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The Journal of Clinical Endocrinology & Metabolism Vol. 89, No. 11 5347-5351
Copyright © 2004 by The Endocrine Society

Intrafamilial Variability of the Deafness and Goiter Phenotype in Pendred Syndrome Caused by a T416P Mutation in the SLC26A4 Gene

Ulrike Napiontek, Guntram Borck, Wiebke Müller-Forell, Nicole Pfarr, Andrea Bohnert, Annerose Keilmann and Joachim Pohlenz

Departments of Communication Disorders (U.N., A.B., A.K.), Neuroradiology (W.M.-F.), and Pediatrics (N.P., J.P.), Hospitals of the Johannes Gutenberg University, Mainz, Germany; and Institut National de la Santé et de la Recherche Médicale U393 (G.B.), Hôpital Necker-Enfants Malades, Paris, France

Address all correspondence and requests for reprints to: Joachim Pohlenz, M.D., Department of Pediatrics, Johannes Gutenberg University of Mainz, Langenbeckstrasse 1, Building 109, D-55101 Mainz, Germany. E-mail: pohlenz{at}kinder.klinik.uni-mainz.de.


   Abstract
Top
 Abstract
Introduction
 Patients and Methods
 Results
 Discussion
 References
 
Pendred syndrome (PS) is the most common cause of syndromic deafness, accounting for more than 5% of all autosomal-recessive hearing loss cases. It is characterized by bilateral sensorineural hearing loss and by goiter with or without hypothyroidism. Mutations in the SLC26A4 gene cause both classical PS and deafness associated with an enlarged vestibular aqueduct without goiter.

To investigate a possible genotype-phenotype correlation in PS, we performed a detailed clinical and genetic study in three adult German sibs with typical PS caused by a common homozygous SLC26A4 mutation, T416P. An audiological long-term follow-up of 23 yr showed that the mutation T416P is associated with a distinct type of hearing loss in each of the three sibs: moderate-to-profound progressive deafness, profound nonprogressive deafness, and a milder but more rapidly progressing form. We show that these phenotypic differences are not caused by either different degrees of inner ear malformations or sequence variations in the GJB2/connexin 26 gene.

Because the thyroid phenotype was also highly variable within the family, with thyroid sizes ranging from normal to large goiters requiring thyroidectomy, this study leads to the conclusion that other environmental and/or genetic factors have an impact on the PS phenotype.


   Introduction
Top
 Abstract
 Introduction
Patients and Methods
 Results
 Discussion
 References
 
PENDRED SYNDROME (PS) is an autosomal-recessive condition characterized by bilateral severe to profound sensorineural hearing loss and enlargement of the thyroid gland (1, 2). Hearing loss is associated with malformations of the inner ear such as an enlarged vestibular aqueduct (EVA) or, less frequently, a Mondini dysplasia in which the upper turns of the cochlea are hypoplastic and form a common cavity (3). Thyroid disease in PS is highly variable. Goiter is present in 80% of the patients with PS and can be associated with primary hypothyroidism. It develops usually in late childhood to early adulthood (4). Because untreated hypothyroidism causes growth and mental retardation, early detection and treatment of hypothyroidism in PS is mandatory (5). Besides the clinical signs of sensorineural hearing loss (SNHL) and goiter, PS is characterized by an iodide organification defect that can be diagnosed by a positive perchlorate discharge test.

The gene mutated in PS, SLC26A4 (also known as PDS), is located on chromosome 7 (7q22.3-q31.1). It encodes pendrin, a 780-amino-acid protein (6). A large number of SLC26A4 mutations causing PS have been reported (see the PS homepage at www.medicine.uiowa.edu/pendredandbor). The PS gene is mainly expressed in the thyroid gland (6, 7), in the kidney (8), and in the inner ear (9). Pendrin is a member of an anion transporter family (10) and has been shown to transport chloride and iodide in vitro (11). In the thyroid, pendrin is localized in the apical membrane of the thyrocyte (12) where it presumably regulates the iodide efflux from the cell (13, 14). In contrast, its function in the inner ear is less well understood. Studies by Royaux et al. (15) suggest that it is important for the composition and resorption of the endolymph and for maintaining of the endocochlear potential.

