The thyroid hormone receptor-β gene mutation R383H is associated with isolated central resistance to thyroid hormone

Resistance to thyroid hormone (RTH) action is due to mutations in the β-isoform of the thyroid hormone receptor (TR-β). RTH patients display inappropriate central secretion of TRH from the hypothalamus and of TSH from the anterior pituitary despite elevated levels of thyroid hormone (T₄ and T₃). RTH mutations cluster in three hot spots in the C-terminal portion of the TR-β. Most individuals with TR-β mutations have generalized resistance to thyroid hormone, where most tissues in the body are hyporesponsive to thyroid hormone. The affected individuals are clinically euthyroid or even hypothyroid depending on the severity of the mutation. Whether TR-β mutations cause a selective form of RTH that only leads to central thyroid hormone resistance is debated. Here, we describe an individual with striking peripheral sensitivity to graded T₃ administration. The subject was enrolled in a protocol in which she received three escalating T₃ doses over a 13-day period. Indexes of central and peripheral thyroid hormone action were measured at baseline and at each T₃ dose. Although the patient's resting pulse rose only 11% in response to T₃, her serum ferritin, alanine aminotransferase, aspartate transaminase, and lactate dehydrogenase rose 320%, 117%, 121%, and 30%, respectively. In addition, her serum cholesterol, creatinine phosphokinase, and deep tendon reflex relaxation time fell (25%, 36%, and 36%, respectively). Centrally, the patient was sufficiently resistant to T₃ that her serum TSH was not suppressed with 200 μg T₃, orally, daily for 4 days. The patient's C-terminal TR exons were sequenced revealing the mutation R383H in a region not otherwise known to harbor TR-β mutations. Our clinical evaluation presented here represents the most thorough documentation to date of the central thyroid hormone resistance phenotype in an individual with an identified TR-β mutation.