HYPERFUNCTIONING THYROID-NODULES IN TOXIC MULTINODULAR GOITER SHARE ACTIVATING THYROTROPIN RECEPTOR MUTATIONS WITH SOLITARY TOXIC ADENOMA

Toxic multinodular goiter is a cause of nonautoimmune hyperthyroidism and is believed to differ in its nature and pathogenesis from toxic ad enoma. Gain-of-function mutations of the TSH receptor gene have been i dentified as a cause of toxic adenoma. The pathogenesis at the molecul ar level of hyperfunctioning nodules in toxic multinodular goiter has yet not been reported. Six patients with a single hot nodule within a multinodular goiter and 11 patients with toxic thyroid adenoma were en rolled in our study. At histology five hyperfunctioning nodules in mul tinodular goiters showed the features of adenomas, and one was identif ied as a hyperplastic nodule. The entire exon 10 of the TSH receptor g ene was directly sequenced after PCR amplification from genomic DNA ob tained from surgical specimens. Functional studies of mutated receptor s were performed in COS-7 cells. Five out of 6 (83%) hyperfunctioning nodules within toxic multinodular goiters harbored a TSH receptor muta tion. A TSH receptor mutation was also evident in the hyperfunctioning nodule that at histology had the features of noncapsulated hyperplast ic nodule. Among toxic adenomas, 8 out of 11 (72%) nodules harbored a TSH receptor mutation. All the mutations were heterozygotic and somati c. Nonfunctioning nodules, whether adenomas or hyperplastic nodules pr esent in association with hyperfunctioning nodules in the same multino dular goiters, had no TSH receptor mutation. All the mutations identif ied had constitutive activity as assessed by cAMP production after exp ression in COS-7 cells. Hyperfunctioning thyroid nodules in multinodul ar goiters recognize the same pathogenetic event (TSH receptor mutatio n) as toxic adenoma. Other mechanisms are implicated in the growth of nonfunctioning thyroid nodules coexistent in the same gland.