Mild hyperthyroidism caused by germline activating TSHR mutation

Program: Abstracts - Orals, Featured Poster Presentations, and Posters
Session: SAT 449-497-Thyroid Neoplasia & Case Reports
Saturday, June 15, 2013: 1:45 PM-3:45 PM
Expo Halls ABC (Moscone Center)

Poster Board SAT-478
Jiao Fu*1, Caecilie Crawley Larsen2, Gad Benjamin Kletter3, Roy E Weiss4, Samuel Refetoff4 and Alexandra M Dumitrescu4
1University of Chicago Medical Center, 2University of Southern Denmark, Denmark, 3Swedish Physician Division, Seattle, WA, 4University of Chicago, Chicago, IL
Background. Nonautoimmue hyperthyroidism due to germline gain of function mutations in the thyrotropin (TSH) receptor (TSHR) is a relatively rare condition. The mechanism of the disease involves two signalling pathways, Gs/adenylyl cyclase and Gq/11 phospholipase C pathways, which are induced by the binding of the TSH to TSHR.

Case report. The propositus, a 13.5 year old boy, presented with a one year history of palpitations at rest due to sinus tachycardia, sleep difficulties and increasing bowel movements. No symptoms of heat intolerance, exophthalmos, tremor, and weight loss were present and no goiter was noted. His mother was diagnosed with hyperthyroidism in her twenties and underwent a total thyroidectomy 10 years later for a presumed hyperfunctioning thyroid nodule and was placed on levothyroxine. His maternal aunt and maternal grandmother were diagnosed with presumed Graves’ disease without having positive antibodies or exophthalmos. The father and a younger brother were unaffected. Thyroid function tests (TFTs) of the propositus revealed a low TSH 0.1 μU/ml (0.4-3.6 μU/ml) and normal thyroid hormone levels with negative antibodies. TFTs of the rest of the family were normal, except for a low normal TSH of 0.8 μU/ml in his maternal aunt. Sequencing the TSHR gene of the propositus revealed a heterozygous mutation in codon 636, TGC to GGC, leading to the substitution of a Cysteine with Glycine (C636G) in the 6th transmembrane domain. His affected mother and maternal aunt harbored the same mutation. The mother’s past treatment explained her normal TFTs. We were unable to obtain samples from the maternal grandmother for testing. This mutation has not been previously reported. However, the C636 position is highly conserved in the GPCR family and computer modeling predicts involvement of the C636G mutation in the activation of the TSHR. Recently, two mutations in the same codon, C636W (1) and C636R (2) were reported. Functional studies showed that expression of these mutant TSHRs resulted in a constitutive activation of the Gs signaling pathway. In contrast, for the Gq/11 pathway, both mutants displayed nearly complete loss-of-function after bovine TSH stimulation compared to the normal TSHR. The Gq/11 pathway was shown to be important for thyroid hormone synthesis and growth (3).

In conclusion, we report a patient with familial nonautoimmune hyperthyroidism due to a novel heterozygous C636G mutation in the TSHR gene inherited from his mother. The symptoms and thyroid tests of the patient were mild, which may be related to the inhibition of the Gq pathway despite the activation of the Gs signalling pathway. Genetic confirmation should be considered in hyperthyroid patients without evidence for autoimmunity even when they present with mild symptoms and absence of goiter.

(1) Winkler F, et al. J Clin Endocrinol Metab. 2010;95:3605-10; (2) Biebermann H, et al J Clin Endocrinol Metab. 2012;97:E228-32; (3) Kero J, et al. J Clin Invest. 2007;117:2399-407.

Disclosure: SR: Consultant, Quest Diagnostics. Nothing to Disclose: JF, CCL, GBK, REW, AMD

*Please take note of The Endocrine Society's News Embargo Policy at

Sources of Research Support: NIH Grant DK15070 awarded to SR, and DK091016 awarded to AMD. Award to JF from China Scholarship Council.