Large Vestibular Aqueduct Syndrome: Audiological, Radiological, Clinical

American Journal of Otolaryngology–Head and Neck Medicine and Surgery 26 (2005) 363–371 www.elsevier.com/locate/amjoto 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 aENT Unit, Neuroscience Department, University of Pisa, 56126 Pisa, Italy bDepartment of Endocrinology and Metabolism, University of Pisa, 56126 Pisa, Italy cDivision of Diagnostic and Interventional Radiology, Department of Oncology, Transplants, and Advanced Technologies in Medicine, University of Pisa, 56126 Pisa, Italy Revised 8 December 2004

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 with sudden, stepwise onset or progression secondary to activities involving minor head trauma, large sudden shifts of The large vestibular aqueduct syndrome (LVAS) is barometric pressure, the Valsalva maneuver, and so forth characterized by the presence of an abnormally large [1-11]. Large vestibular aqueduct syndrome is considered to vestibular aqueduct (LVA) generally associated with fluctu- be the most frequent morphogenetic cause of hearing loss in ating, progressive sensorineural hearing loss (SNHL), often children [12], although its frequency is probably under- estimated [3,12,13]. It is often associated with other T Corresponding author. ENT Unit, Neuroscience Department, Uni- congenital inner ear anomalies, the most common being an versity of Pisa, 56126 Pisa, Italy. Tel.: +39 50 992625; fax: +39 50 550307. abnormally large vestibule, an enlarged semicircular canal, or E-mail address: [email protected] (S. Berrettini). a hypoplastic cochlea [9,14,15], although according to some

0196-0709/$ – see front matter D 2005 Elsevier Inc. All rights reserved. doi:10.1016/j.amjoto.2005.02.013 364 S. Berrettini et al. / American Journal of Otolaryngology–Head and Neck Medicine and Surgery 26 (2005) 363–371 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, posi- tional, 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 LVAwas 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 Fig. 1. Volume rendering of the labyrinth showing the enlarged (15/17 patients). High-resolution MRI was performed with a endolymphatic duct/sac complex (arrow), together with the cochlea, Signa 1.5 T machine (GE/Medical Systems). An acquisition vestibule, and semicircular canals. was performed on each ear using a 3-in circular surface coil for signal reception, with a 3D, T2-weighted, fast spin- authors, SNHL associated with LVA as the only radiograph- echo sequence in the axial plane (TR 5000, TE 275, echo ically detectable inner ear anomaly constitutes a separate train length 64, partition thickness 0.5 mm, 72 partitions, clinical entity [1,15]. field of view 12 cm, matrix 512 Â 512). A single excitation Large vestibular aqueduct syndrome may be associated was acquired and the imaging time was 7 minutes and with nonsyndromic [16] as well as syndromic forms of 22 seconds [31]. SNHL, such as the Pendred’s syndrome (PS) [17-21] and Images were transferred to a high-end graphics the branchiootorenal syndrome [22]. Moreover, we have workstation (Dextroscope; Volume Interactions/Bracco, recently reported on 3 consecutive, unrelated pediatric Singapore), and volume analysis was performed with a patients in whom LVAS was associated with SNHL and dedicated software. distal renal tubular acidosis (dRTA) [23]. The software embedded with the workstation allows a Concerning the genetics of LVAS, it has been postulated rapid segmentation and provides a fast and intuitive method to be inherited as an autosomal recessive trait [5,24]. to generate 3D models with a volume rendering algorithm. Recently, the locus for nonsyndromic SNHL associated The 3D models of the membranous labyrinth were with LVAS has been mapped to the same chromosomal displayed with a stereoscopic view. Using hand-tracking region as the PS locus, 7q31 [25,26], and it has been devices, it was possible to isolate the vestibular duct and sac reported that the gene responsible for the PS, the PDS,is from the membranous labyrinth. also mutated in patients with LVA associated with non- A volume is calculated by counting bvisibleQ voxels and syndromic SNHL [16,21,27,28]. multiplying them by the voxel dimensions as obtained from In this paper, we describe the clinical, audiological, the DICOM (Digital Imaging and Communication in radiological, and genetic features of a group of 17 patients Medicine) 3.0 data source. affected with LVA, studied by means of high-resolution The user needs to specify a rectangular box that magnetic resonance imaging (HR-MRI) of the inner ear with completely includes the volume of interest and a voxel 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. S.F., m, 12 yrs (case 9) -20 -10