Mutations in SLC26A4 cause not only classical PS but also an autosomal-recessive form of nonsyndromic deafness, DFNB4 (16), and hearing loss associated with EVA without thyroid pathology (17, 18). Altogether, SLC26A4 mutations might be responsible for more than 5% of all cases of autosomal-recessive deafness (19).

Although more than 80 SLC26A4 mutations have been reported, the reasons for the large phenotypic variability in PS, DFNB4, and recessive deafness with EVA remain unknown. We here report a study on the intrafamilial phenotypic variability in three German sibs with PS caused by a common homozygous SLC26A4 mutation.


   Patients and Methods
Top
 Abstract
 Introduction
 Patients and Methods
Results
 Discussion
 References
 
Patients

The three patients were recruited from the Department of Communication Disorders at Mainz University Hospitals, Germany. All individuals and their parents gave written informed consent for participation in this study, which was approved by the respective Institutional Review Boards.

Audiological examinations

The following audiological methods were used during follow-up: behavioral observation audiometry, visual reinforcement audiometry, free-field play audiometry, and air and bone conduction pure tone audiometry. These methods were applied according to the age and the mental development of the patients. Furthermore, speech audiometry with age-adapted speech material was performed. Testing was done with and without hearing aids.

We determined hearing thresholds by electrophysiological measurements such as auditory brain stem response or electro-cochleography. The interval between audiological follow-up examinations ranged from a few days to 3 yr depending on the progression of hearing impairment and well-being of the patients. The total number of audiograms available for this study was more than 30 in each patient.

The degree of hearing loss was defined as follows: mild, 30–55 dB; moderate, 56–70 dB; severe, 71–90 dB; and profound, more than 90 dB.

Molecular genetic analyses

DNA was extracted from peripheral blood leukocytes following a standard protocol (QIAGEN, Hilden, Germany). For mutation detection, all 21 exons of the SLC26A4 gene were amplified from genomic DNA by PCR as described previously (20) using primer pairs published elsewhere (6, 21). PCR was followed by direct sequencing of PCR products in both directions on an automated sequencing system (ABI 377; Applied Biosystems, Weiterstadt, Germany). The mutation 1246A->C (T416P) is located in exon 10, which was amplified using the PCR primer pair 10F-5'-ATACTCAGCGAAGGTCTTGCA-3' and 10R-5'-GCCATTCCTCGACTTGTTCTCTG-3'. Numbering of the nucleotides is based on the SLC26A4 cDNA sequence with the A of the translation initiation codon ATG being nucleotide +1.

The mutation 1246A->C creates a new site for the restriction endonuclease BanII. Digestion with BanII was performed as recommended by the manufacturer (New England Biolabs, Frankfurt am Main, Germany).

We analyzed the GJB2 gene in the three affected sibs by direct sequencing. The single coding exon (exon 2) was PCR amplified in two overlapping fragments and sequenced on an ABI 3100 sequencer. Primer pairs and PCR conditions are available on request.

Neuroradiological examinations

A high-resolution computed tomography (HR-CT) scan of the temporal bones with a slice thickness of 1.5 mm was performed in patient 1. High-resolution axial T2-weighted magnetic resonance imaging (MRI) scans of the temporal bones were obtained from all three affected sibs and reviewed by the same neuroradiologist. For three-dimensional reconstruction, highly T2-weighted images in constructive-interference-in-steady-state sequence were analyzed by multi-intensity projection to give a spatial resolution of 0.8 x 0.8 x 0.8 mm (22, 23).

An EVA was defined as a vestibular aqueduct larger than 1.5 mm at a point midway between the endolymphatic sac and the vestibule. To be classified as Mondini dysplasia, the cochlea also had to be abnormal, with incomplete partition and a scala communis.

