner ear anomalies
1.
2.
3.
4.
5.
6.
7.
8.
9.
SL (f, 50 y)
BI (f, 17 y)
BM (f, 43 y)
EA (m, 30 y)
SG (m, 18 y)
PM (m, 8 y)
MC (f, 4 y)
IM (f, 30 y)
SF (m, 12 y)
R:
R:
R:
R:
R:
R:
R:
R:
R:
0.28, L: 0.3
0.32, L: 0.93
0.21, L: 0.23
0.4, L: 1.55
0.44, L: not detectable
0.68, L: not detectable
0.09, L: 0.78
1.07, L: 0.97
1.01, L: 1.18
R: 47, L: 81
R: 101, L: 81
R: 105, L: 108
R: 113, L: 108
R: 103, L: 48
R: 55, L: normal hearing
98 (COR)
R: 95, L: 100
R: 103, L: 103
10. DVS (m, 21 y)
11. SP (m, 22 y)
12. DMA (m, 35 y)
13. DMB (f, 33 y)
14. PF (m, 27 y)
15. PN (f, 30 y)
16. KI (f, 22 y)
17. DPF (m, 18 y)
R:
R:
R:
R:
R:
R:
R:
R:
0.74, L: 0.72
1.16, L: 1.78
0.76, L: 0.42
0.52, L: 0.6
0.72, L: 0.85
0.65, L: 0.73
0.81, L: 1.64
0.3, L: 0.23
R:
R:
R:
R:
R:
R:
R:
R:
Absent
Absent
Absent
Absent
Absent
Absent
Absent
Absent
Dilatation of the vestibule, of the apical turn of the
cochlea and of the LSC bilaterally
Dilatation of the vestibule bilaterally
Absent
Mondini deformity bilaterally
Mondini deformity bilaterally
Absent
Absent
Absent
Dilatation of the vestibule bilaterally
103, L: 91
105, L: 100
105, L: 108
103, L: 107
103, L: 98
100, L:95
96, L: 98
92, L: 95
Pure-tone audiometry average is between 500-1000-2000 Hz. LSC indicates lateral semicircular canal.
7 months in case 9; 2 years in case 10, 12, 13; 18 months in
cases 14 and 15; and 8 months in case 17). The hearing loss
had a sudden onset in 5 patients (cases 2, 3, 8, 11, and 16),
in correspondence with some triggering activity. It was
progressive in 12 of 17 patients (cases 1– 8, 11, 14 – 16) and
presented fluctuations in 5 of 17 patients (cases 2, 3, 5, 6,
and 11). One of the 2 patients with unilateral LVA also
presented a hearing deficit in the contralateral ear, which
manifested some years later and was less severe than in the
affected one (case 5).
Among the 15 adult patients who underwent vestibular
function tests, only 7 complained of vestibular disturbances,
although all but 2 (case 5 and 17) exhibited a marked
vestibular deficit when studied with the caloric stimulation
test. There was no strict correspondence between the side of
the vestibular deficit and the side of enlarged vestibular
aqueduct (EVA) in these patients; infarct case 3 with a
bilateral LVA presented a right vestibular hypofunction, case
4 with a right LVA presented a bilateral vestibular
hypofunction, and case 8 with a bilateral LVA presented a
left vestibular hypofunction.
Of the 17 patients, 10 were clinically affected by PS; all
of them presented goiter and positive perchlorate discharge
test, and 8 of 10 presented a mild hypothyroidism, whereas
2 of 10 had a normal thyroid function. In these patients,
serum anti-Tg, anti-TPO, and anti–TSH-receptor antibodies
were undetectable, whereas in all of them serum Tg levels
were increased. Another patient (case 16) had previously
undergone thyroidectomy for goiter abroad, and the
functional evaluation of the thyroid and the perchlorate discharge test could not be performed. Six patients lacked any
pathological alterations of the thyroid: of these, 3 patients
presented LVAS associated with dRTA (one of these
patients, case 7, was not submitted to perchlorate discharge
test, because of very young age), whereas the other 3 showed
a nonsyndromic hearing loss associated with LVA.
