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Novel TSHR germline mutation (Met463Val) masquerading as Graves' disease in a large Welsh kindred with hyperthyroidism

Fuhrer, D., Warner, J., Sequeira, R., Paschke, R., Gregory, John Welbourn ORCID: and Ludgate, Marian Elizabeth 2000. Novel TSHR germline mutation (Met463Val) masquerading as Graves' disease in a large Welsh kindred with hyperthyroidism. Thyroid: Official Journal of the American Thyroid Association 10 (12) , pp. 1035-1041. 10.1089/thy.2000.10.1035

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Hereditary nonautoimmune hyperthyroidism is caused by activating germline mutations in the thyrotropin (TSH) receptor (TSHR) gene. We describe an extended Welsh kindred with toxic thyroid hyperplasia affecting 8 family members in three generations and a history consistent with thyrotoxicosis in a further three generations now deceased. A novel heterozygous germline mutation (ATG --> GTG; Met463Val) was identified in the second membrane spanning TSHR region in 6 relatives with thyrotoxicosis and goiter and absence of TSHR antibodies. Screening of 5 additional family members led to the identification of 2 siblings with the mutation, who were asymptomatic at the time, although subsequent thyroid function tests in these children showed suppressed serum TSH and increased serum free triiodothyronine (FT3) and free thyroxine (FT4) concentrations. Functional studies of the novel TSHR germline mutation demonstrated a constitutive activation of the cAMP pathway, which in the thyroid controls both thyroid hormone production and stimulation of thyroid growth. The molecular diagnosis in this family has clinical implications: genetic counseling is required, and primary thyroid ablation should be advocated as the preferred treatment in the patients with the constitutively activating TSHR germline mutation.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
Subjects: R Medicine > R Medicine (General)
R Medicine > RZ Other systems of medicine
Publisher: Mary Ann Liebert
ISSN: 1050-7256
Last Modified: 14 May 2024 15:28

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