Jump to ContentJump to Main Navigation
Show Summary Details
More options …

Journal of Pediatric Endocrinology and Metabolism

Editor-in-Chief: Kiess, Wieland

Ed. by Bereket, Abdullah / Darendeliler, Feyza / Dattani, Mehul / Gustafsson, Jan / Luo, Fei Hong / Mericq, Veronica / Ogata, Tsutomu / Toppari, Jorma


IMPACT FACTOR 2017: 1.086

CiteScore 2017: 1.07

SCImago Journal Rank (SJR) 2017: 0.465
Source Normalized Impact per Paper (SNIP) 2017: 0.580

Online
ISSN
2191-0251
See all formats and pricing
More options …
Volume 29, Issue 7

Issues

High prevalence of DUOX2 mutations in Japanese patients with permanent congenital hypothyroidism or transient hypothyroidism

Kumihiro Matsuo / Yusuke Tanahashi
  • Corresponding author
  • Department of Pediatrics, Asahikawa Medical University, 2-1-1-1 Midorigaoka-Higashi, Asahikawa 078-8510, Japan, Tel.: +81-166-68-2481, Fax: +81-166-68-2489
  • Email
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
/ Tokuo Mukai / Shigeru Suzuki / Toshihiro Tajima
  • Department of Pediatrics, Hokkaido University Graduate School of Medicine, Sapporo 060-638, Japan
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
/ Hiroshi Azuma / Kenji Fujieda
Published Online: 2016-05-11 | DOI: https://doi.org/10.1515/jpem-2015-0400

Abstract

Background: Dual oxidase 2 (DUOX2) mutations are a cause of dyshormonogenesis (DH) and have been identified in patients with permanent congenital hypothyroidism (PH) and with transient hypothyroidism (TH). We aimed to elucidate the prevalence and phenotypical variations of DUOX2 mutations.

Methods: Forty-eight Japanese DH patients were enroled and analysed for sequence variants of DUOX2, DUOXA2, and TPO using polymerase chain reaction-amplified direct sequencing.

Results: Fourteen sequence variants of DUOX2, including 10 novel variants, were identified in 11 patients. DUOX2 variants were more prevalent (11/48, 22.9%) than TPO (3/48, 6.3%) (p=0.020). The prevalence of DUOX2 variants in TH was slightly, but not significantly, higher than in PH. Furthermore, one patient had digenic heterozygous sequence variants of both DUOX2 and TPO.

Conclusions: Our results suggest that DUOX2 mutations might be the most common cause of both PH and TH, and that phenotypes of these mutations might be milder than those of other causes.

Keywords: congenital hypothyroidism; DUOX2; dyshormonogenesis; permanent congenital hypothyroidism; transient hypothyroidism

Dedicated to: Professor Kenji Fujieda, who sadly passed away on March 19, 2010, during the completion of this work.

References

  • 1.

    Toublanc JE. Comparison of epidemiological data on congenital hypothyroidism in Europe with those of other parts of the world. Horm Res 1992;38:230–5.Google Scholar

  • 2.

    Dubuis JM, Glorieux J, Richer F, Deal CL, Dussault JH, et al. Outcome of severe congenital hypothyroidism: closing the developmental gap with early high dose levothyroxine treatment. J Clin Endocrinol Metab 1996;81:222–7.Google Scholar

  • 3.

    Park SM, Chatterjee VK. Genetics of congenital hypothyroidism. J Med Genet 2005;42:379–89.Google Scholar

  • 4.

    Moreno JC, Bikker H, Kemper MJ, van Trotsenburg AS, Baas F, et al. Inactivating mutations in the gene for thyroid oxidase 2 (THOX2) and congenital hypothyroidism. N Engl J Med 2002;347:95–102.Google Scholar

  • 5.

    Zamproni I, Grasberger H, Cortinovis F, Vigone MC, Chiumello G, et al. Biallelic inactivation of the dual oxidase maturation factor 2 (DUOXA2) gene as a novel cause of congenital hypothyroidism. J Clin Endocrinol Metab 2008;93:605–10.Web of ScienceGoogle Scholar

  • 6.

    Maruo Y, Takahashi H, Soeda I, Nishikura N, Matsui K, et al. 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 2008;93:4261–7.Google Scholar

  • 7.

    Vigone MC, Fugazzola L, Zamproni I, Passoni A, Di Candia S, et al. Persistent mild hypothyroidism associated with novel sequence variants of the DUOX2 gene in two siblings. Hum Mutat 2005;26:395.Google Scholar

  • 8.

    Varela V, Rivolta CM, Esperante SA, Gruñeiro-Papendieck L, Chiesa A, et al. 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 2006;52:182–91.Google Scholar

  • 9.