Five of the 10 patients with PS had mutations in the PDS
gene. We identified 2 novel mutations (G497R and L465W)
in the exon 13 nucleotide 1489 GYC and the exon 11
nucleotide 1226 G YA [34]. The other mutations had
already been reported (T410M, R409H, T508N, guanine
IVS8 1001 + 1 adenine) [33,35]. Four patients presented
compound heterozygosis (cases 9, 10, 12, 13), whereas 1
patient (case 11) had a single heterozygous mutation
(G497R). The other patients with a clinical diagnosis of
PS did not show any mutation of the PDS gene, whereas
molecular analysis of the PDS gene is not completed yet in
1 patient with a clinical diagnosis of PS (case 17) and in the
patient who previously underwent thyroidectomy (case 16).
No evidence of mutations of the PDS gene was found in the
3 patients with EVA syndrome associated with dRTA or the
3 patients with nonsyndromic LVAS.
4. Discussion
Enlarged vestibular aqueduct syndrome is described as the
most common imaging finding in individuals with SNHL
dating to infancy or childhood [12,36]. The earliest description of the EVA syndrome was made by Mondini in 1971
[37], whereas it was Valvassori and Clemis [15] who, using
polytomography, first described the association between
EVA and SNHL in 50 cases and coined the term LVAS.
They defined the large vestibular aqueduct as having a large
antero-posterior diameter (N 1.5 mm), often associated with
profound, nonprogressive sensorineural hearing loss [15].
Large vestibular aqueduct syndrome has been reported to
be bilateral in 55% to 94% of cases [6,12,38]; some authors
claim a slight female preponderance [6,12], whereas others
report the inverse [38]. In our group, LVA was found to be
bilateral in 15 of 17 cases (88%).
The audiological features of SNHL in patients affected
by LVAS have been described by many authors: SNHL may
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S. Berrettini et al. / American Journal of Otolaryngology – Head and Neck Medicine and Surgery 26 (2005) 363 – 371
be mild to profound, and patients affected by LVAS without
hearing impairment have also been reported [2,8,9,14,39].
In a variable percentage of cases (11%-65%), it has been
described to be fluctuant and progressive [1,3-5,7,39], often
with sudden, stepwise onset or progression (50% of cases,
according to Walsh et al [6]), secondary to trigger activities
such as those involving the Valsalva maneuver, minor head
trauma, scuba diving, jogging, common colds, and so forth
[1-9]. When bilateral, the hearing deficit is generally
reported to be asymmetrical [9]. Sensorineural hearing loss
onset may be from birth to adolescence, with the highest
frequency in childhood [3-5,7,9]. In our group of LVA
patients, the degree of the hearing deficit varied among the
patients: it was moderate to profound. In accord with the
literature data, the hearing loss onset or diagnosis has been
dated to childhood in all our patients but one (case 1), in
whom SNHL started during adolescence. In 5 (29.4%) of
17 cases, the hearing deficit typically started suddenly after
some characteristic triggering event. It was progressive in
12 (70.5%) of 17 patients and presented fluctuations in
5 (29.4%) of 17 patients. It is worth noting that all the patients with nonprogressive hearing deficit were those whose
hearing loss was already severe or profound at the moment
of diagnosis, dated in each one to the prelingual period
(cases 9, 10, 12, 13, and 17). In such patients at so early an
age, it is difficult to establish hearing loss progression.
Some authors mention a conductive component in a
minority of their patients (17 –38%), probably caused by
decreased mobility of the stapes, due in turn to increased
perilymphatic or endolymphatic pressure [3,5,6,8,9,12,15].
Ten of our patients (59%) presented a conductive component, a percentage that is slightly high in comparison with
data in the literature. The presence of an air-bone gap in
patients with EVA syndrome could be the reason why such
subjects often present better hearing and communicative
results with conventional hearing aids than expected, given
the degree of hearing loss. In fact, some of our patients with
profound bilateral hearing loss (7 –11 and 16) exhibited
satisfactory hearing outcomes with conventional hearing
aids, despite the degree of the hearing deficit, whereas 2 of
them (patients 3 and 4) received a cochlear implant, without
any surgical problem and presenting satisfactory postoperative outcomes, similar to those of patients with normal
inner ears; so according to literature data, cochlear
implantation is to be considered a viable option for such
patients [40-45].
