Characteristics of patients with late manifestation of resistance thyroid hormone syndrome: a single-center experience

Resistance to thyroid hormone (RTH) is a rare genetic disease caused by reduced tissue sensitivity to thyroid hormone. The hallmark of RTH is elevated serum levels of thyroid hormone with unsuppressed thyrotropin (TSH). However, the most common form of RTH results from minor defects in the ligand-binding domain or hinge domain of the TR beta gene, resulting in impaired T3-induced transcriptional activity, often showing mild presentation. Early diagnosis can be challenging. The objective of the current study was to characterize this specific group of RTH patients. This was a retrospective study. Patients diagnosed as RTH with TR beta mutations were enrolled in a single institute between 2004 and 2014. A total of 14 patients were diagnosed as RTH with mutation in THb gene. The median age at diagnosis was 22.5 (IQR: 13.25-32.75). Goiter was the most common clinical finding. TSH was significantly elevated after TRH injection (median peak was 21.83 mu IU/l, IQR: 13.59-31.48), 9.2-fold compared to the basal level. We found 10 mutations in TR beta gene, all located in the last four exons, and including one novel mutation, H271D. In vitro study found that H271D mutation reduced TR affinity to T3. Four patients with intact thyroid were diagnosed after 16 years old, defined as late manifestation. Compared to those diagnosed before 10 years old, patients with late manifestation presented with normal growth and mental development. Interestingly, three of them carried R438H mutation. We identified a novel p.H271D mutation in TR beta associated with RTH. Endocrinologists should be alert that RTH is frequently found in euthyroid patients with mild symptoms and often leads to misleading diagnosis as well as inappropriate treatment.