Advertisement

European Journal of Pediatrics

, Volume 171, Issue 7, pp 1133–1137 | Cite as

Sporadic congenital nonautoimmune hyperthyroidism caused by P639S mutation in thyrotropin receptor gene

  • Patrizia Agretti
  • Giuseppina De Marco
  • Martina Biagioni
  • Antonio Iannilli
  • Marco Marigliano
  • Aldo Pinchera
  • Paolo Vitti
  • Valentino Cherubini
  • Massimo TonaccheraEmail author
Case Report

Abstract

Germline mutations of thyrotropin receptor (TSHR) gene determining a constitutive activation of the receptor were identified as a molecular cause of familial or sporadic congenital nonautoimmune hyperthyroidism (OMIM: 609152) (Nat Genet 7:396–401, 1994; N Engl J Med 332:150–154, 1995; Acta Endocrinol (Copenh) 100:512–518, 1982). We report the case of an Italian child subjected to the first clinical investigation at 24 months for an increased growth velocity; biochemical investigation showed high FT4 and FT3 serum values and undetectable thyrotropin in the absence of anti-thyroid antibodies; the thyroid gland was normal at ultrasound examination. Treatment with methimazole was started at the age of 30 months when her growth velocity was high and the bone age was advanced. DNA was extracted from her parents’, brother’s, and the patient’s blood. Exons 9 and 10 of the TSHR gene were amplified by polymerase chain reaction and subjected to direct sequencing. In proband, a heterozygous substitution of cytosine to thymine determining a proline to serine change at position 639 (P639S) of the TSHR was detected while the parents and brothers of the propositus, all euthyroid, showed only the wild-type sequence of the TSHR gene. This mutation was previously described as somatic in patients affected by hyperfunctioning thyroid nodules and as germline in a single Chinese family affected by thyrotoxicosis and mitral valve prolapse. This constitutively activating mutation is able to activate both the cyclic AMP and the inositol phosphate metabolic pathways when expressed in a heterologous system. In conclusion, we describe the first case of sporadic congenital nonautoimmune hyperthyroidism caused by de novo germinal P639S mutation of TSHR.

Keywords

Sporadic congenital nonautoimmune hyperthyroidism Thyrotoxicosis Thyrotropin receptor Genetic analysis Germline mutation 

Notes

Acknowledgments

We are grateful to Ministero Dell’Universita’ e Della Ricerca Scientifica e Tecnologica and Ministero Della Sanita for funding.

Conflict of interest

The authors declare that they have no conflict of interest.

