Sporadic congenital nonautoimmune hyperthyroidism caused by P639S mutation in thyrotropin receptor gene
- 266 Downloads
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.
KeywordsSporadic congenital nonautoimmune hyperthyroidism Thyrotoxicosis Thyrotropin receptor Genetic analysis Germline mutation
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.
- 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
- 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
- 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
- 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.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.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.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.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