Abstract
Pendred syndrome is an autosomal recessive disorder characterised by sensorineural hearing loss and thyroid dyshormonogenesis. It is caused by mutations in the PDS/SLC26A4 gene (OMIM 605646) encoding for pendrin. Hypothyroidism in Pendred syndrome can be—although rarely—present from birth and therefore diagnosed by neonatal screening. The aim of our study was to identify patients with Pendred syndrome among a historical cohort of patients with congenital hypothyroidism (CH) identified by neonatal screening, and to find their mutations in the PDS/SLC26A4 gene. We investigated 197 Czech Caucasian children with CH detected by the neonatal screening between the years 1985 and 2005. The clinical diagnosis of Pendred syndrome was based on the laboratory and sonographic signs of thyroid dyshormonogenesis in association with sensorineural hearing loss. In subjects clinically diagnosed with Pendred syndrome, we sequenced all exons and exon-intron boundaries of the PDS/SLC26A4 gene. Hearing loss was present in 10/197 children with screening-detected CH. Of these, three fulfilled the diagnostic criteria of Pendred syndrome. Two patients were compound heterozygotes for PDS/SLC26A4 mutations: patient 1 carried c.2089+1G>A / c.3G>C and patient 2 carried p.Tyr530His / p.Val422Asp. Two of the four identified mutations were novel (c.3G>C in patient 1 and p.Val422Asp in patient 2). The third patient was free of mutations in the PDS/SLC26A4 gene, representing a phenocopy. In conclusion, our results indicate the rarity of Pendred syndrome as a cause of CH. The identification of two novel mutations expands the spectrum of mutations in the PDS/SLC26A4 gene and emphasizes their marked allelic heterogeneity.
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Abbreviations
- CH:
-
Congenital hypothyroidism
- PDS/SLC26A4 :
-
Gene for pendrin
- EVA:
-
Enlarged vestibular aqueduct
- OAE:
-
Otoacoustic emissions
- ABR:
-
Auditory brainstem response
- tT4:
-
Total thyroxine
- TSH:
-
Thyrotropin
References
Abramowicz MJ, Targovnik HM, Varela V, Cochaux P, Krawiec L, Pisarev MA, Propato FV, Juvenal G, Chester HA, Vassart G (1992) Identification of a mutation in the coding sequence of the human thyroid peroxidase gene causing congenital goiter. J Clin Invest 90:1200–1204
Al Taji E, Biebermann H, Limanova Z, Hnikova O, Zikmund J, Dame C, Grueters A, Lebl J, Krude H (2007) Screening for mutations in transcription factors in a Czech cohort of 170 patients with congenital and early-onset hypothyroidism: Identification of a novel PAX8 mutation in dominantly inherited early-onset non-autoimmune hypothyroidism. Eur J Endocrinol 156:521–529
Antonarakis SE; the Nomenclature Working Group (1998) Recommendations for a nomenclature system for human gene mutations. Hum Mutat 11:1–3
Bargman GJ, Gardner LI (1967) Otic lesions and congenital hypothyroidism in the developing chick. J Clin Invest 46:1828–1839
Batsakis JG, Nishiyama RH (1962) Deafness with sporadic goiter. Pendred’s syndrome. Arch Otolaryngol 76:401–406
Blons H, Feldmann D, Duval V, Messaz O, Denoyelle F, Loundon N, Sergout-Allaoui A, Houang M, Duriez F, Lacombe D, Delobel B, Leman J, Catros H, Journel H, Drouin-Garraud V, Obstoy MF, Toutain A, Oden S, Toublanc JE, Couderc R, Petit C, Garabedian EN, Marlin S (2004) Screening of SLC26A4 (PDS) gene in Pendred’s syndrome: a large spectrum of mutations in France and phenotypic heterogeneity. Clin Genet 66:333–340
Borck G, Roth C, Martine U, Wildhardt G, Pohlenz J (2003) Mutations in the PDS gene in German families with Pendred’s syndrome: V138F is a founder mutation. J Clin Endocrinol Metab 88:2916–2921
Coakley JC, Keir EH, Connelly JF (1992) The association of thyroid dyshormonogenesis and deafness (Pendred syndrome): experience of the Victorian Neonatal Thyroid Screening Programme. J Paediatr Child Health 28:398–401
Coyle B, Coffey R, Armour JA, Gausden E, Hochberg Z, Grossman A, Britton K, Pembrey M, Reardon W, Trembath R (1996) Pendred syndrome (goitre and sensorineural hearing loss) maps to chromosome 7 in the region containing the nonsyndromic deafness gene DFNB4. Nat Genet 12:421–423
Coyle B, Reardon W, Herbrick JA, Tsui LC, Gausden E, Lee J, Coffey R, Grueters A, Grossman A, Phelps PD, Luxon L, Kendall-Taylor P, Scherer SW, Trembath RC (1998) Molecular analysis of the PDS gene in Pendred syndrome. Hum Mol Genet 7:1105–1112
Debruyne F, Vanderschueren-Lodeweyckx M, Bastijns P (1983) Hearing in congenital hypothyroidism. Audiology 22:404–409
Everett LA, Glaser B, Beck JC, Idol JR, Buchs A, Heyman M, Adawi F, Hazani E, Nassir E, Baxevanis AD, Sheffield VC, Green ED (1997) Pendred syndrome is caused by mutations in a putative sulphate transporter gene (PDS). Nat Genet 17:411–422
Fraser GR (1965) Association of congenital deafness with goitre (Pendred’s syndrome) a study of 207 families. Ann Hum Genet 28:201–249
