Background: Sporadic and familial autosomal dominant non-autoimmune hyperthyroidism (S/FANH) is caused by activating germline mutations in the TSH Receptor (TSHR) gene. These patients lack TSHR-Ab, show diffuse uptake on radionuclide thyroid scan and often lack positive family history due to variable penetrance. Because of these overlapping features, S/FANH is difficult to distinguished from Graves disease without autoimmune features. Therefore, 2012 European Thyroid Association recommends genetic testing for TSHR gene in such patients. However, there is lack of knowledge on the prevalence of these mutations in white-European adult hyperthyroid patients.
Aim: We aim to assess the prevalence of activating TSHR mutation in adult hyperthyroid patients with features suggestive of S/FANH (absence of autoimmunity and diffuse thyroid uptake on radionuclide scan).
Method: We retrospectively and prospectively collected clinical data and DNA (from blood/saliva) for adult white-European hyperthyroid patients, who lacked evidence of clinical and biochemical thyroid autoimmunity (absence of Graves ophthalmopathy or TSHR-Ab) and had diffuse uptake on thyroid scintigraphy. All of these patients underwent genetic test for TSHR gene.
Results: We recruited 79 patients from three centres in the south-west, UK. Genotyping was unsuccessful in 4 samples. The genotyping of TSHR gene did not identify previously known/novel activating mutation in any patients. One patient had rare likely benign variant (c.1001T>C, P.Ile334Thr, exon 10, population freq=0.003%). The variant is in the less conserved extracellular domain and it is outside the mutation hotspot region.
Conclusion: Activating germline TSHR mutations are rare in adult hyperthyroid patients with diffuse uptake on thyroid scintigraphy but without TSHR-Ab. Our study does not support routine genetic testing for TSHR gene in such patients.