TSHR Gly413Ser in familial nonautoimmune hyperthyroidism: a case report

Familial nonautoimmune hyperthyroidism (FNAH) is a rare disorder caused by activating germline variants in the thyroid-stimulating hormone receptor gene (TSHR) and can mimic antibody-negative Graves' disease. We report a family with hyperthyroidism and the TSHR variant Gly413Ser and provide clinical, segregation, and functional evidence that this p10-region variant is a novel cause of FNAH.

The disorder was recognized after a 15-year-old boy presented with abdominal pain and diarrhea and was found to have suppressed thyrotropin, high-normal free thyroxine, and slightly elevated free triiodothyronine, without thyrotropin receptor antibodies (TRAb) or ophthalmopathy. Family review revealed multigenerational TRAb-negative hyperthyroidism. Genetic testing identified NM_000369.5(TSHR):c.1237G>A, p.(Gly413Ser), initially classified as a variant of uncertain significance. Twelve family members were investigated: nine affected individuals carried the variant, and three unaffected relatives tested negative. Age at diagnosis ranged from 10 to 73 years. Antithyroid drugs gave symptom relief, but relapse occurred after withdrawal; definitive (ablative) treatment was performed in all but one of the affected family members. Basal cyclic adenosine monophosphate (cAMP) production by the Gly413Ser variant was approximately threefold increased, with unchanged inositol 1-phosphate and thyrotropin-stimulated responses.

TSHR Gly413Ser is a pathogenic activating variant causing FNAH. Persistent TRAb-negative hyperthyroidism, especially with familial clustering, should prompt TSHR genetic testing and cascade evaluation.