dB HL 0 2. Material and methods 10 20 30 We report on 17 patients, 9 males and 8 females, affected 40 by LVAS, with a mean age of 24.7 years, ranging from 4 to 50 60 50 years. 70 80 Each patient underwent a complete audiological and 90 100 clinical evaluation: apart from family and clinical history 110 evaluation and an otomicroscopic examination, the tests 120 250 500 1000 2000 4000 8000 included impedance audiometry, the stapedius reflex thresh- Hz old test, and brainstem auditory-evoked potentials, for all, Fig. 2. Pure tone audiogram of patient 9, showing the presence of an air- and pure-tone audiometry (PTA, 0.5-1-2-4-8 kHz) for bone gap bilaterally. S. Berrettini et al. / American Journal of Otolaryngology–Head and Neck Medicine and Surgery 26 (2005) 363–371 365 threshold value. Voxels inside the volume of interest, and thyroidectomy, was not submitted to the evaluation of voxel values above the specified threshold, will be counted thyroid function nor to perchlorate discharge test. toward the final volume value. Finally, each patient underwent mutation analysis of the High-resolution CT was performed with a 4-row CT PDS gene, as described in previous studies [33]. (Light Speed Plus; GE Medical Systems) with a collimation of 1.25 mm, section thickness 0.63 mm, pitch 3, 0.8 s 3. Results rotation tube, 120 kVp, 200 mAs, in the axial and coronal planes. Images were reconstructed at 0.63-mm interval with A summary description of each patient’s case is provided a bone algorithm [32]. in Tables 1 and 2. An enlargement of the membranous ED/ The diameters of the vestibular aqueduct (VA) and the ES complex was disclosed by HR-MR bilaterally in 15 cases endolymphatic duct (ED) and sac (ES) were measured by (30 ears) and unilaterally in the other 2 (right-sided in both). axial CT and axial MRI scans, respectively. A VA was In the patients who underwent HR-CT, it confirmed the considered to be enlarged if its caliber, measured midway presence of an enlargement of the bony VA in every ear in between the common crus and external aperture, was greater which HR-MR had revealed an enlarged ED and ES. than or equal to 1.5 mm [15]. The mean volume of ED and ES complex, measured on The HR-MR investigations of the inner ear were repeated 3D reconstructions of the membranous labyrinth as de- in 6 patients some years after the diagnosis of LVAS (range scribed, was 0.67 mL, ranging from 0.09 to 1.78 mL. 4–10 years, mean 5.6 years) to assess any variations in the In 12 patients, LVA was the only radiographically volume of the ED and ES; 4 of 6 patients presented a bilateral detectable inner ear anomaly, whereas in 5 patients it was LVA, whereas 2 of 6 patients presented a unilateral LVA. accompanied by other inner ear abnormalities: bilateral The MRI data sets of those patients were coregistered, dilatation of the vestibule, the apical turn of the cochlea, and and the volume of the vestibular aqueduct was then the lateral semicircular canal in patient 9, bilateral dilatation calculated by using a 3D workstation (Dextroscope; Volume of the vestibule in patients 10 and 17, and bilateral classical Interactions/Bracco), to see whether the volume had Mondini deformity in patients 12 and 13. changed over time. The volume of the ED/ES complex remained stable in Image coregistration was performed with a semiauto- the 6 patients who underwent serial HR-MR of the inner ear, matic registration method (multipoint plus freehand fusion). and particularly the 2 cases of these 6 with unilateral LVA Three anatomical landmarks were visually