Interestingly, one of the 2 patients with unilateral LVA
subsequently developed a progressive hearing deficit in the
radiologically normal ear; the hearing deficit in the
morphologically normal ear had a later onset and was less
severe than in the ear with EVA. This is a novel finding, as
the literature contains no reports of cases of unilateral LVA
at CT and above all unilateral enlarged endolymphatic duct
and enlarged endolymphatic sac (EES) at MRI, with a
bilateral hearing deficit; in 1997, Dahlen et al [46] reported
on a patient with bilateral SNHL and unilateral LVA at CT
scan, in which MRI disclosed the presence of an EES in the
CT-normal ear. We can suppose that in such cases the
development of an abnormally widened VA is an epiphenomenon of some endolymphatic hydro-electrolytic disorder, which is probably the cause of both the hearing deficit
and enlargement of the VA and ES.
Vestibular symptoms are reported in less than one third of
cases and range from severe episodic vertigo to occasional
unsteadiness in adults, whereas incoordination and imbalance predominate in children [24]. Vestibular hypofunction
seems to be more frequent [1,3,6,39,47,48], whereas
additional otologic symptoms are variable and nonspecific,
such as tinnitus and occasional aural fullness [24]. Seven of
our patients complained of vestibular disturbances, despite
the marked vestibular deficit found in 13 of the 15 patients in
whom vestibular function was studied.
Diagnosis of LVA is radiological. Computed tomography
scan shows the bony labyrinth anatomy, and an axial CT
with 1.5-mm sections generally provides the best view of
the VA from the vestibule to the posterior surface of the
petrous bone, so the VA diameter can be measured midway
between the outer aperture and common crus [38,46,49-52].
Magnetic resonance imaging discloses the fluid-filled
spaces of the inner ear, and the high contrast of fluid in
the membranous labyrinth, especially on T2-weighted
images, allows for visualization of the membranous
labyrinth with exquisite detail [4,31]. Moreover, MRI is
the only imaging technique that enables visualization of the
extra-osseous portion of the ES. Three-dimensional reconstructions from MRI data sets are often helpful to detect the
sac and other inner ear structures and to better define their
morphological features [4,31], so that MRI is considered
superior to CT in LVAS evaluation by some authors [49,50].
Not all authors agree on the criteria for defining the
vestibular aqueduct as large, but the most accepted criterion
is that suggested by Valvassori and Clemis [15]: a vestibular
aqueduct is considered large whenever its antero-posterior
diameter is 1.5 mm or more, as measured via CT scans
midway between the outer aperture and common crus
[3,7,15,46,50]. Enlargement of the endolymphatic duct-sac
complex is also measured at the midpoint between the
posterior margin of the petrous bone and the common crus;
it is difficult to measure consistently because of the
variability of the extracanalicular portion of the ES [38].
Literature reports of correlations between CT and MRI
findings are inconsistent: cases with LVA at CT and normal
inner ear at MRI have been reported, as have cases of EES
at MRI with normal bony VA at CT [19,46,49]. In our study
group, we found a strict correspondence between CT and
MRI in those cases for which both had been performed: in
fact, the presence of enlarged ED and ED detected via MRI
was confirmed by CT in every case it was performed.
Literature reports generally describe a correlation between the side of the more enlarged VA and ES, and the side
of the more marked SNHL, and conclude that a markedly
widened VA is usually associated with profound hearing
S. Berrettini et al. / American Journal of Otolaryngology – Head and Neck Medicine and Surgery 26 (2005) 363 –371
loss [4,46,49,53], although a strict correlation between the
size of the VA and ES and the degree of hearing deficit has
not been established [3,4,7,46,53]. In our patients, we could
not observe a strict correlation between the size of the ED/
ES complex and the degree of the hearing deficit; at any
rate, each of our patients who presented a very large ED/ES
complex volumes ( N1 mL) exhibited also a profound
hearing deficit.
In 2002, Naganawa et al [54] performed serial MRI
examinations in 2 patients with bilateral LVAS and
unilateral fluctuations of hearing before and during periods
of hearing loss exacerbation and found that EES volumes
and signal intensity varied dynamically in both patients,
independent of degree of hearing loss.
