Pendred syndrome is an autosomal recessive inherited disorder. Obligatory features are profound deafness in childhood and defective organic binding of iodine in the thyroid gland. Therefore, goiter is a common symptom. Hypoplasia of the cochlea is another feature. Recently, the gene for Pendred syndrome was identified.We describe a boy whose sensorineural hearing loss in both ears progressed rapidly from about 50 to 60 dB at the age of 3 years and 3 months to more than 100 dB at the age of 4 years and 4 months. This loss was preceded by a medical history of a progressive hearing loss. The progressive nature of the hearing loss motivated a search for the cause. Dysplasia of the cochlea and a widened vestibular aqueduct were found. The results of thyroid function tests were normal, but he had an elevated level of thyroglobulin. The diagnosis of Pendred syndrome was confirmed by the positive results of a potassium perchlorate test, indicating defective organic binding of iodine in the thyroid gland. It is possible that the widened vestibular aqueduct was responsible for the increase in the hearing impairment. Aside from the branchio-otorenal syndrome, Pendred syndrome is the only other known genetic disorder with a widened vestibular aqueduct. If a child has progressive sensorineural deafness and a widened vestibular aqueduct, it is important to consider a diagnosis of Pendred syndrome. A widened vestibular aqueduct may help to elucidate the pathophysiologic characteristics of hearing loss in these genetic types of deafness in childhood.Pendred,an English general physician, described in 1896 an Irish family with 10 children, 5 sons and 5 daughters. Two of the girls were congenitally deaf and developed large goiters at the age of 13 years. Almost 3 decades later, Braindescribed 4 additional multiaffected families. In 1958, Morgans and Trotterdemonstrated that the thyroid enlargement was caused by an impairment of thyroxine synthesis due to a defect in the incorporation of inorganic iodide into the thyroglobulin molecule where it is bound to tyrosine radicals, the so-called organification of iodine. The degree of intrathyroidal organification of iodine can be measured easily in vivo during iodine I 131 uptake studies. Administration of certain inorganic anions, such as potassium perchlorate or thiocyanate, results in discharge of the anorganic (nonorganificated) iodine pool, which can be measured as a decrease in I131uptake over the thyroid gland. In a normal thyroid gland, this washout effect accounts for less than 10% of the total thyroidal iodine pool because organification of iodine is rapid and little inorganic iodine is present. Intermediate levels of iodine discharge following potassium perchlorate exposure are now also considered to be an essential diagnostic criterion of Pendred syndrome.Brainand Deraemaekershowed the autosomal recessive pattern of inheritance. Fraser et alconfirmed this pattern in an extensive study of 207 families comprising 334 cases of Pendred syndrome. Atypical families have been described with pseudodominance, especially regarding enlargement of the thyroid gland.Mondini dysplasia, normal hearing thresholds, and positive results of a potassium perchlorate test were reported in 3 of 4 mothers of children with Pendred syndrome.The hearing loss is thought to be congenital and is certainly prelingual in most cases.Fraserstated that it is not known whether the deafness is truly congenital or rapidly progressive after birth; however, it is certain that by the age that reliable audiometry is possible, progression of the hearing loss is no longer detectable. In many cases, profound deafness in childhood is reported. There are occasional reportsof a milder hearing impairment. Until now, only 3 case reports have described some fluctuation or progression of the hearing loss.Hypoplasia of the cochlea in Pendred syndrome was proved by the results of histological study of the inner ear,conventional polytomographic studies, and early generation computed tomographic (CT) scanning of the temporal bones in patients with this syndrome.Dysplasia of the cochlea (Mondini dysplasia) is a frequent but nonobligatory feature in Pendred syndrome.Successful gene linkage studieshave recently been followed by the identification of the geneand mutation analysis.We report a case of Pendred syndrome showing progressive sensorineural deafness in childhood during the third year of life and dysplasia of the cochlea in combination with a widened vestibular aqueduct. There may be a causal relation between the widened vestibular aqueduct and the progressive hearing loss. Moreover, strong changes in cerebrospinal fluid pressure along the widened vestibular aqueduct may make the cochlea vulnerable to damage.REPORT OF A CASEA 4-year-old boy was referred to the pediatric audiological unit of the Otorhinolaryngology Department, Nijmegen University, Nijmegen, the Netherlands, because