identified by the also exhibited unilateral LVA upon the second HR-MR. radiologist in the MRI 3D images corresponding respec- The degree of SNHL in the affected ears (32 ears with tively to the middle tract of the superior and lateral LVA) ranged from moderate to profound, with a PTA from semicircular canals, and the initial part of the basal turn of 47 to 113 dB HL and a downsloping (29 ears) or U-shaped the cochlea. A marker was manually placed on each of the (3 ears) hearing threshold curve; only 2 ears (patients 1 and identified points. Once the markers were placed in both 6) presented a moderate hearing deficit, 4 ears (patients 1, 2, datasets the software produced a preliminary combined 10, and 17) exhibited a severe hearing deficit, whereas in the coregistered 3D model. The 3D model was then displayed remaining 26 ears the deficit was profound. A conductive as a fused 3D image incorporating the magnetic resonance component was present in 10 of our patients, 19 ears (cases data. An assessment was made by the radiologist by visually 1–3, 5, 8–11, 16 and 17), whereas in 1 patient it was not inspecting the fused 3D images to determine the accuracy of tested (case 7: the patient was too young). The average of image coregistration. In the case of incorrect superimposi- the air-bone gap was calculated between the frequencies of tion of labyrinth components, a manual adjustment of the 500-1000-2000 Hz and ranged between 3 and 26.6 dB HL, data was made. By using the volume rendering of the MRI with a mean value of 15.2 dB HL. Two of our patients data, the membranous tract of the vestibular aqueduct (cases 3 and 4) received a cochlear implant in adult life acquired at different time intervals was isolated and without intraoperative perilymph gusher and with good displayed both in the same 3D model. The radiological postoperative outcomes, 14 patients are traditional hearing- study of all the patients, both HR-CT and HR-MR aid users, and 1 patient (case 6), with a unilateral moderate investigations, has been performed and evaluated by the hearing deficit, does not use hearing aids. same radiologist, expert in the imaging study of the petrous We did not find a clear correspondence between volumes bone. Also, the measurements of the diameters, the 3D of ED/ES complex and the degree of the hearing deficit; we reconstructions, and the analysis of the volumes of the ED/ only found that all the patients with ED/ES complex volume ES complexes have been performed by the same radiologist. greater than 1 mL exhibited a profound hearing loss. Each patient also underwent a functional and ultrasono- The age at which hearing loss was diagnosed varied graph evaluation of the thyroid and a perchlorate (KClO4) widely, although it was reached in childhood or adolescence discharge test to reveal the presence of the PS, as previously in all patients: from 7 months to 15 years, with a mean age described [33], apart from 2 patients: 1 patient was not of 3.9 years. It should be underscored that in 8 (cases 7, 9, submitted to perchlorate discharge test, because she was too 10, 12–15, and 17) the hearing loss was probably congeni- young (4 years old) and 1 patient, previously submitted to tal and diagnosed at different ages (13 months in case 7; 366 .Bretn ta./Aeia ora fOoayglg–edadNc eiieadSrey2 20)363–371 (2005) 26 Surgery and Medicine Neck and Otolaryngology–Head of Journal American / al. et Berrettini S. Table 1 Audiological, clinical, and genetic features of our group of patients Case Side Age of PTA (dB HL) Conductive component Sudden hearing Fluctuations Progression Vestibular function Syndromic aspects Mutations of LVA hearing loss (average between 500- impairment of hearing of hearing of PDS gene onset/diagnosis 1000-2000 Hz) (dB HL) (after triggers) function loss 1. SL (f, 50 y) Bilateral 15 y left, R: 47, L: 81 + (R: 6.6, L: 11.6) ÀÀ+ Left hypofunction Nonsyndromic LVA Absent 45 y right 2. BI (f, 17 y) Bilateral 5 y R: 101, L: 81 + (R: 25, L: 13.3) + + + Bilateral hypofunction Nonsyndromic LVA Absent 3. BM (f, 43 y) Bilateral 3 y R: 105, L: 108 + (R: 16.6, L:20) + + + Right hypofunction Nonsyndromic LVA Absent 