A typical right thoracic idiopathic scoliosis with a 50° curve. Genetic identification of the curve as being progressive when it is in the 20° curve range may allow minimally invasive fusionless surgery at that time, rather than waiting for progression to the point where fusion is necessary. Photo courtesy Texas Scottish Rite Hospital


Published 11/1/2007

On the genetic frontier: Idiopathic scoliosis

Scoliosis is derived from the Greek “skoleosis,” which means “a crookedness.” But for orthopaedic surgeons specializing in this challenging disease, scoliosis is often far more than a simple crookedness. The use of growing rods, titanium ribs, and advanced surgical techniques has helped thousands, but researchers continue to look for ways to advance the science.

The AAOS has endorsed an information statement on scoliosis screening in schools (see article here). And recently, AAOS Now senior science writer Annie Hayashi sat down with James W. Ogilvie, MD, past president of the Scoliosis Research Society (SRS); Nancy H. Miller, MD, Johns Hopkins University; Carol Wise, PhD, Texas Scottish Rite Hospital for Children; and Alain Moreau, PhD, head of the molecular genetics lab for musculoskeletal diseases at the Ste-Justine University Hospital Centre, Montréal, Canada, to discuss the present state of the science and what can be expected in the future.

Ms. Hayashi: How would you describe the present state of the science of identifying genes associated with idiopathic scoliosis (IS)?

Dr. Ogilvie: This science is moving very rapidly. There are dozens of genetic markers for IS, some of which have been published or will be published shortly.

Dr. Wise: What has been enabling are the changes in technology and having large collections of patients. Our greatest limitation is research funding money.

Dr. Moreau: Most likely, scoliosis is not a purely genetic disease. Although genetic factors are important, a “cross talk” between genetics and some environmental factors is evident. The nature of these environmental factors, however, is unclear. The underlying genetic defects may be present at birth, but because the clinical manifestations usually occur at adolescence or prepubescence, scoliotic deformities must be triggered by environmental factors, which also include hormonal changes associated with puberty.

Increased levels of estrogen at puberty could explain why girls are more affected in number and severity than boys. Blood tests can now identify children at risk of developing scoliosis. We need to do more work on phenotype and trying to make sense of that and correlating it to genotype.

Dr. Ogilvie: In our lab, we are working to identify genetic markers with prognostic significance. The task of identifying the actual genes and mutations is a longer term project that may give us an understanding of the biomechanics or the biochemical pathway that leads to a curved spine.

Dr. Miller: As with many complex, genetic diseases, I think we will find markers on many different chromosomes. Once we find a genetic marker, I do think the environmental influences will then be a step to understanding the markers or genes.

Dr. Wise: Finding associated markers is here and now; functional studies as well as understanding exposures and environmental factors will all be important factors in the longer term.

Dr. Miller: Funding societies are encouraging collaborative efforts combining both approaches, which may actually push us toward clinically relevant answers sooner.

Ms. Hayashi: Is there currently an effective blood test to identify the presence of a genetic marker for early stage scoliosis patients? If not, when might one be available and what are the obstacles to producing it?

Dr. Ogilvie: At the recent SRS meeting, we reported on version 1.0 of a prototype test. A more advanced version of the test will be in clinical trial soon and we anticipate that it should be available to clinicians in early 2009.

We have a DNA-based genetic test obtained through saliva. The test will be used for different things. We are focusing on prognosticating severity, not just the occurrence of the disease. Scoliosis is easy to diagnose with standard methods but we are trying to do something that has been impossible until now.

Dr. Moreau: We started clinical trials in Montreal in June 2006. We have initiated similar trials in Hong Kong and plan to start them in Milano in early 2008.

Prospective studies using the lymphocytes of two IS patient types—children at the early stage of the disease and asymptomatic children at risk of developing the disease—confirmed the diagnostic and prognostic values of this test. By looking at children whose parents have scoliosis, we were able to identify which children would develop the condition. We are now monitoring the disease progression in those children.

This biochemical factor is an essential part of how scoliosis begins, accelerates, and progresses as a disease. It has been tested prospectively in patients with early stage scoliosis as well as in affected children. We are using healthy elementary and high school students as a control group to establish the international reference pediatric values for these factors.

The biochemical test we are using has a high degree of accuracy—91.4 percent. We hope this test will be available in the marketplace in 2008. This is a different approach but it does seem to be successful in the general population.

