“I see 30 patients a day, and probably 25 of them have scoliosis,” said Dr. Raggio. “The first time you have to look a child in the eye and acknowledge ‘You’ve followed all the rules, you’ve worn your brace faithfully, but your curve has gotten worse and now you need surgery anyway’ is the same moment you know you’d rather never have that conversation again.”
Published 11/1/2010
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Sally T. Halderman
OREF grant recipients look for genetic link
Pediatric orthopaedic surgeon Cathleen Raggio, MD, knows firsthand how tough it is to tell children they have adolescent idiopathic scoliosis (AIS). Even though 90 percent of children with AIS never need treatment, about 10 percent will eventually need bracing or surgery. Those who need bracing must wear their braces 22 hours a day for at least a year. Still, bracing doesn’t work for every fifth child—and there’s no way to predict which child won’t respond.
Cathleen Raggio, MD |
A 2007 Orthopaedic Research and Education Foundation (OREF) grant to explore “Identification of a Locus for Adolescent Idiopathic Scoliosis on Chromosome 12p” may help Dr. Raggio eliminate that troubling conversation. The grant enables Dr. Raggio and principal investigator Philip F. Giampietro, MD, PhD, a pediatrician and medical geneticist, to expand their investigation of a strong AIS linkage signal they found on chromosome 12 from 7 to 700 families.
The project aims not only to confirm the strength of the signal in a larger population but also to narrow the region of interest. “Our original linkage interval spans 95 known genes, many involved in neuromuscular and connective tissue development in a way that makes their implication in scoliosis plausible,” noted Dr. Giampietro. “Zeroing in may give us important information about scoliosis risk factors and better tools to tailor treatment planning and predict response. Down the road, understanding which specific genes are involved may give us insight into what’s going on at a molecular level and help us find new treatment targets.”
Dr. Raggio shares Dr. Giam-pietro’s enthusiasm. “It would make me very happy if our braces and spinal fusions became obsolete techniques,” she said. “I don’t want a better hammer; I want a new way of looking at this disease.”
The Giampietro/Raggio team was the first to find the potential scoliosis gene on chromosome 12, but other groups have identified additional scoliosis susceptibility genes. Another long-term research goal will focus on understanding how all the pieces of the genetic puzzle fit together.
“I see 30 patients a day, and probably 25 of them have scoliosis,” said Dr. Raggio. “The first time you have to look a child in the eye and acknowledge ‘You’ve followed all the rules, you’ve worn your brace faithfully, but your curve has gotten worse and now you need surgery anyway’ is the same moment you know you’d rather never have that conversation again.”
A, Radiograph of a child with AIS. B, Photograph of the same child wearing a Boston brace. (Reprinted from Parent S, Newton PO, Wenger DR: Adolescent Idiopathic Scoliosis: Etiology, anatomy, natural history, and bracing, in Bono CM (ed): Instructional Course Lectures Spine, Vol 2, Rosemont, Ill., American Academy of Orthopaedic Surgeons/North American Spine Society, 2010 pp 89-96.)
Serendipity and shared interest
Dr. Giampietro met Dr. Raggio more than 20 years ago at Long Island Jewish Hospital, and they were reunited when his medical genetics fellowship at Weill Cornell Medical College landed him next door to the Hospital for Special Surgery (HSS), where Dr. Raggio was an attending physician. He was interested in the genetics of orthopaedic conditions and participated in the scoliosis and general orthopaedics grand rounds at HSS.
Dr. Raggio was establishing a scoliosis registry as a first step in her quest to find better tools to understand the disorder and improved treatment options to offer her young patients. She soon realized that Dr. Giampietro’s expertise could increase her registry’s scope to include genetics.
“We began meeting with families and collecting samples for gene mapping studies,” Dr. Giampietro recalled.
The collaboration didn’t miss a beat when Dr. Giampietro moved on to the Marshfield Clinic in Marshfield, Wis., where several of his new colleagues contributed their time and expertise to the effort.
Funding from the Seaver Foundation supported preliminary work that identified the strong chromosome 12 linkage signal in 7 extended families. That data lent strength to their successful application for an OREF grant. The Scoliosis Research Society (SRS) recently awarded Dr. Giampietro a research grant that will support research to narrow down the interval on chromosome 12p.
“Our recruitment for the larger study has been a little slower than we hoped,” Dr. Giampietro said. “We’ve enrolled about 200 families and have recently reached out to additional colleagues in orthopaedics. Our additional SRS support will enable us to expand our recruiting. Ulrich Broeckel, MD, professor of pediatrics at the Medical College of Wisconsin and a member of the Wisconsin Genomics Initiative, will begin genotyping samples collected through the OREF grant.”
“Our ultimate goal is to use our current support as a springboard to apply for funding by the National Institutes of Health (NIH),” said Dr. Raggio. “OREF grants are a perfect bridge to build momentum and attract additional funding and investigators. OREF funding gives you the ability to build the baseline data that NIH likes to see.”
Sally T. Halderman is a contributing writer for OREF and can be reached at communications@oref.org