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What are Multiple Osteochondromas (MO)?

MO, also called multiple hereditary exostoses (MHE, or HME), is an ultra-rare (MO affects approximately 20 individuals per million lives) genetic musculoskeletal condition in which multiple benign bone tumors, also known as osteochondromas (OCs) or exostoses, develop on bones. MO is typically diagnosed in early childhood, with a median age at diagnosis of 3 years due to symptomatic OCs. These OCs are comprised of growth plate-like cartilage cap overlying a bony base and originate as an outgrowth of growth plates, but frequently detach from the growth plate as a child grows. OCs form at the end of most long bones and on flat bones, such as the hip, shoulder blade or ribs. These can be discerned visually and by clinical exam. The image below illustrates the appearance of OCs at multiple locations around the knees and ankles. The inward bent of the knees (valgus of the knee) is also apparent.

Appearance of OCs:

(Images reproduced from Bovée. J.V. (2008) Orphanet Journal of Rare Diseases, 3, 3)

MO is phenotypically variable and associated with skeletal abnormalities including short stature, joint deformity including dislocation of the hand or valgus deformity of the knee, bowed bones and limb length discrepancies, and early onset osteoarthritis. Functional problems and morbidity occur due to pain, reduced mobility and range of motion, entrapment of blood vessels, nerves, tendons and spinal cord compression. Of patients with MO, 70% often undergo surgeries, sometimes in excess of 20, to remove OCs or address deformities. In 2-5% of patients with MO, OCs become neoplastic during adulthood.

Once bone growth is complete in late adolescence and early adulthood, it is believed that new OCs do not form; however, existing OCs can still grow and cause morbidity. Disease severity has been classified according to the number of OCs detected at a certain age as well as the number of sites with deformities or functional limitations. From a registry of 529 patients, 62% were deemed to be moderate to severe,  while the remainder presented with milder disease.

Palovarotene has been previously shown to inhibit the downstream signaling of bone morphogenetic protein (BMP) receptors via Smads 1/5/8 in FOP. Since it is believed that the mutations which cause MO also result in excess BMP signaling through Smads 1/5/8, we believe palovarotene may also inhibit this pathway in MO. In this manner, palovarotene treatment could potentially reduce morbidity and deformity and preserve function in patients with MO.