January 30, 2005
New Inherited Disease Can Cause Early Aortic Rupture
Researchers have identified a new inherited syndrome that can cause
the heart's aorta to rupture earlier than other aortic aneurysm
syndromes, such as Marfan syndrome. They said the newly identified
syndrome is a relatively common disorder, which can be corrected with
surgery if it is diagnosed early.
“We'd like clinicians to know that there are important, unambiguous distinguishing features of this new syndrome that are different from Marfan syndrome and other forms of aortic aneurysm.”
Harry C. Dietz
The researchers also found that the new genetic disorder offers
important lessons about the complexities of disease-causing
malfunctions in a particular gene which produces the receptor for a
protein known as transforming growth factor beta (TGFβ).
TGFβ is a chemical messenger that influences the growth and
other physiological functions of cells. Receptors are proteins embedded
in the membranes of cells, which activate cell responses when a
chemical messenger such as TGFβ plugs into them.
The researchers, led by Howard Hughes Medical Institute investigator
Harry C. Dietz, published their discovery of the new syndrome in an
advance online publication on January 30, 2005 in the journal
. Dietz and his colleagues at Johns Hopkins School of
Medicine collaborated on the studies with researchers from Ghent
University Hospital in Belgium, McGill University in Canada,
Northwestern University School of Medicine, University of Wuerzberg in
Germany, and New York University School of Medicine.
According to Dietz, there had been considerable controversy over
whether mutations in the TGF receptor could cause Marfan syndrome, a
genetic disorder that affects connective tissues and causes dilation of
blood vessels and abnormal heart valves. People with the disease can
suffer abrupt, lethal aortic rupture. It had been known that an
underlying genetic cause of Marfan syndrome is a deficiency of the
structural protein fibrillin-1, said Dietz.
However, he said, some individuals had symptoms that resembled
Marfan syndrome, but did not satisfy all the diagnostic criteria for
the disease. “It was a big question mark in everyone's mind about
what this all meant,” said Dietz. “We were seeing people in
our clinic with inherited forms of aortic aneurysm who did not have
Marfan syndrome, but who did have a number of distinguishing features.
These included widely spaced eyes, cleft palate, divided uvula, and
premature fusion of the skull bones. These people had aneurysms that
behaved differently from any other previously described inherited form
of aortic aneurysm.
“The aneurysms in such patients were widely distributed
throughout the arterial circulation, rather than strictly at the aortic
root near the heart,” said Dietz. “They were very
aggressive in early childhood and often led to death; and they also
were demonstrated to tear and rupture at a smaller size that was not
associated with risk in any other known aortic aneurysm
Analysis of these patients' tissues suggested that they had
fundamental disorders in the behavior of their cells, said Dietz. The
researchers considered defects in TGFβ receptor as a possible
cause, because studies in mice had shown TGFβ signaling to be
important in the development of blood vessels, and the face and
Analysis of one type of TGFβ receptor gene in ten families with
the disease revealed that six of these families had mutations that
might be predicted to reduce signaling. The mutations were found in
only one of two copies of the gene in these families.
“That was a curious finding, because we had previously
associated too much TGFβ signaling with features of Marfan
syndrome,” said Dietz. “But here was a suggestion that too
little TGFβ signaling could lead to manifestations of this new
condition that had some overlap with Marfan syndrome.
“We reasoned that it might be possible that a mutation that
caused too little signaling could lead to compensatory events that
might lead to excessive TGFβ signaling,” said Dietz. When
the scientists analyzed the genetic activity in the patients' tissues,
they discovered that many genes regulated by TGFβ were, indeed,
“When we analyzed samples of aortic wall cells from these
patients, we found overexpression of TGFβ-responsive genes like
collagen genes and the connective tissue growth factor gene,”
said Dietz. They also found evidence of activation along the signaling
pathway regulated by TGFβ.
Furthermore, in the other four families with the disorder, the
researchers found mutations in a second type of TGFβ receptor that
cooperates with the first type to propagate signaling in the cell.
Dietz emphasized that the findings illustrate the importance of
taking into account compensatory mechanisms in understanding the origin
of genetic disease. “We have to respect the complexity of
biological systems,” he said. “It's easy to infer that in a
tightly controlled artificial system, when you take away half the
receptor, you should get less signaling. But this disorder shows that
you have to respect the fact that this is not a fully controlled
system; that there are attempts at compensation in biological systems.
Those compensatory effects are going to be difficult to predict with
certainty, but they have important implications for understanding the
pathogenesis of disease and developing new treatment
Thus, Dietz and his colleagues are planning additional studies of
families with the disorder, as well as mouse models, to understand the
complexities of such signaling disorders and how to best treat
He said that there are drugs on the market that both lower blood
pressure and reduce TGFβ signaling. While such drugs might be a
“magic bullet” that both relieves stress on the fragile
aorta and corrects altered cell signaling, Dietz pointed out that the
molecular effects of such drugs might also be detrimental in some
tissues and at select critical points in development.”
Dietz emphasized that early clinical recognition of the new disorder
is critical to treatment. “This new syndrome seems to be
relatively common, and it can cause aortic rupture earlier than other
aortic aneurysm syndromes,” he said. “We'd like clinicians
to know that there are important, unambiguous distinguishing features
of this new syndrome that are different from Marfan syndrome and other
forms of aortic aneurysm.
We have shown that, once diagnosed, surgery is successful if done
early in individuals with this new syndrome.” According to Dietz,
such diagnosis will require going beyond the use of echocardiograms and
listening to heart sounds. Additional steps such as examining for a
cleft uvula and wide-set eyes and performing a three-dimensional
computerized tomographic scans are necessary to diagnose the syndrome,