4. EA (m, 30 y) Bilateral 6 y R: 113, L: 108 ÀÀÀ+ Bilateral hypofunction Pendred Absent 5. SG (m, 18 y) Right 7 y R: 103, L: 48 + (R: 26.6) À + + Normal Distal renal tubular Absent acidosis 6. PM (m, 8 y) Right 8 y R: 55, L: ÀÀ+ + Not executed Distal renal tubular Absent normal hearing acidosis 7. MC (f, 4 y) Bilateral 13 mo 98 (COR) Not tested ÀÀ+ Not executed Distal renal tubular Absent (congenital?) acidosis 8. IM (f, 30 y) Bilateral 5 y R: 95, L: 100 + (R: 18.3, L: 23.3) + À + Left hypofunction (16 y) Pendred syndrome Absent 9. SF (m, 12 y) Bilateral 7 mo R: 103, L: 103 + (R: 15, L: 23.3) ÀÀÀBilateral hypofunction Pendred syndrome R409H/L465W (congenital?) 10. DVS Bilateral 2 y R: 103, L: 91 + (R: 5, L: 8.3) ÀÀÀBilateral hypofunction Pendred syndrome T410M/L465W (m, 21 y) (congenital?) 11. SP (m, 22 y) Bilateral 3 y R: 105, L: 100 + (R: 13.3, L: 18.3) + + + Bilateral areflexia Pendred syndrome G497R/wt 12. DMA Bilateral 2 y R: 105, L: 108 ÀÀÀÀBilateral areflexia Pendred syndrome T505N7glV1001 + 1A (m, 35 y) (congenital?) 13. DMB Bilateral 2 y R: 103, L: 107 ÀÀÀÀBilateral areflexia Pendred syndrome T505N7glV1001 + 1A (f, 33 y) (congenital?) 14. PF (m, 27 y) Bilateral 18 mo R: 103, L: 98 ÀÀÀ+ Bilateral hypofunction Pendred syndrome Absent (congenital?) 15. PN (f, 30 y) Bilateral 18 mo R: 100, L:95 ÀÀÀ+ Bilateral hypofunction Pendred syndrome Absent (congenital?) 16. KI (f, 22 y) Bilateral 4 y R: 96, L: 98 + (R: 18.3, L: 20) + À + Bilateral hypofunction ? (patient previously Not completed submitted to thyroidectomy) 17. DPF Bilateral 8 mo R: 92, L: 95 + (R: 3, L: 3.3) ÀÀÀNormal Pendred syndrome Not completed (m, 18 y) (congenital?) Pure-tone audiometry average is 0.5-1-2 kHz. COR indicates conditioned-oriented responses. R, right; L, left; wt, wild type. 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. SL (f, 50 y) R: 0.28, L: 0.3 R: 47, L: 81 Absent 2. BI (f, 17 y) R: 0.32, L: 0.93 R: 101, L: 81 Absent 3. BM (f, 43 y) R: 0.21, L: 0.23 R: 105, L: 108 Absent 4. EA (m, 30 y) R: 0.4, L: 1.55 R: 113, L: 108 Absent 5. SG (m, 18 y) R: 0.44, L: not detectable R: 103, L: 48 Absent 6. PM (m, 8 y) R: 0.68, L: not detectable R: 55, L: normal hearing Absent 7. MC (f, 4 y) R: 0.09, L: 0.78 98 (COR) Absent 8. IM (f, 30 y) R: 1.07, L: 0.97 R: 95, L: 100 Absent 9. SF (m, 12 y) R: 1.01, L: 1.18 R: 103, L: 103 Dilatation of the vestibule, of the apical turn of the cochlea and of the LSC bilaterally 10. DVS (m, 21 y) R: 0.74, L: 0.72 R: 103, L: 91 Dilatation of the vestibule bilaterally 11. SP (m, 22 y) R: 1.16, L: 1.78 R: 105, L: 100 Absent 12. DMA (m, 35 y) R: 0.76, L: 0.42 R: 105, L: 108 Mondini deformity bilaterally 13. DMB (f, 33 y) R: 0.52, L: 0.6 R: 103, L: 107 Mondini deformity bilaterally 14. PF (m, 27 y) R: 0.72, L: 0.85 R: 103, L: 98 Absent 15. PN (f, 30 y) R: 0.65, L: 0.73 R: 100, L:95 Absent 16. KI (f, 22 y) R: 0.81, L: 1.64 R: 96, L: 98 Absent 17. DPF (m, 18 y) R: 0.3, L: 0.23 R: 92, L: 95 Dilatation of the vestibule bilaterally 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 Five of the 10 patients with PS had mutations in the PDS cases 14 and 15; and 8 months in case 17). The hearing loss gene. We identified 2 novel mutations (G497R and L465W) had a sudden onset in 5 patients (cases 2, 3, 8, 11, and 16), in the exon 13 nucleotide 1489 GYC and the exon 11 in correspondence with some triggering activity. It was nucleotide 1226 GYA [34]. The other mutations had progressive in 12 of 17 patients (cases 1–8, 11, 14–16) and already been reported (T410M, R409H, T508N, guanine presented fluctuations in 5 of 17 patients (cases 2, 3, 5, 6, IVS8 1001 + 1 adenine) [33,35]. Four patients presented and 11). One of the 2 patients with unilateral LVA also compound heterozygosis (cases 9, 10, 12, 13), whereas 1 presented a hearing deficit in the contralateral ear, which patient (case 11) had a single heterozygous mutation manifested some years later and was less severe than in the (G497R). The other patients with a clinical diagnosis of affected one (case 5). PS did not show any mutation of the PDS gene, whereas Among the 15 adult patients who underwent vestibular molecular analysis of the PDS gene is not