Shared Sporadic and Somatic Thyrotropin Receptor Mutations Display More ActiveIn VitroActivities than Familial Thyrotropin Receptor Mutations

Abstract

Background: Germline thyrotropin receptor (TSHR) mutations are associated with sporadic congenital nonautoimmune hyperthyroidism and familial nonautoimmune hyperthyroidism. Somatic TSHR mutations are associated with toxic thyroid nodules (TTNs). The objective of the study was to define a relation of the clinical appearance and the in vitro activity (IVA) of the TSHR mutations described by several authors for these thyroid disorders. Methods: We analyzed the IVAs published as linear regression analysis (LRA) of the constitutive activity as a function of the TSHR expression and the basal cyclic adenosine monophosphate (cAMP) values to determine differences between exclusively somatic, exclusively familial, and shared sporadic and somatic TSHR-mutations. Further, we investigated correlations of the LRAs/basal cAMP values with clinical activity characteristics (CACs) of TTNs, such as largest diameter of the TTN and the age of the patient at thyroid surgery. Results: Shared sporadic and somatic mutations showed higher median LRA (14.5) and higher median basal cAMP values (fivefold) than exclusively familial mutations (6.1, p ¼ 0.0002; 2.9-fold, p < 0.0001, respectively). Moreover, mutations shared between sporadic congenital nonautoimmune hyperthyroidism and toxic thyroid nodules (TTNs) showed higher median LRA/basal cAMP values ( p < 0.0001) than exclusively somatic mutations in TTNs (5.1; 3.89-fold, respectively). Exclusively somatic mutations and exclusively familial mutations showed no significant difference in their median LRA values ( p ¼ 0.786) but a significant difference for basal cAMP values ( p ¼ 0.0006). The two examined CACs showed no correlation with the IVA characterized by LRA/ basal cAMP values or with the presence or absence of a TSHR-mutation. Conclusions: This systematic analysis of published constitutively activating TSHR-mutations, their CACs, and their IVA provides evidence for higher IVA of shared sporadic and somatic TSHR mutations as compared with familial TSHR mutations. CACs of somatic TSHR mutations in TTNs did not have a clear association with the IVA as characterized by LRA or basal cAMP values.

TSH measurement is not an appropriate screening test for autonomous functioning thyroid nodules: a retrospective study of 368 patients

“…Gain-of-function mutations of the TSHR or GNAS are the main cause of AFTN. More than 40 TSHR mutations have been reported, but the correlation between the in vitro activity of a mutated receptor and the clinical phenotype is weak (18). Therefore, the heterogeneity in clinical behaviour of AFTN is probably not caused by differences in causal TSHR mutations.…”

Novel germline mutation (Leu512Met) in the thyrotropin receptor gene (TSHR) leading to sporadic non-autoimmune hyperthyroidism

“…SCNAH mutations also display higher active in vitro activities than familial TSHR gene mutations. This is likely because strong germline mutations are negatively selected and may result in spontaneous abortions [22, 23]. …”

“…No genotype-phenotype relationship has been reported in patients with germline TSHR gene mutations suggesting that other epigenetic and/or environmental factors maybe involved [23]. Further characterization is needed, emphasizing the need for these cases to be identified and reported.…”

Knoten in der Schilddrüse – Histologie und Zytologie

“…In der Mehrzahl der autonomen Adenomen können somatische "gain-of-function" Mutationen des TSH-Rezeptor-Gens (selten auch Keimbahnmutationen) nachgewiesen werden, die zur konstitutiven Aktivierung des TSH-Rezeptors und einem Wachstumsvorteil der betroffenen Zellen mit Ausbildung eines Tumors führen [22]. Histologisch können autonome Adenome entweder nicht von den üblichen Adenomen unterschieden werden oder sie zeigen eine ähnliche Morphologie wie Basedow-Strumen.…”