References

  1. 1.
    Agretti P, De Marco G, Collecchi P, Chiovato L, Vitti P, Pinchera A, Tonacchera M (2003) Proper targeting and activity of a nonfunctioning thyroid-stimulating hormone receptor (TSHR) combining an inactivating and activating TSHR mutation in one receptor. M Eur J Biochem 270:3839–3847CrossRefGoogle Scholar
  2. 2.
    Aycan Z, Ağladıoğlu SY, Ceylaner S, Cetinkaya S, Baş VN, Peltek Kendirici HN (2010) Sporadic nonautoimmune neonatal hyperthyroidism due to A623V germline mutation in the thyrotropin receptor gene. J Clin Res Ped Endo 2:168–172CrossRefGoogle Scholar
  3. 3.
    Duprez L, Parma J, Van Sande J, Allgeier A, Leclère J, Schvartz C, Delisle MJ, Decoulx M, Orgiazzi J, Dumont J et al (1994) Germline mutations in the thyrotropin receptor gene cause non-autoimmune autosomal dominant hyperthyroidism. Nat Genet 7:396–401PubMedCrossRefGoogle Scholar
  4. 4.
    Fuhrer D, Warner J, Sequeira M, Paschke R, Gregory J, Ludgate M (2000) Novel TSHR germline mutation (Met463Val) masquerading as Graves’ disease in a large Welsh kindred with hyperthyroidism. Thyroid 10:1035–1041PubMedCrossRefGoogle Scholar
  5. 5.
    Führer D, Wonerow P, Willgerodt H, Paschke R (1997) Identification of a new thyrotropin receptor germline mutation (Leu629Phe) in a family with neonatal onset of autosomal dominant nonautoimmune hyperthyroidism. J Clin Endocrinol Metab 82:4234–4238PubMedCrossRefGoogle Scholar
  6. 6.
    Gether U, Lin S, Ghanouni P, Ballesteros JA, Weinstein H, Kobilka BK (1997) Agonists induce conformational changes in transmembrane domains III and VI of the beta2 adrenoceptor. EMBO J 16:6737–6747PubMedCrossRefGoogle Scholar
  7. 7.
    Gozu HI, Bircan R, Krohn K, Müller S, Vural S, Gezen C, Sargin H, Yavuzer D, Sargin M, Cirakoglu B, Paschke R (2006) Similar prevalence of somatic TSH receptor and Gsalpha mutations in toxic thyroid nodules in geographical regions with different iodine supply in Turkey. Eur J Endocrinol 155:535–545PubMedCrossRefGoogle Scholar
  8. 8.
    Gozu HI, Lublinghoff J, Bircan R, Paschke R (2010) Genetics and phenomics of inherited and sporadic non-autoimmune hyperthyroidism. Mol Cell Endocrinol 322:125–134PubMedCrossRefGoogle Scholar
  9. 9.
    Hebrant A, van Staveren WC, Maenhaut C, Dumont JE, Leclère J (2011) Genetic hyperthyroidism: hyperthyroidism due to activating TSHR mutations. Eur J Endocrinol 164:1–9PubMedCrossRefGoogle Scholar
  10. 10.
    Holzapfel HP, Wonerow P, von Petrykowski W, Henschen M, Scherbaum WA, Paschke R (1997) Sporadic congenital hyperthyroidism due to a spontaneous germline mutation in the thyrotropin receptor gene. J Clin Endocrinol Metab 82:3879–3884PubMedCrossRefGoogle Scholar
  11. 11.
    Khoo DH, Parma J, Rajasoorya C, Ho SC, Vassart G (1999) A germline mutation of the thyrotropin receptor gene associated with thyrotoxicosis and mitral valve prolapse in a Chinese family. J Clin Endocrino Metab 84:1459–1462CrossRefGoogle Scholar
  12. 12.
    Kopp P, Van Sande J, Parma J, Duprez L, Gerber H, Joss E, Jameson JL, Dumont JE, Vassart G (1995) Brief report: congenital hyperthyroidism caused by a mutation in the thyrotropin-receptor gene. N Engl J Med 332:150–154PubMedCrossRefGoogle Scholar
  13. 13.
    Kopp P (2001) The TSH receptor and its role in thyroid disease. Cell Mol Life Sci 58:1301–1322PubMedCrossRefGoogle Scholar
  14. 14.
    Lueblinghoff J, Mueller S, Sontheimer J, Paschke R (2010) Lack of consistent association of thyrotropin receptor mutations in vitro activity with the clinical course of patients with sporadic non-autoimmune hyperthyroidism. J Endocrinol Invest 33:228–233PubMedGoogle Scholar
  15. 15.
    Parma J, Duprez L, Van Sande J, Hermans J, Rocmans P, Van Vliet G, Costagliola S, Rodien P, Dumont JE, Vassart G (1997) Diversity and prevalence of somatic mutations in the thyrotropin receptor and Gs alpha genes as a cause of toxic thyroid adenomas. J Clin Endocrinol Metab 82:2695–2701PubMedCrossRefGoogle Scholar
  16. 16.
    Polak M, Legac I, Vuillard E, Guibourdenche J, Castanet M, Luton D (2006) Congenital hyperthyroidism: the fetus as a patient. Horm Res 65:235–242PubMedCrossRefGoogle Scholar
  17. 17.
    Schwab KO, Söhlemann P, Gerlich M, Broecker M, Petrykowski W, Holzapfel HP, Paschke R, Grüters A, Derwahl M (1996) Mutations of the TSH receptor as cause of congenital hyperthyroidism. Exp Clin Endocrinol Diabetes 104:124–128PubMedCrossRefGoogle Scholar
  18. 18.
    Thomas JS, Leclere J, Hartemann P, Duheille J, Orgiazzi J, Petersen M, Janot C, Guedenet JC (1982) Familial hyperthyroidism without evidence of autoimmunity. Acta Endocrinol (Copenh) 100:512–518Google Scholar
  19. 19.
    Tonacchera M, Banco M, Lapi P, Di Cosmo C, Perri A, Montanelli L, Moschini L, Gatti G, Gandini D, Massei A, Agretti P, De Marco G, Vitti P, Chiovato L, Pinchera A (2004) Genetic analysis of TTF-2 gene in children with congenital hypothyroidism and cleft palate, congenital hypothyroidism, or isolated cleft palate. Thyroid 14:584–588PubMedCrossRefGoogle Scholar
  20. 20.
    Tonacchera M, Chiovato L, Pinchera A, Agretti P, Fiore E, Cetani F, Rocchi R, Viacava P, Miccoli P, Vitti P (1998) Hyperfunctioning thyroid nodules in toxic multinodular goiter share activating thyrotropin receptor mutations with solitary toxic adenoma. J Clin Endocrinol Metab 83:492–498PubMedCrossRefGoogle Scholar
  21. 21.
    Tonacchera M, Vitti P, Agretti P, Ceccarini G, Perri A, Cavaliere R, Mazzi B, Naccarato AG, Viacava P, Miccoli P, Pinchera A, Chiovato L (1999) Functioning and nonfunctioning thyroid adenomas involve different molecular pathogenetic mechanisms. J Clin Endocrinol Metab 84:4155–4158PubMedCrossRefGoogle Scholar
  22. 22.
    Vitti P, Elisei R, Tonacchera M, Chiovato L, Mancusi F, Rago T, Mammoli C, Ludgate M, Vassart G, Pinchera A (1993) Detection of thyroid-stimulating antibody using Chinese hamster ovary cells transfected with cloned human thyrotropin receptor. J Clin Endocrinol Metab 76:499–503PubMedCrossRefGoogle Scholar
  23. 23.
    Zakarija M, McKenzie JM (1983) Pregnancy-associated changes in the thyroid-stimulating antibody of Graves’ disease and the relationship to neonatal hyperthyroidism. J Clin Endocrinol Metab 57:1036–1040PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2012

Authors and Affiliations

  • Patrizia Agretti
    • 1
  • Giuseppina De Marco
    • 1
  • Martina Biagioni
    • 2
  • Antonio Iannilli
    • 2
  • Marco Marigliano
    • 2
  • Aldo Pinchera
    • 1
  • Paolo Vitti
    • 1
  • Valentino Cherubini
    • 2
  • Massimo Tonacchera
    • 1
    • 3
    Email author
  1. 1.Dipartimento di Endocrinologia e Metabolismo, Centro Eccellenza AmbiSENUniversità di PisaPisaItaly
  2. 2.S.O.D. Diabetologia PediatricaAzienda Ospedaliero-Universitaria Ospedali Riuniti AnconaAnconaItaly
  3. 3.Dipartimento di EndocrinologiaUniversità di PisaPisaItaly

Personalised recommendations