completed yet in function tests, only 7 complained of vestibular disturbances, 1 patient with a clinical diagnosis of PS (case 17) and in the although all but 2 (case 5 and 17) exhibited a marked patient who previously underwent thyroidectomy (case 16). vestibular deficit when studied with the caloric stimulation No evidence of mutations of the PDS gene was found in the test. There was no strict correspondence between the side of 3 patients with EVA syndrome associated with dRTA or the the vestibular deficit and the side of enlarged vestibular 3 patients with nonsyndromic LVAS. aqueduct (EVA) in these patients; infarct case 3 with a bilateral LVA presented a right vestibular hypofunction, case 4. Discussion 4 with a right LVA presented a bilateral vestibular hypofunction, and case 8 with a bilateral LVA presented a Enlarged vestibular aqueduct syndrome is described as the left vestibular hypofunction. most common imaging finding in individuals with SNHL Of the 17 patients, 10 were clinically affected by PS; all dating to infancy or childhood [12,36]. The earliest descrip- of them presented goiter and positive perchlorate discharge tion of the EVA syndrome was made by Mondini in 1971 test, and 8 of 10 presented a mild hypothyroidism, whereas [37], whereas it was Valvassori and Clemis [15] who, using 2 of 10 had a normal thyroid function. In these patients, polytomography, first described the association between serum anti-Tg, anti-TPO, and anti–TSH-receptor antibodies EVA and SNHL in 50 cases and coined the term LVAS. were undetectable, whereas in all of them serum Tg levels They defined the large vestibular aqueduct as having a large were increased. Another patient (case 16) had previously antero-posterior diameter (N1.5 mm), often associated with undergone thyroidectomy for goiter abroad, and the profound, nonprogressive sensorineural hearing loss [15]. functional evaluation of the thyroid and the perchlorate dis- Large vestibular aqueduct syndrome has been reported to charge test could not be performed. Six patients lacked any be bilateral in 55% to 94% of cases [6,12,38]; some authors pathological alterations of the thyroid: of these, 3 patients claim a slight female preponderance [6,12], whereas others presented LVAS associated with dRTA (one of these report the inverse [38]. In our group, LVA was found to be patients, case 7, was not submitted to perchlorate discharge bilateral in 15 of 17 cases (88%). test, because of very young age), whereas the other 3 showed The audiological features of SNHL in patients affected a nonsyndromic hearing loss associated with LVA. by LVAS have been described by many authors: SNHL may 368 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 scan, in which MRI disclosed the presence of an EES in the hearing impairment have also been reported [2,8,9,14,39]. CT-normal ear. We can suppose that in such cases the In a variable percentage of cases (11%-65%), it has been development of an abnormally widened VA is an epiphe- described to be fluctuant and progressive [1,3-5,7,39], often nomenon of some endolymphatic hydro-electrolytic disor- with sudden, stepwise onset or progression (50% of cases, der, which is probably the cause of both the hearing deficit according to Walsh et al [6]), secondary to trigger activities and enlargement of the VA and ES. such as those involving the Valsalva maneuver, minor head Vestibular symptoms are reported in less than one third of trauma, scuba diving, jogging, common colds, and so forth cases and range from severe episodic vertigo to occasional [1-9]. When bilateral, the hearing deficit is generally unsteadiness in adults, whereas incoordination and imbal- reported to be asymmetrical [9]. Sensorineural hearing loss ance predominate in children [24]. Vestibular hypofunction onset may be from birth to adolescence, with the highest seems to be more frequent [1,3,6,39,47,48],whereas frequency in childhood [3-5,7,9]. In our group of LVA additional otologic symptoms are variable and nonspecific, patients, the degree of the hearing deficit varied among the such as tinnitus and occasional aural fullness [24]. Seven of patients: it was