Double variants in TSHR and DUOX2 in a patient with hypothyroidism: case report
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Zerin Sasivari
Abstract
Thyroid dyshormonogenesis (TDH) is characterized by the defective synthesis of thyroid hormones. We present a patient with congenital hypothyroidism (CH) who presented in newborn screening with elevated serum thyroid-stimulating hormone (TSH), decreased free thyroxine (fT4) and increased thyroglobulin (Tg) concentrations. Ultrasound scan revealed a properly structured thyroid gland. Treatment with L-thyroxine was initiated. At the age of 2 years, thyroxine replacement was stopped. The patient remained untreated until 6 years of age when TSH levels progressively increased and L-thyroxine treatment was restarted at a dose of 12.5 μg/day. Genetic analysis revealed a double heterozygosity for likely pathogenic variants of dual oxidase 2 (DUOX2) and thyroid stimulating hormone receptor (TSHR). Both genes were earlier shown to be associated with CH. In a literature review, our patient was compared to previously published patients with similar clinical characteristics, and a good genotype-phenotype correlation was identified.
Author contributions: Sasivari Z analyzed the patient’s dossier and wrote the paper. Seebauer B is responsible for genetic investigation. Szinnai G, Konrad D and Seebauer B provided critical feedback and helped shape the manuscript. Lang-Muritano M treated the patient from birth and was the supervisor of this paper.
Research funding: None declared.
Employment or leadership: None declared.
Honorarium: None declared.
Competing interest: The authors declare that they have no conflict of interest.
References
1. Rastogi MV, LaFranchi SH. Congenital hypothyroidism. Orphanet J Rare Dis 2010;5:17.10.1186/1750-1172-5-17Search in Google Scholar PubMed PubMed Central
2. Illig R, Largo RH, Qin Q, Torresani T, Rochiccioli P, et al. Mental development in congenital hypothyroidism after neonatal screening. Arch Dis Child 1987;62:1050–5.10.1136/adc.62.10.1050Search in Google Scholar PubMed PubMed Central
3. Szinnai G. Clinical genetics of congenital hypothyroidism. Endocr Dev 2014;26:60–78.10.1159/000363156Search in Google Scholar PubMed
4. Abe K, Narumi S, Suwanai AS, Adachi M, Muroya K, et al. Association between monoallelic. Eur J Endocrinol 2018;178:137–44.10.1530/EJE-16-1049Search in Google Scholar PubMed
5. Persani L, Calebiro D, Cordella D, Weber G, Gelmini G, et al. Genetics and phenomics of hypothyroidism due to TSH resistance. Mol Cell Endocrinol 2010;322:72–82.10.1016/j.mce.2010.01.008Search in Google Scholar PubMed
6. Salerno M, Capalbo D, Cerbone M, De Luca F. Subclinical hypothyroidism in childhood – current knowledge and open issues. Nat Rev Endocrinol 2016;12:734–46.10.1038/nrendo.2016.100Search in Google Scholar PubMed
7. Pfarr N, Korsch E, Kaspers S, Herbst A, Stach A, et al. Congenital hypothyroidism caused by new mutations in the thyroid oxidase 2 (THOX2) gene. Clin Endocrinol (Oxf) 2006;65:810–5.10.1111/j.1365-2265.2006.02672.xSearch in Google Scholar PubMed
8. 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:E544–53.10.1210/jc.2013-3618Search in Google Scholar PubMed
9. Alberti L, Proverbio MC, Costagliola S, Romoli R, Boldrighini B, et al. Germline mutations of TSH receptor gene as cause of nonautoimmune subclinical hypothyroidism. J Clin Endocrinol Metab 2002;87:2549–55.10.1210/jcem.87.6.8536Search in Google Scholar PubMed
10. 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;81:80–103.10.1159/000358198Search in Google Scholar PubMed
11. Nicholas AK, Serra EG, Cangul H, Alyaarubi S, Ullah I, et al. Comprehensive screening of eight known causative genes in congenital hypothyroidism with gland-in-situ. J Clin Endocrinol Metab 2016;101:4521–31.10.1210/jc.2016-1879Search in Google Scholar PubMed PubMed Central
