A Rare Case of Heterozygous Gain of Function Thyrotropin Receptor Mutation Associated with Development of Thyroid Follicular Carcinoma

Abstract

Activating mutations in thyrotropin receptor (TSHR) have been previously described in the context of nonautoimmune hyperthyroidism and thyroid adenomas. We describe, for the first time, a mutation in TSHR contributing to follicular thyroid carcinoma (FTC) in an adolescent. A 12-year-old girl presented with a right-sided neck swelling, increasing in size over the previous four weeks. Clinical examination revealed a firm, nontender thyroid nodule. Ultrasound scan of the thyroid showed a heterogeneous highly vascular mass. Thyroid function tests showed suppressed TSH [<0.03mU/L], normal FT4 [10.1pmol/L, 9-19], and raised FT3 [9.1pmol/L, 3.6-6.4]. Thyroid [TPO and TRAB] antibodies were negative. A right hemithyroidectomy was performed and the histology of the sample revealed follicular carcinoma with mild to moderate nuclear pleomorphism and evidence of capsular and vascular invasion (pT1b). Sanger sequencing of DNA extracted from the tumour tissue revealed a missense somatic mutation (c.1703T>C, p.Ile568Thr) in TSHR. Papillary thyroid carcinomas constitute the most common thyroid malignancy in childhood, while FTC is rare. FTC due to TSHR mutation suggests an underlying, yet to be explored, molecular pathway leading to the development of malignancy. The case is also unique in that the clinical presentation of FTC as a toxic thyroid nodule has not been previously reported in children.

Figure 1

Thyroid ultrasound scan shows a round well circumscribed heterogeneous, highly vascular mass arising from the right lobe of the thyroid, measuring 21 x 17 x 17 mm.

Figure 2

(a) Tumour and a capsule with a vessel containing tumour cells, arrow (H&E, x80); (b) tumour cells aggregate within the vessel lumen of the capsule (HE, x360); (c) intravascular tumour cell aggregate covered by endothelial cells (CD34, x100).

Figure 3

Schematic representation of TSHR containing 10 exons (numbered 1-10 in red) with the introns represented by the horizontal line joining the exons. The grey region represents the untranslated region (UTR). The position of the variant at the position 1703 is shown in exon 10.