Hereditary Multiple Exostoses - Genetics

Genetics

HME is an autosomal dominant hereditary disorder. This means that a patient with HME has a 50% chance of transmitting this disorder to his or her children. Most individuals with HME have a parent who also has the condition, however, approximately 10% -20% of individuals with HME have the condition as a result of a spontaneous mutation and are thus the first person in their family to be affected.

HME has thus far been linked with mutations in three genes.

• EXT1 which maps to chromosome 8q24.1

• EXT2 which maps to 11p13

• EXT3 which maps to the short arm of Chromosome 19 (though its exact location has yet to be precisely determined)

Mutations in these genes typically lead to the synthesis of a truncated EXT protein which does not function normally. It is known that EXT proteins are important enzymes in the synthesis of heparan sulfate, however the exact mechanism by which altered synthesis of heparan sulfate that could lead to the abnormal bone growth associated with HME is unclear. It is thought that normal chondrocyte proliferation and differentiation may be affected, leading to abnormal bone growth.Since the HME genes are involved in the synthesis of a glycan (heparan sulfate), HME may be considered a congenital disorder of glycosylation according to the new CDG nomenclature suggested in 2009.

For individuals with HME who are considering starting a family, preimplantation genetic testing and prenatal diagnosis are available to determine if their unborn child has inherited the disease. HME has a 96% penetrance, which means that if the disease is indeed transmitted to a child, he/she will have a 96% of actually manifesting the disease, and 4% chance of having the disease but never manifesting it.