[Thyroglobulin gene abnormalities]

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, 54 cases from 43 families were identified in Japan. The patients presented either transient elevation of serum TSH during infancy or growing giant goiters from childhood. Among 15 patients who were born after initiation of neonatal screening in 1979, 13 patients were identified by high serum TSH. In contrast, the major manifestation in patients born before 1979 is persistent growth of goiters with euthyroidism or subclinical hypothyroidism. Among 25 mutations, Cys1264Arg and Cys1077Arg are hot spots. The Cys1264Arg patients were found all over Japan, but the Cys1077Arg patients were confined to a small village of a southern island in Japan. The occurrence of the thyroglobulin mutations in the 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 the thyroid, 25 patients underwent surgical treatment. Among them, 11 patients suffered from thyroid cancers, most of which were of the papillary type. We found two BRAF activating mutations Val599Glu and Cys600Gln 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 inevitable, and 40% of the removed thyroids contained thyroid cancers, some of which were caused by activating mutations of the BRAF gene.