The group of Dumont and Vassart were among the first to suggest that any molecular lesion leading to constitutive activation of the cAMP cascade could be responsible for the growth and functional properties of autonomous thyroid nodules [
1]. In support of this, it was shown that transgenic mice with thyroid expression of the adenosine A2 receptor mimic the phenotype of thyroid autonomy in humans [
2]. In the first and pivotal study by the Brussels lab in 1993, 9 out of 11 toxic thyroid nodules harboured an activating TSHR mutation [
3]. Subsequent studies comprising larger sample series showed that TSHR mutations are not only present in up to 82% of solitary toxic nodules [
4‐
11] but also in autonomous nodules within toxic multinodular goitres [
12‐
14]. The majority of these mutations were localised in the TSHR transmembrane domain and only rarely in the extracellular domain [
15]. All TSHR mutations were confined to clonal autonomous tissue (=somatic mutations) and were heterozygous in line with a gain-of-function mutation exerting a dominant effect [
16]. Furthermore, using archival tissues of euthyroid goitres from an iodine deficient area, somatic TSHR mutations were identified in microscopic areas with high 125-I labelling indicating autonomous tissues on autoradiography [
17]. This finding illustrates that gain-of-function TSHR mutations are implicated in the early steps of thyroid autonomy. In parallel, Gs-alpha mutations (gsp) which likewise confer constitutive cAMP activation were detected in 5–30% of toxic thyroid nodules, that did not harbour a TSHR mutation, sustaining the initial hypothesis that alterations of several proteins may indeed contribute to constitutive activation of the cAMP pathway as a hallmark of thyroid autonomy.