A somatic mutation in the thyrotropin receptor gene in a patient with an autonomous nodule within a multinodular goiter

Thyrotropin (TSH) is the prime regulator of thyroid cell growth and function and acts through the thyrotropin receptor (TSHR) located on the surface membrane of thyrocytes. Somatic heterozygous mutations that cause TSHR activation in the absence of TSH have been found in toxic adenomas and in hot nodules of multinodular goiters. Clinically and histologically heterogeneous nodules can share common gain-of-function mutations. Mutation prevalence varies greatly and is inversely related to iodine intake of the population. We report a Greek patient presenting with subclinical hyperthyroidism due to a fast-growing autonomous hyperplastic nodule in a long-standing multinodular goiter. Direct DNA sequencing showed that the hot nodule harbored a somatic heterozygous activating TSHR mutation: substitution of glutamine for leucine in the third transmembrane helix. This mutation (L512Q) was recently described in two solitary toxic adenomas. This report expands the spectrum of mutations shared by dissimilar hot nodules, supporting a common mechanism for nonautoimmune thyroid autonomy. The identification of the L512Q substitution demonstrates that gain-of-function TSHR mutations are encountered in Greece, although iodine deficiency has been significantly corrected over the last three decades.