    Pfarr N, Korsch E, Kaspers S, Herbst A, Stach A, et al. Congenital hypothyroidism caused by new mutations in thyroid oxidase 2 (THOX2) gene. Clin Endocrinol (Oxf) 2006;65:810–5.Google Scholar

  • 10.

    Ohye H, Fukata S, Hishinuma A, Kudo T, Nishihara E, et al. A novel homozygous missense mutation of the dual oxidase 2 (DUOX2) gene in an adult patient with large goiter. Thyroid 2008;18:561–6.Web of ScienceGoogle Scholar

  • 11.

    Tonacchera M, De Marco G, Agretti P, Montanelli L, Di Cosmo C, et al. Identification and functional studies of two new dual-oxidase 2 (DUOX2) mutations in a child with congenital hypothyroidism and a eutopic normal-size thyroid gland. J Clin Endocrinol Metab 2009;94:4309–14.Web of ScienceGoogle Scholar

  • 12.

    Hoste C, Rigutto S, Van Vliet G, Miot F, De Deken X. Compound heterozygosity for a novel hemizygous missense mutation and a partial deletion affecting the catalytic core of the H2O2-generating enzyme DUOX2 associated with transient congenital hypothyroidism. Hum Mutat 2010;31:E1304–19.Web of ScienceGoogle Scholar

  • 13.

    De Marco G, Agretti P, Montanelli L, Di Cosmo C, Bagattini B, et al. Identification and functional analysis of novel dual oxidase 2 (DUOX2) mutations in children with congenital or subclinical hypothyroidism. J Clin Endocrinol Metab 2011;96:E1335–9.Google Scholar

  • 14.

    Narumi S, Muroya K, Asakura Y, Aachi M, Hasegawa T. Molecular basis of thyroid dyshormonogenesis: genetic screening in population-based Japanese patients. J Clin Endocrinol Metab 2011;96:E1838–42.Web of ScienceGoogle Scholar

  • 15.

    Yoshizawa-Ogasawara A, Ogikubo S, Satoh M, Narumi S, Hasegawa T. Congenital hypothyroidism caused by a novel mutation of the dual oxidase 2 (DUOX2) gene. J Pediatr Endocrinol Metab 2013;26:45–52.Google Scholar

  • 16.

    Kasahara T, Narumi S, Okasora K, Takaya R, Tamai H, et al. Delayed onset congenital hypothyroidism in a patient with DUOX2 mutations and maternal iodine excess. Am J Med Genet A 2013;161A:214–7.Google Scholar

  • 17.

    Jin HY, Heo SH, Kim YM, Kim GH, Choi JH, et al. High frequency of DUOX2 mutations in transient or permanent congenital hypothyroidism with eutopic thyroid glands. Horm Res Paediatr 2014;82:252–60.Google Scholar

  • 18.

    Cangul H, Aycan Z, Kendall M, Bas VN, Saglam Y, et al. A truncating DUOX2 mutation (R434X) causes severe congenital hypothyroidism. J Pediatr Endocrinol Metab 2014;27:323–7.Google Scholar

  • 19.

    Muzza M, Rabbiosi S, Vigone MC, Zamproni I, Cirello V, et al. The clinical and molecular characterization of patients with dyshormonogenic congenital hypothyroidism reveals specific diagnostic clues for DUOX2 defects. J Clin Endocrinol Metab 2014;99:E544–53.Web of ScienceGoogle Scholar

  • 20.

    Abe K, Narumi S, Suwanai AS, Hamajima T, Hasegawa T. Pseudodominant inheritance in a family with nonautoimmune hypothyroidism due to biallelic DUOX2 mutations. Clin Endocrinol (Oxf) 2015;83:394–8.Web of ScienceGoogle Scholar

  • 21.

    Wang F, Lu K, Yang Z, Zhang S, Lu W, et al. Genotypes and phenotypes of congenital goitre and hypothyroidism caused by mutations in dual oxidase 2 genes. Clin Endocrinol (Oxf) 2014;81:452–7.Web of ScienceGoogle Scholar

  • 22.

    Nagasaki K, Minamitani K, Anzo M, Adachi M, Ishii T, et al. Guidelines for mass screening of congenital hypothyroidism (2014 revision). Clin Pediatr Endocrinol 2015;24:107–33.Google Scholar

  • 23.

    Léger J, Olivieri A, Donaldson M, Torresani T, Krude H, et al. European Society for Paediatric Endocrinology consensus guidelines on screening, diagnosis, and management of congenital hypothyroidism. Horm Res Paediatr 2014;81:80–103.Web of ScienceGoogle Scholar

  • 24.

