Ann Pediatr Endocrinol Metab.  2018 Dec;23(4):235-239. 10.6065/apem.2018.23.4.235.

Nonautoimmune congenital hyperthyroidism due to p.Asp633Glu mutation in the TSHR gene

• Cho WK
• Ahn MB
• Jang W
• Chae H
• Kim M
• Suh BK

• KMID: 2432285
• DOI: http://doi.org/10.6065/apem.2018.23.4.235

Abstract

Most cases of congenital hyperthyroidism are autoimmune forms caused by maternal thyroid stimulating antibodies. Nonautoimmune forms of congenital hyperthyroidism caused by activating mutations of the thyrotropin receptor (TSHR) gene are rare. A woman gave birth to a boy during an emergency cesarean section at 33 weeks of gestation due to fetal tachycardia. On the 24th day of life, thyroid function tests were performed due to persistent tachycardia, and hyperthyroidism was confirmed. Auto-antibodies to TSHR, thyroid peroxidase, and thyroglobulin were not found. The patient was treated with propylthiouracil and propranolol, but hyperthyroidism was not well controlled. At 3 months of age, the patient had craniosynostosis and hydrocephalus, and underwent a ventriculoperitoneal shunt operation. Direct sequencing of the TSHR gene showed a heterozygous mutation of c.1899C>A (p.Asp633Glu) in exon 10. No mutations were discovered in any of the parents in a familial genetic study. We have reported a case of sporadic nonautoimmune congenital hyperthyroidism, by a missense mutation of the TSHR gene, for the first time in South Korea.

Keyword

Hyperthyroidism; Nonautoimmune; Thyrotropin receptor; Germ-line mutation

MeSH Terms

Cesarean Section
Craniosynostoses
Emergencies
Exons
Female
Germ-Line Mutation
Humans
Hydrocephalus
Hyperthyroidism*
Immunoglobulins, Thyroid-Stimulating
Iodide Peroxidase
Korea
Male
Mutation, Missense
Parents
Parturition
Pregnancy
Propranolol
Propylthiouracil
Receptors, Thyrotropin
Tachycardia
Thyroglobulin
Thyroid Function Tests
Ventriculoperitoneal Shunt
Immunoglobulins, Thyroid-Stimulating
Iodide Peroxidase
Propranolol
Propylthiouracil
Receptors, Thyrotropin
Thyroglobulin

Figure

• 

  Fig. 1. Direct sequencing analysis of TSHR. The proband was heterozygous for the missense mutation c.1899C>A (p.Asp633Glu). The same base change was not present in his father or mother. The base substitution mutation is indicated by a red arrow.

Reference

References

1. Kopp P, van Sande J, Parma J, Duprez L, Gerber H, Joss E, et al. Brief report: congenital hyperthyroidism caused by a mutation in the thyrotropin-receptor gene. N Engl J Med. 1995; 332:150–4.

2. Gozu HI, Lublinghoff J, Bircan R, Paschke R. Genetics and phenomics of inherited and sporadic non-autoimmune hyperthyroidism. Mol Cell Endocrinol. 2010; 322:125–34.

3. Agretti P, De Marco G, Biagioni M, Iannilli A, Marigliano M, Pinchera A, et al. Sporadic congenital nonautoimmune hyperthyroidism caused by P639S mutation in thyrotropin receptor gene. Eur J Pediatr. 2012; 171:1133–7.

4. Aycan Z, Ağladıoğlu SY, Ceylaner S, Cetinkaya S, Baş VN, Kendirici HN. Sporadic nonautoimmune neonatal hyperthyroidism due to A623V germline mutation in the thyrotropin receptor gene. J Clin Res Pediatr Endocrinol. 2010; 2:168–72.

5. van der Kaay DC, Wasserman JD, Palmert MR. Management of neonates born to mothers with Graves' disease. Pediatrics. 2016; 137.

6. de Roux N, Polak M, Couet J, Leger J, Czernichow P, Milgrom E, et al. A neomutation of the thyroid-stimulating hormone receptor in a severe neonatal hyperthyroidism. J Clin Endocrinol Metab. 1996; 81:2023–6.