A typical right thoracic idiopathic scoliosis with a 50° curve. Genetic identification of the curve as being progressive when it is in the 20° curve range may allow minimally invasive fusionless surgery at that time, rather than waiting for progression to the point where fusion is necessary. Photo courtesy Texas Scottish Rite Hospital
James W. Ogilvie, MD, is past president of the Scoliosis Research Society and has been associate editor of the Spine Journal since 1987. Currently a staff surgeon at Shriners Hospital for Children in Salt Lake City, Utah, Dr. Ogilvie is a founder, director, and the chief medical officer of Axial Biotech, Inc., a company focused on the use of genetics and the development of minimally invasive, motion preserving implants to advance the diagnosis and treatment of diseases and deformities of the human spine.
Nancy H. Miller, MD, is an orthopaedic surgeon/scientist at The Children’s Hospital in Denver, and a consultant to the department of orthopaedic surgery at Johns Hopkins University. Dr. Miller is heading up a National Institutes of Health-funded study looking at the possible genetic factors in idiopathic scoliosis.
Alain Moreau, PhD, is director of the bone molecular genetics and skeletal malformations laboratories at the Ste-Justine University Hospital Centre, Montréal, Canada. His research on a diagnostic blood test to identify the presence of a genetic marker is being underwritten by Paradigm Spine, LLC, a company that focuses on development of less invasive and tissue-sparing treatments for spinal diseases.
Carol Wise, PhD, is director of molecular genetics at Texas Scottish Rite Hospital for Children. She led a 10-year study to identify the first gene (CHD7) associated with idiopathic scoliosis. The study is outlined in the May 2007 issue of the American Journal of Human Genetics.

Dr. Wise: I would like to point out that even the genes without major effects give us critically important clues in marking a pathway. As we find these genes, we’ll start to put the pieces of the puzzle together. Thinking in terms of function can give us an idea of what’s controlling this disease.

Dr. Miller: That’s an important point. We all have different but complementary approaches. As an academician, I want to see the genetic factors.

This will potentially lead me to the embryological development. The key to what actually influences the growth of the spinal cord is truly exciting for me.

Ms. Hayashi: If the genes associated with IS can be identified through a readily available DNA or genetic screening test, what impact do you think it will have for orthopaedic surgeons?

Dr. Ogilvie: For 80 percent to 90 percent of patients, the test will be very good news, resulting in less surveillance, fewer doctor visits, fewer X-rays, and fewer braces. We anticipate that such a test will discriminate progressive curves from nonprogressive or brace-responsive curves and open the way for novel interventions such as minimally invasive fusion surgery. Right now, we don’t know how to apply those treatments because we can’t discriminate between progressive and nonprogressive scoliosis.

I think we will see a shift in the way scoliosis is diagnosed. We will be able to make evidence-based decisions in clinics.

Dr. Moreau: We are also working on pharmacologic treatments to prevent or slow the progression of the disease, which could have an enormous impact. One day, we may be able to identify children who are at risk or still asymptomatic and be able to give them the correct treatment at the correct moment. I anticipate that in the early stages, patients will have customized pharmacotherapy, in conjunction with other treatments, to prevent and eventually reverse scoliosis.

Dr. Miller: It’s somewhat odd to consider that we are trying to treat scoliosis nonsurgically. I love to operate, but there will always be things to fix and procedures to do.

This is all for the betterment of patients. It is very difficult to tell a 14-year-old lacrosse player who has been wearing a brace for a year or two that she needs a 10- or 12-level spinal fusion. And this will not be her last spinal surgery. The question is to address this disorder in a different way.

Dr. Ogilvie: Years ago, ulcers required surgery; now, they’re treated with a pill. Ulcers have become a medical—not a surgical—disease. I anticipate that the research on scoliosis will result in favorable nonsurgical outcomes as well.

Ms. Hayashi: How soon will we be able to achieve those goals?

Dr. Moreau: Optimistically, maybe 10 to 12 years because this is not a homogenous group. We won’t have the same solutions for everyone. By observing plasma levels of molecular and biochemical markers, clinicians will be better able to monitor bracing efficacy as well as improve bracing systems. This will help us to identify the best brace for a specific child.

Based on these changes, orthopaedic surgeons will be able to alter treatment options. Instead of putting a child in the same brace for 2 to 3 years to determine its effectiveness, physicians may be able to determine whether this is the most appropriate brace for the patient within a month, based on specific markers.

Dr. Wise: I agree—10 to 12 years is optimistic. But who knows, there may be a “eureka” moment when we discover something that is fairly straightforward. That’s what we all hope for.

Dr. Ogilvie: Well, I am going to have to be more optimistic than that because we are doing things now in a week or less that used to take a decade to do, thanks to the advanced technologies that are available to genotype scientists. I think that we ought to have information that could radically change our treatment in 2 to 3 years.

Dr. Moreau: The problem is not just the discovery platform to define or to identify new compounds or a new approach. Getting approval from the U.S. Food and Drug Administration (FDA) and all the repository agencies takes time, especially with a shift from what has essentially been a device field toward the pharmaceutical or pharmacologic field. The required clinical trials will be costly and will take time.

Dr. Ogilvie: I agree. I think that we will refine and focus on pharmacologic solutions within the next decade. Within the next 2 or 3 years, we will see hybrid devices that can be used in early-stage scoliosis that will radically change our therapeutic approach. I think devices will come first, pills and infusions will come next, then recombinant molecules in the 10-to-15 year range.

Dr. Miller: The FDA is significantly involved in pharmaceuticals. I believe that a pharmaceutical solution is at least 10 years away. I also think we are closer to novel surgical methods—in perhaps just 5 to 10 years.

Annie Hayashi is the senior science writer for AAOS Now. She can be reached at hayashi@aaos.org