In this study, we performed serial HR-MRI in 6 patients
(4 with bilateral and 2 with unilateral LVA): in 5 patients the
hearing loss was stable, whereas in 1 patient with a bilateral
LVA, the hearing threshold worsened in one ear during the
period between the first and the second MRI investigation
(case 1). In none of these 6 patients did we find any changes
in the volume of the ED/ES complex in the serial HR-MR.
Therefore, also in our series it seems that hearing loss
progression is not correlated with ED and ES volumes.
Generally, LVAS is nonfamilial. A genetic predisposition
is evident in a portion of patients affected by LVAS [3-5,
7,24]. Most reported cases are sporadic single cases, but,
recently, familial cases have been reported, and some authors
suggest an autosomal recessive inheritance in families with
members affected by LVAS [4,5,8,24]. Large vestibular
aqueduct syndrome may be associated with both nonsyndromic and syndromic forms of SNHL, such as PS [18,19],
branchiootorenal syndrome [22,55], and, recently, we have
described an association of LVAS with dRTA [23,56].
The relationship between LVAS and the PS has recently
stimulated much attention, because it is so common. In fact,
the PS is the most frequent form of syndromic SNHL.
Pendred’s syndrome is an autosomal recessive disease
characterized by goiter, sensorineural deafness, and defective
iodide organification. Sensorineural hearing loss is generally
prelingual and frequently associated with a wide range of
morphological inner ear anomalies, such as the Mondini
deformity, LVA, and others [18,57-60]. Recently, the
presence of LVA in association with a widened endolymphatic duct and sac has been described as a constant feature of
the PS inner ear [19,20,57,61,62]. In 1996, the gene
responsible for PS, the PDS gene (the pendrin gene), was
mapped to chromosome 7q31 and has subsequently been
cloned [27]. Numerous PDS mutations have now been
identified in affected patients, suggesting a wide allelic
heterogeneity [63-68]. The PDS gene encompasses 21 exons,
contains 2343-bp open reading frame, and encodes for a
780–amino acid protein with 11 putative transmembrane
domains. The pendrin gene appears to function as an iodidechloride transporter and is expressed at the level of the apical
pole of thyrocytes of the distal nephron [69]. Moreover, it has
recently been demonstrated to be expressed at the level of
369
the fetal and adult mouse inner ear, in regions involved in the
regulation of the endolymphatic fluid composition, such as
the endolymphatic duct and sac, distinct areas of the utricle
and saccule, and the external sulcus region within the cochlea
[70,71]. These observations may be important to our
understanding of the mechanisms of inner ear pathology in
patients with PDS mutations: abnormal endolymphatic
hydro-electrolyte balance and osmotic pressure may be the
underlying causes of an abnormal development of the VA,
ED, and ES, their enlargement and consequent SNHL.
Of these 17 patients affected with LVA, 10 were affected
by PS, 3 by LVAS associated with dRTA, and, finally, 3 by
nonsyndromic SNHL associated with LVAS, whereas in
1 patient, the one previously submitted to thyroidectomy, it
was not possible to study thyroid function nor to perform
perchlorate discharge test. All the patients with the nonsyndromic form of LVAS and with LVAS associated with
dRTA were single sporadic cases, whereas 7 of the 10 patients with PS were sporadic cases, and the other 4 were
2 pairs of siblings.
In the 10 patients affected with PS, clinical involvement
of the thyroid was highly variable, and in 1 patient (case 9)
it was discovered only after evidence of inner ear
malformation was found. The mild degree of thyroid
symptoms, so frequently reported in patients with PS, could
be the reason why the presence of PS goes undiagnosed in
many cases of EVA.
In our study group, we were able to find PDS mutations
only in patients affected with PS and not in any of the
patients with nonsyndromic LVA or in those with LVA
associated with dRTA; moreover, 4 of the patients with PS
did not present PDS mutations, whereas in 2 patients the
molecular analysis has not been completed yet (cases 16
and 17). The 4 patients with PS without PDS mutation had
an indistinguishable phenotype from that of patients with PS
and PDS mutations. We must suppose that in the patients
without PDS mutations the development of EVA, both
syndromal (PS) or nonsyndromal, could be due to other
factors apart from PDS mutations, such as environmental
factors or other genetic dysfunctions. The literature contains
some reports of cases of PS with LVA and nonsyndromic
LVA in which no PDS gene mutations were found: in these
cases, the presence of mutations at the level of intronic or
regulatory sequences of the PDS gene, as well as the
involvement of other genes, has been supposed [26,28].
