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

Resistance to thyroid hormone (RTH) action is due to mutations in the beta- isoform of the thyroid hormone receptor (TR-beta). RTH patients display ina ppropriate central secretion of TRH from the hypothalamus and of TSH from t he anterior pituitary despite elevated levels of thyroid hormone (T-4 and T -3). RTH mutations cluster in three hot spots in the C-terminal portion of the TR-beta. Most individuals with TR-beta mutations have generalized resis tance to thyroid hormone, where most tissues in the body are hyporesponsive to thyroid hormone. The affected individuals are clinically euthyroid or e ven hypothyroid depending on the severity of the mutation. Whether TR-beta mutations cause a selective form of RTH that only leads to central thyroid hormone resistance is debated. Here, we describe an individual with strikin g peripheral sensitivity to graded T-3 administration. The subject was enro lled in a protocol in which she received three escalating T-3 doses over a 13-day period. Indexes of central and peripheral thyroid hormone action wer e measured at baseline and at each T-3 dose. Although the patient's resting pulse rose only 11% in response to T-3, her serum ferritin, alanine aminot ransferase, aspartate transaminase, and lactate dehydrogenase rose 320%, 11 7%, 121%, and 30%, respectively. In addition, her serum cholesterol, creati nine phosphokinase, and deep tendon reflex relaxation time fell (25%, 36%, and 36%, respectively). Centrally, the patient was sufficiently resistant t o T-3 that her serum TSH was not suppressed with 200 mu g T-3, orally, dail y for 4 days. The patient's C-terminal TR exons were sequenced revealing th e mutation R383H in a region not otherwise known to harbor TR-beta mutation s. Our clinical evaluation presented here represents the most thorough docu mentation to date of the central thyroid hormone resistance phenotype in an individual with an identified TR-beta mutation.