Gaudino R, Garel C, Czernichow P, Leger J (2005) Proportion of various types of thyroid disorders among newborns with congenital hypothyroidism and normally located gland: a regional cohort study. Clin Endocrinol (Oxf) 62:444–448
Gillam MP, Kopp P (2001) Genetic defects in thyroid hormone synthesis. Curr Opin Pediatr 13:364–372
Mangklabruks A, Billerbeck AE, Wajchenberg B, Knobel M, Cox NJ, DeGroot LJ, Medeiros-Neto G (1991) Genetic linkage studies of thyroid peroxidase (TPO) gene in families with TPO deficiency. J Clin Endocrinol Metab 72:471–476
Meyerhoff WL (1979) Hypothyroidism and the ear: electrophysiological, morphological, and chemical considerations. Laryngoscope 89:1–25
Napiontek U, Borck G, Muller-Forell W, Pfarr N, Bohnert A, Keilmann A, Pohlenz J (2004) Intrafamilial variability of the deafness and goiter phenotype in Pendred syndrome caused by a T416P mutation in the SLC26A4 gene. J Clin Endocrinol Metab 89:5347–5351
Phelps PD, Coffey RA, Trembath RC, Luxon LM, Grossman AB, Britton KE, Kendall-Taylor P, Graham JM, Cadge BC, Stephens SG, Pembrey ME, Reardon W (1998) Radiological malformations of the ear in Pendred syndrome. Clin Radiol 53:268–273
Reardon W (1992) Genetic deafness. J Med Genet 29:521–526
Reardon W, Coffey R, Chowdhury T, Grossman A, Jan H, Britton K, Kendall-Taylor P, Trembath R (1999) Prevalence, age of onset, and natural history of thyroid disease in Pendred syndrome. J Med Genet 36:595–598
Reardon W, Coffey R, Phelps PD, Luxon LM, Stephens D, Kendall-Taylor P, Britton KE, Grossman A, Trembath R (1997) Pendred syndrome-100 years of underascertainment? QJM 90:443–447
Reardon W, Trembath RC (1996) Pendred syndrome. J Med Genet 33:1037–1040
Royaux IE, Belyantseva IA, Wu T, Kachar B, Everett LA, Marcus DC, Green ED (2003) Localization and functional studies of pendrin in the mouse inner ear provide insight about the etiology of deafness in pendred syndrome. J Assoc Res Otolaryngol 4:394–404
Royaux IE, Suzuki K, Mori A, Katoh R, Everett LA, Kohn LD, Green ED (2000) Pendrin, the protein encoded by the Pendred syndrome gene (PDS), is an apical porter of iodide in the thyroid and is regulated by thyroglobulin in FRTL-5 cells. Endocrinology 141:839–845
Scott DA, Wang R, Kreman TM, Andrews M, McDonald JM, Bishop JR, Smith RJ, Karniski LP, Sheffield VC (2000) Functional differences of the PDS gene product are associated with phenotypic variation in patients with Pendred syndrome and non-syndromic hearing loss (DFNB4). Hum Mol Genet 9:1709–1715
Scott DA, Wang R, Kreman TM, Sheffield VC, Karniski LP (1999) The Pendred syndrome gene encodes a chloride-iodide transport protein. Nat Genet 21:440–443
Seeman P, Malikova M, Raskova D, Bendova O, Groh D, Kubalkova M, Sakmaryova I, Seemanova E, Kabelka Z (2004) Spectrum and frequencies of mutations in the GJB2 (Cx26) gene among 156 Czech patients with pre-lingual deafness. Clin Genet 66:152–157
Sheffield VC, Kraiem Z, Beck JC, Nishimura D, Stone EM, Salameh M, Sadeh O, Glaser B (1996) Pendred syndrome maps to chromosome 7q21–34 and is caused by an intrinsic defect in thyroid iodine organification. Nat Genet 12:424–426
Steel KP, Bussoli TJ (1999) Deafness genes: expressions of surprise. Trends Genet 15:207–211
Uziel A, Gabrion J, Ohresser M, Legrand C (1981) Effects of hypothyroidism on the structural development of the organ of Corti in the rat. Acta Otolaryngol 92:469–480
Valvassori GE, Clemis JD (1978) The large vestibular aqueduct syndrome. Laryngoscope 88:723–728
Acknowledgements
We wish to thank Prof. J. Pohlenz and colleagues at the Hospital of the Johannes Gutenberg University, Mainz, Germany for providing us with the currently used primer sequences and PCR conditions. We are grateful to L. Cerny, M. Finkova, R. Havlik, V. Janstova, J. Klabochova, E. Novakova, R. Pomahacova, M. Skacha, J. Skvor, H. Vavrova, J. Venhacova and J. Zikmund for their assistance in clinical evaluations. K. Rakova is acknowledged for expert technical assistance. We also thank Prof. C. J. H. Kelnar and Prof. G. Van Vliet for a critical review of the manuscript. The cooperation of the patients and their families is greatly appreciated.
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The study was supported by grants of the Czech Ministry of Education (MSM 0021620814) and Charles University in Prague (GAUK 2008/2007).
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Banghova, K., Taji, E.A., Cinek, O. et al. Pendred syndrome among patients with congenital hypothyroidism detected by neonatalscreening: identification of two novel PDS/SLC26A4 mutations. Eur J Pediatr 167, 777–783 (2008). https://doi.org/10.1007/s00431-007-0588-7
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DOI: https://doi.org/10.1007/s00431-007-0588-7