Moreover, the role of a single PDS mutation in our patient
with PS who was heterozygous for PDS mutations is
unclear. Cases of nonsyndromic LVA or PS and heterozygosis for PDS mutations have been reported in the literature,
and in such cases mutations of intronic or regulatory
sequences of the PDS gene have also been supposed to be
involved [26,28].
In conclusion, we wish to emphasize the frequent role of
LVAS in the pathogenesis of SNHL and the overall wide
variability in its audiological features. In every case of SNHL
of unknown origin, the possible presence of LVA should be
370
S. Berrettini et al. / American Journal of Otolaryngology – Head and Neck Medicine and Surgery 26 (2005) 363 – 371
investigated via inner ear HR-MRI, especially if dating back
to infancy or childhood. Moreover, it should be underscored
that LVAS is often part of some syndromic diseases, most of
which are PS, which is often misdiagnosed because of the
varying degree of thyroid symptoms. Thyroid function and
perchlorate discharge tests should be performed on every
case of LVAS, together with molecular analysis of the PDS
gene, if available. Furthermore, we would like to underscore
the role of hydro-electrolyte and acid-base endolymphatic
fluid disorders in the pathogenesis of EVA syndrome, as
documented by recent studies on PDS expression in the
inner ear [70,71] and the association between LVAS and
dRTA, which in its recessive form is related to the alteration
of the B1 subunit of H+-ATPase (ATP6B1), found in high
concentrations in both the distal nephron and the inner ear
epithelia [55]. In fact, PDS mutations cause an alteration of
iodide-chloride transport (pendrin), and in recessive dRTA,
ATP6B1 mutations cause an alteration of a proton pump as
well. As they are expressed in the inner ear, both could
theoretically lead to hydro-electrolyte and acid-base imbalance of inner ear fluids. The exact mechanism leading to
the development of LVA, enlarged endolymphatic duct, and
EES is unclear, but future elucidation of this process would
furnish an important contribution to our understanding of,
and ability to treat, LVAS, and, consequently, SNHL
associated with LVAS.
References
[1] Jackler RK, De La Cruz A. The large vestibular aqueduct syndrome.
Laryngoscope 1989;99:1238 - 43.
[2] Levenson MJ, Parisier SC, Jacobs M, et al. The large vestibular
aqueduct syndrome in children. Arch Otolaryngol Head Neck Surg
1989;115:54 - 8.
[3] Irving RM, Jackler RK. Large vestibular aqueduct syndrome. Curr
Opin Otolaryngol Head Neck Surg 1997;5:267 - 71.
[4] Tong KA, Harsenberger HR, Dahlen RT, et al. Large vestibular
aqueduct syndrome: a genetic disease? AJR Am J Roentgenol
1997;168:1097 - 101.
[5] Abe S, Usami S, Shinkawa H, et al. Three familial cases of hearing
loss associated with enlargement of the vestibular aqueduct. Ann Otol
Rhinol Laryngol 1997;106:1063 - 9.
[6] Walsh RM, Ayshford CA, Chavda SV, et al. Large vestibular aqueduct
syndrome. ORL J Otorhinolaryngol Relat Spec 1999;61:41 - 4.
[7] Nowak KC, Messner AH. Isolated large vestibular aqueduct syndrome
in a family. Ann Otol Rhinol Laryngol 2000;109:40 - 4.
[8] Satoh H, Nonomura N, Takahashi S. Four cases of familial hearing
loss with large vestibular aqueducts. Eur Arch Otorhinolaryngol
1999;256:83 - 6.
[9] Govaerts PJ, Casselman J, Daemers K, et al. Audiological findings in
large vestibular aqueduct syndrome. Int J Pediatr Otorhinolaryngol
1999;51:157 - 64.
[10] Okumura T, Takahashi H, Honjo I, et al. Sensorineural hearing loss
in patients with large vestibular aqueduct. Laryngoscope 1995;105:
289 - 93.
[11] Belenky WM, Madgy DN, Leider JS, et al. The enlarged vestibular
aqueduct syndrome (EVA syndrome). Ear Nose Throat J 1993;72:
746 - 51.
