FREE NEJM E-TOC    HOME   |   SUBSCRIBE   |   CURRENT ISSUE   |   PAST ISSUES   |   COLLECTIONS   |   Search Term  Advanced Search

Sign in | Get NEJM's E-Mail Table of Contents — Free | Subscribe

Previous Volume 347:95-102 July 11, 2002 Number 2 Next

	Full Text PDF PDA Full Text PowerPoint Slide Set Supplementary Materials Add to Personal Archive Add to Citation Manager Notify a Friend E-mail When Cited PubMed Citation

ABSTRACT

Background Several genetic defects are associated with permanent congenital hypothyroidism. Immunologic, environmental, and iatrogenic (but not genetic) factors are known to induce transient congenital hypothyroidism, which spontaneously resolves within the first months of life. We hypothesized that molecular defects in the thyroid oxidase system, which is composed of at least two proteins, might be involved in the pathogenesis of permanent or transient congenital hypothyroidism in babies with defects in iodide organification, for which the oxidase system is required.

Methods Nine patients were recruited who had idiopathic congenital hypothyroidism (one with permanent and eight with transient hypothyroidism) and an iodide-organification defect and who had been identified by the screening program for congenital hypothyroidism. The DNA of the patients and their relatives was analyzed for mutations in the genes for thyroid oxidase 1 (THOX1 ) and 2 (THOX2 ).

Results The one patient with permanent and severe thyroid hormone deficiency and a complete iodide-organification defect had a homozygous nonsense mutation in the THOX2 gene that eliminates all functional domains of the protein. Three of the eight patients with mild transient congenital hypothyroidism and a partial iodide-organification defect had heterozygous mutations in the THOX2 gene that prematurely truncate the protein, thus abolishing its functional domains.

Conclusions Biallelic inactivating mutations in the THOX2 gene result in complete disruption of thyroid-hormone synthesis and are associated with severe and permanent congenital hypothyroidism. Monoallelic mutations are associated with milder, transient hypothyroidism caused by insufficient thyroidal production of hydrogen peroxide, which prevents the synthesis of sufficient quantities of thyroid hormones to meet the large requirement for thyroid hormones at the beginning of life.

Source Information

From the Department of Pediatric Endocrinology, Emma Children's Hospital (J.C.M., H.B., M.J.E.K., A.S.P.T., J.J.M.V., T.V., C.R.-S.), and the Neurozintuigen Laboratory (F.B.), Academic Medical Center, University of Amsterdam, Amsterdam.

Address reprint requests to Dr. Moreno at P.O. Box 22700, 1100 DE Amsterdam, the Netherlands, or at j.c.moreno{at}amc.uva.nl.

Full Text of this Article

This article has been cited by other articles:

