Context: Defects in thyroglobulin (Tg) synthesis are one of the causes of thyroid dyshormonogenesis. Only few mutations in Tg gene have been described.

Objectives: We describe a novel Tg gene mutation and discuss the mechanisms by which it causes dyshormonogenesis with subsequent malignant transformation.

Cases: Two siblings aged 20 and 19 yr presented with recurrent goiters for which they had undergone multiple thyroid surgeries since early childhood. The older sibling was diagnosed with metastatic follicular thyroid carcinoma at age 15 yr.

Methods: The entire coding region and intron-exon boundaries of the Tg gene were amplified and sequenced from the patients. We also sequenced the boundaries of exon 5 and intron 5 from both parents. RT-PCR amplification of a cDNA fragment encompassing exon 4-6 was also performed.

Results: A homozygous G to A point mutation at position +1 of the splice donor site of intron 5 (g.IVS5 + 1G>A) was detected in both patients whereas a monoallelic mutation was found in their parents. RT-PCR amplification of a cDNA fragment covering exons 4-6 revealed a 191 bp fragment in the patients and 351 bp and 191 bp fragments in the parents. Sequence analysis of these two fragments confirmed deletion of exon 5 in the 191 bp fragment.

Conclusions: Aberrant splicing occurred as a result of the g. IVS5 + 1G>A mutation, which caused fusion of exons 4 and 6, resulting in the frame shift at codon position 141and a premature stop codon at position 147 (FS141 > 147X). The malignant transformation is likely due to prolonged TSH stimulation.