Multiple Osteochondromas (MO; previously known as multiple hereditary exostosis) is an autosomal dominant genetic\ncondition that is characterized by the formation of cartilaginous bone tumours (osteochondromas) at multiple sites in the\nskeleton, secondary bursa formation and impingement of nerves, tendons and vessels, bone curving, and short stature. MO\nis also known to be associated with arthritis, general pain, scarring and occasional malignant transformation of\nosteochondroma into secondary peripheral chondrosarcoma. MO patients present additional complains but the relevance\nof those in relation to the syndromal background needs validation. Mutations in two enzymes that are required during\nheparan sulphate synthesis (EXT1 or EXT2) are known to cause MO. Previously, we have used zebrafish which harbour\nmutations in ext2 as a model for MO and shown that ext22/2 fish have skeletal defects that resemble those seen in\nosteochondromas. Here we analyse dental defects present in ext22/2 fish. Histological analysis reveals that ext22/2 fish have\nvery severe defects associated with the formation and the morphology of teeth. At 5 days post fertilization 100% of ext22/2\nfish have a single tooth at the end of the 5th pharyngeal arch, whereas wild-type fish develop three teeth, located in the\nmiddle of the pharyngeal arch. ext22/2 teeth have abnormal morphology (they were shorter and thicker than in the WT)\nand patchy ossification at the tooth base. Deformities such as split crowns and enamel lesions were found in 20% of ext2+/2\nadults. The tooth morphology in ext22/2 was partially rescued by FGF8 administered locally (bead implants). Our findings\nfrom zebrafish model were validated in a dental survey that was conducted with assistance of the MHE Research\nFoundation. The presence of the malformed and/or displaced teeth with abnormal enamel was declared by half of the\nrespondents indicating that MO might indeed be also associated with dental problems.
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