Familial hyperthyroidism due to mutations in TSH receptor

Familial hyperthyroidism due to mutations in the TSH receptor (also known as familial non-autoimmune autosomal dominant hyperthyroidism, or hereditary toxic thyroid hyperplasia) is a rare genetic disorder caused by gain-of-function mutations in the TSHR gene, which encodes the thyroid-stimulating hormone (TSH) receptor. These mutations lead to constitutive activation of the TSH receptor, meaning the receptor is permanently switched on even without TSH stimulation. This results in unregulated overproduction of thyroid hormones by the thyroid gland, causing hyperthyroidism that is not mediated by autoimmune mechanisms — distinguishing it from Graves' disease. The condition primarily affects the endocrine system, specifically the thyroid gland, and can present with symptoms typical of hyperthyroidism including tachycardia (rapid heart rate), weight loss, heat intolerance, tremor, irritability, anxiety, diarrhea, and diffuse goiter (enlarged thyroid). In some families, the condition manifests in infancy or childhood, while in others it may not become clinically apparent until adulthood. Affected individuals characteristically have suppressed TSH levels with elevated free T3 and free T4, and importantly, thyroid autoantibodies (such as TSH receptor antibodies) are absent. Treatment can be challenging because the hyperthyroidism tends to relapse after discontinuation of antithyroid drugs (such as methimazole or propylthiouracil), since the underlying cause is a permanently activated receptor rather than an autoimmune process. Definitive treatment typically requires thyroid ablation, either through total thyroidectomy (surgical removal of the thyroid) or radioiodine therapy, followed by lifelong thyroid hormone replacement. Early recognition and genetic testing are important for distinguishing this condition from autoimmune hyperthyroidism and for screening at-risk family members.

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

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