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

Abstract

In adults, autonomous adenomas of the thyroid causing hyperthyroidism are relatively common and are most often due to somatic mutations that increase the constitutive activity of the thyroid-stimulating hormone receptor (TSHR). By contrast, autonomous adenomas in hyperthyroid children are exceptional and reports of their clinical and molecular characteristics are few. We reviewed papers describing 16 autonomous adenomas due to a somatic mutation activating the TSHR and diagnosed in patients younger than 18 years, to which we added two of our own unpublished observations in a 4- and 8-year-old with the same TSHR mutation (c.CAG>CAC; p.Asp633His). This revealed that (a) autonomous adenomas occur more often in the right lobe (11 of 14 with available information) and the associated hyperthyroidism tends to be more severe, possibly reflecting the richer vascular supply of the right thyroid lobe, and (b) mutations found in benign adenomas in children have been associated with cancer in adults, suggesting that malignancy requires a second ‘hit' at a later age.

Making Sense of Pharmacology: Inverse Agonism and Functional Selectivity

“…Activation of the TSH receptor not only increases thyroid hormone production and secretion, but also stimulates growth and proliferation of thyrocytes ( Vassart and Dumont, 1992 ; Postiglione et al, 2002 ). Notably, activating TSH receptor mutations appears to be the cause of some thyroid cancers with corresponding hyperthyroidism ( Grob et al, 2014 ; Kyrilli et al, 2017 ; Mon et al, 2018 ). Moreover, many cancers are known to overexpress receptors, which, as discussed above, can result in enhanced constitutive activity that may play a role in cancer progression and metastasis ( Li et al, 2005 ; Dorsam and Gutkind, 2007 ; Moody et al, 2016 ; Insel et al, 2018 ; Xu et al, 2018 ).…”

Developmental Abnormalities of the Thyroid

“…94 In addition to germline mutations, somatic TSHR gene mutations account for about 80% of "hot" nodules causing nonautoimmune hyperthyroidism of adult or childhood onset. [95][96][97] In one case, fetal tachycardia suggested prenatal onset of hyperthyroidism. 98…”

Thyroid Adenomas in Children

“…Важно отметить, что содержание циркулирующего тиреотропного гормона не является показателем тяжести симптомов, обусловленных тиреотоксикозом [25]. Положительные титры антител к тиреоглобулину чаще выявляют в группе с раком (20%), чем у пациентов с фолликулярной аденомой (5%), но их наличие свидетельствует об аутоиммунном процессе [30].…”