Case reports

Patients 1 (female), 2 (male), and 3 (female) were born to nonconsanguineous parents who originate from the same small town in Germany. The parents have normal hearing, no signs of hypothyroidism, and no goiter. Hearing loss was diagnosed at ages 2 yr 6 months, 1 yr 7 months, and 2 yr 4 months in patients 1, 2, and 3, respectively. It was bilateral and sensorineural in all three individuals, prelingual in patients 1 and 2, and postlingual in patient 3. The initial hearing impairment degree ranged from mild in patient 3 to severe-profound in patients 1 and 2 so that hearing aids were fitted. None of the three patients reported symptoms suggestive of vestibular dysfunction.

Besides hearing loss, all three sibs had primary hypothyroidism with high serum TSH and low T4 concentrations, which was diagnosed at ages 12 months (patient 1) and 3 months (patient 2) and at birth (patient 3). A routine TSH newborn screening was not available at that time in Germany. All three patients were treated with thyroid hormone immediately after diagnosis, and doses were adjusted for age in the follow-up. Thyroid function tests were normal under T4 replacement therapy. However, patients 1 and 2 required thyroidectomy because a progressive goiter developed, whereas patient 3 had a thyroid gland with a volume in the normal range (15 ml at age 23 yr; normal = 10–25 ml). In patient 1, thyroidectomy was performed at the age of 22 yr and in patient 2 at 17 yr of age after rapid progression of his goiter; within 11 months, his thyroid volume doubled from 29 to 58 ml. At the time of their respective thyroidectomies, both patients 1 and 2 were euthyroid under thyroid hormone substitution. Perchlorate discharge tests were not performed.

Intelligence varied from normal in patient 3 to borderline in patient 2 (IQ was 79 at age 7 yr) to mildly mentally retarded in patient 1 (IQ was 66 and 62 at 9 and 14 yr, respectively). At their last visit to our hospital, patients 1, 2, and 3 were aged 35, 28, and 26 yr, respectively.


   Results
Top
 Abstract
 Introduction
 Patients and Methods
 Results
Discussion
 References
 
Molecular genetic diagnosis of PS and GJB2 sequence analysis

Sequencing of all 21 SLC26A4 exons from genomic DNA detected the same mutation in the three affected sibs: a homozygous A->C mutation at position 1246 of the cDNA sequence (1246A->C; Fig. 1Go). This missense mutation is located in exon 10 of the gene and predicts an amino acid change from threonine to proline at position 416 of the pendrin protein (T416P).



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  		FIG. 1. Detection of the 1246A->C (T416P) mutation. Chromatograms showing a part of the SLC26A4 exon 10 sequence. All affected individuals (patients 1, 2, and 3) are homozygous for the A->C mutation (bottom, arrow), whereas their unaffected parents are heterozygous (nucleotides A and C, middle). The amino acid change from threonine to proline is indicated in red letters above the nucleotide sequence. A wild-type sequence is shown on the top.

 
The mutation 1246A->C creates a new restriction site for BanII. Using this restriction enzyme assay, we confirmed homozygosity for the mutation in the three affected sibs and showed that their parents are heterozygous carriers of the mutation (Fig. 2Go).



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  		FIG. 2. Confirmation of the mutation by BanII digestion. Pedigree of the family and restriction enzyme analysis. Males are represented by squares, females by circles. Half-filled black and white symbols represent clinically unaffected individuals, whereas affected individuals are shown in black. In the wild type, the PCR product of exon 10 (232 bp) remains uncut when digested with BanII (WT digested). When the mutation is present, digestion of the PCR product with BanII produces fragments of 157 and 75 bp in homozygous individuals. The heterozygous parents have three bands (232, 157, and 75 bp). MW, Molecular weight.

 
Direct sequencing of the GJB2/connexin 26 gene in all three sibs did not reveal any mutation.

Audiological long-term follow-up

Audiological follow-up was between 23 and 25 yr in the three patients with PS.

