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 / Toppari, Jorma


IMPACT FACTOR 2018: 1.239

CiteScore 2018: 1.22

SCImago Journal Rank (SJR) 2018: 0.507
Source Normalized Impact per Paper (SNIP) 2018: 0.562

Online
ISSN
2191-0251
See all formats and pricing
More options …
Volume 29, Issue 5

Issues

Congenital hypothyroidism and thyroid dyshormonogenesis: a case report of siblings with a newly identified mutation in thyroperoxidase

David P. SparlingORCID iD: http://orcid.org/0000-0001-5940-1544 / Kendra Fabian
  • Division of Pediatric Endocrinology, Diabetes, and Metabolism, Department of Pediatrics, Columbia University, New York, NY, USA
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
/ Lara Harik / Vaidehi Jobanputra / Kwame Anyane-Yeboa / Sharon E. Oberfield
  • Division of Pediatric Endocrinology, Diabetes, and Metabolism, Department of Pediatrics, Columbia University, New York, NY, USA
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
/ Ilene Fennoy
  • Corresponding author
  • Division of Pediatric Endocrinology, Diabetes, and Metabolism, Department of Pediatrics, Columbia University, New York, NY, USA
  • Email
  • Other articles by this author:
  • De Gruyter OnlineGoogle Scholar
Published Online: 2016-02-19 | DOI: https://doi.org/10.1515/jpem-2015-0253

Abstract

Background: Thyroid dyshormonogenesis continues to be a significant cause of congenital hypothyroidism. Over time, forms of thyroid dyshormonogenesis can result in goiter, which can lead to difficult management decisions as the pathologic changes can both mimic or lead to thyroid cancer.

Methods: Herein we describe the cases of two brothers diagnosed with congenital hypothyroidism, with initial findings consistent with thyroid dyshormonogenesis. One brother eventually developed multinodular goiter with complex pathology on biopsy, resulting in thyroidectomy.

Results: Whole exome sequencing revealed the brothers carry a novel frameshift mutation in thyroperoxidase; the mutation, while not previously described, was likely both deleterious and pathogenic.

Conlcusions: These cases highlight the complex pathology that can occur within thyroid dyshormonogenesis, with similar appearance to possible thyroid cancer, leading to complex management decisions. They also highlight the role that a genetic diagnosis can play in interpreting the impact of dyshormonogenesis on nodular thyroid development, and the need for long-term follow-up in these patients.

Keywords: congenital hypothyroidism; multinodular goiter; thyroid dyshormonogenesis; thyroperoxidase; whole-exome sequencing

References

  • 1.

    Kratzsch J, Pulzer F. Thyroid gland development and defects. Best Pract Res Clin Endocrinol Metab 2008;22:57–75.Google Scholar

  • 2.

    Castanet M, Polak M, Bonaiti-Pellie C, Lyonnet S, Czernichow P, et al. Nineteen years of national screening for congenital hypothyroidism: familial cases with thyroid dysgenesis suggest the involvement of genetic factors. J Clin Endocrinol Metab 2001;86:2009–14.Google Scholar

  • 3.

    Leger J, Marinovic D, Garel C, Bonaiti-Pellie C, Polak M, et al. Thyroid developmental anomalies in first degree relatives of children with congenital hypothyroidism. J Clin Endocrinol Metab 2002;87:575–80.Google Scholar

  • 4.

    Szinnai G. Genetics of normal and abnormal thyroid development in humans. Best Pract Res Clin Endocrinol Metab 2014;28:133–50.Google Scholar

  • 5.

    Moreno JC, Klootwijk W, van Toor H, Pinto G, D’Alessandro M, et al. Mutations in the iodotyrosine deiodinase gene and hypothyroidism. N Eng J Med 2008;358:1811–8.Google Scholar

  • 6.

    Pardo V, Rubio IG, Knobel M, Aguiar-Oliveira MH, Santos MM, et al. Phenotypic variation among four family members with congenital hypothyroidism caused by two distinct thyroglobulin gene mutations. Thyroid 2008;18:783–6.Google Scholar

  • 7.

    Pohlenz J, Rosenthal IM, Weiss RE, Jhiang SM, Burant C, et al. Congenital hypothyroidism due to mutations in the sodium/iodide symporter. Identification of a nonsense mutation producing a downstream cryptic 3’ splice site. J Clin Invest 1998;101:1028–35.Google Scholar

  • 8.

    Spitzweg C, Morris JC. Genetics and phenomics of hypothyroidism and goiter due to NIS mutations. Mol Cell Endocrinol 2010;322:56–63.Google Scholar

  • 9.

    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

  • 10.

    Grasberger H, Refetoff S. Genetic causes of congenital hypothyroidism due to dyshormonogenesis. Curr Opin Pediatr 2011;23:421–8.Web of ScienceGoogle Scholar

  • 11.