moderate to profound. In accord with the our patients complained of vestibular disturbances, despite literature data, the hearing loss onset or diagnosis has been the marked vestibular deficit found in 13 of the 15 patients in dated to childhood in all our patients but one (case 1), in whom vestibular function was studied. whom SNHL started during adolescence. In 5 (29.4%) of Diagnosis of LVA is radiological. Computed tomography 17 cases, the hearing deficit typically started suddenly after scan shows the bony labyrinth anatomy, and an axial CT some characteristic triggering event. It was progressive in with 1.5-mm sections generally provides the best view of 12 (70.5%) of 17 patients and presented fluctuations in the VA from the vestibule to the posterior surface of the 5 (29.4%) of 17 patients. It is worth noting that all the pa- petrous bone, so the VA diameter can be measured midway tients with nonprogressive hearing deficit were those whose between the outer aperture and common crus [38,46,49-52]. hearing loss was already severe or profound at the moment Magnetic resonance imaging discloses the fluid-filled of diagnosis, dated in each one to the prelingual period spaces of the inner ear, and the high contrast of fluid in (cases 9, 10, 12, 13, and 17). In such patients at so early an the membranous labyrinth, especially on T2-weighted age, it is difficult to establish hearing loss progression. images, allows for visualization of the membranous Some authors mention a conductive component in a labyrinth with exquisite detail [4,31]. Moreover, MRI is minority of their patients (17–38%), probably caused by the only imaging technique that enables visualization of the decreased mobility of the stapes, due in turn to increased extra-osseous portion of the ES. Three-dimensional recon- perilymphatic or endolymphatic pressure [3,5,6,8,9,12,15]. structions from MRI data sets are often helpful to detect the Ten of our patients (59%) presented a conductive compo- sac and other inner ear structures and to better define their nent, a percentage that is slightly high in comparison with morphological features [4,31], so that MRI is considered data in the literature. The presence of an air-bone gap in superior to CT in LVAS evaluation by some authors [49,50]. patients with EVA syndrome could be the reason why such Not all authors agree on the criteria for defining the subjects often present better hearing and communicative vestibular aqueduct as large, but the most accepted criterion results with conventional hearing aids than expected, given is that suggested by Valvassori and Clemis [15]: a vestibular the degree of hearing loss. In fact, some of our patients with aqueduct is considered large whenever its antero-posterior profound bilateral hearing loss (7–11 and 16) exhibited diameter is 1.5 mm or more, as measured via CT scans satisfactory hearing outcomes with conventional hearing midway between the outer aperture and common crus aids, despite the degree of the hearing deficit, whereas 2 of [3,7,15,46,50]. Enlargement of the endolymphatic duct-sac them (patients 3 and 4) received a cochlear implant, without complex is also measured at the midpoint between the any surgical problem and presenting satisfactory postoper- posterior margin of the petrous bone and the common crus; ative outcomes, similar to those of patients with normal it is difficult to measure consistently because of the inner ears; so according to literature data, cochlear variability of the extracanalicular portion of the ES [38]. implantation is to be considered a viable option for such Literature reports of correlations between CT and MRI patients [40-45]. findings are inconsistent: cases with LVA at CT and normal Interestingly, one of the 2 patients with unilateral LVA inner ear at MRI have been reported, as have cases of EES subsequently developed a progressive hearing deficit in the at MRI with normal bony VA at CT [19,46,49]. In our study radiologically normal ear; the hearing deficit in the group, we found a strict correspondence between CT and morphologically normal ear had a later onset and was less MRI in those cases for which