12. Fu C, Luo S, Zhang S, Wang J, Zheng H, et al. Next-generation sequencing analysis of DUOX2 in 192 Chinese subclinical congenital hypothyroidism (SCH) and CH patients. Clin Chim Acta 2016;458:30–4.10.1016/j.cca.2016.04.019Search in Google Scholar PubMed
13. Fu C, Wang J, Luo S, Yang Q, Li Q, et al. Next-generation sequencing analysis of TSHR in 384 Chinese subclinical congenital hypothyroidism (CH) and CH patients. Clin Chim Acta 2016;462:127–32.10.1016/j.cca.2016.09.007Search in Google Scholar PubMed
14. 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;82:252–60.10.1159/000362235Search in Google Scholar PubMed
15. Satoh M, Aso K, Ogikubo S, Yoshizawa-Ogasawara A, Saji T. Hypothyroidism caused by the combination of two heterozygous mutations: one in the TSH receptor gene the other in the DUOX2 gene. J Pediatr Endocrinol Metab 2015;28:657–61.10.1515/jpem-2014-0078Search in Google Scholar PubMed
16. de Filippis T, Gelmini G, Paraboschi E, Vigone MC, Di Frenna M, et al. A frequent oligogenic involvement in congenital hypothyroidism. Hum Mol Genet 2017;26:2507–14.10.1093/hmg/ddx145Search in Google Scholar PubMed
17. Park KJ, Park HK, Kim YJ, Lee KR, Park JH, et al. DUOX2 mutations are frequently associated with congenital hypothyroidism in the Korean population. Ann Lab Med 2016;36:145–53.10.3343/alm.2016.36.2.145Search in Google Scholar PubMed PubMed Central
18. Sun F, Zhang JX, Yang CY, Gao GQ, Zhu WB, et al. The genetic characteristics of congenital hypothyroidism in China by comprehensive screening of 21 candidate genes. Eur J Endocrinol 2018;178:623–33.10.1530/EJE-17-1017Search in Google Scholar PubMed PubMed Central
19. Fan X, Fu C, Shen Y, Li C, Luo S, et al. Next-generation sequencing analysis of twelve known causative genes in congenital hypothyroidism. Clin Chim Acta 2017;468:76–80.10.1016/j.cca.2017.02.009Search in Google Scholar PubMed
©2019 Walter de Gruyter GmbH, Berlin/Boston
Articles in the same Issue
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Articles in the same Issue
- Frontmatter
- Editorial
- Hypo- and hyperthyroidism in early life – new developments
- Letters to the Editor
- Optic nerve sheath diameter appraisal in children affected by diabetic ketoacidosis
- Optic nerve sheath diameter ultrasound measurement to evaluate cerebral edema in children with diabetic ketoacidosis
- Original Articles
- Novel ABCD1 gene mutations in Iranian pedigrees with X-linked adrenoleukodystrophy
- Phenylketonuric patients represent their disease
- Mapping of IDUA gene variants in Pakistani patients with mucopolysaccharidosis type 1
- Genetic testing of two Pakistani patients affected with rare autosomal recessive Fanconi-Bickel syndrome and identification of a novel SLC2A2 splice site variant
- Sex differences in infant body composition emerge in the first 5 months of life
- Characterization of the duration of treatment with diazoxide in infants with prolonged hyperinsulinism (PHI)
- Clinical, biochemical and gender characteristics of 97 prepubertal children with premature adrenarche
- The adjustment of 17-hydroxyprogesterone cut-off values for congenital adrenal hyperplasia neonatal screening by GSP according to gestational age and age at sampling
- The role of vitamin D replacement therapy in serum FGF23 concentration in children with myelomeningocele compared with healthy children – a preliminary study
- Genetic analyses in a cohort of Portuguese pediatric patients with congenital hypothyroidism
- Congenital hypothyroidism in preterm infants: a 3- to 8-year longitudinal study in southern Thailand
- Case Reports
- A case of PHACE syndrome with growth hormone deficiency and abnormal thyroid functions
- A novel DCAF17 homozygous mutation in a girl with Woodhouse-Sakati syndrome and review of the current literature
- Acquired von Willebrand’s syndrome caused by primary hypothyroidism in a 5-year-old girl
- Double variants in TSHR and DUOX2 in a patient with hypothyroidism: case report
