ESPE Abstracts

Background: Resistance to thyroid hormone (RTH) is a rare clinical syndrome characterized by end organ resistance due to mutations in the thyroid hormone receptor (THRB) gene. The combination of RTH and congenital hypothyroidism (associated with thyroid agenesis or ectopic gland) has been reported in at least 6 genetically proven cases.

Case report: We report an 8-year-old girl, diagnosed with congenital hypothyroidism at 3 weeks of age after neonatal screening showed TSH (Thyroid Stimulating Hormone) >300 mIU/L. Subsequent thyroid function tests confirmed the diagnosis, and she began treatment with Levothyroxine. At 33 days of age, she had thyroid scintigraphy which showed an ectopic thyroid gland in the sublingual region. However, despite adequate weight-based thyroxine dosing, and adequate free T4 and free T3 levels, TSH remained elevated (TSH 50-70 mIU/L). Her physical and mental development was normal; she was clinically euthyroid despite the abnormal TSH. Her TSH elevation indicated thyroid hormone resistance, so genetic sequencing of the THRB gene was performed, and identified a heterozygous pathogenic variant, THRB c.1312C>T (p.Arg438Cys). This variant, which affects the ligand binding domain of the nuclear hormone receptor, has previously been reported in patients with thyroid hormone resistance. Literature review identified 6 other case reports with THRB mutations and thyroid agenesis (2 cases) or ectopic thyroid (4 cases). To the best of our knowledge this is the first case with this specific variant presenting with the combination of ectopic thyroid and THR. At the age of 7 years, she developed a sublingual swelling due to enlargement of the ectopic gland, in response to the persistently elevated TSH. Ultrasound showed the presence of a thyroid nodule. Investigations showed a very high thyroglobulin level and negative antibodies. In view of the known association with chronic thyroid enlargement and thyroid cancer, she underwent a PET scan, which showed no concerning features. Excision of the ectopic thyroid is planned.

Conclusion: THRB mutations should be considered in cases of congenital hypothyroidism, in which TSH is refractory despite adequate levothyroxine replacement. However, even with adequate thyroxine replacement chronic TSH elevation may give rise to thyroid enlargement with the potential for malignant transformation. In such cases, surgical excision of the ectopic thyroid may be considered.