[12] Puls T, Van Fraeyenhoven L. Large vestibular aqueduct syndrome
with mixed hearing loss: a case report. Acta Otorhinolaryngol Belg
1997;51:185 - 9.
[13] Callison DM, Horn KL. Large vestibular aqueduct syndrome: an
overlooked etiology for progressive childhood hearing loss. J Am
Acad Audiol 1998;9:285 - 91.
[14] Emmet JR. The large vestibular aqueduct syndrome. Am J Otolaryngol 1985;6:387 - 415.
[15] Valvassori GE, Clemis JD. The large vestibular aqueduct syndrome.
Laryngoscope 1978;88:723 - 8.
[16] Abe S, Usami S, Hoover DM, et al. Fluctuating sensorineural
hearing loss associated with enlarged vestibular aqueduct maps to
7q31, the region containing the Pendred gene. Am J Med Genet
1999;82:322 - 8.
[17] Pendred V. Deaf-mutism and goitre. Lancet 1896;II:532.
[18] Cremers CWRJ, Bolder C, Admiraal RJC, et al. Progressive
sensorineural hearing loss and a widened vestibular aqueduct in
Pendred syndrome. Arch Otolaryngol Head Neck Surg 1998;124:
501 - 5.
[19] Phelps PD, Mahoney CFO, Luxon LM. Large endolymphatic sac.
A congenital deformity of the inner ear shown by magnetic resonance
imaging. J Laryngol Otol 1997;111:754 - 6.
[20] Fugazzola L, Mannavola D, Cerutti N, et al. Molecular analysis of the
Pendred’s syndrome gene and magnetic resonance imaging studies of
the inner ear are essential for the diagnosis of true Pendred’s
syndrome. J Clin Endocrinol Metab 2000;85:2469 - 75.
[21] Scott DA, Wang R, Kreman TM, et al. Functional differences of
the PDS gene product are associated with phenotypic variation in
patients with Pendred syndrome and non-syndromic hearing loss
(DFNB4). Hum Mol Genet 2000;9:1709 - 15.
[22] Stinckens C, Standaert L, Casselman JW, et al. The presence of a
widened vestibular aqueduct and progressive sensorineural hearing
loss in the branchio-oto-renal syndrome. A family study. Int J Pediatr
Otorhinolaryngol 2001;59:163 - 72.
[23] Berrettini S, Forli F, Sellari Franceschini S, et al. Distal renal tubular
acidosis associated with isolated large vestibular aqueduct and
sensorineural hearing loss. Ann Otol Rhinol Laryngol 2002;111:
385 - 91.
[24] Griffith AJ, Arts HA, Downs C, et al. Familial large vestibular
aqueduct syndrome. Laryngoscope 1996;106:960 - 5.
[25] Sheffield VC, Kraiem Z, Beck JC, et al. Pendred syndrome maps to
chromosome 7q21-34 and is caused by an intrinsic defect in thyroid
iodine organification. Nat Genet 1996;12:424 - 6.
[26] Coyle B, Coffey R, Armour JAL, et al. Pendred syndrome (goitre and
sensorineural hearing loss) maps to chromosome 7 in the region
containing the nonsyndromic deafness gene DFNB4. Nat Genet
1996;12:421 - 3.
[27] Everett LA, Glaser B, Beck JC, et al. Pendred syndrome is caused by
mutations in a putative sulphate transporter gene (PDS). Nat Genet
1997;17:411 - 22.
[28] Usami S, Abe S, Weston MK, et al. Non-syndromic hearing loss
associated with enlarged vestibular aqueduct is caused by PDS
mutations. Hum Genet 1999;104:188 - 92.
[29] Stephens D. Audiological terms. Definitions, protocols and guidelines
in genetic hearing impairment. London7 Whurr Publishers Ltd; 2001.
p. 9 - 14.
[30] Fitzgerald G, Hallpike CS. Studies in the human vestibular function:
observations on the directional preponderance of caloric nystagmus
resulting from cerebral lesions. Brain 1942;65:115 - 37.
[31] Neri E, Caramella D, Cosottini M, et al. High-resolution magnetic
resonance and volume rendering of the labyrinth. Eur Radiol
2000;10:114 - 8.
