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Journal of Clinical Endocrinology & Metabolism , doi:10.1210/jc.2006-0142
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The Journal of Clinical Endocrinology & Metabolism Vol. 91, No. 7 2678-2681
Copyright © 2006 by The Endocrine Society

BRIEF REPORT

Goitrous Congenital Hypothyroidism and Hearing Impairment Associated with Mutations in the TPO and SLC26A4/PDS Genes

Nicole Pfarr1, Guntram Borck1, Andrew Turk, Ulrike Napiontek, Annerose Keilmann, Wibke Müller-Forell, Peter Kopp and Joachim Pohlenz

Children’s Hospital (N.P., J.P.), Departments of Ear, Nose, and Throat and Communication Disorders (U.N., A.K.), and Institute of Neuroradiology (W.M.-F.), Hospitals of the Johannes Gutenberg University, D-55101 Mainz, Germany; Institut National de la Santé et de la Recherche Médicale U781 (G.B.), Hôpital Necker-Enfants Malades, F-75015 Paris, France; and Division of Endocrinology, Metabolism, and Molecular Medicine (A.T., P.K.), Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611

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


   Abstract
Top
 Abstract
Introduction
 Patient and Methods
 Results
 Discussion
 References
 
Context: Pendred syndrome (PS) and thyroid peroxidase (TPO) deficiency are autosomal-recessive disorders that result in thyroid dyshormonogenesis. They share congenital hypothyroidism, goiter, and an iodide organification defect as common features. Whereas the hallmark of PS is sensorineural deafness, other forms of congenital hypothyroidism may also lead to hearing impairment. Therefore, a definite diagnosis may be difficult and require molecular genetic analyses.

Case Report: The propositus presented at birth with primary hypothyroidism and goiter. He also had congenital bilateral moderate hearing loss, and PS was suspected.

Methods: We sequenced the SLC26A4/PDS and TPO genes in the propositus and tested familial segregation of mutations in all available family members who were phenotypically normal. The functional consequences of the identified pendrin mutation (p.R776C) were studied in vitro.

Results: Sequencing of the SLC26A4/PDS gene revealed a single monoallelic missense mutation in the propositus (p.R776C). This mutation, which was inherited from his unaffected mother, has previously been identified in an individual with deafness and an enlarged vestibular aqueduct. Sequencing of the TPO gene revealed compound heterozygosity for a novel nonsense mutation (p.Q235X) and a known missense mutation (p.Y453D). The mutant pendrin (p.R776C) retained its ability to transport iodide in vitro.

Conclusions: These results show that the propositus carries three sequence variants in two genes: a monoallelic SLC26A4/PDS sequence variant and compound heterozygous TPO mutations. Our study illustrates that if only a single heterozygous SLC26A4/PDS mutation is found in a patient with goiter and deafness, other genetic explanations should be considered.


   Introduction
Top
 Abstract
 Introduction
Patient and Methods
 Results
 Discussion
 References
 
MOST CASES OF congenital hypothyroidism are associated with thyroid dysgenesis (~80%). More rarely (~10–15%), congenital hypothyroidism is caused by dyshormonogenesis, inborn defects in one of the steps required for thyroid hormone synthesis. Mutations in a number of genes encoding enzymes and transporters expressed in the thyroid gland can cause dyshormonogenesis (1). Among them, biallelic mutations in the thyroid peroxidase (TPO) gene are a common cause of defective thyroid hormone synthesis (2). TPO is a 933-amino acid membrane glycoprotein involved in catalyzing iodide oxidation, iodination of tyrosine residues, and coupling of mono- and diiodotyrosyl to generate T3 and T4 (3). The association of goiter, positive perchlorate test indicating impaired iodide organification, and sensorineural hearing loss is referred to as Pendred syndrome (PS) (4, 5). It is caused by biallelic mutations in the SLC26A4/PDS gene, which encodes a 780-amino acid anion transporter called pendrin (6). The diagnosis of PS without ancillary tests (perchlorate test, magnetic resonance imaging of the inner ear) may not be reliable because of the possibility of phenocopies in which deafness and goiter are caused by environmental or distinct genetic factors (7). Moreover, mutations in the SLC26A4/PDS gene are found in not only patients with PS but also individuals afflicted with nonsyndromic hearing loss with enlarged vestibular aqueduct (EVA) (8, 9). Because both TPO defects and PS may present with goiter, hypothyroidism, and a positive perchlorate test (10), a definite etiologic diagnosis is impossible without molecular diagnosis in individuals who have a concomitant hearing impairment.

