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Odontogenic lesions are rare, but can be associated with significant morbidity. While their molecular determinants are unknown, they likely express many genes common to normal odontogenesis. This study evaluated the histology and mRNA expression of an unusual odontogenic lesion in a patient with a confirmed history of tricho-dento-osseous syndrome. Methods: Decalcified, frozen 8 µm sections of the lesion were cut and mounted on glass slides and stained with hematoxylin/eosin for analysis. The expression of multiple genes associated with normal odontogenesis and related pathologies were evaluated by RT-PCR, where possible in samples of the hard and soft tissue components of the lesion. Results: Histological examination showed the lesion had large areas of irregular, dentine-like material, enamel matrix, areas of woven immature bone and multiple fully mineralised tooth crowns. Although most of the gene transcripts were amplified from both samples, some, including DLX3/7 and Collagen I demonstrated differential expression. Conclusions: This study shows the gene expression profile of aberrant odontogenesis with associated odontoma formation is similar to that of normal tooth and the genes expressed in other odontogenic lesions. While the role of altered gene expression in the development of such lesions has previously been postulated from transgenic models, this is the only report of an odontogenic lesion in a patient with TDO, and begins to elucidate possible gene interactions key to its development.