| Budget Amount *help |
¥3,000,000 (Direct Cost: ¥3,000,000)
Fiscal Year 2005: ¥1,400,000 (Direct Cost: ¥1,400,000)
Fiscal Year 2004: ¥1,600,000 (Direct Cost: ¥1,600,000)
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| Research Abstract |
Congenital hypothyroidism is caused either by abnormal development of thyroid glands or by inborn errors of thyroid hormone synthesis. Thyroglobulin mutations which caused overt Cretins with physical and mental development impairment were once believed rare. However, since the discovery of mild hypothyroidism due to thyroglobulin mutations, 53 cases from 42 families were identified in Japan. The patients presented either transient elevation of serum TSH during infancy or growing giant goiters from childhood. Among 16 patients who were born after initiation of neonatal screening in 1979, 12 patients were identified by high serum TSH. Contrary, the major manifestation of the patients born before 1979 is persistent growth of goiters with euthyroidsm or subclinical hypothyroidism. Among 27 mutations, C1264R and C1077R are frequently identified. The C1264R patients were found all over Japan, but the C1077R patients were confined in a small village of a southern island in Japan. The occurrence of the thyroglobulin mutations in general population is 1/67,000. The pathogenesis of abnormal thyroglobulin is defective intracellular transport. The histological findings include empty colloid in the follicles and distended ER filling the entire cytoplasm of the thyrocytes. An in vitro expression study showed that abnormal thyroglobulin was not secreted from cultured cells. Because of persistent growth of goiter, 26 patients underwent surgical treatment. Among them, 11 patients suffered from thyroid cancers, most of which are of papillary type. We found two BRAF activating mutations V599E and C600Q in five patients tested.
In conclusion, we found many patients with thyroglobulin mutations in Japan. They were found by high serum TSH at neonatal screening or persistent growth of goiters in adults. Surgical treatments were frequently performed, and 42% of the removed thyroids contained thyroid cancers, some of which were caused by activating mutations of the BRAF gene.
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