Researchers at Shriners Hospitals for Children — Canada discover cause of debilitating bone disease known as MDMHB
(Montreal, Canada) Shriners Hospitals for Children® — Canada is the first, worldwide, to identify the genetic defect underlying a painful bone disease that causes an unusual series of symptoms including severe tooth decay, osteoporosis and spine fractures in teenagers. Led by Frank Rauch, M.D., a pediatrician, and Pierre Moffatt, Ph.D., a basic scientist at Shriners Hospitals for Children—Canada, the team discovered that a part of the RUNX2 gene was duplicated, and therefore caused a disease called metaphyseal dysplasia with maxillary hypoplasia and brachydactyly or MDMHB. They were able to link the unusual series of symptoms observed in patients to the changes in observed in the RUNX2 gene, which is essential for creating bone forming cells. In doing so, they established that these changes in the RUNX2 gene result in disordered bone cell production which is the cause of MDMHB. The discovery is published in The American Journal of Human Genetics this month.
What does this disease look like?
MDMHB was first named and described over 30 years ago by The Montreal Children’s Hospital’s Fahed Halal, M.D. In 1982, he published his findings which included the physical characteristics of 12 children and their family members who all had the same unusual series of symptoms: fractures of the spinal column (not due to accident), very low bone density, crumbling teeth and large collarbones. Bones in the arms, legs and pelvis also looked unusually large on X-rays and sometimes scoliosis was present. The first patients to come to Shriners Hospitals for Children — Canada with this disease were seen in 1992 by pediatrician Gilles Chabot, M.D., who referred them to metabolic bone disease expert Francis Glorieux, M.D., Ph.D.
The outcome of this disease for patients is a life in pain. Their teeth break easily and can be so painful that they have them pulled by the age of 20. As these patients grow, many have breaks in their back bones, similar to what occurs in elderly people with osteoporosis.
Research to find the cause of MDMHB
In 2003, Dr. Rauch saw a new teenage patient in the Metabolic Bone Clinic at Shriners Hospitals for Children — Canada. The patient complained of back pain and had the physical characteristics that matched the already-described MDMHB. He went on to examine relatives and found that three other teens and two adults were affected in the same way.
“We obtained X-rays, performed bone density tests and took samples for DNA analysis,” says Dr. Rauch. “However, at that time the technology did not exist to identify the disease-causing gene in such a group. But two years ago, a consortium was set up for finding rare disease genes in Canada. With their support we could get the samples analyzed at the Genome Centres in Montreal and Toronto, and we detected a problem in the RUNX2 gene in all affected family members.”
With genetic results in hand, Dr. Rauch asked for Dr. Moffatt’s help to uncover the mystery behind MDMHB. Why was this extra piece of gene causing these physical symptoms? Dr. Moffatt found that the genetic change leads to a more active and higher amount of RUNX2 protein inside cells. Why this causes osteoporosis in teenagers is not yet clear.
Helping affected children
Currently, the bone-building treatment which was pioneered at Shriners Hospitals for Children — Canada for patients with osteogenesis imperfecta (brittle bone disease) is being used also for MDMHB patients. “It increases bone density and minimizes bone pain,” says Dr. Rauch, “but it does not directly affect the underlying problem in this disease.”
“Now that we know the cause, we can identify patients with this disease earlier. So we can address their problems earlier, such as treating children before they have breaks in their back bones. We can also better manage the tooth problem and hopefully prevent the crumbling. Currently, many people with this disease simply have all of their teeth extracted, but by doing so, the jaw bones become thinner and thinner with time. Finding a mechanism to preserve the teeth, while minimizing pain would be a better alternative.” concluded Dr. Rauch.
According to Dr. Moffatt, this type of research is like being a detective. “You begin to piece together the different clues. We have found the culprit, the duplication in the RUNX2 gene, but we don’t have all the details, the how and the why, we don’t have the whole story—this is only the beginning” When asked what the next steps are, he further explained that “In order to push our research further and to fully understand the mechanisms underlying the disease, we need to identify and see more patients, in other words, with more information we will be able to further validate our results and develop more targeted treatments.”
Testing is available right now
If you are a doctor and have patients presenting with these symptoms or your child has these symptoms and would like to get tested and treatment, Shriners Hospital for Children — Canada asks that you refer to the hospital’s Metabolic Bone Clinic by calling 514-282-6971 locally, the toll free number 1-800-361-7256 extension 6971 or faxing the referral to 514-282-7221.
About Shriners Hospitals for Children
Shriners Hospitals for Children is changing lives every day through innovative pediatric specialty care, world-class research and outstanding medical education. The 22 facilities in the United States, Canada and Mexico provide advanced care for children with orthopaedic conditions, burns, spinal cord injuries, and cleft lip and palate. Shriners Hospitals for Children is a 501(c)(3) nonprofit organization and relies on the generosity of donors. All donations are tax deductible to the fullest extent permitted by law. For more information, visit www.shrinershospitalsforchildren.org.
For more information about the programs and services of our Montreal, Canada, hospital, visit www.shrinershospitalsforchildren.org/canada.