High incidence of thyroid cancer in long-standing goiters with thyroglobulin mutations

In this paper, we report the high prevalence of thyroid malignancy in patients with thyroglobulin mutations in Japan. Mutations of the thyroglobulin gene cause defective thyroid hormone synthesis, resulting in congenital hypothyroidism. Since our report in 1999 on the thyroglobulin mutations C1264R and C1996S, we have identified 14 adult patients (7 males and 7 females) from 9 unrelated families. They visited hospitals for treatment of huge goiters that first appeared in childhood. Persistent growth of the thyroid gland, probably caused by thyrotropin (TSH) stimulation, partially compensated thyroid hormone production, resulting in lowered serum TSH concentrations in turn. Consequently, many patients had to undergo multiple operations. Of 11 patients who had undergone surgery, 7 had thyroid cancers. Of five patients whose thyroid tissue was available, we found a heterozygous activating mutation, either V599E or K600E, in cancerous tissue from each of 2 patients. From these observations, we conclude that goiter resulting from thyroglobulin mutations is associated with thyroid cancer.