An international team of researchers has discovered the gene for Cornelia de Lange syndrome, a disabling, multisystem genetic disease that affects an estimated one in 10,000 children. The finding is expected to lead to a genetic test, enabling rapid and definitive diagnosis of the syndrome, as well as prenatal testing for families who already have one child with the disease.
Geneticists from The Children's Hospital of Philadelphia and Drexel University College of Medicine in Philadelphia led the study. In pinpointing the gene, they used an innovative research approach that may lend itself to investigations of other genetic conditions, particularly "orphan diseases:" rare, poorly understood disorders.
The lead researchers, Ian D. Krantz, MD, of Children's Hospital, and Laird G. Jackson, MD, of Drexel University College of Medicine, together maintain the world's largest database of patients with Cornelia de Lange syndrome (CdLS), drawing on clinical records and genetic samples first gathered 30 years ago.
Named for a Dutch physician who first described it in 1933, the syndrome often includes mental retardation, impaired growth, heart defects, gastroesophageal reflux and feeding problems, impaired vision, hearing loss, and upper limb abnormalities, including missing fingers or hands. There are typically distinctive facial features, such as thin eyebrows that join together, long eyelashes, thin lips and excessive body hair. In the past, CdLS was often fatal in infancy; now, most children with the condition live into adulthood.
"This discovery is exciting for a number of reasons," said Julie Mairano, executive director of the Cornelia de Lange Syndrome Foundation, based in Avon, Conn. "It will pave the way for genetic tests to confirm a diagnosis and provide comfort for parents who already have one child with the syndrome. It will raise awareness of the disease among physicians and scientists, and, most importantly, focus interest on better treatments for children with Cornelia de Lange syndrome."
When a genetic test for CdLS is developed, said Dr. Krantz, physicians will be able to provide a definitive diagnosis to confirm or rule out a clinical diagnosis. The test will also assist genetic counselors. "Fortunately," says Dr. Krantz, "the disease has a low recurrence risk. Families having one child affected by CdLS have only a one percent chance that a subsequent child will be affected. When a prenatal test is developed, we will determine before birth whether the fetus is among that one percent."
At Children's Hospital, Dr. Krantz directs a full-service clinic for children with CdLS, the only program in the world offering comprehensive services for children with the condition. At this clinic, which attracts patients from around the globe, specialists from a variety of medical disciplines treat each child's specific constellation of symptoms. Treatments may include heart medications, tube feeding and hand surgery.
The long-term goal of the gene discovery, of course, is to improve clinical treatments for the syndrome.
The National Institute of Child Health and Human Development, part of the National Institutes of Health, funded the study. Drs. Krantz and Jackson are both long-standing members of the Cornelia de Lange Syndrome Foundation Clinical Advisory Board. Dr. Jackson was the first medical director of the Foundation
The study's co-authors represent five hospitals and eight universities from four countries. In addition to The Children's Hospital of Philadelphia and Drexel University College of Medicine, co-authors participated from the University of Pennsylvania School of Medicine, Philadelphia; Nemours Children's Clinic, Wilmington, Del.; Geneva University Hospital, Switzerland; the University of Genoa, Italy; the University of Nevada School of Medicine; University Medical Centre, Hamilton, Ontario, Canada; Michigan State University; the University of Utah Health Sciences Center; and the University of California, Irvine.