Uncovering Genes Behind Cartilage Tumors and Vascular Anomalies Using Genomic Sequencing

Background: Ollier disease (OD) and Maffucci syndrome (MS) are rare disorders that increase the risk of cancers in cartilage tissue. These tumors can lead to severe skeletal deformities beginning in childhood. People with OD or MS are also at an increased risk of blood vessel disorders and specific cancers. Researchers want to learn more about what causes these disorders. Objective: To understand the genetic causes of OD and MS. Eligibility: People aged 2 years and older who have OD or MS with cartilage tumors or blood vessel disorders. Design: Participants will stay at the NIH clinic for 5 days. They will undergo these procedures: A physical exam with blood tests. DXA (dual-energy X-ray absorptiometry) scan. The DXA scan measures the density of bones. Participants will lie on a table while a machine uses low-level X-rays to scan their body. MRI (magnetic resonance imaging) scan. An MRI uses strong magnets to take pictures of the tissues inside the body. Participants will lie on a table that slides into a large tube. A contrast dye may be injected through a needle inserted into a vein in the arm. X-rays. Some participants may have full-body X-rays instead of an MRI. X-rays take pictures of bones and other internal tissues and organs, such as the heart, lungs, and airways. PET (positron emission tomography) and CT (computed tomography) scans. Adult participants will have 2 other scans. The PET scan will include a radioactive injection into a vein. They will also have a full-body CT scan.

Study Design: The study will recruit and enroll up to 100 patients with Ollier disease (OD) and Maffucci syndrome (MS) over five years. Each participant will be seen at the NIH Clinical Center (CC) for an inpatient study visit of 5 days or longer. During that visit, the following procedures will be performed: dual-energy x-ray absorptiometry (DXA), whole-body X-ray, magnetic resonance angiography (MRA), whole-body positron emission tomography (PET) scan, a magnetic resonance imaging (MRI), and brain single-voxel magnetic resonance spectroscopy. After being seen at the NIH CC by the study team, the participants will receive a summary of all the results of the tests and consults completed at the NIH. Family members enrolled for genome sequencing will not undergo any clinical evaluations at the NIH CC. Dr. Gordon will oversee the implementation of the study at the NIH. Dr. Marini was involved in the original NIH grant application and has retired but she retains an appointment at the NIH as a Scientist Emeritus/ Volunteer. Dr. Marini will serve on the protocol as a Senior Clinical Consultant and work at the NIH CC. She will not consent participants but will be present at many of the study visits. Members of the JHU study team will have permission to work and/or observe at the NIH; they will however not be considered part of the NIH study team and will not be identified as NIH Associate Investigators. Objectives: Ollier disease (OD) and Maffucci syndrome (MS), are characterized by multiple enchondromas that result in severe skeletal deformities during early childhood and an increased risk for chondrosarcomas and other malignancies. Patients with MS also have vascular anomalies. 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. The risk for chondrosarcoma in OD is up to 45.8% and in MS up to 57.1%. Currently, the only treatment for patients with these disorders is surgical; there is no effective pharmacologic therapy. We identified heterozygous germline loss of function variants in PTPN11 (encoding a non-receptor protein tyrosine phosphatase SHP2) causing MC. In preliminary studies, we also identified the PTPN11 R138X variant in a retiform hemangioendothelioma of a patient with MS and the germline PTPN11 L560F variant in a patient with OD. PTPN11 encodes SHP2, a cytosolic protein tyrosine phosphatase involved in an early step in RAS/MAPK signaling downstream of several receptor tyrosine kinases including EGFR and FGFR. Using immunoblot analysis we measured the expression of the end products of this pathway, pERK1 and 2 in fibroblasts from patients with MC and OD and observed decreased expression of pERK1 and 2 in patients compared to the controls (Sobreir trial.show_full_description

* INCLUSION CRITERIA: Patients \>=2 years of age, male or female, of any ethnicity and age will be included if diagnosed with a disorder characterized by cartilage tumors or vascular anomalies.