    Rapaport R, Sills I, Patel U, Oppenheimer E, Skuza K, et al. Thyrotropin-releasing hormone stimulation tests in infants. J Clin Endocrinol Metab 1993;77:889–94.Google Scholar

  • 25.

    Simpser T, Rapaport R. Update on some aspects of neonatal thyroid disease. J Clin Res Pediatr Endocrinol 2010;2:95–9.Google Scholar

  • 26.

    Adzhubei IA, Schmidt S, Peshkin L, Ramensky VE, Gerasimova A, et al. A method and server for predicting damaging missense mutations. Nat Methods 2010;7:248–9.Web of ScienceGoogle Scholar

  • 27.

    Ng PC, Henikoff S. SIFT: predicting amino acid changes that affect protein function. Nucleic Acids Res 2003;31:3812–4.Google Scholar

  • 28.

    Song Y, Ruf J, Lothaire P, Dequanter D, Andry G, et al. Association of duoxes with thyroid peroxidase and its regulation in thyrocytes. J Clin Endocrinol Metab 2010;95:375–82.Google Scholar

  • 29.

    Hulur I, Hermanns P, Nestoris C, Heger S, Refetoff S, et al. A single copy of the recently identified dual oxidase maturation factor (DUOXA) 1 gene produces only mild transient hypothyroidism in a patient with a novel biallelic DUOXA2 mutation and monoallelic DUOXA1 deletion. J Clin Endocrinol Metab 2011;96:E841–5.Web of ScienceGoogle Scholar

  • 30.

    Grasberger H, De Deken X, Mayo OB, Raad H, Weiss M, et al. Mice deficient in dual oxidase maturation factors are severely hypothyroid. Mol Endocrinol 2012;26:481–92.Google Scholar

  • 31.

    Colin IM, Poncin S, Levêque P, Gallez B, Gérard AC. Differential regulation of the production of reactive oxygen species in Th1 cytokine-treated thyroid cells. Thyroid 2014;24:441–52.Google Scholar

  • 32.

    Carvalho DP, Dupuy C. Role of the NADPH oxidases DUOX and NOX4 in thyroid oxidative stress. Eur Thyroid J 2013;2:160–7.Google Scholar

  • 33.

    Moreno JC, Visser TJ. New phenotypes in thyroid dyshormonogenesis: hypothyroidism due to DUOX2 mutations. Endocr Dev 2007;10:99–117.Google Scholar

About the article

Received: 2015-10-07

Accepted: 2016-03-29

Published Online: 2016-05-11

Published in Print: 2016-07-01


Author contributions: All the authors have accepted responsibility for the entire content of this submitted manuscript and approved submission.

Research funding: This work was partly supported by a Grant-in-Aid for Creative Bio-scientific Research from Asahikawa Medical College.

Employment or leadership: None declared.

Honorarium: None declared.

Competing interests: The funding organisation(s) played no role in the study design; in the collection, analysis, and interpretation of data; in the writing of the report; or in the decision to submit the report for publication.


Citation Information: Journal of Pediatric Endocrinology and Metabolism, Volume 29, Issue 7, Pages 807–812, ISSN (Online) 2191-0251, ISSN (Print) 0334-018X, DOI: https://doi.org/10.1515/jpem-2015-0400.

Export Citation

©2016 by De Gruyter.Get Permission

Citing Articles

Here you can find all Crossref-listed publications in which this article is cited. If you would like to receive automatic email messages as soon as this article is cited in other publications, simply activate the “Citation Alert” on the top of this page.

[1]
Min Jung Kwak
Annals of Pediatric Endocrinology & Metabolism, 2018, Volume 23, Number 4, Page 169
[2]
Bin Yu, Wei Long, Yuqi Yang, Ying Wang, Lihua Jiang, Zhengmao Cai, and Huaiyan Wang
Frontiers in Genetics, 2018, Volume 9
[3]
Xi Chen, Xiaohong Kong, Jie Zhu, Tingting Zhang, Yanwei Li, Guifeng Ding, and Huijuan Wang
International Journal of Endocrinology, 2018, Volume 2018, Page 1
[4]
Helmut Grasberger, Mohamed Noureldin, Timothy D. Kao, Jeremy Adler, Joyce M. Lee, Shrinivas Bishu, Mohamad El-Zaatari, John Y. Kao, and Akbar K. Waljee
Scientific Reports, 2018, Volume 8, Number 1
[5]
Christine E. Cherella and Ari J. Wassner
International Journal of Pediatric Endocrinology, 2017, Volume 2017, Number 1
[6]
Héctor M. Targovnik, Cintia E. Citterio, and Carina M. Rivolta
Best Practice & Research Clinical Endocrinology & Metabolism, 2017, Volume 31, Number 2, Page 195

Comments (0)

Please log in or register to comment.
Log in