there was some doubt about his hearing. He was the third child of the family. There was no known consanguinity. The parents and the older brother and sister did not have any complaints of hearing impairment, and there was no history of early childhood deafness in their family. The pregnancy and delivery were uneventful. He was born at term with a birth weight of 3900 g and length of 57 cm. His motor development was normal. At the age of 9 months, the Ewing sign was normal. His mother said that there was more response in the Ewing sign the first time in comparison with the hearing tests administered in our setting at the age of 2½ years. He babbled during the first year of life and responded well to his mother's singing until his first birthday. In his second year, his baby talk gradually decreased. He had gained an understanding of some words. According to the parents, communication with this child was more difficult than it was with the 2 older children. At the age of 2½ years, hearing impairment was diagnosed and confirmed by the results of brainstem audiometry 3 months later. A hearing loss of 50 to 60 dB was found (Table 1). The middle ears were well aerated. Six months later, the results of audiometric testing confirmed the parents' suspicions that there was an additional increase in the hearing impairment after a relatively mild head trauma. This hearing loss was again confirmed by the results of brainstem audiometry at the age of 3 years and 4 months, which showed a 70-dB loss in the right ear and no response in the left ear.Audiometric Tests Showing Progressive and Fluctuating Hearing Levels*See table graphicThe results of CT scanning of the petrous bones revealed bilateral dysplasia of the cochlea and a widened vestibular aqueduct (Figure 1, Figure 2, and Figure 3). The parents would not grant permission for vestibular testing. Recently, pure-tone audiometry at the age of 4 years and 3 months demonstrated a 100-dB hearing impairment in both ears. Hearing in the right ear has shown the most improvement recently. The results of testing at the age of 3 years showed normal intelligence and also some autistic behavior.Figure 1.Computed tomographic scan of the left ear. The star indicates the normal size of the internal acoustic canal; the arrow, a widened vestibular aqueduct.Figure 2.Computed tomographic scan of the left ear. The black arrows indicate hypoplasia of the cochlea; the white arrow, a widened vestibular aqueduct.Figure 3.Computed tomographic scan of the right ear. The star indicates the normal size of the internal acoustic canal; the white arrow, a widened vestibular aqueduct.Owing to the rapid progression of the hearing impairment, the patient was examined thoroughly in search of the cause. The thyroglobulin concentration was elevated on 2 occasions with levels of 128 and 60 µg/L (normal value <50 µg/L) (194 and 91 pmol/L [normal value <75 pmol/L]). There were no dysmorphic features. The thyroid gland could not be palpated. At the age of 4 years, his height was 107.5 cm (90th percentile) and his weight was 17.1 kg. He was euthyroid. The results of laboratory tests showed the following values, which were all within the normal range: total thyroxine, 116 nmol/L (9.0 µg/dL); free thyroxine, 13.6 pmol/L (1.0 ng/dL); free thyroxine percentage, 0.0117%; total triiodothyronine, 2.8 nmol/L (181 ng/dL); and thyrotropin, 2.72 mIU/L. The results of thyroid scanning showed that the gland had a normal size and configuration. A discharge rate of 24% was found in the results of the potassium perchlorate test, confirming the clinical diagnosis of Pendred syndrome. We performed mutation analysis of the Pendred syndrome putative sulphate transporter (PDS) gene by exon-specific polymerase chain reaction amplification and DNA sequencing, as described before.This analysis enabled us to screen the entire PDSregion of the proband for mutations.We found 2 missense mutations: 1558T to G (1558T→G) and 1375A to G (1375A→G). The 1558T→G mutation changes a leucine at position 445 into a tryptophan (L445W). Interestingly, this mutation has also been found in another Dutch family with Pendred syndrome (P.H., written communication, February 1997). The 1375A→G mutation changes a glutamic acid residue at position 384 into a glycine (E384G) and has not been described before. However, since this mutation changes the second base of exon 10, it is also possible that the 1375A→G mutation causes aberrant splicing of the PDSmessenger RNA. The effect of the mutation on the PDSmessenger RNA has not been investigated. Everett et alidentified several conserved amino acid positions by aligning the pendrin protein with 5 other sulphate transporter proteins. Both mutations found in the proband alter a conserved amino acid.COMMENTIn this patient with rapidly progressive sensorineural hearing impairment, an early diagnosis of Pendred syndrome was established although he was completely euthyroid and