Constitutive activation of the cAMP pathway by activating TSHR mutation stimulates both thyrocyte proliferation and function. Thus they lead to formation of toxic thyroid nodules (TTNs) and ultimately hyperthyroidism. The in vitro activity of the various TSH-receptor mutation varies from 27 fold cAMP increase over the wild type TSH receptor. One previous study invrestigated a possible genotype to phenotype relation in TTNs with somatic TSHR mutation with a negative result.
TSHR mutations have been identified in 52(70.2%) of 74 TTNs in a recent study. In order to investigate the genotype-phenotype relation in TTNs we compared the clinical and laboratory findings of these patient (nodules) with or without TSHR mutation.
Most strikingly, nodule volume was found significantly higher in the mutation + groups (Z:-2,803;P:0,005). No significant difference between iodine sufficient and deficient regions of Turkey was established for all of the clinical and laboratory findings. Genotype-phenotype relation was also evaluated for the different in vitro basal cAMP fold increases of the somatic TSH receptor mutations over the wild type TSH-receptor. No statistical difference was noticed for the clinical (age, time for euthyroidism, cumulative dose of propylthiouracil (PTU), nodule and thyorid volume) and laboratory (TSH, FT4, FT3)) findings between groups of different basal cAMP fold (basal fold ≤2, n=5, fold 25, n=15 fold ≥5, n=8).
TSH at the start of PTU treatment was found significantly lower in the mutation (+) group (Z:-2.058; P: 0,040). FT3 level was also found higher in the mutation positive groups, but it was not significant (Z:-1.755; P: 0,079). No significant difference was found between mutation +/− groups for serum level of FT4, age, gender, thyroid volume, time to euthyroidism until the end of PTU treatment and cumulative dose PTU for establishment of euthyroidism.
No significant difference was found between TSHR D727E variant +/− nodules for thyroid and nodule volume, time to euthyroidism after begin of PTU treatment, cumulative dose of PTU for establishment of euthyroidism and serum levels of FT3, FT4. Serum level of TSH was found significantly lower in the variant positive groups (Z:-2,385; P:0,017).
Our results suggest that hot nodules with a somatic TSHR mutation are larger than those without a TSHR mutation.