[32] Neri E, Caramella D, Panconi M, et al. Virtual endoscopy of the
middle ear. Eur Radiol 2001;11:41 - 9.
[33] Bogazzi F, Raggi F, Ultimieri F, et al. A novel mutation in the pendrin
gene associated with Pendred’s syndrome. Clin Endocrinol 2000;52:
279 - 85.
[34] Bogazzi F, Russo D, Raggi F, et al. Mutations in the SLC26A4
(pendrin) gene in patients with sensorineural deafness and enlarged
vestibular aqueduct. J Endocrinol Invest 2004;27(5):430 - 5.
S. Berrettini et al. / American Journal of Otolaryngology – Head and Neck Medicine and Surgery 26 (2005) 363 –371
[35] Lopez-Bigas N, Rabionet R, de Cid R, et al. Splice-site mutation in
PDS gene may result in intrafamilial variability for deafness in
Pendred syndrome. Hum Mutat 1999;14:520 - 6.
[36] Jackler RK, Luxford WM, House WF. Congenital malformations of
the inner ear: a classification based on embryogenesis. Laryngoscope
1987;97(Suppl 40):2 - 14.
[37] Mondini C. Caroli Mundini Anatomica surdi nati sectio. De
bononiensi scientiarum et artium. Instituto atque Academia commentarii. 1791:419 - 31.
[38] Reussner LA, Dutcher PO, House WF. Large vestibular aqueduct
syndrome with massive endolymphatic sacs. Otolaryngol Head Neck
Surg 1995;113:606 - 10.
[39] Yetiser S, Kertmen M, Özkaptan Y. Vestibular disturbance in patients
with large vestibular aqueduct syndrome (LVAS). Acta Otolaryngol
(Stockh) 1999;119:641 - 6.
[40] Aschendorff A, Marangos N, Laszig R. Large vestibular aqueduct
syndrome and its implication for cochlear implant surgery. Am J
Otolaryngol 1997;18:S57.
[41] Au G, Gibson W. Cochlear implantation in children with large
vestibular aqueduct syndrome. Am J Otolaryngol 1999;20:183 - 6.
[42] Bent JP, Chute P, Parisier SC. Cochlear implantation in children with
enlarged vestibular aqueducts. Laryngoscope 1999;109:1019 - 22.
[43] Miyamoto RT, Bichey BG, Wynne MK, et al. Cochlear implantation
with large vestibular aqueduct syndrome. Laryngoscope 2002;112:
1178 - 82.
[44] Bichey BG, Hoversland JM, Wynne MK, et al. Changes in quality of
life and the cost-utility associated with cochlear implantation in
patients with large vestibular aqueduct syndrome. Otol Neurotol
2002;23:323 - 7.
[45] Vescan A, Parnes L, Cucci RA, et al. Cochlear implantation and
Pendred’s syndrome mutation in monozygotic twins with large
vestibular aqueduct syndrome. J Otolaryngol 2002;31:54 - 7.
[46] Dahlen RT, Harnsberger HR, Gray SD, et al. Overlapping thin section
fast spin echo MR of the large vestibular aqueduct syndrome:
comparison with CT. Am J Neuroradiol 1997;18:67 - 75.
[47] Schessel DA, Nedzelski JM. Presentation of large vestibular aqueduct
syndrome to a dizziness unit. J Otolaryngol 1992;21:265 - 9.
[48] Okumura T, Takahashi H, Honjo I, et al. Vestibular function in
patients with large vestibular aqueduct. Acta Otolaryngol (Stockh)
Suppl 1995;520:323 - 6.
[49] Harnsberger HR, Dahlen RT, Shelton C, et al. Advanced techniques
in magnetic resonance imaging in the evaluation of the large endolymphatic duct and sac syndrome. Laryngoscope 1995;105:1037 - 42.
[50] Okamoto K, Ito J, Furusawa T, et al. Large vestibular aqueduct
syndrome with high CT density and high MR signal intensity. Am J
Neroradiol 1997;18:482 - 4.
[51] Mafee MF, Charletta D, Kumar A, et al. Large vestibular aqueduct and
congenital sensorineural hearing loss. Am J Neuroradiol 1982;13:
805 - 19.