did not have a goiter. The hearing loss proved to be very progressive, as documented by the results of objective audiometric tests. Molecular analysis of the coding region of the PDSgene of the proband revealed 2 disease-causing mutations, confirming the clinical diagnosis of Pendred syndrome.In the 1960s and 1970s, Pendred syndrome was considered to be a relatively frequent cause of profound childhood deafness. In 1958, the potassium perchlorate test proved to be a reliable diagnostic test for Pendred syndrome in individuals with congenital sensorineural deafness.Goiter was a common feature. In 1964, more than 200 cases had been reported in the literature. The earliest report on more moderate hearing impairment dates from 1964.Nevertheless, sensorineural hearing impairment of less than 80 dB is reported rarely. No long-term follow-up data on the hearing impairment are available in these cases. Progression or fluctuation of the hearing impairment has only been described in 3 case reportsof Pendred syndrome. One reportmentioned 20-dB progression of hearing loss in a patient. Another reportdescribed 10- to 20-dB progression combined with episodic vertigo, tinnitus, and occasional vomiting. More recently, a case reportdescribed fluctuating and recovering hearing impairment in the best ear combined with episodic vertigo.Dysplasia of the cochlea is a frequent but nonobligatory feature of Pendred syndrome.Magnetic resonance imaging in female siblings with Pendred syndrome showed bilateral enlargement of the vestibular aqueduct and Mondini dysplasia.Recently, axial CT scanning of the temporal bones in 3 of 6 patients with Pendred syndrome showed a widened vestibular aqueduct and dysplasia of the cochlea.These 3 adult patients with Pendred syndrome and a widened vestibular aqueduct were described as having profound congenital sensorineural hearing impairment. In addition, it was stated that 80% of confirmed cases of Pendred syndrome will have inner ear anomalies, such as a widened vestibular aqueduct.Dysplasia of the cochlea and a widened vestibular aqueduct can also be part of the branchio-otorenal syndrome. Recently, this was reported to be present in 11 of 24 ears of patients with this branchio-otorenal syndrome.The widened vestibular aqueduct may be responsible for the progression in hearing impairment. This phenomenon has only recently been found in 2 different genetic syndromes with hearing impairment, the branchio-otorenal syndrome and even more recently in Pendred syndrome. Other than these 2 distinct genetic syndromes, there are only a few descriptions of sisters and brothers with profound deafness in childhood and a widened vestibular aqueduct without a diagnosis of a genetic syndrome.Nevertheless, it is still difficult to prove the assumption that the widened vestibular aqueduct is fully responsible for the progressive hearing loss. In the X-recessive progressive mixed stapes gusher syndrome (DFN3), it has been shown that the gush of perilymph after opening the footplate is conducted through the internal acoustic canal.Lateral widening of the internal acoustic canal and vestibule has been demonstrated with CT scanning, and various authorsconsider this to be pathognomonic in many cases. Long-term follow-up of affected individuals in a large Dutch pedigreehas shown stability of the conductive component and an increase in the sensorineural component. The increase in the sensorineural component may be the result of fluctuations in cerebrospinal fluid pressure that are conducted into the cochlea, owing to the too-wide communication along the internal acoustic canal. Long-term family studies on the branchio-otorenal syndrome and Pendred syndrome with long-term audiological follow-up and corresponding axial CT scanning or magnetic resonance imaging of the petrous bones may be able to show whether there is an increase in the sensorineural component of the hearing loss and whether this is correlated with the presence of a widened vestibular aqueduct. The genes for the branchio-otorenal syndrome and Pendred syndrome have recently been identified.The clinical genetic diagnosis of Pendred syndrome can now be confirmed by mutation analysis of the PDSgene involved (P.H., written communication, February 1998).Therefore, the clinical phenotype can be redefined based on the genotype. This could help to elucidate the significance of the widened vestibular aqueduct in the progression of hearing impairment in the patient described herein. This case report shows that a euthyroid situation without an enlarged thyroid gland, hypoplasia of the cochlea, and a widened vestibular aqueduct may be the phenotype of Pendred syndrome. Two further questions arise: How frequently can this phenotype be based on the results of genotype studies in Pendred syndrome? How frequently is a widened vestibular aqueduct the result of Pendred syndrome?VPendredDeaf mutism and goitre.Lancet.1896;11:532.WRBrainHeredity in simple goitre.QJM.1927;20:303-319.MEMorgansWRTrotterAssociation of congenital deafness with goitre: the nature of the thyroid defect.Lancet.1958;1:607-609.GVassartJEDumotSRefetoffThyroid disorders.In: Scriver CR, Beaudet A, Sly WS, Valle D, eds. The Inherited Basis of Metabolic Disease. 