• Maruo, Y., Takahashi, H., Soeda, I., Nishikura, N., Matsui, K., Ota, Y., Mimura, Y., Mori, A., Sato, H., Takeuchi, Y. (2008). Transient Congenital Hypothyroidism Caused by Biallelic Mutations of the Dual Oxidase 2 Gene in Japanese Patients Detected by a Neonatal Screening Program. J. Clin. Endocrinol. Metab. 93: 4261-4267 [Abstract] [Full Text]  
• Pacquelet, S., Lehmann, M., Luxen, S., Regazzoni, K., Frausto, M., Noack, D., Knaus, U. G. (2008). Inhibitory Action of NoxA1 on Dual Oxidase Activity in Airway Cells. J. Biol. Chem. 283: 24649-24658 [Abstract] [Full Text]  
• Leonardi, D., Polizzotti, N., Carta, A., Gelsomino, R., Sava, L., Vigneri, R., Calaciura, F. (2008). Longitudinal Study of Thyroid Function in Children with Mild Hyperthyrotropinemia at Neonatal Screening for Congenital Hypothyroidism. J. Clin. Endocrinol. Metab. 93: 2679-2685 [Abstract] [Full Text]  
• Moreno, J. C., Klootwijk, W., van Toor, H., Pinto, G., D'Alessandro, M., Leger, A., Goudie, D., Polak, M., Gruters, A., Visser, T. J. (2008). Mutations in the Iodotyrosine Deiodinase Gene and Hypothyroidism. NEJM 358: 1811-1818 [Abstract] [Full Text]  
• Ginabreda, M. G. P, Cardoso, L. C, Nobrega, F. M, Ferreira, A. C F, Goncalves, M. D. C, Vaisman, M., Carvalho, D. P (2008). Negative correlation between thyroperoxidase and dual oxidase H2O2-generating activities in thyroid nodular lesions. Eur J Endocrinol 158: 223-227 [Abstract] [Full Text]  
• Deladoey, J., Pfarr, N., Vuissoz, J.-M., Parma, J., Vassart, G., Biesterfeld, S., Pohlenz, J., Van Vliet, G. (2008). Pseudodominant Inheritance of Goitrous Congenital Hypothyroidism Caused by TPO Mutations: Molecular and in Silico Studies. J. Clin. Endocrinol. Metab. 93: 627-633 [Abstract] [Full Text]  
• Zamproni, I., Grasberger, H., Cortinovis, F., Vigone, M. C., Chiumello, G., Mora, S., Onigata, K., Fugazzola, L., Refetoff, S., Persani, L., Weber, G. (2008). Biallelic Inactivation of the Dual Oxidase Maturation Factor 2 (DUOXA2) Gene as a Novel Cause of Congenital Hypothyroidism. J. Clin. Endocrinol. Metab. 93: 605-610 [Abstract] [Full Text]  
• Song, Y., Driessens, N., Costa, M., De Deken, X., Detours, V., Corvilain, B., Maenhaut, C., Miot, F., Van Sande, J., Many, M.-C., Dumont, J. E. (2007). Roles of Hydrogen Peroxide in Thyroid Physiology and Disease. J. Clin. Endocrinol. Metab. 92: 3764-3773 [Abstract] [Full Text]  
• Johnson, K. R., Marden, C. C., Ward-Bailey, P., Gagnon, L. H., Bronson, R. T., Donahue, L. R. (2007). Congenital Hypothyroidism, Dwarfism, and Hearing Impairment Caused by a Missense Mutation in the Mouse Dual Oxidase 2 Gene, Duox2. Mol. Endocrinol. 21: 1593-1602 [Abstract] [Full Text]  
• Grasberger, H., De Deken, X., Miot, F., Pohlenz, J., Refetoff, S. (2007). Missense Mutations of Dual Oxidase 2 (DUOX2) Implicated in Congenital Hypothyroidism Have Impaired Trafficking in Cells Reconstituted with DUOX2 Maturation Factor. Mol. Endocrinol. 21: 1408-1421 [Abstract] [Full Text]  
• Orient, A., Donko, A., Szabo, A., Leto, T. L., Geiszt, M. (2007). Novel sources of reactive oxygen species in the human body. Nephrol Dial Transplant 22: 1281-1288 [Full Text]  
• Milenkovic, M., De Deken, X., Jin, L., De Felice, M., Di Lauro, R., Dumont, J. E, Corvilain, B., Miot, F. (2007). Duox expression and related H2O2 measurement in mouse thyroid: onset in embryonic development and regulation by TSH in adult. J Endocrinol 192: 615-626 [Abstract] [Full Text]  
• Moskwa, P., Lorentzen, D., Excoffon, K. J. D. A., Zabner, J., McCray, P. B. Jr., Nauseef, W. M., Dupuy, C., Banfi, B. (2007). A Novel Host Defense System of Airways Is Defective in Cystic Fibrosis. Am. J. Respir. Crit. Care Med. 175: 174-183 [Abstract] [Full Text]  
