Published online before print March 9, 2005, 10.1148/radiol.2352031583
(Radiology 2005;235:537-540.)
© RSNA, 2005
CT of the Ear in Pendred Syndrome1
Moshe Goldfeld, MD,
Benjamin Glaser, MD,
Elias Nassir, MD,
John Moshe Gomori, MD,
Elitsur Hazani, MD and
Nassir Bishara, MD
1 From the Departments of Radiology (M.G.) and Internal Medicine (E.N., E.H., N.B.), Western Galilee Hospital, Nahariya 22100, Israel; and Department of Internal Medicine, Endocrinology and Metabolism Service (B.G.), and Department of Radiology (J.M.G.), Hadassah-Hebrew University, Medical Center, Jerusalem, Israel. Received September 25, 2003; revision requested December 8; final revision received June 20, 2004; accepted July 26. Address correspondence to M.G. (e-mail: goldme1@yahoo.com).
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ABSTRACT
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PURPOSE: To prospectively determine the structural anomalies of the inner ear by using thin-section computed tomography (CT) in an extended family with Pendred syndrome.
MATERIALS AND METHODS: Ethics committee approved the study, and informed consent was obtained from every patient or from parents of patients under legal age. Twelve patients (three females and nine males aged 7–47 years) with Pendred syndrome (all from the same ethnic isolate and with the same mutation in the PDS gene) were evaluated for inner-ear malformation at thin-section CT. Both ears were evaluated. Presence or absence of interscalar septum between upper and middle turns of the cochlea was evaluated, and vestibule and vestibular aqueduct were examined for enlargement. Modiolus was determined to be present or absent (modiolar deficiency). CT scans were evaluated in consensus by two radiologists (M.G., J.M.G.).
RESULTS: All patients had inner ear malformation on both sides. Modiolus was absent and vestibule was enlarged on both sides in all 12 patients. Interscalar septum was absent in 18 (75%) of 24 ears. In eight patients, interscalar septum was absent in both ears, whereas in two patients, it was absent on only one side. Aqueduct was enlarged in 20 (80%) of 24 ears. In nine patients, both ears had enlarged aqueducts, while in two patients, only one side was abnormal.
CONCLUSION: Inner ear malformation is an invariable finding in Pendred syndrome. Modiolus deficiency and vestibular enlargement were the most consistent anomalies in this population with Pendred syndrome.
© RSNA, 2005
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INTRODUCTION
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Pendred syndrome is a recessively inherited disorder characterized by dyshormonogenic goiter associated with sensory-neural deafness, described by Vaughan Pendred in 1896 (1). It is the commonest form of syndromic hearing loss and accounts for upwards of 10% of hereditary deafness (2). In most cases, deafness is profound and prelingual, whereas in others, slowly progressive and fluctuating hearing loss has been documented (2,3). Hearing loss may follow a traumatic event, infection, or episode of endolymphatic hydrops (endolymphatic edema) (4).
Some patients with Pendred syndrome present with vestibular symptoms and vestibular test abnormalities (3,5,6). The goiter is multinodular and may grow to a large size, necessitating surgical decompression. Patients are generally euthyroid, although some patients have variable degrees of hypothyroidism. The thyroid glands of affected individuals cannot organify iodide efficiently, and 10%–80% of iodine taken up by the gland is discharged after administration of perchlorate. This constitutes the basis of the perchlorate discharge test that is used for the diagnosis of Pendred syndrome.
Pendred syndrome is inherited as an autosomal recessive trait, which was mapped to chromosome 7 by means of homozygocity mapping (7) and linkage analysis (8). A positional cloning approach was then used to identify the responsible gene, a novel gene (PDS) coding for a protein (pendrin) initially thought to function as a sulfate transporter (9). Subsequent studies excluded sulfate transport activity (10) and suggested that the protein functions as a membrane-bound chloride-iodine transporter (11).
Structural abnormalities of the ear, consisting of absence of the central bony spiral (ie, spiral osseous lamina) of the cochlea and vestibular aqueduct enlargement, have been described (12,13). Large vestibular aqueduct is well known to be associated with hearingloss (14,15). Modiolar deficiency and large vestibular aqueducts have been observed to be associated in deaf patients (15,16). Despite this well-known association, modiolar deficiency was not, to our knowledge, described in Pendred syndrome. Similarly, vestibular enlargement has not been, to our knowledge, described with this disease, even when the patients studied presented with vestibular disease (3,5). Thus, the purpose of our study was to prospectively determine the structural anomalies of the inner ear in an extended family with Pendred syndrome by using thin-section spiral CT.