7th ed. New York, NY: McGraw-Hill Book Co; 1995:2883-2928.RDeraemaekerCongenital deafness and goiter.Am J Hum Genet.1956;8:253-256.GRFraserMEMorgansWRTrotterThe syndrome of sporadic goitre and congenital deafness.QJM.1960;29:279-295.GRFraserAssociation of congenital deafness with goitre (Pendred's syndrome).Ann Hum Genet.1965;28:201-248.GRFraserDeafness with goiter (Pendred's syndrome).In: The Causes of Profound Deafness in Childhood. Baltimore, Md: The Johns Hopkins University Press; 1976:11-25.GMBaxTypical and atypical cases of Pendred's syndrome in one family.Acta Endocrinol (Copenh).1966;53:264-270.TJohnsenMSSorensenUFelot-RasmussenJFriisThe variable intrafamiliar expressivity in Pendred's syndrome.Clin Otolaryngol.1989;14:395-399.LRNilssonNBorgforsIGamstorpHEHolstGLidenNonendemic goitre and deafness.Acta Paediatr.1964;53:117-131.CWRJCremersHet syndroom van Pendred: een autosomaal recessief syndroom met doofheid en een synthesestoornis in de schildklier.T Kindergeneesk.1976;44:89-99.CWRJCremersHet syndroom van Pendred.Ned Tijdschr Geneeskd.1977;121:1202-1205.TJohnsenCLarsenJFriisFHougaard-JensenPendred's syndrome: acoustic vestibular and radiologic findings in 17 unrelated patients.J Laryngol Otol.1987;101:1187-1192.TJohnsenHVidebaekKPOlesenCT-scanning of the cochlea in Pendred's syndrome.Clin Otolaryngol.1989;14:389-393.YKabakkayaEBakanMRYigitogluGGokceMDoganPendred's syndrome.Ann Otol Rhinol Laryngol.1993;102:285-288.VKDasPendred syndrome with episodic vertigo, tinnitus and vomiting and normal bithermal caloric responses.J Laryngol Otol.1987;101:721-722.IAyerbeMNégrevergneJMSanchez-FernandezRUcelayYAlbisuSurdité génétique et syndrome de Pendred.Rev Laryngol Otol Rhinol (Bord).1997;118:113-117.JHvidberg-HansenMBJorgensenThe inner ear in Pendred's syndrome.Acta Otolaryngol (Stockh).1968;66:129-135.TJohnsenMBJorgensenSJohnsenMondini cochlea in Pendred's syndrome.Acta Otolaryngol (Stockh).1986;102:239-247.PIllumHWKiaerJHvidberg-HansenFifteen cases of Pendred's syndrome.Arch Otolaryngol.1972;96:297-304.WReardonRCoffeyPDPhelpsPendred syndrome: 100 years of underascertainment?QJM.1997;90:443-447.VCSheffieldZKraiemJCBeckPendred syndrome maps to chromosome 7q21-34 and is caused by an intrinsic defect in thyroid iodine organification.Nat Genet.1996;12:424-426.BCoyleRCoffeyJAArmourPendred syndrome (goitre and sensorineural hearing loss) maps to chromosome 7 in the region containing the nonsyndromic deafness gene DFNB4.Nat Genet.1996;12:421-423.PCouckeGVan CampODemirhanThe gene for Pendred syndrome is located between D7S501 and D7S692 in 1.7-cM region on chromosome 7q.Genomics.1997;40:48-54.EGausdenBGoyleJAArmourPendred syndrome: evidence for genetic homogeneity and further refinement of linkage.J Med Genet.1997;34:126-129.LAEverettBGlaserJCBeckPendred syndrome is caused by mutations in a putative sulphate transporter gene (PDS).Nat Genet.1997;17:411-422.WReardonRCoffeyMEPembreyPitfalls in practice-diagnosis and misdiagnosis in Pendred syndrome.J Audiol Med.1997;6:1-9.ONakagawaSItoOHanyuFemale siblings with Pendred syndrome.Intern Med.1994;33:369-372.AChenMFrancisLNiPhenotypic manifestations of branchio-otorenal syndrome.Am J Med Genet.1995;58:365-370.AJGriffithHAArtsCDownsFamilial large vestibular aqueduct syndrome.Laryngoscope.1996;106:960-965.SAbeSUsamiHShinkawaThree familial cases of hearing loss associated with enlargement of the vestibular aqueduct.Ann Otol Rhinol Laryngol.1997;106:1063-1069.MGlasscokThe stapes gusher.Arch Otolaryngol.1973;98:82-91.CWRJCremersGCHJHombergenJJScaffPLMHuygenWSVolkersAJLGPinckersX-progressive mixed deafness with perilymphatic gusher during stapes surgery.Arch Otolaryngol.1985;111:249-254.OMichelJBreunsbachRMatthiasDas angeborene Liquordrucklabyrinth.HNO.1991;39:486-490.PDPhelpsWReardonMPembreySBellmanLLuxonX-linked deafness stapes gusher and a distinctive defect of the inner ear.Neuroradiology.1991;33:326-330.JMTalbotDFWilsonComputed tomographic diagnosis of the X-linked congenital mixed deafness fixation of the stapedial footplate and perilymphatic gusher.Am J Otol.1994;15:177-182.ATankLSParnesX-linked progressive mixed hearing loss: computed tomography findings.Ann Otol Rhinol Laryngol.1994;103:655-657.CWRJCremersAudiologic features of the X-linked progressive mixed deafness syndrome with perilymphatic gusher during stapes surgery.Am J Otol.1985;6:243-246.Accepted for publication February 11, 1998.Reprints: Cor W. R. J. Cremers, MD, PhD, Department of Otorhinolaryngology, University Hospital Nijmegen, PO Box 9101, 6500 HB Nijmegen, the Netherlands.
JAMA Otolaryngology - Head & Neck Surgery – American Medical Association
Published: May 1, 1998