Here we report a boy who was clinically diagnosed to have PS. However, sequencing of the SLC26A4/PDS gene detected only a monoallelic mutation. Subsequent analysis of the TPO gene revealed that he is compound heterozygous for mutations in this gene.


   Patient and Methods
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 Abstract
 Introduction
 Patient and Methods
Results
 Discussion
 References
 
Case report

The propositus is the third child of healthy unrelated parents of German origin. His parents and two sisters have no signs of hypothyroidism, no goiter, and no hearing loss. The boy was born with a birth weight of 4250 g and a length of 54 cm (both 90–97th percentile). Physical examination was normal. Newborn screening at 5 d of age revealed an elevated TSH. Two days later, his serum TSH was 362 µU/ml (normal 0–8), free T3 1.0 pg/ml (normal 2.2–5.4), and free T4 0.17 ng/dl (normal 1.5–2.6). T4 replacement therapy (50 µg/d) was initiated immediately, and 4 wk later his thyroid function tests were normal. Thyroid antibodies were negative. Ultrasound revealed an enlarged thyroid gland, and serum thyroglobulin was elevated (72 ng/ml; normal < 55).

A detailed audiological examination, performed at 1 month of age because no otoacoustic emissions had been detected, showed thresholds at 55 dB (right ear) and 50 dB (left) on auditory brain stem response analysis, consistent with bilateral moderate hearing loss. Auditory brain stem response thresholds improved to 30 dB (right) and 40 dB (left) at 13 months. These results were confirmed by audiometry, showing that his subjective hearing reactions were normal. His mental and motor development was normal. Currently the 2-yr-old boy is euthyroid with a daily dose of 62.5 µg L-thyroxine.

His mother was examined at the age of 34 yr. She had no goiter and was euthyroid. Pure-tone audiometry and magnetic resonance imaging of the temporal bones showed no abnormality.

Sequence analysis of the SLC26A4/PDS and TPO genes

After written informed consent was obtained, DNA of all family members was extracted from blood leukocytes (QIAGEN, Hilden, Germany).

Mutational analysis of all 21 SLC26A4/PDS exons and all 17 TPO exons was performed as described previously (11, 12). PCR was followed by bidirectional sequencing on an automated sequencer (ABI 377, Applied Biosystems, Darmstadt, Germany). We analyzed six markers located in the SLC26A4/PDS gene: the microsatellite D7S2459 and five single-nucleotide polymorphisms (rs3817613, rs2395911, rs3801940, rs1858929, and rs982915).

RNA was prepared from lymphocytes and isolated using the QIAamp RNA blood mini kit (QIAGEN). Primers for RT-PCR were 14-RT-F 5'-CTTGGAATGGCCTTGGAAGCAT-3' and 21-RT-R 5'-CTGGACGCTGCCAAATCGTCTG-3'.

Construction of plasmids and iodide transport assay

The human wild-type SLC26A4/PDS cDNA was generated by RT-PCR using total RNA from normal human thyroid tissue. The cDNA was then subcloned into the XhoI and BamHI sites of pCMX. Construction of the SLC26A4/PDS mutant, c.2326C > T (p.R776C), was performed using the Quikchange kit (Stratagene, La Jolla, CA) (primers: sense, 5'-GATGAGGCTATGTGTACACTTGC-3', antisense, 5'-GCAAGTGTACACATAGCCTCATC-3'). The accuracy of the construct was confirmed by sequencing. Pendrin-mediated iodide efflux was determined as reported previously (13, 14).


   Results
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 Abstract
 Introduction
 Patient and Methods
 Results
Discussion
 References
 
Detection of a heterozygous SLC26A4/PDS mutation

Sequencing of all SLC26A4/PDS-coding exons revealed a single heterozygous mutation in exon 21 in the propositus: c.2326C > T (Fig. 1AGo). This mutation leads to the replacement of the arginine at position 776 with a cysteine (p.R776C). The mutation was inherited from his mother. The patient’s unaffected sisters were also heterozygous for R776C (Fig. 1BGo). We did not find R776C in 100 control chromosomes, confirming an earlier report suggesting that it is not a common polymorphism (15).