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MATERIALS AND METHODS
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Patients
The ethics committee at Western Galilee Hospital approved the study. Informed consent was obtained from every patient or from the parents of patients under legal age. Twelve patients, three females and nine males, were prospectively studied for inner ear abnormalities at CT. All patients belonged to the same extended family that was well known to have Pendred syndrome. The mean age of the patients studied was 21.9 years, and the median age was 20.5 years. Age range was 7–47 years. All 12 patients had prelingual deafness, and the diagnosis of Pendred syndrome was based on clinical evidence (goiter and deafness). Mutation analysis was performed in 11 of 12 patients, and all were found to be homozygous for the 1220 delt mutation (9). One patient refused to give material for genetic analysis. The study was performed prospectively.
CT Procedure and Image Interpretation
CT examination of the temporal bone was performed with a double–detector row CT scanner (CT Twin Flash; Philips, Haifa, Israel) in the transverse plane by using a spiral technique, with a pitch of 0.7, section width of 1 mm, and an interval reconstruction of 0.5 mm. Images were reconstructed by using a bone algorithm in the transverse plane. Hard-copy CT images were reviewed for anatomic disarrangements of the inner ear, including vestibular aqueduct enlargement, deficiency of the modiolus, and absence of the interscalar septum between the middle and apical turns of the cochlea. The vestibule was examined for enlargement. The modiolus was considered deficient when, on a midmodiolar section, a bony polyhedral structure, centered in the cochlea, could not be seen.
The vestibular aqueduct width was measured as described by Valvassori and Clemis (17) in the middle portion of the descending limb. A width of 1.5 mm or more was considered to indicate enlargement. Vestibular enlargement was determined subjectively by considering the relative size of the vestibule and the lateral semicircular canal. CT images were read by two experienced radiologists (M.G., J.M.G.) in consensus. Both radiologists are board certified in Israel (J.M.G. is also board certified in the United States and has a certificate of added qualification in neuroradiology; J.M.G. and M.G. have 23 and 14 years of experience in head and neck imaging, respectively). The readers were aware that the population studied consisted of patients with Pendred syndrome.
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RESULTS
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The modiolus was deficient and the vestibule was enlarged in all 24 ears evaluated (in 12 patients) (Table). The interscalar septum between the upper and the middle turn of the cochlea was absent in 18 ears, bilaterally in eight patients and unilaterally in two patients (total of 10 patients), constituting 75% of the 24 ears studied. In two patients, both ears had normally visible interscalar septum. Enlarged vestibular aqueduct was observed in 20 ears, bilaterally in nine patients and unilaterally in two patients (total of 11 patients), constituting 80% of the ears studied (Figure). In one patient, the vestibular aqueduct was normal on both sides, and in two patients, the vestibular aqueduct was enlarged on only one side. In no patient was the interscalar septum present and the vestibular aqueduct of normal size in the same ear.
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Figure a. Transverse CT scans of the middle ear in a 47-year-old patient with Pendred syndrome. (a) Modiolus is not discernible (short arrow). Vestibular aqueduct (arrowheads) and vestibule (long arrow) are enlarged. (b) Interscalar septum between upper and middle turn of the cochlea is absent (arrow).
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Figure b. Transverse CT scans of the middle ear in a 47-year-old patient with Pendred syndrome. (a) Modiolus is not discernible (short arrow). Vestibular aqueduct (arrowheads) and vestibule (long arrow) are enlarged. (b) Interscalar septum between upper and middle turn of the cochlea is absent (arrow).
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DISCUSSION
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There is no agreement in the literature as to the most frequent abnormality in the ear in patients with Pendred syndrome. Cochlear defect described as "Mondini malformation" was cited as an almost constant finding in a radiologic study performed with conventional tomography (6). The precise anatomic disarrangement is not clarified in that text, but according to the technology used (conventional tomography), we suppose that the authors referred to the absence of the interscalar septum. More recent radiologic studies performed with CT and magnetic resonance imaging yielded cochlear abnormalities consisting of the absence of the upper turn (which results from the absence of the interscalar septum) to be present in only 20% of the patients with Pendred syndrome studied (13).
We looked at the cochlea for two distinct anomalies: absence of the upper turn of the cochlea and deficiency of the modiolus. Absence of the upper turn of the cochlea was found in 75% of the ears in our study. The distribution of this abnormality was variable among the patients, and it occurred bilaterally most of the time (eight of 10 patients). Two patients had the anomaly in only one ear, however. Modiolus deficiency was seen in 100% of the ears in this series. Malformed modiolus was described in the radiologic literature in association with vestibular aqueduct enlargement (15,16) and other inner ear abnormalities (18). The modiolus malformation was described in histologic studies of Pendred syndrome (19), but to our knowledge, there is no radiologic description of modiolus malformation in Pendred syndrome.
