Enchondromas are common benign cartilage tumors of bone. They can occur as 
solitary lesions or as multiple lesions in enchondromatosis (Ollier and Maffucci 
diseases). Clinical problems caused by enchondromas include skeletal deformity 
and the potential for malignant change to chondrosarcoma. The extent of skeletal 
involvement is variable in enchondromatosis and may include dysplasia that is 
not directly attributable to enchondromas. Enchondromatosis is rare, obvious 
inheritance of the condition is unusual and no candidate loci have been 
identified. Enchondromas are usually in close proximity to, or in continuity 
with, growth-plate cartilage. Consequently, they may result from abnormal 
regulation of proliferation and terminal differentiation of chondrocytes in the 
adjoining growth plate. In normal growth plates, differentiation of 
proliferative chondrocytes to post-mitotic hypertrophic chondrocytes is 
regulated in part by a tightly coupled signaling relay involving parathyroid 
hormone related protein (PTHrP) and Indian hedgehog (IHH). PTHrP delays the 
hypertrophic differentiation of proliferating chondrocytes, whereas IHH promotes 
chondrocyte proliferation. We identified a mutant PTH/PTHrP type I receptor 
(PTHR1) in human enchondromatosis that signals abnormally in vitro and causes 
enchondroma-like lesions in transgenic mice. The mutant receptor constitutively 
activates Hedgehog signaling, and excessive Hedgehog signaling is sufficient to 
cause formation of enchondroma-like lesions.