Hereditary multiple exostoses

Hereditary multiple exostoses is a condition in which people develop multiple benign (noncancerous) bone tumors called exostoses. The number of exostoses and the bones on which they are located vary greatly among affected individuals. The exostoses are not present at birth, but approximately 96 percent of affected people develop multiple exostoses by the time they are 12 years old. Once people with hereditary multiple exostoses reach adult height and their bones stop growing, the development of new exostoses also usually stops.

Multiple exostoses can disrupt bone growth and can cause growth disturbances of the arms, hands, and legs, leading to short stature. Often these bone growth disturbances do not affect the right and left limb equally, resulting in uneven limb lengths (limb length discrepancy). Multiple exostoses may also result in pain, limited range of joint movement, and pressure on nerves, blood vessels, the spinal cord, and tissues surrounding the exostoses.

Exostoses are typically benign; however, in some instances these tumors become malignant (cancerous). Researchers estimate that people with hereditary multiple exostoses have a 1 in 20 to 1 in 200 lifetime risk of developing cancerous exostoses (sarcomas).

The incidence of hereditary multiple exostoses is estimated to be 1 in 50,000 individuals. This condition occurs more frequently, however, in some isolated populations. The incidence is approximately 1 in 1,000 in the Chamorro population of Guam and 1 in 77 in the Ojibway Indian population of Manitoba, Canada.

Mutations in the EXT1 and EXT2 genes cause hereditary multiple exostoses. The EXT1 gene and the EXT2 gene provide instructions for producing the proteins exostosin-1 and exostosin-2, respectively. The two exostosin proteins bind together and form a complex found in a cell structure called the Golgi apparatus, which modifies newly produced enzymes and other proteins. In the Golgi apparatus, the exostosin 1 and 2 complex modifies a protein called heparan sulfate so it can be used by the cell.

When there is a mutation in exostosin-1 or exostosin-2, heparan sulfate cannot be processed correctly and is nonfunctional. Although heparan sulfate is involved in many bodily processes, it is unclear how the lack of this protein contributes to the signs and symptoms of hereditary multiple exostoses.

If the condition is caused by a mutation in the EXT1 gene it is called hereditary multiple exostoses type 1. A mutation in the EXT2 gene causes hereditary multiple exostoses type 2. While both type 1 and type 2 involve multiple exostoses, the severity of symptoms associated with exostoses seems to be greater in type 1.

Researchers estimate that about 15 percent of people with hereditary multiple exostoses have no mutation in either the EXT1 or the EXT2 gene. It is not known why multiple exostoses form in these people.

This condition is inherited in an autosomal dominant pattern, which means one copy of the altered gene in each cell is sufficient to cause the disorder.

In some cases, an affected person inherits the mutation from one affected parent. Other cases result from new mutations in the gene and occur in people with no history of the disorder in their family.