||5R03CA256535-02 Interpret this number
||Johns Hopkins University
||Genome-Wide Sequencing to Identify the Genes Responsible for Enchondromatoses and Related Malignant Tumors
We propose to investigate the molecular bases of Ollier disease (OD) and Maffucci syndrome (MS), rare
diseases characterized by multiple enchondromas leading to severe skeletal deformities and an increased risk
for chondrosarcomas and other malignancies. Our central hypothesis is that OD and MS are under-
recognized cancer susceptibility syndromes caused by variants in multiple genes that disrupt few
connected pathways and that pathogenic variants in these genes also cause isolated forms of other
OD is characterized by multiple enchondromas with onset in early childhood, typically unilateral in
distribution with a predilection for the appendicular skeleton. MS is characterized by multiple enchondromas
distributed bilaterally and combined with vascular anomalies and in ~13% of the cases the disease is noticeable
in the first year of age. Both disorders can cause multiple swellings on the extremity, deformity around the joints,
limitations in joint mobility, scoliosis, bone shortening, leg-length discrepancy, gait disturbances, bone pain,
pathological fractures, facial asymmetry and cranial nerve palsies. The risk of developing a chondrosarcoma in
OD and MS is ~ 30%. In addition, these patients also have a higher risk of developing gliomas, juvenile granulosa
cell tumor of ovary and vascular malignancies. The molecular bases of OD and MS is not completely understood.
Currently, the only treatment for patients with OD and MS is surgical; there is no pharmacologic therapy.
The NIH- Common Fund's Gabriella Miller Kids First Pediatric Research Program enabled us to perform
germline whole genome sequencing in 75 individuals with OD or MS and their parents and through the Baylor-
Hopkins Center for Mendelian Genomics we have performed germline whole exome sequencing on 63
individuals with OD or MS. Here, we propose an analytical approach to analyze this data and identify the
molecular bases of OD and MS and to use this information to investigate the cause of isolated gliomas.
Disruption of the HIF-1 pathway in individuals with Ollier disease and Maffucci syndrome.
, Martin R.
, Wohler E.
, Partan E.S.
, Walek E.
, Salman S.
, Groepper D.
, Kratz L.
, Cernach M.
, Jesus-Garcia R.
, et al.
PLoS genetics, 2022 Dec; 18(12), p. e1010504.