In patient 1, hearing impairment was moderate (in low frequencies) to profound in the first years and more severe in high frequencies. The diagnosis was confirmed by auditory brain stem response. Hearing impairment significantly worsened between 16 and 24 yr with a mean progression of 20–30 dB over all frequencies (representative audiograms are shown in Fig. 3Go A). When last examined at the age of 34 yr, she had profound bilateral SNHL.



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  		FIG. 3. Audiological long-term follow-up in three sibs with PS. Selection of representative audiograms showing the evolution of hearing loss in patients 1–3. Audiograms made at different ages are superposed (y, years). The left ear is represented on the right and vice versa. In patients 1 (A) and 2 (B), the first shown audiogram (red) was a free-field behavioral observation audiometry (results are shown on the right ear side and represent the less affected ear); the following ones are air conduction pure-tone audiometries. For patient 3 (C), all audiograms are air conduction pure-tone audiometries.

 
On the contrary, the hearing impairment was overall nonprogressive in patient 2 despite some fluctuation, especially during childhood and adolescence. Like in his older sister, his hearing loss was more severe in high frequencies (Fig. 3BGo). At his first presentation to our hospital at the age of 19 months, hearing loss ranged from moderate in low frequencies to profound in high frequencies. An electro-cochleography performed 3 months later detected potentials at 100 dB on the right and 90 dB on the left side, confirming the diagnosis of profound bilateral SNHL. During the following years and until his last visit at age 28 yr, his audiogram remained almost unchanged (Fig. 3BGo).

Finally, patient 3 had the mildest hearing impairment of the three children at diagnosis. At 2 yr 4 months her hearing loss was of mild degree. However, there was a bilateral progression of 50–60 dB over 23 yr (Fig. 3CGo). After an electro-cochleography detected potentials at 100 dB on the right and 110 dB on the left side (at 25 yr of age), the implantation of a cochlear implant was proposed but finally rejected by the patient.

Neuroradiological examination

Malformations of the inner ear are a frequent finding in PS (3). However, the relationship between the presence of an EVA or a Mondini malformation and the severity of deafness remains largely unknown. We therefore compared the HR-CT and MRI scans of the temporal bones in the three PS patients. Representative scans including three-dimensional reconstructions are shown in Fig. 4Go. All three sibs had an EVA that was more pronounced on the left side in patients 1 (Fig. 4Go, A–C) and 3 and symmetrical in patient 2 (Fig. 4DGo). Patient 3 also had a dysplastic cochlea containing only two turns, consistent with a mild form of Mondini malformation. No Mondini dysplasia was seen in patients 1 and 2.



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  		FIG. 4. Neuroradiological examinations showing EVAs. A and B, HR-CT of the right (A) and left (B) temporal bone, showing the widening of the vestibular aqueduct (arrow) in patient 1. C, MRI scan demonstrating the ampullar enlargement of the vestibular aqueduct into the cerebello-pontine cistern of both sides with emphasis on the left (arrows) in patient 1. D, MRI scan of the temporal bone with bilateral widening of the vestibular aqueduct (arrows) and additional ampullary cyst in the cerebello-pontine cistern (star) in patient 2.

 

   Discussion
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
References
 
A large number of mutations in the SLC26A4 gene have been found in homozygous or compound heterozygous state in PS as well as in autosomal-recessive deafness associated with EVA. However, the intra- and interfamilial variability associated even with the same SLC26A4 mutation remains poorly understood (24). Indeed, a given mutation can lead to classical PS in one family and to SNHL without goiter in another and may also be associated with intrafamilial phenotypic variability.

The aim of this study was to compare the audiological and goiter phenotype of three PS cases from the same German family. We detected a homozygous mutation, T416P, in all three affected sibs, which gave us the unique opportunity to investigate differences in the phenotype of these individuals having a similar genetic background. T416P is known to cause PS and has been found in many PS cases of European origin. Together with another missense mutation (L236P) T416P is the most frequently reported mutation in the SLC26A4 gene (18, 21, 25, 26, 27, 28). It affects an extracellular threonine residue located in the loop between the ninth and the tenth transmembrane domain of pendrin. T416P leads to an almost complete loss of iodide transport capacity of the mutant protein (28). In mammalian cells, the mutant pendrin is retained in the endoplasmic reticulum, preventing its proper localization at the plasma membrane (29).

