Abnormal ossification in thanatophoric dysplasia

Thanatophoric dysplasia (TD) is a lethal human bone dysplasia characterized by severe dwarfism. It pathogenesis is thought to involve an abnormal ossifying fibrous tissue that disrupts the skeletal growth plate. We employed a combined morphologic, immunohistochemical and biochemical approach to better define the nature of this tissue in growth plate cartilage from 15 TD fetuses and infants in whom the abnormality was observed. The tissue was organized into tufts comprised of a cap of interstitial connective tissue, a transition region containing preosteoblastic cells near the cap and osteoblastic cells near the base, and a mineralized base which formed the subchondral bone trabeculae. The morphology of the cells and the presence of type I collagen in all regions of the tufts suggested that they were foci of membraneous ossification. However, elements of cartilage matrix (type II collagen, proteoglycan, link protein) were identified in the pericellular matrix of the osteoblastic cells and adjacent osteocytic cells. These observations suggest that a peculiar form of ossification occurs in the TD growth plate and may be involved in the pathogenesis of the disorder.