At least three severe, potentially fatal genetic
diseases leave patients with aortas so flimsy that they can
rupture in pregnancy and labor or even in lesser
activities, often without warning. Beta blockers, curbing
exercise, proactive blood vessel surgery and other
approaches can be helpful, but their usefulness varies
according to which disease and when they're offered.
Now a large follow-up study of more than 50 families
by a multi-institutional team led by Johns Hopkins
scientists should bring better guidelines for treating the
disorders. The work, published Aug. 24 in The New
England Journal of Medicine, closely compares patients
having one of two types of the lesser known disorders,
Loeys-Dietz syndrome or Ehlers-Danlos syndrome, with
better-understood Marfan syndrome. It stresses the
importance of comprehensive clinical evaluations when
diagnosing the diseases.
People with Loeys-Dietz syndrome have wide-set eyes, a
cleft palate or split uvula (the tissue that hangs down in
the back of the throat) and a convoluted arrangement of the
body's blood vessels, in addition to aggressive swelling of
the aorta. In these patients, the aorta breaks at a much
smaller size than it does in people with Marfan syndrome or
most other causes of aortic aneurysm.
Both Marfan and Ehlers-Danlos syndromes are similar
heritable conditions with overlapping symptoms that affect
the connective tissue, the tissue that holds the body
together. Marfan syndrome can affect many body systems,
including the skeleton, eyes, heart and blood vessels,
nervous system, skin and lungs. The vascular variant of
Ehlers-Danlos also affects skin, muscles and ligaments and
causes hypermobility of joints and fragile blood vessels
that tear easily.
"This study shows that both clinical and molecular
analyses can distinguish patients with Loeys-Dietz syndrome
from those with either Marfan syndrome or vascular
Ehlers-Danlos syndrome," said Harry Dietz, director of the
William S. Smilow Center for Marfan Syndrome Research at
Johns Hopkins, a professor in the
McKusick-Nathans Institute of Genetic Medicine and a
Howard Hughes Medical Institute investigator.
"Distinguishing these conditions is essential in many ways.
For example, when compared to Marfan syndrome, Loeys-Dietz
patients are at high risk of rupturing their blood vessels
at smaller dimensions, at a younger age and in a wider
distribution throughout the body. They are also at a much
greater risk of tear or rupture of blood vessels or the
uterus during pregnancy. When compared to people with
vascular Ehlers-Danlos syndrome, patients with Loeys-Dietz
syndrome do much better with cardiovascular surgery,
highlighting the importance of aggressive surgical
intervention for this disorder.
"Because Loeys-Dietz shares so many symptoms with
other conditions like Marfan or vascular Ehlers-Danlos," he
said, "it's critical that diagnostic distinctions are made
The researchers gathered detailed information on
patients' physical characteristics, their symptoms, course
of disease and timing and effect of treatments. They also
used gene analysis of the DNA sequences that encode for two
proteins, the transforming growth factor-beta protein
receptors type 1 (TGF-betaR1) and type 2 (TGF-betaR2). All
cases of Loeys-Dietz studied so far have mutations in
either TGF-betaR1 or TGF-betaR2.
The two TGF-beta receptors act together to bind
TGF-beta, a family of signaling molecules that controls
cell growth, movement, activity and death by controlling
whether certain genes are turned on or off. TGF-beta
receptors normally are found on the cell's surface, facing
the outside of the cell, where TGF-beta can be found
The receptors contain specialized domains--dubbed
kinase domains--that, when bound by TGF-beta, add a
chemical phosphate group to molecules that set in motion a
dominolike effect within the cell to activate other
chemical reactions that eventually lead to changes in
cellular growth or movement or activity.
Nearly all Loeys-Dietz patients studied thus far have
mutations in or near the kinase domains in their TGF-beta
receptors. The mutations are passed on through families;
however, syndrome-causing mutations also have been found in
patients whose parents were not affected.
"The bottom line here is that looking for TGF-beta
receptor mutations will be most useful in patients who have
features shared by multiple syndromes," Dietz said.
A diagnostic test is available at Johns Hopkins' DNA
The researchers were funded by the National Marfan
Foundation, William S. Smilow Center for Marfan Syndrome
Research, Howard Hughes Medical Institute, Robert Wood
Johnson Foundation, Dana and Albert "Cubby" Broccoli Center
for Aortic Diseases, Bijzonder Onderzoeksfonds of Ghent
University, National Institutes of Health, National
Institute of Child Health and Human Development and Fund
for Scientific Research-Flanders.
Authors on this paper from Johns Hopkins are Bart
Loeys, Tammy Holm, George Thomas, Gretchen Oswald, Duke
Cameron and Dietz.