More than 21 families with inactivating TSHR mutations have been published. Their phenotype varies from euthyroid hyperthyrotropinemia (compound heterozygous) to severe congenital hypothyroidism (homozygous) with thyroid hypoplasia.
Current methods to precisely classify mutants with only a slight increase of the basal activity as constitutively active are limited. The results concerning the level of the basal activity can be influenced by the vector and/or the cell system. Reexamination of previously described constitutively active TSHR germline mutations did not show constitutive activity for R310C and N670S as tested in COS-7 cells. Moreover, mutations L677V and T620I identified in hot thyroid carcinomas and previously characterized in CHO and in 3T3-Vill cell lines, respectively, F666L identified in a patient with hot thyroid nodules, I691F in a family with nonautoimmune hyperthyroidism displayed no constitutive activity for Gαs signaling. Therefore, beside the extensive clinical characterization, future characterizations of TSHR mutations regarding their constitutive activity status should also include linear regression analysis (LRA) of constitutive activity at least for borderline cases.
For 17 constitutively activating TSHR mutations found in 24 families with familial non autoimmune hyperthyroidism (FNAH) no direct relation of the in vitro activity of the TSHR mutation (basal cAMP value) and the age at onset of hyperthyroidism and the severity of clinical course was found and even for the same TSHR mutation different clinical courses in different families were described. For twelve case reports of sporadic non-autoimmune hyperthyroidism (SNAH) no clear evidence for a consistent relation of the TSHR mutations in vitro activity determined by LRA with the clinical course of patients with SNAH was found. This suggests that the clinical course is more likely influenced by further genetic/epigenetic and environmental factors than by the in-vitro activity of the TSHR mutation itself.
However, a systematic analysis of published constitutively activating TSHR mutations and their clinical and in vitro activities provides evidence for a higher in vitro activity of shared sporadic and somatic TSHR mutations as compared to familial TSHR mutations. The few cases of sporadic non-autoimmune hyperthyroidism for which very active clinical progression were reported most likely contributed significantly to the higher LRA activity of the shared sporadic and somatic TSHR mutations.
30 Apr - 04 May 2011
European Society of Endocrinology