CONSTITUTIVELY ACTIVATING TSH RECEPTOR MUTATIONS AS THE CAUSE OF TOXIC THYROID ADENOMA, MULTINODULAR TOXIC GOITER AND AUTOSOMAL-DOMINANT NON AUTOIMMUNE HYPERTHYROIDISM

cAMP stimulates both the growth and differentiated thyroid function of the thyroid gland. In toxic nodules the clinical observation of hyper thyroidism together with TSH independent growth of the hot nodule sugg ests 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 toxi c multinodular goiters. Constitutively activating TSH receptor germlin e mutations are expected to lead to toxic hyperplasia. Sequencing of t he TSH receptor gene in families with hereditary non autoimmune hypert hyroidism led to the identification of constitutively activating TSH r eceptor mutations in 7 families. Moreover, sporadic TSH receptor germl ine mutations have been identified in 3 children with severe congenita l nonautoimmune hyperthyroidism. Therefore, in cases of clustering of non autoimmune hyperthyroidism in families and in cases of sporadic co ngenital hyperthyroidism with thyroid hyperplasia and no evidence for an autoimmune etiology a search for TSH receptor gene mutations is nec essary to appropriately direct the therapy of these patients.