Clinical and genetic investigation of 136 Japanese patients with congenital hypothyroidism
-
Tatsushi Tanaka
Abstract
Objectives
Congenital hypothyroidism (CH) is the most common congenital endocrine disorder. Recent advances in genetic testing have revealed its causative mutations in some CH patients. However, the underlying etiology remains unknown in most patients. This study aimed to perform clinical and genetic investigation in Japanese CH patients to uncover genotype-phenotype correlations.
Methods
We enrolled 136 Japanese patients with transient or permanent CH between April 2015 and March 2017, and performed next-generation sequencing of 19 genes implicated in CH.
Results
We identified potentially pathogenic bi-allelic variants in DUOX2, TSHR, and TPO in 19, 5, and 1 patient, respectively (autosomal recessive), and a potentially pathogenic mono-allelic variant in NKX2-1 (autosomal dominant) in 1 patient. Molecular genetic diagnosis was highly suggested in 26 patients (19%) from 23 families. We also detected a potentially pathogenic mono-allelic variant in five recessive genes (DUOX2, TSHR, TG, DUOXA2, and TPO) in 31 unrelated patients (23%), although the pathogenicity of these variants remains inconclusive. Patients with bi-allelic DUOX2 variants showed a more severe clinical presentation in infancy than those with bi-allelic TSHR variants. However, this trend reversed beyond infancy. There were no statistical differences in initial thyroid stimulating hormone, free thyroxine, thyroglobulin, and levothyroxine dose as of March 2017 between patients with bi-allelic and mono-allelic DUOX2 variants.
Conclusions
The prevalence of potentially-pathogenic variants in Japanese CH patients was similar to that found by previous reports. Our study demonstrates a genotype-phenotype correlation in Japanese CH patients.
Acknowledgments
We would like to thank the patients and their families for participating in this study, and the clinicians for providing patient samples and information. We thank the Core Laboratory of the Nagoya City University Graduate School of Medical Sciences. We also thank Ms. Masami Banno and Ms. Yumiko Sato (our laboratory staff).
Research funding: None declared.
Author contributions: All the authors have accepted responsibility for the entire content of this submitted manuscript and approved submission.
Competing interests: The funding organization(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.
Employment or leadership: None declared.
Honorarium: None declared.
Informed consent: Written informed consent for the study was obtained from all the patients’ parents.
References
1. Ford G, LaFranchi SH. Screening for congenital hypothyroidism: a worldwide view of strategies. Best Pract Res Clin Endocrinol Metab 2014;28:175–87. https://doi.org/10.1016/j.beem.2013.05.008.Search in Google Scholar PubMed
2. Kendirci HN, Aycan Z, Sağsak E, Keskin M, Çetinkaya S. The evaluation of transient hypothyroidism in patients diagnosed with congenital hypothyroidism. Turk J Med Sci 2015;45:745–50. https://doi.org/10.3906/sag-1404-109.Search in Google Scholar
3. Gaudino R, Garel C, Czernichow P, Leger J. Proportion of various types of thyroid disorders among newborns with congenital hypothyroidism and normally located gland: a regional cohort study. Clin Endocrinol 2005;62:444–8. https://doi.org/10.1111/j.1365-2265.2005.02239.x.Search in Google Scholar PubMed
4. Szinnai G. Clinical genetics of congenital hypothyroidism. Endocr Dev 2014;26:60–78. https://doi.org/10.1159/000363156.Search in Google Scholar PubMed
5. Nagasaki K, Minamitani K, Anzo M, Adachi M, Ishii T, Onigata K, et al. Guidelines for mass screening of congenital hypothyroidism (2014 revision). Clin Pediatr Endocrinol 2015;24:107–33. https://doi.org/10.1297/cpe.24.107.Search in Google Scholar PubMed PubMed Central
6. Wang F, Liu C, Jia X, Liu X, Xu Y, Yan S, et al. Next-generation sequencing of NKX2.1, FOXE1, PAX8, NKX2.5, and TSHR in 100 Chinese patients with congenital hypothyroidism and athyreosis. Clin Chim Acta 2017;470:36–41. https://doi.org/10.1016/j.cca.2017.04.020.Search in Google Scholar PubMed
7. 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. https://doi.org/10.1210/jc.2011-1573.Search in Google Scholar PubMed
8. Maruo Y, Nagasaki K, Matsui K, Mimura Y, Mori A, Fukami M, et al. Natural course of congenital hypothyroidism by dual oxidase 2 mutations from the neonatal period through puberty. Eur J Endocrinol 2016;174:453–63. https://doi.org/10.1530/eje-15-0959.Search in Google Scholar
9. Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, 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. https://doi.org/10.1038/gim.2015.30.Search in Google Scholar PubMed PubMed Central