[52] Schroeder AA, Kuhn J. Large vestibular aqueduct syndrome. Am J
Otolaryngol 2000;21:433 - 4.
[53] Okamoto K, Ito J, Furusawa T, et al. MRI of enlarged endolymphatic
sacs in the large vestibular aqueduct syndrome. Neuroradiology 1998;
40:167 - 72.
371
[54] Naganawa S, Koshikawa T, Fukatsu H, et al. Serial MR imaging
studies in enlarged endolymphatic duct and sac syndrome. Eur Radiol
2002;12:S114 - 7.
[55] Chen A, Francis M, Ni L, et al. Phenotypic manifestations of
branchiootorenal syndrome. Am J Med Genet 1995;58:365 - 70.
[56] Karet FE, Finberg KE, Nelson RD, et al. Mutations in the gene
encoding B1 subunit of H+-ATPase cause renal tubular acidosis with
sensorineural deafness. Nat Genet 1999;21:84 - 90.
[57] Cremers CWRJ, Admiraal RJC, Huygen PLM, et al. Progressive
hearing loss, hypoplasia of the cochlea and widened vestibular
aqueducts are very common features in Pendred’s syndrome. Int J
Pediatr Otorhinolaryngol 1998;45:113 - 23.
[58] Reardon W, Coffey R, Phelps PD, et al. Pendred syndrome —
100 years of underascertainment? Q J Med 1997;90:443 - 7.
[59] Reardon W, Coffey R, Chowdhury T, et al. Prevalence, age of onset,
and natural history of thyroid disease in Pendred syndrome. J Med
Genet 1999;36:595 - 8.
[60] Iwasaki S, Usami S, Abe S, et al. Long-term audiological feature in
Pendred syndrome caused by PDS mutation. Arch Otolaryngol Head
Neck Surg 2001;127:705 - 8.
[61] Reardon W, O Mahoney CF, Trembath R, et al. Enlarged vestibular
aqueduct: a radiological marker of Pendred syndrome, and mutation
of the PDS gene. Q J Med 2000;93:99 - 104.
[62] Masmoudi S, Charfedine I, Hmani M, et al. Pendred syndrome:
phenotypic variability in two families carrying the same PDS
missense mutation. Am J Med Genet 2000;90:38 - 44.
[63] Fujita S, Sando I. Three-dimensional course of the vestibular
aqueduct. Eur Arch Otorhinolaryngol 1996;253:122 - 5.
[64] Greinwald Jr JH, Wayne S, Chen AH, et al. Localization of a novel
gene for nonsyndromic hearing loss (DFNB17) to chromosome
region 7q31. Am J Med Genet 1998;78:107 - 13.
[65] Li XC, Everett LA, Lalwani AK, et al. A mutation in PDS causes
nonsyndromic recessive deafness. Nat Genet 1998;18:215 - 7.
[66] Ishinaga H, Shimizu T, Yuta A, et al. Pendred’s syndrome with goiter
and enlarged vestibular aqueducts diagnosed by Pds gene mutation.
Head Neck 2002;24:710 - 3.
[67] Lopez-Bigas N, Melchionda S, de Cid R, et al. Identification of five
new mutations of PDS/SLC26A4 in Mediterranean families with
hearing impairment. Hum Mutat 2001;16:1 - 4.
[68] Kitamura K, Takahashi K, Noguchi Y, et al. Mutations of the Pendred
syndrome gene (PDS) in patients with large vestibular aqueduct.
Acta Otolaryngol 2000;120:137 - 41.
[69] Royaux IE, Suzuki K, Mori A, et al. Pendrin, the protein encoded by
the Pendred syndrome gene (PDS), is an apical porter of iodide in the
thyroid and is regulated by thyroglobulin in FRTL-5 cells. Endocrinology 2000;141:839 - 45.
[70] Everett LA, Morsli H, Wu DK, et al. Expression pattern of the
mouse ortholog of the Pendred’s syndrome gene (Pds) suggests a key
role for pendrin in the inner ear. Proc Natl Acad Sci U S A 1999;96:
9727 - 32.
[71] Everett LA, Belyantseva IA, Noben-Trauth K, et al. Targeted
disruption of mouse Pds provides insight about the inner-ear
defects encountered in Pendred syndrome. Hum Mol Genet 2001;
10:153 - 61.