Diagnosis of Resistance to Thyroid Hormone due to a Rare Mutation in the Thyroid Hormone Receptor Beta Gene in a Patient Previously Presumed to Have Graves' Disease

Abstract

Clinicians may confuse an impaired sensitivity to thyroid hormone with hyperthyroidism and offer an inappropriate treatment. We report a diagnosis of resistance to thyroid hormone (RTH) caused by a rare mutation in the thyroid hormone receptor beta gene in a patient previously presumed to have Graves' disease. We have found only one published case of a novel point mutation, c.749T>C (p.Ile250Thr variant) associated with 50% reduction in thyroid hormone receptor binding affinity for triiodothyronine in the I250T mutant; it was found in this patient. A 66-year-old male veteran, with a history of non-ischemic cardiomyopathy and arrhythmias, was referred by a cardiologist with concerns for a possible thyrotropin (TSH) adenoma on account of elevated TSH and free thyroxine (FT4) levels. Pituitary imaging was negative. He was previously treated with radioiodine for presumptive Graves' disease in the civilian sector. Examination revealed a goiter with no nodules. Repeat TSH and FT4 levels were elevated and also free triiodothyronine (FT3) and reverse triiodothyronine. These findings and other test results were consistent with RTH, which was confirmed by genetic testing. Mutation analysis showed the patient to be heterozygous for the p.Ile250Thr variant. He later developed hypothyroidism. Resistance to thyroid hormone can be misdiagnosed as hyperthyroidism with consequent inappropriate treatment. Treatment is not needed in most RTH-beta patients. Thyroid ablation should generally be avoided. Clinicians must be cautious whenever they encounter concurrent elevation of TSH, FT4, and FT3. This RTH-beta patient has a rare I250T mutant of the thyroid hormone receptor beta gene, the second reported case in the literature.