T416P has been reported both in patients with PS and in those affected by hearing loss with EVA. The three sibs we report here have typical PS on the basis of bilateral early-onset SNHL with EVA, hypothyroidism, and goiter. However, the severity of both the goiter and the deafness phenotype widely varied between affected individuals in the family. Whereas patients 1 and 2 had to undergo thyroidectomy because of rapidly growing goiters, patient 3 has a thyroid gland of normal size. Such intrafamilial variability with regard to the goiter phenotype has been observed in some PS families before, but its causes remain unknown. Iodine intake might be one factor influencing the development of goiter in PS. However, because all affected individuals live in the same environmental background and because thyroid function tests were normal when investigated, it is tempting to speculate that other genetic factors have an impact on the phenotypic variability in PS. Larger studies are needed to determine whether early thyroid hormone treatment has a beneficial effect on the development of goiter in PS as the clinical course of patient 3 suggests.

Similarly, there was a surprising variability of hearing impairment in the reported family. Whereas all three patients presented with the typical bilateral SNHL, which was more severe in high frequencies, both severity and progression of deafness were variable. Despite the presence of the same mutation, three distinct deafness types were observed. Whereas patient 1 had a progressive course of disease resulting in bilateral profound SNHL, patient 2 was affected by an early-onset profound deafness without major progression. Finally, patient 3 initially had the less severe deafness phenotype, which, however, progressed more rapidly. The reasons for this intrafamilial variability are not known. All three sibs had a comparable degree of EVA, excluding the hypothesis that the severity of the inner ear malformation could be a major determinant of the observed variability (30). Also, the only patient who had a mild form of Mondini dysplasia (patient 3) was the one with the best initial hearing, showing that there is no clear genotype-phenotype correlation for the T416P mutation. However, additional studies are needed to better characterize the phenotypes associated with this and other SLC26A4 mutations (31).

There have been reports on hearing-impaired subjects with mutations in both the SLC26A4 and the GJB2 genes (28). This is not surprising considering that these genes are the two most commonly mutated genes in congenital deafness (32). Direct sequencing of the GJB2 gene in the affected members of our family did not detect any mutation, excluding an additional defect in connexin 26 as a cause for the different degrees of hearing impairment.

Phenotypic variability in PS has been documented before. However, these reports, which do not provide a follow-up, have either been published before the cloning of the SLC26A4 gene (33) or deal with mutations rarely found in European populations (34). We present a detailed clinical long-term follow-up demonstrating a marked intrafamilial variability in PS caused by one of the most common mutations in the SLC26A4 gene. These results confirm the importance of neuroradiological and molecular genetic investigations for the diagnosis of PS (35). So far, one cannot exclude that the causes of intrafamilial variability may be different for the thyroid disease and hearing impairment. Additional investigations, including studies of animal models of PS and recessive deafness with EVA (36, 37), will help to better understand the role of pendrin with regard to hearing and to thyroid hormone synthesis.


   Acknowledgments
 
We thank Samuel Refetoff (University of Chicago) for critical discussion and review of the manuscript and Laurence Colleaux (Hôpital Necker, Paris) for support.


   Footnotes
 
This work was supported in part by the University of Mainz - Mainzer Forschungsförderung (MAIFOR) (to J.P.). G.B. was supported by an INSERM fellowship.

U.N. and G.B. contributed equally to this work.

Abbreviations: EVA, Enlarged vestibular aqueduct; HR-CT, high-resolution computed tomography; MRI, magnetic resonance imaging; PS, Pendred syndrome; SNHL, sensorineural hearing loss.

Received May 27, 2004.

Accepted July 26, 2004.


   References
Top
 Abstract
 Introduction
 Patients and Methods
 Results
 Discussion
 References
 

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