Recent studies directed the focus of the ear malformation in Pendred syndrome toward the vestibular aqueduct enlargement (5,20–22), and its presence was even suggested as the most likely presentation of Pendred syndrome and almost an obligatory finding for its diagnoses (5,22). We found that vestibular aqueduct enlargement was a frequent but not constant finding in our population, being present in 80% of ears. This abnormality was inconsistent among some patients, being absent unilaterally in two patients, and in one patient, the vestibular aqueduct was normal on both sides. The presence of modiolus deficiency in all the ears in our study, even in patients with normal-sized vestibular aqueducts, suggests that the modiolus defect may be even more tightly associated with hearing loss than vestibular aqueduct enlargement.
We were not aware of any radiologic description of vestibular enlargement at CT in Pendred syndrome. Surprisingly, this was found in all patients in our study, despite the absence of clinical vestibular disease. Since vestibular tests were not done in our study, the presence of subtle defects in vestibular function cannot be excluded. Vertigo and vestibular test disturbances were described previously in some patients with Pendred syndrome (3,5,6). In a mouse model of Pendred syndrome, vestibular disease appeared to be a common feature, and microscopic vestibular malformation was identified, although the vestibule was not cited as enlarged (23). Our study differs from previous studies in that we found modiolus deficiency and vestibular enlargement to be present bilaterally in all patients with Pendred syndrome. Large vestibular aqueduct and absence of the upper turn of the cochlea were found frequently but were not a constant finding in our patient population and may be present as a unilateral abnormality. This difference with published series may partially result from methodologic issues, since imaging techniques used in previous studies varied and since thin-section CT is a relatively recent modality. A bias may be introduced in our study, as the readers were aware that the population studied consisted of patients diagnosed with Pendred syndrome.
Phenotype variability associated with different PDS mutations may also explain some of the discrepancies in the literature. More than 40 PDS mutations have been identified in patients with complete Pendred syndrome, in some patients with nonsyndromic congenital deafness (DFNB4, MIM 600791), and in most patients with enlarged vestibular aqueduct syndrome (MIM 603545) (24). Furthermore, the presence of a mixture of mutations in different genes associated with hearing loss in the same patient and in families is known to occur, creating tremendous difficulty in defining the phenotype associated with a single mutation.
To our knowledge, this is the first study in which phenotypic variability was looked at carefully in a cohort of patients with Pendred syndrome who were all homozygous for the same mutation. In a single genetic isolate such as this, which is known to have Pendred syndrome and a tradition of consanguineous marriages, we anticipate that all affected individuals are also genetically quite homogeneous at loci other than that of the Pendred gene. Interestingly, despite this genetic homogeneity and the presence of profound hearing loss in all ears, the radiologic findings were not identical in all patients, and some patients had important radiologic differences between their own ears.
Recent experimental studies suggest that a failure in the pendrin normal-anion-transporting function causes an endolymphatic disturbance in ionic homeostasis that leads subsequently to anatomic malformations and thus to deafness and vertigo (23,25). In a mouse model, the inner ear was shown to develop normally with deterioration later, supporting the hypothesis that the ultimate pathologic lesion is secondary to environmental conditions, which are secondary to pendrin deficiency (23). A temporal window between the normal development of the inner ear and its later destruction secondary to pendrin deficiency may explain the variability in onset of deafness in Pendred syndrome, which, although usually prelingual, may also present postlingually.
External environment factors, such as trauma, infection, or hydrops, may be the trigger or contribute to the deafness. Thus, the destruction of the inner ear may progress after birth, and a temporal window for treatment may exist. As the youngest patient in our study was 7 years old and as the entire population studied had prelingual deafness, we cannot support or refute this theory. However, close evaluation of newborns homogeneous for PDS mutations in this population may provide important data on the progressive development of inner ear dysfunction in this cohort.
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FOOTNOTES
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Authors stated no financial relationship to disclose.
Author contributions: Guarantors of integrity of entire study, M.G., B.G.; study concepts, M.G., B.G., E.N., E.H., N.B.; study design, M.G., B.G., E.N., E.H.; literature research, M.G., B.G., E.N.; clinical studies, E.N., N.B.; data acquisition, M.G., B.G.; data analysis/interpretation, M.G., J.M.G.; statistical analysis, M.G.; manuscript preparation, definition of intellectual content, editing, and revision/review, M.G., B.G.; manuscript final version approval, M.G., B.G., J.M.G.
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ABSTRACT
INTRODUCTION
