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," said Harry
Dietz, 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," Dietz said, "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, 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," Dietz said, "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," Dietz said. "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
also have been found in patients whose parents were not
affected.
All cases have had mutations in either the gene for
transforming growth factor-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,"
Loeys said. "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 suggested.
"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," Dietz said. "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 from Johns Hopkins 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.