10. Matsuo K, Tanahashi Y, Mukai T, Suzuki S, Tajima T, Azuma H, et al. High prevalence of DUOX2 mutations in Japanese patients with permanent congenital hypothyroidism or transient hypothyroidism. J Pediatr Endocrinol Metabol 2016;29:807–12. https://doi.org/10.1515/jpem-2015-0400.Search in Google Scholar PubMed
11. Jin HY, Heo SH, Kim YM, Kim GH, Choi JH, Lee BH, et al. High frequency of DUOX2 mutations in transient or permanent congenital hypothyroidism with eutopic thyroid glands. Horm Res Paediatr 2014;82:252–60. https://doi.org/10.1159/000362235.Search in Google Scholar PubMed
12. Park KJ, Park HK, Kim YJ, Lee KR, Park JH, Park JH, et al. DUOX2 mutations are frequently associated with congenital hypothyroidism in the Korean population. Ann Lab Med 2016;36:145–53. https://doi.org/10.3343/alm.2016.36.2.145.Search in Google Scholar PubMed PubMed Central
13. Fan X, Fu C, Shen Y, Li C, Luo S, Li Q, et al. Next-generation sequencing analysis of twelve known causative genes in congenital hypothyroidism. Clin Chim Acta 2017;468:76–80. https://doi.org/10.1016/j.cca.2017.02.009.Search in Google Scholar PubMed
14. Muzza M, Rabbiosi S, Vigone MC, Zamproni I, Cirello V, Maffini MA, et al. The clinical and molecular characterization of patients with dyshormonogenic congenital hypothyroidism reveals specific diagnostic clues for DUOX2 defects. J Clin Endocrinol Metabol 2014;99:E544–53. https://doi.org/10.1210/jc.2013-3618.Search in Google Scholar PubMed
15. Moreno JC, Bikker H, Kempers MJ, van Trotsenburg AS, Baas F, de Vijlder JJ, et al. Inactivating mutations in the gene for thyroid oxidase 2 (THOX2) and congenital hypothyroidism. N Engl J Med 2002;347:95–102. https://doi.org/10.1056/nejmoa012752.Search in Google Scholar PubMed
16. Maruo Y, Takahashi H, Soeda I, Nishikura N, Matsui K, Ota Y, 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. https://doi.org/10.1210/jc.2008-0856.Search in Google Scholar PubMed
17. Yoshizawa-Ogasawara A, Abe K, Ogikubo S, Narumi S, Hasegawa T, Satoh M. Transient congenital hypothyroidism caused by compound heterozygous mutations affecting the NADPH-oxidase domain of DUOX2. J Pediatr Endocrinol Metab 2016;29:363–71. https://doi.org/10.1515/jpem-2014-0479.Search in Google Scholar PubMed
18. Narumi S, Muroya K, Abe Y, Yasui M, Asakura Y, Adachi M, et al. TSHR mutations as a cause of congenital hypothyroidism in Japan: a population-based genetic epidemiology study. J Clin Endocrinol Metab 2009;94:1317–23. https://doi.org/10.1210/jc.2008-1767.Search in Google Scholar PubMed
19. Grasberger H, Refetoff S. Genetic causes of congenital hypothyroidism due to dyshormonogenesis. Curr Opin Pediatr 2011;23:421–8. https://doi.org/10.1097/mop.0b013e32834726a4.Search in Google Scholar
20. Moreno JC, Visser TJ. New phenotypes in thyroid dyshormonogenesis: hypothyroidism due to DUOX2 mutations. Endocr Dev 2007;10:99–117. https://doi.org/10.1159/000106822.Search in Google Scholar PubMed
21. Kanda K, Mizuno H, Sugiyama Y, Imamine H, Togari H, Onigata K. Clinical significance of heterozygous carriers associated with compensated hypothyroidism in R450H, a common inactivating mutation of the thyrotropin receptor gene in Japanese. Endocrine 2006;30:383–8. https://doi.org/10.1007/s12020-006-0018-z.Search in Google Scholar PubMed
22. Fugazzola L, Cerutti N, Mannavola D, Vannucchi G, Fallini C, Persani L, et al. Monoallelic expression of mutant thyroid peroxidase allele causing total iodide organification defect. J Clin Endocrinol Metab 2003;88:3264–71. https://doi.org/10.1210/jc.2002-021377.Search in Google Scholar PubMed
23. de Filippis T, Gelmini G, Paraboschi E, Vigone MC, Di Frenna M, Marelli F, et al. A frequent oligogenic involvement in congenital hypothyroidism. Hum Mol Genet 2017;26:2507–14. https://doi.org/10.1093/hmg/ddx145.Search in Google Scholar PubMed
24. Watanabe Y, Bruellman RJ, Ebrhim RS, Abdullah MA, Dumitrescu AM, Refetoff S, et al. Congenital hypothyroidism due to oligogenic mutations in two Sudanese families. Thyroid 2019;29:302–4. https://doi.org/10.1089/thy.2018.0295.Search in Google Scholar PubMed PubMed Central
25. Aycan Z, Cangul H, Muzza M, Bas VN, Fugazzola L, Chatterjee VK, et al. Digenic DUOX1 and DUOX2 mutations in cases with congenital hypothyroidism. J Clin Endocrinol Metab 2017;102:3085–90. https://doi.org/10.1210/jc.2017-00529.Search in Google Scholar PubMed PubMed Central
26. Pinsker JE, McBayne K, Edwards M, Jensen K, Crudo DF, Bauer AJ. Transient hypothyroidism in premature infants after short-term topical iodine exposure: an avoidable risk? Pediatr Neonatol 2013;54:128–31. https://doi.org/10.1016/j.pedneo.2012.10.005.Search in Google Scholar PubMed
© 2020 Walter de Gruyter GmbH, Berlin/Boston
