Two rare TSH receptor amino acid substitutions in toxic thyroid adenomas

Abstract

Seven transmembrane (7TM) receptors play important roles in various biologic signal transduction systems, including endocrine and neural regulation. Mutations in these receptors cause various health disorders. Gain-of-function mutations in the thyroid stimulating hormone receptor (TSHR) gene result in hyperthyroidism [1]. In addition to germ-line mutations, somatic mutations of the TSHR gene and the adenylate cyclase-stimulating G α protein (GNAS) gene are responsible for toxic adenoma and toxic multinodular Abstract. Toxic adenoma and toxic multinodular goiter (TMNG) are common causes of hyperthyroidism in iodinedeficient regions, but they are relatively rare in iodine-sufficient regions, including Japan. Constitutive activating mutations of the thyroid stimulating hormone receptor (TSHR) gene and adenylate cyclase-stimulating G α protein (GNAS) gene are frequent in these thyrotoxic disorders. Here we report two cases of rare TSHR gene mutations in Japanese thyrotoxicosis patients. In Case 1, we observed multiple toxic nodules with thyrotoxicosis, and in Case 2, we detected a solitary toxic nodule in an 8-year-old girl. In both cases, ultrasonography showed thyroid nodules and scintigraphy revealed increased uptake. Total thyroidectomy was performed for Case 1 and a hemi-thyroidectomy was performed for Case 2. Genetic analysis of the resected tissues revealed an I568F mutation in Case 1 and a S281I mutation in the TSHR gene in Case 2. The I568F mutation was located in the second extracellular loop, and the S281I mutation was located in the N-terminal extracellular domain of the TSH receptor. In Case 1, the mutation was restricted to the largest nodule, and was not detected in other functioning nodules or non-nodule thyroid tissue. Bi-allelic expression of the TSHR gene was confirmed by reverse transcription-polymerase chain reaction in both tumors. Both the I568F and S281I mutations were studied previously in vitro, and were revealed to cause basal activation of the protein kinase A pathway. Case 1 represents the second reported case of an I568F mutation and Case 2 represents the third reported case of an S281I mutation.

Clinical Significance of Thyroid-Stimulating Hormone Receptor Gene Mutations and/or Sodium-Iodine Symporter Gene Overexpression in Indeterminate Thyroid Fine Needle Biopsies

“…In regards to the prevalence of TSHR mutations in this nodule series, it was 4.7%. All the TSHR mutations are known mutations that were previously reported in AFTNs, and are somatic gain-of-function mutations (Figure 1 ) ( 36 – 39 ). In previous studies, somatic mutations of TSHR gene have been reported in toxic adenomas and toxic multinodular goiters, with a frequency ranging from 8 to 82% of cases ( 40 , 41 ).…”

Autonomous Adenomas Caused by Somatic Mutations of the Thyroid-Stimulating Hormone Receptor in Children

“…This yielded 8 publications [2,12,13,14,15,16,17,18] describing 16 autonomous adenomas in which a somatic TSHR mutation had been documented in 14 patients younger than 18 years (1 patient had 3 autonomous adenomas). To these, we added 2 of our own unpublished patients, who are described in detail below.…”

Hipertiroidismo

“…10 Mutações somáticas dos genes TSHR (recetor da TSH) e da subunidade proteica G provocam a ativação constitutiva do recetor de TSH e provocam o crescimento do adenoma e a produção descontrolada de HT. 11 No AT, ao contrário do que se passa na DG e em outras causas autoimunes, analiticamente não se verifica a presença de anticorpos (nem TRAb nem TPO) que se liguem ao recetor de TSH na glândula tiroideia. 10…”