Simona Censi

Background: Resistance to TSH is defined as reduced sensitivity to normal, biologically-active TSH, and abnormally high levels of TSH are needed to achieve normal levels of thyroid hor-mones. Case Presentation: A 15-year-old female patient, having been treated since childhood with levothyrox-ine for hyperthyrotropinemia was referred to our institution complaining of tachycardia after the levothy-roxine therapy had been increased. Thyroid ultrasound features were normal, and thyroid antibodies were negative. The therapy was gradually tapered in light of the symptoms, although subclinical hypothyroid-ism was evident at thyroid function tests. First-degree relatives were tested for thyroid function, and the father was also found to have a previously-unknown subclinical hypothyroidism. The patient underwent genetic testing for TSH receptor (TSHR) gene mutations, which revealed a gene variant hitherto not described: p.C598R (c.1792T>C). The father was also tested and was found to carry the same mutation, while other first-degree relatives were wild-type for the TSHR gene. An in-silico analysis was performed, which revealed a loss-of-function phenotype corresponding to the described variant, suggesting a novel loss-of-function TSH receptor gene mutation. Conclusion: In this case report, we present a novel loss-of-function gene mutation in the TSH receptor gene associated with a TSH resistance phenotype.