Up to date, 12 patients with sporadic non-autoimmune hyperthyroidism (SNAH) caused by sporadic germline mutations in the TSHR gene have been reported. Nearly, all case reports discussed possible associations of the TSHR mutations in vitro activity (IVA) with the clinical course (CC). Therefore, we analyzed this question in a systematic review of the case reports and investigated the TSHR mutations IVA in selected cases.
Recently, linear regression analysis (LRA) of constitutive activity as a function of TSHR expression determined by 125I-bTSH binding or FACS analysis compared to the wt TSHR was described as a more reliable way of characterizing the IVA of a constitutively activating TSHR mutation. Therefore, we determined the LRAs 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 CC with the IVA of the mutated TSHR. The LRAs 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). Only 4 of 10 investigated clinical signs namely prematurity, early onset of goiter (<15 months), eye signs (proptosis and eyelid retraction) and craniosynostosis are associated with a high LRA (>10). Furthermore, mental retardation, craniosynostosis and eye signs are associated with an early onset (<1.5 months) and a long duration (>3 years) of insufficiently treated hyperthyroidism. The comparison of the CCs of patients harboring the same mutation (M453T, S505N) showed no relation of the clinical activity with a high LRA.
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 mutations IVA determined by LRA with the CC of patients with SNAH.
03 - 07 May 2008
European Society of Endocrinology