Generalized resistance to thyroid hormone

Generalized resistance to thyroid hormone (RTH), also known as Refetoff syndrome or thyroid hormone resistance syndrome, is a rare genetic condition in which the body's tissues have a reduced sensitivity to thyroid hormones despite elevated circulating levels of free thyroxine (T4) and triiodothyronine (T3). The hallmark biochemical finding is elevated thyroid hormone levels with a non-suppressed (normal or elevated) thyroid-stimulating hormone (TSH), distinguishing it from hyperthyroidism. The condition is most commonly caused by mutations in the THRB gene, which encodes the thyroid hormone receptor beta. Because resistance affects multiple tissues simultaneously, patients often present with a variable clinical picture that can include goiter, attention deficit hyperactivity disorder (ADHD), learning disabilities, tachycardia, short stature, and delayed bone maturation. The clinical presentation of generalized RTH is highly variable, even within the same family. Many individuals are clinically euthyroid because the elevated thyroid hormone levels compensate for the tissue resistance. However, some patients may exhibit features suggestive of both hypothyroidism (such as growth retardation, delayed bone age, and hearing impairment) and hyperthyroidism (such as resting tachycardia and hyperactivity). Goiter is one of the most common findings and results from chronic TSH stimulation of the thyroid gland. Affected children may present with learning difficulties, behavioral problems, and recurrent ear infections with associated hearing loss. Treatment of generalized RTH is largely supportive and individualized. In many cases, no treatment is required because the elevated thyroid hormone levels adequately compensate for the receptor defect. It is critically important that patients are not misdiagnosed with hyperthyroidism and inappropriately treated with antithyroid drugs or thyroid ablation, as this can worsen symptoms of hypothyroidism. In symptomatic cases, particularly those with significant tachycardia, beta-blockers may be used. Supraphysiologic doses of levothyroxine (T4) or triiodothyroacetic acid (TRIAC) have been used in select cases to overcome tissue resistance, particularly to suppress TSH and reduce goiter size or address specific symptoms.

Data sourced from FDA regulatory filings and ClinicalTrials.gov. Updated periodically.

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