What is MHE (Multiple Hereditary Exostoses)?
MHE / MO / HME (MHE) is a genetic bone disorder in which benign cartilage-capped bone tumors grow outward from the metaphyses of long bones, growth plates or from the surface of flat bones throughout the body. The severity of this disease varies widely. Some patients may have as few as two tumors, but most patients develop many more and the numbers of tumors can run into the hundreds.
MHE affects roughly 1 in 50,000 people. Most individuals with MHE have a parent who also has this condition, however approximately 10% of individuals with MHE have this condition as a result of a spontaneous mutation and are thus the first person in their family to be affected. Offspring of an affected individual have a 50% risk of inheriting the altered gene for MHE.
MHE sufferers develop cartilage-capped bone tumors called Exostoses / Osteochondroma which may be sessile or pedunculated and vary widely in size and shape. Pedunculated Exostoses / Osteochondroma have a Broccoli like appearance with a stalk with majority growth towards the end of the stalk. Sessile Exostoses / Osteochondroma have a broad-base attachment to the outer bone, called the "cortex" and have a lumpy / bumpy appearance.
Photograph of the legs of a 26-year old male showing multiple lumps leading to deformity
Photograph of young boy with exostoses and accompanying x-rays
Exostoses / Osteochondromas can cause numerous problems, including compression of peripheral nerves or blood vessels, irritation of tendons and muscles resulting in pain and loss of motion, skeletal deformity, short stature, limb length discrepancy, chronic pain and fatigue, mobility issues, early onset of arthritis and an increased risk of developing malignant tumor transformation (chondro-sarcoma). The reported risk of malignancy is 2%-5% over a lifetime.
It is not uncommon for MHE patients to undergo numerous surgical procedures throughout their lives to remove painful or deforming Exostoses / Osteochondromas. Following these surgeries, abnormal scarring can occur with keloid formation. MHE patients also need to undergo surgeries to correct the bone deformities as well as limb length discrepancies and improve range of motion. New scientific findings are also showing autism relevant behavioral phenotypes connected to MHE.
X-Rays depicting MHE Tumors and their effects on bone growth and deformity
Surgery, physical therapy and pain management are currently the only options available to MHE patients, and their success rates vary from patient to patient. Many struggle with chronic pain, fatigue and mobility problems throughout their lives.
Picture of limb lengthening and bone deformity correction with Bilateral External Fixators
There are two known genes found to cause MHE. They are EXT1 located on chromosome 8q23-q24 and EXT2 located on chromosome 11p11-p12. Approximately 60% to 70% of mutations are located in the EXT1 gene and 20% to 30% are located in the EXT2 gene. In 10% to 20% of patients, no mutation is found. EXT1 and EXT2 have been identified as tumor suppressor genes since loss of heterozygosity at these loci occurs in MHE patients whose benign tumors transform into chondrosarcomas.
These genes encode Golgi-associated glycosyltransferases (exostosin-1 and exostosin-2) that are responsible for the synthesis of heperan sulfate (HS), a key component of cell surface-associated HS-rich proteoglycans (HSPGs) such as syndecan and glypican and matrix-associated proteoglycans including perlecan. Both EXT1 and EXT2 are needed for HS synthesis since the proteins form multimeric complexes in the Golgi.
The HS chains of HSPGs impact a number of signaling proteins critical to skeletal development, such as Indian hedgehog (IHh), Fibroblast Growth Factor (FGFs), Bone Morphogenetic Proteins (BMP's) and Wnt. The HSPGs can function as co-receptors for some of these proteins, but can also influence their distribution, range of action, stability and action on target cells. In general, the HME-associated phenotypes are widely believed to arise from impaired HS synthesis and accompanying HS deficiency in the skeleton and other tissues and organs. However, it remains unclear how the HS deficiency alters cell signaling within the cartilage and/or surrounding perichondrium in developing and growing skeletal elements, as well as, whether it may also affect other processes and events leading to the clinical HME phenotypes.
You must have genetic testing preformed and your MHE mutation (disease-causing allele) must be found before prenatal diagnosis can be performed. Analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at about 15-18 weeks' gestation or chorionic villus sampling (CVS) at about 10-12 weeks' gestation.
Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.
Developed in the early 1990's, Preimplantation genetic diagnosis (PDG) is the process of removing a cell from an in vitro fertilization embryo for genetic testing before transferring the embryo to the uterus. You must have genetic testing preformed and your MHE / MO / HME mutation (disease-causing allele) must be found before PGD can be performed. If you are considering PGD, you should research as many fertility centers as possible. Success rates can vary; consider asking the success rate using PGD for single gene disorders and ages of the woman. You may also want to inquire how long the fertility center has been preforming PGD.