Long-Term Follow-Up of a Patient with Sporadic Nonautoimmune Hyperthyroidism Due to a Thyrotropin-Receptor Mutation (D619G)

ABSTRACT Objective: Sporadic nonautoimmune hyperthyroidism caused by germline mutations of the thyrotropin receptor (TSHR) gene is a very rare disease that manifests as severe congenital hyperthyroidism. We describe a case presenting with sporadic nonautoimmune hyperthyroidism during adolescence. Methods: Laboratory data, imaging, histopathology, clinical follow-up, and DNA sequencing were evaluated. Results: The patient was born at term with a normal birth weight but showed increased growth velocity at approximately 7 months. He had no medical consultation before tachycardia was detected at a school physical examination at the age of 13 years. Thyroid function tests confirmed hyperthyroidism with negative anti-TSHR antibodies. After maintaining methimazole therapy for 12 years, he underwent total thyroidectomy, and the weight of the resected thyroid tissue was 131 g. The subsequent histopathologic findings showed an encapsulated follicular adenoma, adenomatous goiter, and hyperplastic changes of the follicular epithelium without stromal lymphoid infiltration in normal parenchyma. Sequence analysis of the TSHR gene showed two compound heterozygous germline variants (R310H and D619G) on different alleles. The TSHRR310H was a nonfunctioning variant from the maternal allele. The TSHR-D619G was previously detected as a somatic mutation in patients with toxic adenomas. The TSHR-D619G mutation, which was absent in his parents, was a de novo mutation on the paternal allele. Conclusion: A TSHR germline mutation (D619G) was identified as the cause of sporadic nonautoimmune hyperthyroidism in a Japanese patient. This patient showed no obvious complications until the age of 13 years, but long-term follow-up with methimazole treatment showed further goiter and benign nodular formation. Abbreviations: MMI methimazole; TRAb thyrotropin-receptor antibody; TSHR thyrotropin receptor