Figure 1
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  		FIG. 1. A, SLC26A4/PDS and TPO mutations identified in the propositus. Sequence electropherograms showing the monoallelic c.2326C > T mutation (top) and compound heterozygous TPO mutations (middle and bottom): c.703C > T and c.1357T > G. B, Pedigree and inheritance of SLC26A4/PDS and TPO mutations. The figure shows the pedigree of the family. Squares represent males and circles females. The propositus is individual II3. The respective SLC26A4/PDS genotype is shown in the upper half of the individuals’ symbols; the TPO genotype in the lower half. Note that individual II3 has inherited one TPO mutation from his father and one mutation each in the TPO and SLC26A4/PDS gene from his mother. See text for details on the mutations. WT, Wild type.

 
Sequencing of the untranslated SLC26A4/PDS exon 1 as well as genotyping of six intragenic markers in the affected child and his parents did not disclose any mutation or major deletion at the SLC26A4 locus. Furthermore, sequencing of exon 21 from lymphoblast-derived cDNA identified the R776C mutation in heterozygous state in the patient, confirming that a deletion of the paternal allele is unlikely.

Detection of two TPO mutations

We next analyzed the TPO gene, which is frequently mutated in goitrous hypothyroidism. Sequencing of exon 7 detected a novel c.703C > T mutation leading to the replacement of the glutamine at position 235 with a stop codon (p.Q235X; Fig. 1AGo). This nonsense mutation was inherited from the father (Fig. 1BGo). The second mutation (c.1357T > G; Fig. 1AGo) in exon 9 substituting a tyrosine with an aspartic acid (p.Y453D) and inherited from the mother (Fig. 1BGo) has been reported previously (16). Q235X was not detected in 100 control chromosomes.

Expression and functional studies of the R776C mutation

Transiently transfected TSA cells expressing NIS alone showed a significant increase in the uptake of iodide, compared with cells transfected with an empty vector (Fig. 2Go). In cells cotransfected with wild-type SLC26A4/PDS and NIS, intracellular iodide accumulation was significantly reduced. Cotransfection of the SLC26A4/PDS R776C mutant with NIS decreased the intracellular iodide accumulation to the same extent as wild-type pendrin, indicating that the ability to mediate iodide efflux is not impaired. To ascertain whether the R776C mutant impairs the function of the wild-type and to mimic the heterozygous situation found in the propositus, wild-type pendrin and R776C were cotransfected together with NIS. There was no suggestion that this mutant impairs the function of the wild type in a dominant-negative manner (Fig. 2Go).


Figure 2
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  		FIG. 2. SLC26A4/PDS-mediated iodide efflux. In cells expressing wild-type SLC26A4/PDS and NIS, intracellular iodide accumulation is significantly reduced, compared with cells expressing only NIS. The R776C mutant decreases the intracellular iodide accumulation to the same extent as wild-type pendrin, indicating that the ability to mediate iodide efflux is not impaired. This is also the case in cells expressing R776C and wild-type pendrin, indicating that the mutant does not interfere with the function of the normal allele. Values are means ± SEM.

 

   Discussion
Top
 Abstract
 Introduction
 Patient and Methods
 Results
 Discussion
References
 
We report a boy presenting with congenital hypothyroidism, goiter, and bilateral hearing loss in whom we detected three mutations in two genes: a monoallelic mutation in the SLC26A4/PDS gene and two distinct TPO mutations. This observation highlights some of the difficulties in making a definite diagnosis in patients with goitrous congenital hypothyroidism and illustrates some of the challenges that may be associated with molecular genetic testing. Initially we entertained a tentative clinical diagnosis of PS, which is characterized by goiter, sensorineural hearing loss, and a positive perchlorate test (5). Moreover, imaging studies reveal that the vast majority of individuals affected by PS have an enlargement of the endolymphatic system (17). Because a magnetic resonance image of the cochlea and a perchlorate test are difficult to perform in infants, we decided to postpone these studies in our patient. Deafness in PS is usually severe to profound, but the propositus presented with only moderate hearing loss. Despite this, the diagnosis of PS was considered because hearing loss can be fluctuating and progressive in PS (18). Moreover, we have recently shown that the deafness phenotype associated with a common SLC26A4/PDS mutation is highly variable, even within a family (19). Taken together, the clinical findings of the propositus were suggestive for PS. We therefore sequenced the SLC26A4/PDS gene and detected a single monoallelic mutation, R776C. Interestingly, this mutation has recently been identified in one allele of two siblings affected with nonsyndromic EVA (15). In this study, the authors found that all patients with classical PS, or EVA with a positive perchlorate test, harbored biallelic SLC26A4/PDS gene mutations, whereas nonsyndromic EVA was associated with one or no mutant allele. In contrast, EVA patients with a normal perchlorate test had no or monoallelic mutations in the SLC26A4/PDS gene (15). Our data demonstrating the R776C mutation in the index patient, but also in the unaffected mother who had a normal hearing and anatomy of the inner ear, together with the functional studies, argue against a pathogenic role of this mutation and suggest that it is a rare, functionally silent variant.

