Researchers at Shriners Hospitals for Children® - Canada discover cause of debilitating bone disease


MONTREAL, Feb. 12, 2013 /CNW Telbec/ - 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 (without 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 they 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 3 other teens and 2 of the 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.

In order to develop tailored therapeutics MDMHB needs to be better understood.
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 Hospitals 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 at  514-282-7221.

To see the article in The American Journal of Human Genetics, click here.


Frank Rauch, M.D.
Director of Clinical Laboratories, Shriners Hospitals for Children®- Canada
Associate Professor of Pediatrics, McGill University

Dr. Frank Rauch obtained his medical degree from the Technical University of Munich, Germany, in 1991. He trained as a pediatrician at the Children's Hospital of Cologne University, Germany, where he also started his research program on bone diseases in children. This was complemented, in 1994, by a 6-month course in genetic laboratory research methods at the Charité University Hospital in Berlin, Germany. A postdoctoral research fellowship (1997 to 1999) brought him to Shriners Hospitals for Children®- Canada in Montreal, where he trained in basic bone biology in Dr. René St-Arnaud's laboratory and performed clinical research projects on pediatric bone diseases with Dr. Francis H. Glorieux.

Since 2001 Dr. Rauch has been a clinician scientist at Shriners Hospitals for Children- Canada. He is also an Associate Professor at the Department of Pediatrics at McGill University. His clinical and scientific work focusses on bone diseases in children and adolescents, in particular osteogenesis imperfecta, a heritable bone disease that leads to frequent fractures. Dr. Rauch has published more than 140 articles in peer-reviewed scientific journals. Since 2009, he has been Editor of the Journal of Musculoskeletal and Neuronal Interactions, an international scientific journal. Dr. Rauch's research program is supported in particular by the Chercheur-boursier clinicien program of the Fonds de la recherche du Québec - Santé, and the Shriners of North America.

Pierre Moffatt, Ph.D.
Investigator, Shriners Hospitals for Children- Canada
Assistant Professor, Department of Human Genetics, McGill University

Dr. Pierre Moffatt obtained his PhD in Pharmacology at Université de Montréal in 1997.  After post-doctoral training at Université Laval and Shriners Hospitals for Children- Canada, Dr. Moffatt worked for 5 years in a local biotech industry as a senior scientist, and subsequently for 2 years at the Faculty of Dentistry of Université de Montréal as a research associate.  He joined Shriners Hospitals for Children- Canada in November 2006. He is also currently an Assistant Professor in the Department of Human Genetics at McGill University.  In 2008 he received the John Haddad's young investigator award from the American Society for Bone and Mineral Research.

Dr. Moffatt's main interest lies in the molecular understanding of skeletal development, growth, and mineralization, in health and disease.  His team is interested in the characterization of a special class of proteins that are secreted outside of the cells or present at the cell surface.  These molecules, typified by ligands and receptors, regulate many different and vital aspects of cell fate and function.  Mainly because they are accessible from outside of cells, these proteins represent attractive targets for therapeutic intervention.  Dr. Moffatt participated in the discovery of many previously uncharacterized molecules that are specifically present in cells of bones.  Currently under investigation are different molecules called Bril, Smpec, and Osteocrin.  Bril is a membrane protein specifically expressed in osteoblasts, specialized cells that deposit and mineralize the collagenous scaffold of the skeleton.  Bril was found to modulate mineralization and is the genetic cause of osteogenesis imperfect type V.  Smpec is present on chondrocytes, cells laying the cartilaginous template required for long bone growth and mineralization.  Osteocrin is a small protein with hormone-like features that is produced by osteoblasts, and was shown to promote longitudinal growth of long bones.  Ongoing characterization of those molecules is achieved through a battery of in vitro (cell culture) and in vivo (mice) models to explore their roles in bone biology.  Functional studies involve the use of various biochemical and molecular biology tools and techniques.

Dr. Moffatt is also actively collaborating with colleagues at Shriners Hospitals for Children- Canada (Dr. Peter Roughley, Dr. Reggie Hamdy, Dr. Frank Rauch), at McGill (Dr. Marc McKee) and at Université de Montreal (Dr. Antonio Nanci) on different aspects pertaining to bones and teeth mineralization and repair.

Video with caption: "An Interview with the Researchers.". Video available at:

Image with caption: "Pierre Moffatt, Ph.D. Investigator, Shriners Hospitals for Children® - Canada. Assistant Professor, Department of Human Genetics, Faculty of Medicine, McGill University. (CNW Group/SHRINERS HOSPITAL FOR CHILDREN (CANADA))". Image available at:

Image with caption: "Frank Rauch, M.D. Director of Clinical Laboratories, Shriners Hospitals for Children® - Canada. Associate Professor of Pediatrics, Faculty of Medicine, McGill University. (CNW Group/SHRINERS HOSPITAL FOR CHILDREN (CANADA))". Image available at:

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NOTE: Additional visuals available on request.

Emmanuelle Rondeau
Communications & Marketing Manager
Shriners Hospitals for Children®- Canada
T: 514.282.6990
C: 514.207.1057


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