Learn some of the signs of SGBS and see how researchers
are manipulating mouse genes to replicate these characteristics.
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Linked to the X chromosome, SGBS occurs predominantly in
males.
Most pediatricians have never heard of SGBS, let
alone seen a child with the syndrome. No one knows what the risks are
for the various cancers, or even the spectrum of medical problems that
occur in SGBS patients.
MICHAEL R. DEBAUN, MD, MPH
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EARLY IN THEIR CAREERS,
physician-scientists typically choose a disease to study. For Scott Saunders,
MD, PhD, assistant professor of pediatrics and of molecular biology and
pharmacology, however, the disease found him. It happened when another
School of Medicine scientist linked a mutated gene to a rare congenital
condition known as Simpson Golabi Behmel Syndrome (SGBS).
That finding redirected Saunders research and eventually
led to a fruitful collaboration with Michael R. DeBaun, MD, MPH, assistant
professor of pediatrics, and to the establishment of the first clinic
and registry for families coping with SGBS.
Included in that group are Patti and Robert Valentine of OFallon
IL, whose son Justin was born in 1991five weeks premature, but weighing
8 lbs, 7oz. The baby couldnt eat or swallow well, his sucking reflex
was poor, and his overall muscle tone was weak.
The root of his problems was a mystery. After Justins
birth, Patti, a former nurse, stood with her newborn sons pediatrician
at the hospital nurses station paging through medical books trying
to identify his condition. Nothing quite fit.
The pediatrician referred Patti and her husband, then an
Air Force lieutenant stationed in Great Falls MT, to a medical geneticist
in Helena. He was able to diagnose Justin with Simpson Golabi Behmel Syndrome
(SGBS), one of several so-called overgrowth syndromes that are characterized
in part by babies with large head and body size.
Michael R. DeBaun, MD, MPH, and Scott Saunders, MD, PhD
Linked to the X chromosome, SGBS occurs predominantly in
males. First described in 1975, half of children with SGBS die at birth,
probably due to heart defects. Those who survive can have a range of conditions
including an enlarged tongue, widely spaced eyes, cleft palate, bone abnormalities
such as extra or fused fingers and toes, and organ abnormalities that
can involve the heart, kidneys, bladder and intestines. In addition, children
with SGBS are at high risk for three childhood cancers: Wilms tumor,
which affects the kidneys, neuroblastoma and liver cancer.
Patti left the geneticists office with Justins
diagnosis and a thin folder of information containing most of what was
then known about SGBS. Over the next nine years, the family was transferred
three times. In each new location, Patti had to find new doctors for Justin
and often found herself educating them about the obscure syndrome.
In 1999, she found DeBaun. While searching the Internet
for information, she found a web page devoted to another overgrowth condition,
Beckwith Wiedemann Syndrome. The site mentioned SGBS and included a picture
of DeBaun.
He looked like a nice guy, so I e-mailed him,
Patti recalls. To her surprise, DeBaun replied within minuteshe
had been checking his e-mail when her message arrived. He informed her
about the Washington University SGBS clinic and registry at St. Louis
Childrens Hospital. A few months later, the Valentine family attended
the clinic.
The Saunders/DeBaun collaboration
began in the late 1980s, when Saunders was studying a group
of little-understood molecules known as heparan sulfate proteoglycans
(HSPGs). HSPGs, which consist of proteins with sugars attached to them,
are now known to be essential for guiding development and growth of bones
and organs in embryos.
In 1997, Saunders joined the faculty at Washington University.
The year before, David Schlessinger, PhD, then a researcher in the Department
of Genetics, had discovered a mutation on the human X chromosome that
linked an HSPG gene to Simpson Golabi Behmel Syndrome. The gene, known
as glypican 3 (gpc3), was related to the HSPG genes that Saunders had
been studying. When he learned about Schlessingers discovery, he
refocused his research on the gpc3 gene and its relation to SGBS.
Physician-scientists like myself rarely have the opportunity
to see our research directly help the types of patients we care for,
says Saunders. HSPGs were the focus of my laboratory research, so
when I learned that gpc3 caused birth defects in childrenthe focus
of my clinical practiceI had to change directions.
To investigate how the gpc3 mutation causes SGBS, Saunders
first engineered a strain of mice that was missing the gpc3 gene. The
mouse model showed many of the same features as SGBS.
As it turned out, Saunders laboratory was only about
50 feet from DeBauns on the 11th floor of St. Louis Childrens
Hospital, and a collaboration was begun.
DeBaun is a pediatric oncologist and epidemiologist interested
in syndromes that predispose children to cancer, such as Beckwith Wiedemann
and SGBS. Hed started a Beckwith Wiedemann registry six years earlier,
and the experience equipped him to efficiently organize an SGBS registry.
Saunders, a neonatologist with expertise in birth defects and molecular
biology, had knowledge that could help reveal the biological mechanism
behind the cancer-causing syndrome.
The two investigators held their first yearly multidisciplinary
clinic in 2000, after the SGBS registry was up and running. Families have
come to the clinic from as far away as Canada and Argentina. Some have
attended all three years because they find it helpful to meet other children
with SGBS and to share experiences.
Most pediatricians have never heard of SGBS, let alone
seen a child with the syndrome, says DeBaun. No one knows
what the risks are for the various cancers, or even the spectrum of medical
problems that occur in SGBS patients.
In time, Saunders and DeBaun hope to answer these questions
through the yearly clinic and the registry. By keeping in touch
with the families and their pediatricians, says Saunders, we
will develop experience about the kinds of things we need to watch for.
Saunders and DeBaun also have developed a test that confirms
which patients have the gpc3 mutation, which they believe is present in
30 to 40 percent of SGBS patients. But they believe other mutations also
must be involved because children with the syndrome show a range of severities.
Why are some children more likely to develop cancer
than others, and can we do anything to prevent those cancers? asks
DeBaun. Such questions require years, if not decades, to answer.
This is just the first step of a long process.
Ultimately, the researchers hope to develop a genetic test
that will determine which children will have a more or less severe form
of SGBS. Hundreds of patients are needed for such analyses, and after
three years, the registry includes just 17 families. That is far
more than anyone else has seen, says DeBaun, but we need more
to learn what wed like to learn.
Fortunately, important clues about SGBS also will come from
Saunders mice. Studies of the mice, for example, will help to identify
the other genes and mutations that are believed to influence the severity
and course of the syndrome.
Already, study of the mice has provided insight into changes
that might occur in human patients. For example, research by others has
suggested that the mice might undergo immune-system changes that make
them susceptible to certain infections. If we can verify that similar
changes do occur in humans, says Saunders, we can help patients
and their families by telling them that they may be at risk for certain
infections.
And patients and families can provide researchers with clues
about changes they should look for in the mice. During this years
SGBS clinic, one mother commented that her son and the other children
in the waiting room all seemed to have knobby knees. A postdoctoral student
in Saunders lab had a short time earlier reported that the knees
of the mice looked overly broad.
That mothers casual observation made us rethink
some of the studies we were doing and may help us ask better questions
about what is happening in the bones of the mice, says Saunders.
As we learn more, we share it in the scientific literature. This
helps other geneticists, who may have an infant in the neonatal intensive
care unit, as they try to determine if their patient has SGBS.
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