    Ris-Stalpers C, Bikker H. Genetics and phenomics of hypothyroidism and goiter due to TPO mutations. Mol Cell Endocrinol 2010;322:38–43.Google Scholar

  • 12.

    Ghossein RA, Rosai J, Heffess C. Dyshormonogenetic goiter: a clinicopathologic study of 56 cases. Endocr Pathol 1997;8:283–92.Google Scholar

  • 13.

    Kumar P, Henikoff S, Ng PC. Predicting the effects of coding non-synonymous variants on protein function using the SIFT algorithm. Nat Protoc 2009;4:1073–81.Web of ScienceGoogle Scholar

  • 14.

    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

  • 15.

    Richards S, Aziz N, Bale S, Bick D, Das S, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med 2015;17:405–24.Web of ScienceGoogle Scholar

  • 16.

    Grosse SD, Van Vliet G. Prevention of intellectual disability through screening for congenital hypothyroidism: how much and at what level? Arch Dis Child 2011;96:374–9.Web of ScienceGoogle Scholar

  • 17.

    Cameo T, Gumer LB, Williams KM, Gomez J, McMahon DJ, Oberfield SE. A retrospective review of newborn screening for congenital hypothyroidism and newborn thyroid disease at a major medical center. Clin Pediatr 2013;52:1054–8.Web of ScienceGoogle Scholar

  • 18.

    Donaldson M, Jones J. Optimising outcome in congenital hypothyroidism; current opinions on best practice in initial assessment and subsequent management. J Clin Res Pediatr Endocrinol 2013;5(Suppl 1):13–22.Google Scholar

  • 19.

    Ruf J, Carayon P. Structural and functional aspects of thyroid peroxidase. Arch Biochem Biophys 2006;445: 269–77.Google Scholar

  • 20.

    Kimura S, Hong YS, Kotani T, Ohtaki S, Kikkawa F. Structure of the human thyroid peroxidase gene: comparison and relationship to the human myeloperoxidase gene. Biochemistry 1989;28:4481–9.Google Scholar

  • 21.

    Avbelj M, Tahirovic H, Debeljak M, Kusekova M, Toromanovic A, et al. High prevalence of thyroid peroxidase gene mutations in patients with thyroid dyshormonogenesis. Eur J Endocrinol 2007;156:511–9.Web of ScienceGoogle Scholar

  • 22.

    Yang Y, Muzny DM, Reid JG, Bainbridge MN, Willis A, Ward PA, et al. Clinical whole-exome sequencing for the diagnosis of mendelian disorders. N Engl J Med 2013;369:1502–11.Google Scholar

  • 23.

    Nguyen MT, Charlebois K. The clinical utility of whole-exome sequencing in the context of rare diseases – the changing tides of medical practice. Clin Genet 2015;88:313–9.Google Scholar

  • 24.

    Corrias A, Mussa A. Thyroid nodules in pediatrics: which ones can be left alone, which ones must be investigated, when and how. J Clin Res Pediatr Endocrinol 2013;5(Suppl 1):57–69.Web of ScienceGoogle Scholar

  • 25.

    Chertok Shacham E, Ishay A, Irit E, Pohlenz J, Tenenbaum-Rakover Y. Minimally invasive follicular thyroid carcinoma developed in dyshormonogenetic multinodular goiter due to thyroid peroxidase gene mutation. Thyroid 2012;22:542–6.Google Scholar

  • 26.

    Raef H, Al-Rijjal R, Al-Shehri S, Zou M, Al-Mana H, et al. Biallelic p.R2223H mutation in the thyroglobulin gene causes thyroglobulin retention and severe hypothyroidism with subsequent development of thyroid carcinoma. J Clin Endocrinol Metab 2010;95:1000–6.Web of ScienceGoogle Scholar

  • 27.

    Francis G, Waguespack SG, Bauer AJ, Angelos P, Benvenga S, et al. Management guidelines for children with thyroid nodules and differentiated thyroid cancer the american thyroid association guidelines task force on pediatric thyroid cancer. Thyroid 2015;25:716–59.Google Scholar

About the article

Corresponding author: Ilene Fennoy, MD, MPH, Division of Pediatric Endocrinology, Diabetes, and Metabolism, Department of Pediatrics, Columbia University Medical Center, 622 West 168th St, PH-5E-522, New York, NY 10032, USA, Phone: +212-305-6559; Fax: +212-305-4778, E-mail:


Received: 2015-06-23

Accepted: 2015-12-14

Published Online: 2016-02-19

Published in Print: 2016-05-01


Citation Information: Journal of Pediatric Endocrinology and Metabolism, Volume 29, Issue 5, Pages 627–631, ISSN (Online) 2191-0251, ISSN (Print) 0334-018X, DOI: https://doi.org/10.1515/jpem-2015-0253.

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]
Sudha Rathna Prabhu and Shriraam Mahadevan
The Indian Journal of Pediatrics, 2018

Comments (0)

Please log in or register to comment.
Log in