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Gene Links Hereditary Intestinal Disorder with Stroke Danger

Gene Links Hereditary Intestinal Disorder with Stroke Danger
Gene Links Hereditary Intestinal Disorder with Stroke Danger


Duke Health News Duke Health News

DURHAM, N.C. -- Two seemingly disparate hereditary syndromes
actually stem, in some patients, from a single genetic defect,
according to Duke University Medical Center geneticists. The
researchers have linked juvenile polyposis -- characterized by
numerous intestinal polyps and an increased colon cancer risk
-- and hereditary hemorrhagic telangiectasia (HHT), which
causes vascular abnormalities that can lead to stroke.

The finding suggests that anyone with juvenile polyposis
should undergo genetic screening, the researchers said.
Physicians should then carefully monitor those with the
mutation for vascular defects and symptoms that can range from
severe nose bleeds to stroke, depending upon where in the body
the aberrations occur. Juvenile polyposis occurs approximately
once in every 16,000 to 100,000 births.

The Duke team, led by Douglas Marchuk, Ph.D., associate
professor of molecular genetics, and research analyst Carol
Gallione, report their findings in the March 13, 2004, issue of
. The work was supported by the National Institutes
of Health.

Although anecdotal evidence had indicated that some patients
with juvenile polyposis also exhibit vascular anomalies, the
current study is the first to clearly define the relationship
between the intestinal disorder and HHT, said the

"This study suggests that the rare cases noted in which
patients show intestinal polyps and vascular abnormalities are
just the tip of the iceberg," said Marchuk. "The two appear to
represent a single syndrome having effects in both the
intestine and the blood vessels. Physicians must start looking
for the vascular lesions in patients with juvenile polyposis --
with particular attention to those organs that may present
suddenly with serious medical consequences."

Juvenile polyposis -- in which as many as 500 polyps line
the large bowel and rectum or, less commonly, the stomach and
small intestine -- is caused by a defect in one of two
different genes, earlier research has shown. Left untreated,
patients with the disease have a 50 percent risk of developing
colon cancer.

Work done previously in Marchuk's lab found that mutations
in two other genes cause HHT. Now, the Duke team reported that
mutations in one of the genes linked to juvenile polyposis,
called MADH4, also spurs the vessel defects characteristic of

In HHT patients, some arteries shunt blood directly to
veins, rather than diffusing the flow through capillary
networks. The high-pressure blood flow in such junctures makes
the vessels susceptible to breaks and bleeding.

The investigators collected blood samples from seven
families in which some individuals had symptoms of juvenile
polyposis and HHT. The team then screened the samples for
mutations in the genes known to cause one or the other

None of the patients had mutations in the genes previously
linked to HHT, the researchers found. Rather, the researchers
showed, mutations in MADH4 caused both the intestinal polyps
and the vascular lesions.

"All patients with MADH4 juvenile polyposis in this study
have at least some vascular symptoms," said Gallione. "Our
results suggest that genetic screening of JP patients might
identify those individuals most at risk for developing vascular
symptoms. In patients at risk, aggressive screening protocols
for blood vessel malformations in the visceral organs may be

The protein encoded by the MADH4 gene, SMAD4, plays a role
in a key cellular pathway that governs cell growth and
differentiation, Marchuk said. Therefore, he speculates, the
genetic defect might lead to a drop in the SMAD4 protein below
some threshold required for blood vessels to sprout into
capillary beds normally, resulting in the vascular deformities
seen in patients with HHT. A similar mechanism is thought to
underlie the vessel lesions in patients with the earlier
established HHT genes.

Collaborators in the research included Gabriela Repetto,
M.D., of the Universidad del Desarrollo in Chile; Eric Leguis,
M.D., and Sabine Tejpar, M.D., of University Hospital
Gasthuisberg in Belgium; Anil Rustgi, M.D., of the University
of Pennsylvania in Philadelphia; Susan Schelley, M.D., of
Stanford University; Grant Mitchell, M.D., and Eric Drouin,
M.D., of Ste Justine Hospital in Montreal; and Cornelius
Westermann, M.D., of St. Antonius Hospital in the

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