Hereditary multiple exostoses
Encyclopedia
Hereditary multiple exostoses (HME) is a rare medical condition in which multiple bony spurs or lumps (also known as exostoses
, or osteochondroma
s) develop on the bones of a child. HME is synonymous with Multiple hereditary exostoses and Multiple osteochondromatosis, which is the preferred term used by the World Health Organization
.
HME can cause pain to people of all ages. To children, this can be especially painful. During exercise, it can cause a significant amount of pain.
of the long bones. HME can lead to the shortening and bowing of bones; affected individuals often have a short stature. Depending on their location the exostoses can cause the following problems: pain or numbness from nerve compression, vascular compromise, inequality of limb length, irritation of tendon and muscle, as well as a limited range of motion at the joints upon which they encroach. A person with HME has an increased risk of developing a rare form of bone cancer called chondrosarcoma
as an adult. Problems may be had in later life and these could include weak bones and nerve damage. The reported rate of transformation ranges from as low as 0.57% to as high as 8.3% of people with HME.
Surgery, physical therapy and pain management are currently the only options available to HME patients, but success varies from patient to patient and many struggle with pain, fatigue and mobility problems throughout their lives.
It is not uncommon for HME patients to undergo numerous surgical procedures throughout their lives to remove painful or deforming exostoses, correct limb length discrepancies or improve range of motion. Usually the treatment can be problematic. The osteocondromas can return in the same places and may be more painful.
HME has thus far been linked with mutations in three genes.
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.
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.
Exostosis
An exostosis is the formation of new bone on the surface of a bone. Exostoses can cause chronic pain ranging from mild to debilitatingly severe, depending on where they are located and what shape they are....
, or osteochondroma
Osteochondroma
Osteochondroma is a type of benign tumor that consists of cartilage and bone. It is a benign capped-cartilage outgrowth, connected to bone by a stalk.It is the most frequently observed neoplasm of the skeleton....
s) develop on the bones of a child. HME is synonymous with Multiple hereditary exostoses and Multiple osteochondromatosis, which is the preferred term used by the World Health Organization
World Health Organization
The World Health Organization is a specialized agency of the United Nations that acts as a coordinating authority on international public health. Established on 7 April 1948, with headquarters in Geneva, Switzerland, the agency inherited the mandate and resources of its predecessor, the Health...
.
HME can cause pain to people of all ages. To children, this can be especially painful. During exercise, it can cause a significant amount of pain.
Pathophysiology
HME is estimated to occur in 1 in 50,000 people. It is characterized by the growth of cartilage-capped benign bone tumours around areas of active bone growth, particularly the metaphysisMetaphysis
The metaphysis is the wider portion of a long bone adjacent to the epiphyseal plate. It is this part of the bone that grows during childhood; as it grows, it ossifies near the diaphysis and the epiphyses...
of the long bones. HME can lead to the shortening and bowing of bones; affected individuals often have a short stature. Depending on their location the exostoses can cause the following problems: pain or numbness from nerve compression, vascular compromise, inequality of limb length, irritation of tendon and muscle, as well as a limited range of motion at the joints upon which they encroach. A person with HME has an increased risk of developing a rare form of bone cancer called chondrosarcoma
Chondrosarcoma
Chondrosarcoma is a cancer composed of cells derived from transformed cells that produce cartilage. Chondrosarcoma is a member of a category of "soft tissue" malignancies known as sarcomas. About 30% of skeletal system cancers are chondrosarcomas...
as an adult. Problems may be had in later life and these could include weak bones and nerve damage. The reported rate of transformation ranges from as low as 0.57% to as high as 8.3% of people with HME.
Treatment
HME begins to manifest itself in childhood and currently has no cure.Surgery, physical therapy and pain management are currently the only options available to HME patients, but success varies from patient to patient and many struggle with pain, fatigue and mobility problems throughout their lives.
It is not uncommon for HME patients to undergo numerous surgical procedures throughout their lives to remove painful or deforming exostoses, correct limb length discrepancies or improve range of motion. Usually the treatment can be problematic. The osteocondromas can return in the same places and may be more painful.
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.
- EXT1EXT1Exostosin-1 is a protein that in humans is encoded by the EXT1 gene.-External links:*...
which maps to chromosome 8q24.1
- EXT2EXT2 (gene)Exostosin-2 is a protein that in humans is encoded by the EXT2 gene.-Interactions:EXT2 has been shown to interact with TRAP1.-External links:*...
which maps to 11p13
- EXT3EXT3 (gene)EXT3 is a human gene.It is associated with hereditary multiple exostoses....
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
Heparan sulfate
Heparan sulfate is a linear polysaccharide found in all animal tissues. It occurs as a proteoglycan in which two or three HS chains are attached in close proximity to cell surface or extracellular matrix proteins...
, 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
Chondrocyte
Chondrocytes are the only cells found in cartilage. They produce and maintain the cartilaginous matrix, which consists mainly of collagen and proteoglycans...
proliferation and differentiation may be affected, leading to abnormal bone growth.
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.
External links
- Hereditary Multiple Exostoses (MHE) Research Foundation's Website
- Medcyclopaedia - Hereditary Multiple Exostises
- GeneReviews: Hereditary Multiple Exostoses
- Information about Multiple Hereditary Exostoses (MHE)
- Hereditary Multiple Exostoses Support Group
- Images of Multiple Hereditary Exostoses (MHE) from Medical Image Database - MedPix