• Bedard, K., Krause, K.-H. (2007). The NOX Family of ROS-Generating NADPH Oxidases: Physiology and Pathophysiology. Physiol. Rev. 87: 245-313 [Abstract] [Full Text]  
• Geiszt, M. (2006). NADPH oxidases: New kids on the block. Cardiovasc Res 71: 289-299 [Abstract] [Full Text]  
• Grasberger, H., Refetoff, S. (2006). Identification of the Maturation Factor for Dual Oxidase: EVOLUTION OF AN EUKARYOTIC OPERON EQUIVALENT. J. Biol. Chem. 281: 18269-18272 [Abstract] [Full Text]  
• Alzahrani, A. S., Baitei, E. Y., Zou, M., Shi, Y. (2006). Metastatic Follicular Thyroid Carcinoma Arising from Congenital Goiter as a Result of a Novel Splice Donor Site Mutation in the Thyroglobulin Gene. J. Clin. Endocrinol. Metab. 91: 740-746 [Abstract] [Full Text]  
• Varela, V., Rivolta, C. M., Esperante, S. A., Gruneiro-Papendieck, L., Chiesa, A., Targovnik, H. M. (2006). Three Mutations (p.Q36H, p.G418fsX482, and g.IVS19-2A>C) in the Dual Oxidase 2 Gene Responsible for Congenital Goiter and Iodide Organification Defect. Clin. Chem. 52: 182-191 [Abstract] [Full Text]  
• Medda, E., Olivieri, A., Stazi, M. A., Grandolfo, M. E, Fazzini, C., Baserga, M., Burroni, M., Cacciari, E., Calaciura, F., Cassio, A., Chiovato, L., Costa, P., Leonardi, D., Martucci, M., Moschini, L., Pagliardini, S., Parlato, G., Pignero, A., Pinchera, A., Sala, D., Sava, L., Stoppioni, V., Tancredi, F., Valentini, F., Vigneri, R., Sorcini, M. (2005). Risk factors for congenital hypothyroidism: results of a population case-control study (1997-2003). Eur J Endocrinol 153: 765-773 [Abstract] [Full Text]  
• Ha, E.-M., Oh, C.-T., Bae, Y. S., Lee, W.-J. (2005). A Direct Role for Dual Oxidase in Drosophila Gut Immunity. Science 310: 847-850 [Abstract] [Full Text]  
• Calebiro, D., de Filippis, T., Lucchi, S., Covino, C., Panigone, S., Beck-Peccoz, P., Dunlap, D., Persani, L. (2005). Intracellular entrapment of wild-type TSH receptor by oligomerization with mutants linked to dominant TSH resistance. Hum Mol Genet 14: 2991-3002 [Abstract] [Full Text]  
• Ameziane-El-Hassani, R., Morand, S., Boucher, J.-L., Frapart, Y.-M., Apostolou, D., Agnandji, D., Gnidehou, S., Ohayon, R., Noel-Hudson, M.-S., Francon, J., Lalaoui, K., Virion, A., Dupuy, C. (2005). Dual Oxidase-2 Has an Intrinsic Ca2+-dependent H2O2-generating Activity. J. Biol. Chem. 280: 30046-30054 [Abstract] [Full Text]  
• Kuliawat, R., Ramos-Castaneda, J., Liu, Y., Arvan, P. (2005). Intracellular Trafficking of Thyroid Peroxidase to the Cell Surface. J. Biol. Chem. 280: 27713-27718 [Abstract] [Full Text]  
• Lanting, C. I., van Tijn, D. A., Loeber, J. G., Vulsma, T., de Vijlder, J. J. M., Verkerk, P. H. (2005). Clinical Effectiveness and Cost-Effectiveness of the Use of the Thyroxine/Thyroxine-Binding Globulin Ratio to Detect Congenital Hypothyroidism of Thyroidal and Central Origin in a Neonatal Screening Program. Pediatrics 116: 168-173 [Abstract] [Full Text]  
• Klebanoff, S. J. (2005). Myeloperoxidase: friend and foe. J. Leukoc. Biol. 77: 598-625 [Abstract] [Full Text]  
• Park, S M, Chatterjee, V K K (2005). Genetics of congenital hypothyroidism. J. Med. Genet. 42: 379-389 [Abstract] [Full Text]  
• El Hassani, R. A., Benfares, N., Caillou, B., Talbot, M., Sabourin, J.-C., Belotte, V., Morand, S., Gnidehou, S., Agnandji, D., Ohayon, R., Kaniewski, J., Noel-Hudson, M.-S., Bidart, J.-M., Schlumberger, M., Virion, A., Dupuy, C. (2005). Dual oxidase2 is expressed all along the digestive tract. Am. J. Physiol. Gastrointest. Liver Physiol. 288: G933-G942 [Abstract] [Full Text]  
