Physical traits, genetic test help with early diagnosis of aneurysm syndrome

A research team led by Johns Hopkins doctors has defined the physical traits and genetic basis of a new aortic aneurysm syndrome that is extremely aggressive and can cause death in early childhood. Early diagnosis of the syndrome and rapid surgical repair of the swollen aorta can save lives, the researchers report in the Jan. 30 advance online section of Nature Genetics.

Based on a review of medical records and experience with new patients, the Johns Hopkins team discovered that people with wide-set eyes, a cleft palate or split uvula (the tissue that hangs down in the back of the throat), and a torturous arrangement of the body's blood vessels also have aggressive swelling of the aorta, the body's biggest blood vessel. In these patients, the aorta breaks at a much smaller size than it does in people with Marfan syndrome or other causes of aneurysm, making identifying these patients critical, the researchers report.

"The severity of the physical traits can vary, but because the aorta ruptures so much sooner than one would expect, patients need to be identified and treated as early as possible and much sooner than is standard medical practice for other causes of aortic aneurysms," says Harry Dietz, M.D., director of the William S. Smilow Center for Marfan Syndrome Research at Johns Hopkins, professor in the McKusick-Nathans Institute of Genetic Medicine, and a Howard Hughes Medical Institute investigator.

The syndrome-defining traits can have a wide range of severity, and some other abnormalities, including congenital heart and brain defects and skeletal abnormalities such as early fusion of the bones of the skull or curvature of the spine, are seen in some patients. "It's too soon to know how common or rare the syndrome might be," says Dietz, "but we know that surgery to fix the aneurysm works if patients are identified in time."

Sadly, one patient who came to the clinic with widely spaced eyes and aortic aneurysm died just a week after being evaluated. At the time of her death, her aneurysm had measured just 4 centimeters (about 1.5 inches) in diameter, and aneurysms in this part of the aorta usually aren't repaired until they measure more than 5 centimeters (about 2 inches).

"It was incredibly unfortunate, but until this patient died we didn't know that the rupture happened so much earlier than in any other condition," says Bart Loeys, M.D., an instructor in pediatrics and genetic medicine in the McKusick-Nathans Institute. "We can now get patients to surgery in time to prevent aortic rupture and save their lives."

The researchers suggest that doctors, particularly those at craniofacial clinics, consider requesting imaging studies to look for aortic aneurysm and abnormal blood vessel organization in patients with the syndrome's physical traits, particularly widely spaced eyes, cleft palate or bifid (split) uvula or early fusion of the skull bones, a condition called craniosynostosis. "It's surprising that a syndrome with this many outward features escaped notice until now," says Dietz, "but now that we know it exists, it's critical that doctors look for it."

For example, the parents of an 18-month-old girl had brought her to the clinic because of a heart murmur caused by a connection between her lungs' main blood vessel and the aorta.

"When I walked by a photo the girl's mother sent for the 2003 holidays, it struck me that the girl's eyes were just slightly wide-set," says Dietz. "We had just figured out the new syndrome, so I asked the girl's local doctor to look in her mouth and tell me if she had a split uvula. The answer was yes. We found that the girl's aorta was already approaching 4 centimeters, so we quickly scheduled surgery, and today she's doing well."

The researchers also found the genetic mutations behind the syndrome, for which a diagnostic test is available at Johns Hopkins' DNA Diagnostic Laboratory. The syndrome runs in families, but syndrome-causing mutations have also been found in patients whose parents were not affected.

All cases have had mutations in either the gene for transforming growth factor-beta (TGF-beta) receptor 1 or that for TGF-beta receptor 2, two halves of the receptor that binds TGF-beta. TGF-beta is a family of signaling molecules that controls cell growth, movement, activity and death by altering expression of many genes.

The researchers from Hopkins, Ghent University Hospital in Belgium and elsewhere are still trying to explain why the syndrome's craniofacial traits can range from quite severe to barely noticeable, even though patients' tortuous blood vessels and swollen aortas are disease hallmarks.

Those diagnosed with the new syndrome have arrived on Loeys' and Dietz's doorstep for a variety of reasons. One young patient was first seen because her aorta was wrapped around her esophagus, making it difficult to eat. An adult patient had been seeking medical evaluation because her father had died suddenly at age 29. Some others had been incorrectly diagnosed with Marfan syndrome and referred to Dietz's well-known center. While there's some overlap, Marfan syndrome's outward physical traits are easily distinguished from those of the new syndrome.

"One case is a curiosity, two cases are intriguing," says Loeys. "But when you see 16 cases in 10 unrelated families, it shows that it's real, particularly when there's a family history that can be traced."

Mutations in the syndrome's responsible genes had not previously been linked to the syndrome's individual characteristics in people. The dozen or so mutations identified so far reduce the ability of the receptor to bind TGF-beta and transmit its signal, but that's only indirectly the cause of the syndrome, Dietz suggests.

"We've found that too much TGF-beta signaling, not too little, is behind lung and heart valve problems in mice with the genetic defect behind Marfan syndrome, and we suspect the same in the new syndrome," says Dietz. "Our studies so far support the idea that these patients' cells compensate for the problems in TGF-beta receptor 1 and 2, but in doing so overshoot what's normal. More work needs to be done to address this issue, which might offer a target for developing medical intervention for these patients."

The Johns Hopkins researchers were funded by the Howard Hughes Medical Institute, the National Heart, Lung and Blood Institute, the National Institute of Arthritis and Musculoskeletal and Skin Diseases and the National Marfan Foundation.

Authors on the paper are Loeys, Dietz, Junji Chen, Enid Neptune, Daniel Judge, Megan Podowski, Tammy Holm, Jennifer Meyers, Carmen Leitch, Nicholas Katsanis, Neda Sharifi, Lauren Xu, Loretha Myers, Philip Spevak and Duke Cameron of Johns Hopkins; Julie De Backer, Jan Hellemans, Paul Coucke and Anne De Paepe of Ghent University Hospital, Belgium; Yan Chen and Daniel Rifkin of New York University School of Medicine; Elaine Davis of McGill University, Montreal, Canada; Catherine Webb, Northwestern University School of Medicine; and Wolfram Kress, University of Wuerzburg, Germany.

http://www.jhu.edu/ and http://www.nature.com/ng