Gabriella Miller Kids First Pediatric Research Program in Enchondromatoses and Related Malignant Tumors

Chondrosarcoma is a malignant tumor that originates from cartilaginous cells. It is the third most common primary malignancy of bone after myeloma and osteosarcoma. It accounts for about 20% of bone tumors and is diagnosed in approximately 600 patients each year in the United States. Up to 40% of the chondrosarcomas arise from an enchondroma. Enchondromas are benign, intramedullary cartilaginous tumors of bone. They can be solitary or multiple and are present in >3% of the population. Enchondromatosis refers to a group of diseases characterized by multiple enchondromas including metachondromatosis (MC), Ollier disease (OD), and Maffucci syndrome (MS) among others. All have skeletal abnormalities with or without associated vascular anomalies that can cause severe limb deformities during early childhood. The risk for chondrosarcoma is up to 30% in OD and MS. Currently, the only treatment for patients with these disorders is surgical; there is no effective pharmacologic therapy. The molecular bases of these two conditions is not well understood.]]>
Families will be included if the proband has 3 or more enchondromas with or without vascular anomalies and if the trio is available for sequencing.]]>
Ollier disease and Maffucci syndrome are characterized by multiple enchondromas that can cause multiple swellings on the extremity, deformity around the joints, Madelung deformity, angular deformity such as genu valgus, gene varum, cubitus valgus, coxa vara and coxa valga, limitations in joint mobility, scoliosis, bone shortening, leg-length discrepancy, gait disturbances, pain and loss of function, pathological fractures, facial asymmetry and cranial nerve palsies and the risk of developing a chondrosarcoma is ~30% in patients with Ollier disease and Maffucci syndrome. In addition, gliomas, acute myeloid leukemia, and juvenile granulosa cell tumors have been found in patients with Ollier disease and pancreatic and hepatic adenocarcinoma, mesenchymal ovarian tumors, brain tumors such as glioma and astrocytoma, and various kinds of sarcomas are observed in patients with Maffucci syndrome (Verdegaal et al., 2011; PMID: 22147000). The molecular basis of this two disorders is not completely understood and currently, there is no effective drug therapy for these disorders. To understand the molecular bases of these disorders, we have recruited a large number of patients with Ollier disease or Maffucci syndrome from many countries world-wide, over the course of the last 10 years. For the current Kids First project whole genome sequencing (WGS) will be performed in 100 case-parent trios.]]>