both had been performed: in severe than in the ear with EVA. This is a novel finding, as fact, the presence of enlarged ED and ED detected via MRI the literature contains no reports of cases of unilateral LVA was confirmed by CT in every case it was performed. at CT and above all unilateral enlarged endolymphatic duct Literature reports generally describe a correlation be- and enlarged endolymphatic sac (EES) at MRI, with a tween the side of the more enlarged VA and ES, and the side bilateral hearing deficit; in 1997, Dahlen et al [46] reported of the more marked SNHL, and conclude that a markedly on a patient with bilateral SNHL and unilateral LVA at CT widened VA is usually associated with profound hearing S. Berrettini et al. / American Journal of Otolaryngology–Head and Neck Medicine and Surgery 26 (2005) 363–371 369 loss [4,46,49,53], although a strict correlation between the the fetal and adult mouse inner ear, in regions involved in the size of the VA and ES and the degree of hearing deficit has regulation of the endolymphatic fluid composition, such as not been established [3,4,7,46,53]. In our patients, we could the endolymphatic duct and sac, distinct areas of the utricle not observe a strict correlation between the size of the ED/ and saccule, and the external sulcus region within the cochlea ES complex and the degree of the hearing deficit; at any [70,71]. These observations may be important to our rate, each of our patients who presented a very large ED/ES understanding of the mechanisms of inner ear pathology in complex volumes (N1 mL) exhibited also a profound patients with PDS mutations: abnormal endolymphatic hearing deficit. hydro-electrolyte balance and osmotic pressure may be the In 2002, Naganawa et al [54] performed serial MRI underlying causes of an abnormal development of the VA, examinations in 2 patients with bilateral LVAS and ED, and ES, their enlargement and consequent SNHL. unilateral fluctuations of hearing before and during periods Of these 17 patients affected with LVA, 10 were affected of hearing loss exacerbation and found that EES volumes by PS, 3 by LVAS associated with dRTA, and, finally, 3 by and signal intensity varied dynamically in both patients, nonsyndromic SNHL associated with LVAS, whereas in independent of degree of hearing loss. 1 patient, the one previously submitted to thyroidectomy, it In this study, we performed serial HR-MRI in 6 patients was not possible to study thyroid function nor to perform (4 with bilateral and 2 with unilateral LVA): in 5 patients the perchlorate discharge test. All the patients with the non- hearing loss was stable, whereas in 1 patient with a bilateral syndromic form of LVAS and with LVAS associated with LVA, the hearing threshold worsened in one ear during the dRTA were single sporadic cases, whereas 7 of the 10 pa- period between the first and the second MRI investigation tients with PS were sporadic cases, and the other 4 were (case 1). In none of these 6 patients did we find any changes 2 pairs of siblings. in the volume of the ED/ES complex in the serial HR-MR. In the 10 patients affected with PS, clinical involvement Therefore, also in our series it seems that hearing loss of the thyroid was highly variable, and in 1 patient (case 9) progression is not correlated with ED and ES volumes. it was discovered only after evidence of inner ear Generally, LVAS is nonfamilial. A genetic predisposition malformation was found. The mild degree of thyroid is evident in a portion of patients affected by LVAS [3-5, symptoms, so frequently reported in patients with PS, could 7,24]. Most reported cases are sporadic single cases, but, be the reason why the presence of PS goes undiagnosed in recently, familial cases have been reported, and some authors many cases of EVA. suggest an autosomal recessive inheritance in families with In our study group, we were able to find PDS mutations members affected by LVAS [4,5,8,24]. Large vestibular only in patients affected with PS and not in any of the aqueduct syndrome may be associated with both nonsyn- patients with nonsyndromic LVA or in those with LVA dromic and syndromic forms of SNHL, such