cAMP stimulates both the growth and differentiated thyroid function of the thyroid gland. In toxic nodules the clinical observation of hyperthyroidism together with TSH independent growth of the hot nodule suggests a chronic activation of the cAMP cascade. Somatic mutations in a gene of the cAMP regulatory cascade leading to constitutive activation of this cascade in toxic nodules were first detected in the G protein Gs alpha. Thereafter constitutively activating TSH receptor mutations were identified in 20-80% of toxic thyroid nodules and in 3 of 6 toxic multinodular goiters. Constitutively activating TSH receptor germline mutations are expected to lead to toxic hyperplasia. Sequencing of the TSH receptor gene in families with hereditary non autoimmune hyperthyroidism led to the identification of constitutively activating TSH receptor mutations in 7 families. Moreover, sporadic TSH receptor germline mutations have been identified in 3 children with severe congenital nonautoimmune hyperthyroidism. Therefore, in cases of clustering of non autoimmune hyperthyroidism in families and in cases of sporadic congenital hyperthyroidism with thyroid hyperplasia and no evidence for an autoimmune etiology a search for TSH receptor gene mutations is necessary to appropriately direct the therapy of these patients.