Variable phenotype associated with Ser505Asn-activating thyrotropin-receptor germline mutation

Constitutively activating thyrotropin-receptor (TSHR) germline mutations have been identified as a molecular cause of hereditary nonautoimmune hyperthyroidism. To date, seven cases of familial and six cases of sporadic nonautoimmune hyperthyroidism have been described associated with 13 different TSHR germline mutations, with a variable clinical course. We report the case of a 12.3-year-old girl with a history of thyrotoxicosis since the age of 11 months who developed diffuse thyroid hyperplasia at the age of 4.5 years. The patient has required continuous moderate-dose antithyroid medication, to maintain euthyroidism. There were no clinical signs of autoimmune thyroid disease and autoantibodies were negative. An activating germline mutation in the TSHR gene was suspected and was found in TSHR exon 10 (Ser505Asn) but was absent in the girl's mother. This same mutation, was first reported in a patient with severe intrauterine hyperthyroidism with early and progressive goiter development. Our patient had a significantly less severe clinical course with later onset compared to the original patient with the same TSHR germline mutation.