Resistance to Thyroid Hormone (RTH) and Resistance to TSH (RTSH)

Resistance to thyroid hormone (RTH) is a syndrome characterized by variable tissue hyporesponsiveness to thyroid hormone (TH). Mutations in both TH receptor (TR) isoforms have been identified, which manifest different phenotypes of RTH, RTH-α, and RTH-β. Patients with the RTH-β phenotype seek medical attention for goiter and abnormal thyroid function tests (TFTs). Biochemically, RTH-β is characterized by elevated TH values in the setting of non-suppressed thyrotropin (TSH) levels. Resistance at the level of the hypothalamus and pituitary leads to elevated TSH, which stimulates TH production; however, reduced action elsewhere results in variable degrees of compensated TH hyporesponsiveness depending on the predominant TH receptor (TR) isoform in the tissue, alpha (α) or beta (β). THRA gene mutations have remained elusive until recently. The first case of RTH-α was identified through whole genome sequencing. Because TRα is not involved in the feedback regulation of the hypothalamic-pituitary-thyroid axis, TFTs are different from patients with RTH-β, namely low or normal T4, high normal T3 and normal or slightly elevated TSH. These mild thyroid abnormalities lead patients to present themselves in non-endocrinological clinical departments. Also, defects in TH transmembrane transport, and metabolism manifest as reduced sensitivity to TH. The phenotype of resistance to TSH is characterized by high serum TSH in the absence of goiter. Patients are often identified at birth through neonatal screening for congenital hypothyroidism Affected individuals have normal or hypoplastic thyroid glands, high serum TSH, and normal or low serum T4 and T3, and symptoms range from euthyroid hyperthyrotropinemia to overt hypothyroidism.