• Rodrigues, C., Jorge, P., Soares, J. P., Santos, I., Salomao, R., Madeira, M., Osorio, R. V., Santos, R. (2005). Mutation screening of the thyroid peroxidase gene in a cohort of 55 Portuguese patients with congenital hypothyroidism. Eur J Endocrinol 152: 193-198 [Abstract] [Full Text]  
• Geiszt, M., Leto, T. L. (2004). The Nox Family of NAD(P)H Oxidases: Host Defense and Beyond. J. Biol. Chem. 279: 51715-51718 [Full Text]  
• Schoen, E. J., Clapp, W., To, T. T., Fireman, B. H. (2004). The Key Role of Newborn Thyroid Scintigraphy With Isotopic Iodide (123I) in Defining and Managing Congenital Hypothyroidism. Pediatrics 114: e683-e688 [Abstract] [Full Text]  
• Quinn, M. T., Gauss, K. A. (2004). Structure and regulation of the neutrophil respiratory burst oxidase: comparison with nonphagocyte oxidases. J. Leukoc. Biol. 76: 760-781 [Abstract] [Full Text]  
• Meeus, L., Gilbert, B., Rydlewski, C., Parma, J., Roussie, A. L., Abramowicz, M., Vilain, C., Christophe, D., Costagliola, S., Vassart, G. (2004). Characterization of a Novel Loss of Function Mutation of PAX8 in a Familial Case of Congenital Hypothyroidism with In-Place, Normal-Sized Thyroid. J. Clin. Endocrinol. Metab. 89: 4285-4291 [Abstract] [Full Text]  
• Morand, S., Agnandji, D., Noel-Hudson, M.-S., Nicolas, V., Buisson, S., Macon-Lemaitre, L., Gnidehou, S., Kaniewski, J., Ohayon, R., Virion, A., Dupuy, C. (2004). Targeting of the Dual Oxidase 2 N-terminal Region to the Plasma Membrane. J. Biol. Chem. 279: 30244-30251 [Abstract] [Full Text]  
• Gillam, M. P., Sidhaye, A. R., Lee, E. J., Rutishauser, J., Stephan, C. W., 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] [Full Text]  
• Gutnisky, V. J., Moya, C. M., Rivolta, C. M., Domene, S., Varela, V., Toniolo, J. V., Medeiros-Neto, G., Targovnik, H. M. (2004). Two Distinct Compound Heterozygous Constellations (R277X/IVS34-1G>C and R277X/R1511X) in the Thyroglobulin (TG) Gene in Affected Individuals of a Brazilian Kindred with Congenital Goiter and Defective TG Synthesis. J. Clin. Endocrinol. Metab. 89: 646-657 [Abstract] [Full Text]  
• Caron, P., Moya, C. M., Malet, D., Gutnisky, V. J., Chabardes, B., Rivolta, C. M., Targovnik, H. M. (2003). Compound Heterozygous Mutations in the Thyroglobulin Gene (1143delC and 6725G->A [R2223H]) Resulting in Fetal Goitrous Hypothyroidism. J. Clin. Endocrinol. Metab. 88: 3546-3553 [Abstract] [Full Text]  
• Morand, S., Chaaraoui, M., Kaniewski, J., Deme, D., Ohayon, R., Noel-Hudson, M. S., Virion, A., Dupuy, C. (2003). Effect of Iodide on Nicotinamide Adenine Dinucleotide Phosphate Oxidase Activity and Duox2 Protein Expression in Isolated Porcine Thyroid Follicles. Endocrinology 144: 1241-1248 [Abstract] [Full Text]  
• Jordan, N., Williams, N., Gregory, J. W., Evans, C., Owen, M., Ludgate, M. (2003). The W546X Mutation of the Thyrotropin Receptor Gene: Potential Major Contributor to Thyroid Dysfunction in a Caucasian Population. J. Clin. Endocrinol. Metab. 88: 1002-1005 [Abstract] [Full Text]  
• Morand, S., Dos Santos, O. F., Ohayon, R., Kaniewski, J., Noel-Hudson, M.-S., Virion, A., Dupuy, C. (2003). Identification of a Truncated Dual Oxidase 2 (DUOX2) Messenger Ribonucleic Acid (mRNA) in Two Rat Thyroid Cell Lines. Insulin and Forskolin Regulation of DUOX2 mRNA Levels in FRTL-5 Cells and Porcine Thyrocytes. Endocrinology 144: 567-574 [Abstract] [Full Text]  
• (2003). Lucina. Arch. Dis. Child. 88: 180-180 [Full Text]  
• Brown, R. S., Demmer, L. A. (2002). The Etiology of Thyroid Dysgenesis--Still an Enigma after All These Years. J. Clin. Endocrinol. Metab. 87: 4069-4071 [Full Text]