Biallelic p.R2223H mutation in the thyroglobulin gene causes thyroglobulin retention and severe hypothyroidism with subsequent development of thyroid carcinoma.

CONTEXT: Dyshormonogenesis due to genetic defect in thyroglobulin (Tg) synthesis and secretion can lead to congenital hypothyroidism. OBJECTIVES: The aim of the study was to analyze the TG gene for the presence of mutations and to study the underlying mechanisms leading to dyshormonogenesis. CASES: Two siblings aged 25 and 31 yr presented with recurrent goitrous hypothyroidism with undetectable serum Tg. The older sibling was diagnosed with follicular variant of papillary thyroid carcinoma (FVPTC) at age 21 and metastatic FVPTC 8 yr later. METHODS: The entire coding region of TG gene was sequenced. BRAF, RAS, and P53 mutations or PAX8/PPAR-gamma rearrangement were screened in the FVPTC. Tg expression was studied by immunohistochemistry. RESULTS: Biallelic c.6725G>A (p.R2223H) and c.6396C>T (p.S2113L) sequence variations were detected in both patients and monoallelic variations in their family members. The c.6396C>T (p.S2113L) sequence variation was found in 14% of 100 population controls, whereas c.6725G>A variation was not present in the controls. Two previously reported polymorphisms (c.2200T>G and c.3082A>G) were present in all the family members. Strong cytoplasmic immunostaining of Tg was observed in the hyperplastic thyroid epithelial cells and weak or no staining in the follicular lumen. Cytoplasmic staining was localized in the endoplasmic reticulum. Reduced staining was found in the FVPTC. Neither RAS, BRAF, or P53 gene mutation nor a PAX8/PPAR-gamma rearrangement was detected in the tumor tissue. CONCLUSIONS: Biallelic c.6725G>A (p.R2223H) mutation causes Tg retention in the endoplasmic reticulum, resulting in dyshormonogenesis. Prolonged TSH stimulation may promote malignant transformation and development of thyroid cancer. The c.6396C>T (p.S2113L) is a novel polymorphism.