Background: Up to date, 14 patients with sporadic non-autoimmune hyperthyroidism (SNAH) caused by sporadic germline mutations in the TSH receptor (TSHR) gene have been reported. Despite considerable differences in the activity of hyperthyroidism, all SNAH case reports concluded that the demonstrated constitutive activity explains the phenotype.
Aim: Recently, linear regression analysis (LRA) of constitutive activity as a function of TSHR expression determined by 125I-bTSH binding or fluorescence activated cell sorting analysis was described as a more reliable way of characterizing the in vitro activity (IVA) of a constitutively activating TSHR mutation. Therefore, we analyzed a possible genotype-phenotype correlation in a systematic review of the case reports and investigated the TSHR mutation's LRA in selected cases.
Material and methods: We determined the LRA for all sporadic germline mutations which had not previously been reported. Moreover, we systematically evaluated all case reports of SNAH for evidence of an association of the clinical course (CC) with the IVA of the mutated TSHR.
Results: The LRA determined were: M453T (5.2+/-0.8), L512Q (4.5+/-0.7), I568T (25.6+/-6.3), F631L (45.9+/-9.4), T632I (14.5+/-2.7), D633Y (16.4+/-6.4). None of the 10 examined clinical signs showed a significant association with the LRA. Moreover, the comparison of the CC of patients harboring the same mutation (S281N, M453T, I568T, S505N) also showed no relation of the clinical activity with a high LRA.
Conclusion: Considering the different diagnostic circumstances, therapeutic strategies and the limitations of a systematic analysis of case reports due to the restricted number of case reports and limited follow-up we found no consistent relation of the TSHR mutation's IVA determined by LRA with the CC of patients with SNAH. This may also be due to the action of genetic, epigenetic, and environmental modifiers.