7. Börgel K, Pohlenz J, Koch HG, Bramswig JH. Long-term carbimazole treatment of neonatal nonautoimmune hyperthyroidism due to a new activating TSH receptor gene mutation (Ala428Val). Horm Res. 2005; 64:203–8.

8. Nishihara E, Fukata S, Hishinuma A, Kudo T, Ohye H, Ito M, et al. Sporadic congenital hyperthyroidism due to a germline mutation in the thyrotropin receptor gene (Leu 512 Gln) in a Japanese patient. Endocr J. 2006; 53:735–40.

9. Bircan R, Miehle K, Mladenova G, Ivanova R, Ivanova R, Sarafova A, et al. Multiple relapses of hyperthyroidism after thyroid surgeries in a patient with long term follow-up of sporadic non-autoimmune hyperthyroidism. Exp Clin Endocrinol Diabetes. 2008; 116:341–6.

10. Kopp P, Jameson JL, Roe TF. Congenital nonautoimmune hyperthyroidism in a nonidentical twin caused by a sporadic germline mutation in the thyrotropin receptor gene. Thyroid. 1997; 7:765–70.

11. Tonacchera M, Agretti P, Rosellini V, Ceccarini G, Perri A, Zampolli M, et al. Sporadic nonautoimmune congenital hyperthyroidism due to a strong activating mutation of the thyrotropin receptor gene. Thyroid. 2000; 10:859–63.

12. Lavard L, Sehested A, Brock Jacobsen B, Muller J, Perrild H, Feldt-Rasmussen U, et al. Long-term follow-up of an infant with thyrotoxicosis due to germline mutation of the TSH receptor gene (Met453Thr). Horm Res. 1999; 51:43–6.

13. Chester J, Rotenstein D, Ringkananont U, Steuer G, Carlin B, Stewart L, et al. Congenital neonatal hyperthyroidism caused by germline mutations in the TSH receptor gene. J Pediatr Endocrinol Metab. 2008; 21:479–86.

14. Grüters A, Schöneberg T, Biebermann H, Krude H, Krohn HP, Dralle H, et al. Severe congenital hyperthyroidism caused by a germ-line neo mutation in the extracellular portion of the thyrotropin receptor. J Clin Endocrinol Metab. 1998; 83:1431–6.

15. Schwab KO, Söhlemann P, Gerlich M, Broecker M, Petrykowski W, Holzapfel HP, et al. Mutations of the TSH receptor as cause of congenital hyperthyroidism. Exp Clin Endocrinol Diabetes. 1996; 104 Suppl 4:124–8.

16. Holzapfel HP, Wonerow P, von Petrykowski W, Henschen M, Scherbaum WA, Paschke R. Sporadic congenital hyperthyroidism due to a spontaneous germline mutation in the thyrotropin receptor gene. J Clin Endocrinol Metab. 1997; 82:3879–84.

17. Scaglia PA, Chiesa A, Bastida G, Pacin M, Domené HM, Gruñeiro-Papendieck L. Severe congenital nonautoimmune hyperthyroidism associated to a mutation in the extracellular domain of thyrotropin receptor gene. Arq Bras Endocrinol Metabol. 2012; 56:513–8.

18. de Roux N, Misrahi M, Chatelain N, Gross B, Milgrom E. Microsatellites and PCR primers for genetic studies and genomic sequencing of the human TSH receptor gene. Mol Cell Endocrinol. 1996; 117:253–6.

19. Esapa CT, Duprez L, Ludgate M, Mustafa MS, Kendall-Taylor P, Vassart G, et al. A novel thyrotropin receptor mutation in an infant with severe thyrotoxicosis. Thyroid. 1999; 9:1005–10.

20. Führer D, Wonerow P, Willgerodt H, Paschke R. Identification of a new thyrotropin receptor germline mutation (Leu629Phe) in a family with neonatal onset of autosomal dominant nonautoimmune hyperthyroidism. J Clin Endocrinol Metab. 1997; 82:4234–8.