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
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
"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
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
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®-
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: http://stream1.newswire.ca/cgi-bin/playback.cgi?file=20130212_C4625_VIDEO_EN_23532.mp4&posterurl=http://photos.newswire.ca/images/20130212_C4625_PHOTO_EN_23532.jpg&clientName=SHRINERS%20HOSPITAL%20FOR%20CHILDREN%20%28CANADA%29&caption=An%20Interview%20with%20the%20Researchers%2E&title=SHRINERS%20HOSPITAL%20FOR%20CHILDREN%20%28CANADA%29%20%2D%20Researchers%20at%20Shriners%20Hospitals%20for%20Children%26%23174%3B%2DCanada%20discover%20cause%20of%20debilitating%20bone%20disease&headline=Researchers%20at%20Shriners%20Hospitals%20for%20Children%26%23174%3B%20%2D%20Canada%20discover%20cause%20of%20debilitating%20bone%20disease
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: http://photos.newswire.ca/images/download/20130212_C4625_PHOTO_EN_23517.jpg
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: http://photos.newswire.ca/images/download/20130212_C4625_PHOTO_EN_23515.jpg
PDF available at: http://stream1.newswire.ca/media/2013/02/12/20130212_C4625_DOC_EN_23593.pdf
PDF available at: http://stream1.newswire.ca/media/2013/02/12/20130212_C4625_DOC_EN_23631.pdf
SOURCE: SHRINERS HOSPITAL FOR CHILDREN (CANADA)
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NOTE: Additional visuals available on request.
Communications & Marketing Manager
Shriners Hospitals for Children®- Canada