This Article Full Text Full Text (PDF) Submit a related Letter to the Editor Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Pfarr, N. Articles by Pohlenz, J. Search for Related Content PubMed PubMed Citation Articles by Pfarr, N. Articles by Pohlenz, J. Related Collections Thyroid

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

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.

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.

This article has been cited by other articles:

				S. Dossena, S. Rodighiero, V. Vezzoli, C. Nofziger, E. Salvioni, M. Boccazzi, E. Grabmayer, G. Botta, G. Meyer, L. Fugazzola, et al. Functional characterization of wild-type and mutated pendrin (SLC26A4), the anion transporter involved in Pendred syndrome J. Mol. Endocrinol., September 1, 2009; 43(3): 93 - 103. [Abstract] [Full Text] [PDF]

				A. Pera, S. Dossena, S. Rodighiero, M. Gandia, G. Botta, G. Meyer, F. Moreno, C. Nofziger, C. Hernandez-Chico, and M. Paulmichl Functional assessment of allelic variants in the SLC26A4 gene involved in Pendred syndrome and nonsyndromic EVA PNAS, November 25, 2008; 105(47): 18608 - 18613. [Abstract] [Full Text] [PDF]

				M. Avbelj, H. Tahirovic, M. Debeljak, M. Kusekova, A. Toromanovic, C. Krzisnik, and T. Battelino High prevalence of thyroid peroxidase gene mutations in patients with thyroid dyshormonogenesis Eur. J. Endocrinol., May 1, 2007; 156(5): 511 - 519. [Abstract] [Full Text] [PDF]