Non-Autoimmune Hyperthyroidism Associated With a Novel Germline Mutation (D633N) in the TSH Receptor

Nonautoimmune hyperthyroidism resulting from an activating germline thyroid-stimulating hormone receptor (TSHR) gene mutation is a rare condition that often presents a diagnostic challenge. We report the case of a 75-year-old woman with a 20-year history of goiter and subclinical hyperthyroidism who presented with overt thyrotoxicosis. Laboratory tests confirmed hyperthyroidism with suppressed TSH, whereas thyrotropin receptor antibody (TRAb) and thyroid-stimulating antibody (TSAb) were negative, making it difficult to distinguish from toxic multinodular goiter. Initial management with potassium iodide was ineffective. Subsequent radioactive iodine (RI) therapy was complicated by severe destructive thyroiditis with worsening thyrotoxicosis and heart failure. Following hormonal control with methimazole (MMI) and dexamethasone, a total thyroidectomy was performed for definitive management, successfully normalizing thyroid function. Histopathology revealed an adenomatous goiter. Postoperative genetic analysis using peripheral blood DNA, prompted by the atypical clinical course, identified a novel heterozygous germline mutation in the TSHR gene: c.1897G > A (p.D633N). This case expands the spectrum of activating TSHR mutations causing nonautoimmune hyperthyroidism. Functional analysis demonstrated modest constitutive activity of the variant, which may explain the unusually late clinical onset. This report underscores the importance of considering nonautoimmune hyperthyroidism, including nonautoimmune hyperthyroidism, in patients with antibody-negative hyperthyroidism, even in elderly individuals without a known family history.