Whereas the functional data presented here demonstrate that R776C retains the ability to mediate iodide efflux, they do not formally prove normal function as a chloride transporter. However, absent mother-to-child transmission of the phenotype argues against simple haploinsufficiency. Our in vitro studies rule out a dominant-negative mechanism of the mutant allele. This, along with the data obtained by Pryor et al. (15), suggests that EVA may be genetically heterogeneous or a polygenic/multifactorial disorder. Lastly, one should also consider that a subset of individuals with a monoallelic SLC26A4/PDS gene mutation might harbor a second unidentified mutation in a noncoding region of this gene. In our patient, analysis of genetic markers excluded at least a major deletion at the SLC26A4 locus.

Based on our functional studies, the goitrous hypothyroidism found in our patient cannot be explained by the SLC26A4/PDS gene mutation. Moreover, the clinical follow-up showed that the boy’s hearing improved, with thresholds close to normal at 13 months of age. This phenomenon, known as delayed maturation of the auditory pathways, is unusual for PS. Therefore, we hypothesized that hearing loss and goiter might be caused by distinct genetic mechanisms. Indeed, the analysis of the TPO gene revealed compound heterozygous mutations that explain the thyroid phenotype. The first one, Q235X, is novel and would lead to a severe truncation of the TPO protein, which is expected to be enzymatically inactive. The second mutation, Y453D, is located in the peroxidase domain and has been previously reported to cause goitrous hypothyroidism (16). Our study illustrates the value, challenges, and limitations of molecular genetic testing in selected patients with congenital hypothyroidism, goiter, and hearing impairment. The importance of screening all SLC26A4/PDS exons by sequencing in individuals with goiter and deafness is well accepted. If only a single heterozygous SLC26A4/PDS mutation is identified, several explanations should be considered. They include a second, unidentified mutation in regulatory or noncoding regions or another cause for the phenotype. The TPO gene is the primary candidate gene in this instance, and our observation indicates that it should be analyzed in patients presenting with goitrous hypothyroidism and hearing impairment with absent or monoallelic SLC26A4/PDS gene mutations.


   Footnotes
 
This work was supported in part by the University of Mainz-MAIFOR (to J.P. and N.P.). G.B. was supported by a Deutsche Forschungsgemeinschaft fellowship. P.K. was supported by 1R01DK63024-01 from the National Institutes of Health/National Institute of Diabetes and Digestive and Kidney Diseases.

Conflicts of interest: The authors declare that they have no competing financial interests.

First Published Online May 9, 2006

1 N.P. and G.B. contributed equally to this work. Back

Abbreviations: EVA, Enlarged vestibular aqueduct; PS, Pendred syndrome; TPO, thyroid peroxidase.

Received January 23, 2006.

Accepted April 28, 2006.


   References
Top
 Abstract
 Introduction
 Patient and Methods
 Results
 Discussion
 References
 

  1. Gillam MP, Kopp P 2001 Genetic defects in thyroid hormone synthesis. Curr Opin Pediatr 13:364–372[CrossRef][Medline]
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  7. Kopp P, Arseven OK, Sabacan L, Kotlar T, Dupuis J, Cavaliere H, Santos CL, Jameson JL, Medeiros-Neto G 1999 Phenocopies for deafness and goiter development in a large inbred Brazilian kindred with Pendred’s syndrome associated with a novel mutation in the PDS gene. J Clin Endocrinol Metab 84:336–341[Abstract/Free Full Text]
  8. Li XC, Everett LA, Lalwani AK, Desmukh D, Friedman TB, Green ED, Wilcox ER 1998 A mutation in PDS causes non-syndromic recessive deafness. Nat Genet 18:215–217[CrossRef][Medline]
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  13. Gillam MP, Sidhaye AR, Lee EJ, Rutishauser J, Stephan CW, Kopp P 2004 Functional characterization of pendrin in a polarized cell system. Evidence for pendrin-mediated apical iodide efflux. J Biol Chem 279:13004–13010[Abstract/Free Full Text]
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