Articles in the same Issue
- Frontmatter
- Original Articles
- Genetic characteristics and follow-up of patients with fatty acid β-oxidation disorders through expanded newborn screening in a Northern Chinese population
- Clinical and genetic investigation of 136 Japanese patients with congenital hypothyroidism
- Institutional experience of newborn screening for inborn metabolism disorders by tandem MS in the Turkish population
- Investigation of the effect of epicardial adipose tissue thickness on cardiac conduction system in children with type 1 diabetes mellitus
- Retrospective evaluation of 85 patients with urea cycle disorders: one center experience, three new mutations
- Circulating chemerin level may be associated with early vascular pathology in obese children without overt arterial hypertension – preliminary results
- A novel diagnostic tool for the evaluation of hypothalamic-pituitary region and diagnosis of growth hormone deficiency: pons ratio
- Growth status of children and adolescents born small for gestational age at full term in Korea: data from the KNHANES-V
- Children with onset-ketoacidosis are admitted to the nearest hospital available, regardless of center size
- Evaluation of α-klotho level in insulin dependent diabetes mellitus (IDDM) children
- Evaluation of the relationship between the one-hour plasma glucose concentration and beta-cell functions and cardiometabolic parameters during oral glucose tolerance test in obese children and adolescents
- Triglycerides/high-density lipoprotein cholesterol is a predictor similar to the triglyceride–glucose index for the diagnosis of metabolic syndrome using International Diabetes Federation criteria of insulin resistance in obese adolescents: a cross-sectional study
- Rapid progressive central precocious puberty: diagnostic and predictive value of basal sex hormone levels and pelvic ultrasound
- Mucopolysaccharidosis III in Mainland China: natural history, clinical and molecular characteristics of 34 patients
- Case Reports
- An infant presenting with extreme hypertriglyceridemia diagnosed as glycogen storage disease type Ia
- A novel heterozygous mutation in the insulin receptor gene presenting with type A severe insulin resistance syndrome
- Isolated premature menarche in two siblings with Neurofibromatosis type 1
- GAD-65 autoantibody associated epilepsy
Articles in the same Issue
- Frontmatter
- Original Articles
- Genetic characteristics and follow-up of patients with fatty acid β-oxidation disorders through expanded newborn screening in a Northern Chinese population
- Clinical and genetic investigation of 136 Japanese patients with congenital hypothyroidism
- Institutional experience of newborn screening for inborn metabolism disorders by tandem MS in the Turkish population
- Investigation of the effect of epicardial adipose tissue thickness on cardiac conduction system in children with type 1 diabetes mellitus
- Retrospective evaluation of 85 patients with urea cycle disorders: one center experience, three new mutations
- Circulating chemerin level may be associated with early vascular pathology in obese children without overt arterial hypertension – preliminary results
- A novel diagnostic tool for the evaluation of hypothalamic-pituitary region and diagnosis of growth hormone deficiency: pons ratio
- Growth status of children and adolescents born small for gestational age at full term in Korea: data from the KNHANES-V
- Children with onset-ketoacidosis are admitted to the nearest hospital available, regardless of center size
- Evaluation of α-klotho level in insulin dependent diabetes mellitus (IDDM) children
- Evaluation of the relationship between the one-hour plasma glucose concentration and beta-cell functions and cardiometabolic parameters during oral glucose tolerance test in obese children and adolescents
- Triglycerides/high-density lipoprotein cholesterol is a predictor similar to the triglyceride–glucose index for the diagnosis of metabolic syndrome using International Diabetes Federation criteria of insulin resistance in obese adolescents: a cross-sectional study
- Rapid progressive central precocious puberty: diagnostic and predictive value of basal sex hormone levels and pelvic ultrasound
- Mucopolysaccharidosis III in Mainland China: natural history, clinical and molecular characteristics of 34 patients
- Case Reports
- An infant presenting with extreme hypertriglyceridemia diagnosed as glycogen storage disease type Ia
- A novel heterozygous mutation in the insulin receptor gene presenting with type A severe insulin resistance syndrome
- Isolated premature menarche in two siblings with Neurofibromatosis type 1
- GAD-65 autoantibody associated epilepsy
