Context: Heterozygous inactivating PAX8 mutations cause congenital hypothyroidism. Although more than 30 mutation carriers have been reported, no histological examination of the thyroid has been conducted. Objective: The objective of this study was to document the histological characteristics of the thyroid tissue harboring a PAX8 mutation. Subjects and Methods: The patient was a 40-yr-old female, whose two children had congenital hypothyroidism and an inactivating PAX8 mutation (p.K80-A84dup). She had normal thyroid function but had a thyroid nodule and received right hemithyroidectomy at age 28 yr. Mutation analyses using DNA derived from multiple sources, namely lymphocytes, nails, and laser capture microdissected thyroid samples, were performed. Results: The PAX8 mutation was detected in the lymphocytes; however, the level of the mutant allele was significantly lower than that of the wild-type allele. This finding was compatible with her somatic mosaic state.Were viewed the histology of her resected thyroid and found a characteristic lesion in the nonneoplastic tissue: dense aggregates of thyrocytes with absent or very small follicles, resembling a fetal thyroid in the late phase of development. Mutation analyses of laser capture microdissected thyroid samples revealed that the fetal-like tissue carried the PAX8 mutation, whereas surrounding morphologically normal tissue and adenoma tissue did not. Conclusions: In our case, the histology of PAX8 mutation-carrying thyroid tissue was characterized by the lack of follicular growth. Our observations provide the first evidence suggesting that the late phase of thyroid development is sensitive to the PAX8 gene dosage and can be disturbed by heterozygous inactivating PAX8 mutations.
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