as PS [18,19], associated with dRTA; moreover, 4 of the patients with PS branchiootorenal syndrome [22,55], and, recently, we have did not present PDS mutations, whereas in 2 patients the described an association of LVAS with dRTA [23,56]. molecular analysis has not been completed yet (cases 16 The relationship between LVAS and the PS has recently and 17). The 4 patients with PS without PDS mutation had stimulated much attention, because it is so common. In fact, an indistinguishable phenotype from that of patients with PS the PS is the most frequent form of syndromic SNHL. and PDS mutations. We must suppose that in the patients Pendred’s syndrome is an autosomal recessive disease without PDS mutations the development of EVA, both characterized by goiter, sensorineural deafness, and defective syndromal (PS) or nonsyndromal, could be due to other iodide organification. Sensorineural hearing loss is generally factors apart from PDS mutations, such as environmental prelingual and frequently associated with a wide range of factors or other genetic dysfunctions. The literature contains morphological inner ear anomalies, such as the Mondini some reports of cases of PS with LVA and nonsyndromic deformity, LVA, and others [18,57-60]. Recently, the LVA in which no PDS gene mutations were found: in these presence of LVA in association with a widened endolym- cases, the presence of mutations at the level of intronic or phatic duct and sac has been described as a constant feature of regulatory sequences of the PDS gene, as well as the the PS inner ear [19,20,57,61,62]. In 1996, the gene involvement of other genes, has been supposed [26,28]. responsible for PS, the PDS gene (the pendrin gene), was Moreover, the role of a single PDS mutation in our patient mapped to chromosome 7q31 and has subsequently been with PS who was heterozygous for PDS mutations is cloned [27]. Numerous PDS mutations have now been unclear. Cases of nonsyndromic LVA or PS and heterozy- identified in affected patients, suggesting a wide allelic gosis for PDS mutations have been reported in the literature, heterogeneity [63-68]. The PDS gene encompasses 21 exons, and in such cases mutations of intronic or regulatory contains 2343-bp open reading frame, and encodes for a sequences of the PDS gene have also been supposed to be 780–amino acid protein with 11 putative transmembrane involved [26,28]. domains. The pendrin gene appears to function as an iodide- In conclusion, we wish to emphasize the frequent role of chloride transporter and is expressed at the level of the apical LVAS in the pathogenesis of SNHL and the overall wide pole of thyrocytes of the distal nephron [69]. Moreover, it has variability in its audiological features. In every case of SNHL recently been demonstrated to be expressed at the level of 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 [13] Callison DM, Horn KL. Large vestibular aqueduct syndrome: an to infancy or childhood. Moreover, it should be underscored overlooked etiology for progressive childhood hearing loss. J Am that LVAS is often part of some syndromic diseases, most of Acad Audiol 1998;9:285-91. [14] Emmet JR. The large vestibular aqueduct syndrome. Am J Otolar- which are PS, which is often misdiagnosed because of the yngol 1985;6:387-415. varying degree of thyroid symptoms. Thyroid function and [15] Valvassori GE, Clemis JD. The large vestibular aqueduct syndrome. perchlorate discharge tests should be performed on every Laryngoscope 1978;88:723-8. case of LVAS, together with molecular analysis of the PDS [16] Abe S, Usami S, Hoover DM, et al. Fluctuating sensorineural gene, if available. Furthermore, we would like to underscore hearing loss associated with enlarged vestibular aqueduct maps to 7q31, the region containing the Pendred gene. Am J Med Genet the role of hydro-electrolyte and acid-base endolymphatic 1999;82:322-8. fluid disorders in the pathogenesis of EVA syndrome, as [17] Pendred V. Deaf-mutism and goitre. Lancet 1896;II:532. documented by recent studies on PDS expression in the [18] Cremers CWRJ, Bolder C, Admiraal RJC, et al. 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