Fragile X Syndrome--Getting the Diagnosis
by Carol Hart, Ph.D.
AAP News Correspondent
From AAP News, vol. 14, no. 5, May 1998
Katie Clapp struggled to find an explanation for her son's
developmental delays and troubling behavior. "We had
inklings very early on," said Katie Clapp, "but Andy
was on the edge of normal. Then by the time he was two it was
really clear." The family consulted a geneticist as well as
other specialists and many tests were done, but no one thought of
fragile X syndrome. It was not until Andy was 31/2 years old that
they got the diagnosis--and then learned their baby girl was also
positive for the mutation. Ms. Clapp is a founder and president
of the FRAXA Research Foundation, which raises funds to support
research into the disorder.
Fragile X is the most common cause of inheritable developmental
delays and mental retardation, yet the diagnosis is often missed
or late.
It can be a difficult diagnosis to suspect during the
child's first year, when signs are minimal, said Franklin
Desposito, M.D., AAP Committee on Genetics Chair and professor of
pediatrics and director of clinical genetics at New Jersey
Medical School of the University of Medicine and Dentistry of New
Jersey.
At least 50% of children do not have the physical characteristics
of fragile X syndrome, such as large ears and long faces, Dr.
Desposito said. The developmental delays and autistic-like
features are not specific for fragile X. "It's not an
easy diagnosis to make on examination alone," he explained.
Additionally, these children's disabilities may not appear
to be that dramatic compared to children with Down's syndrome
or severe cerebral palsy, commented Ave M. Lachiewicz, M.D.,
FAAP, medical director of the Fragile X Clinic at Duke University
Medical Center. "These are often very cute children, and
there's perhaps some denial on the part of the
practitioner," she said.
According to Dr. Lachiewicz, awareness of fragile X syndrome is
improving. All the same, parents commonly say that the
pediatrician initially dismissed their concerns and questions.
"It worries me that pediatricians often don't take the
parents seriously when parents express concern about
developmental delays," Dr. Lachiewicz said. "The delay
in diagnosis loses time when they could be providing the child
with early intervention."
When to Suspect and When to Test
The gene for the fragile X protein, FMR1, was discovered in
1991. The defect, a trinucleotide repeat, was a new molecular
mechanism of disease that has since been found in other inherited
disorders, such as Huntington's disease. The number of
repeats in the CGG (cytosine-guanine-guanine) sequence correlates
roughly with clinical severity. Persons with 50-200 repeats are
carriers who may show no or mild signs. With higher number of
repeats, DNA methylation inactivates the gene, according to Owen
Rennert, M.D., FAAP, professor and chairman of pediatrics, and
head, division of genetics, Georgetown University.
One in 259 women is a carrier, and the prevalence of the full
mutation is 1 in 2000 males. Many are simply learning disabled
while others are mentally retarded.
"This is a highly prevalent condition," Dr. Rennert
advised clinicians. "Fragile X should be suspected whenever
the pediatrician is confronted by a boy with unexplained mental
retardation, developmental delay, or behavioral signs such as
hand-flapping, hyperactivity, autistic features or attention
deficits, particularly if there is a family history of affected
males."
About 70% of girls carrying the mutation will have not signs of
fragile X; others may be mildly affected or mentally retarded,
Dr. Rennert said.
While a family history of retarded males is an important clue,
the lack of such a history does not rule out the possibility of
fragile X syndrome, Drs. Rennert and Desposito both pointed out.
Dr. Desposito described a recent consultation for a 4-month-old
with cleft palate who had been brought in by his grandmother. On
speaking to the grandmother, he learned the mother also had a
cleft palate. The girls in the family had all had some learning
problems, and the family snapshots showed long faces with large
ears. Dr. Desposito opted to test for fragile X despite the fact
that the males in the family--the baby's two uncles--were
normal. The test came back positive.
Diagnosis is critical, Drs. Rennert and Desposito said, for
guiding therapy and offering a prognosis to the family. Often
families have undergone an odyssey of consultations before
getting the diagnosis, and there is emotional relief in finally
learning an explanation and a cause, Dr. Desposito commented.
Knowing What to Expect and How to Help
"It was not a good diagnosis," Ms. Clapp said,
"But I was glad to know at last. The symptoms are so broad,
with learning delays, anxiety and behavior problems, you
don't know what to think. You assume either you're a bad
parent or you have a bad child."
The diagnosis also helped in getting her son proper services and
treatment, she said.
Children with fragile X syndrome, for example, tend to be highly
social despite their anxiety in eye-to-eye interactions. When
Andy Clapp was put in a special education class, his mother said,
his behavior rapidly deteriorated as he began to imitate the
mannerisms and disabilities of his classmates. He changed from
"Mr. Hyde" to "Dr. Jekyll" after he was
placed in a blended class where an aide modifies the schoolwork
to fit Andy's abilities. This inclusion approach often works
well for fragile X children who are imitative and social, Ms.
Clapp said.
The general principles in caring for these children are to
optimize their strengths, to reinforce positive behaviors, and to
design interventions that remediate their difficulties, Dr.
Rennert remarked. In particular, children with fragile X are
likely to need help with communication and attention skills.
Cluttered or repetitive speech can be improved through work with
a speech therapist. Communications between the family and a mute
child can be enhanced by symbols and pictures that are meaningful
to the child. Many fragile X children have hyperactivity or
attention deficit disorder (ADD), and stimulants and drug
combinations may improve behavior and functioning.
Impact on Whole Family
As a diagnosis, fragile X affects not only the child and parents,
but the siblings, aunts, and cousins who may be at risk for
passing on the mutation. Pediatricians need to take some
responsibility for prevention in the extended family, Dr.
Lachiewicz commented. "It's not enough to say, 'You
might consider seeing a genetic counselor.' They should be
saying, 'Your family needs genetic counseling.'"
Families are not always ready to think through the implications
of the diagnosis immediately, Dr. Lachiewicz said.
"Sometimes we'll talk to a family and three years later
we'll get a phone call from an aunt or cousin of the affected
child. These are family members who didn't want to hear about
it then and now are ready."
The Duke Fragile X Clinic was formed to make genetic counseling
accessible whenever the family needs more information. Recently
the clinic staff met with a young woman whose brother had been
diagnosed seven years earlier, when she was in her early teens.
She came in with her boyfriend because they were planning their
future together and needed to understand their risk of having
children with fragile X.
"It's very sad," said Dr. Lachiewicz, "but
it's so important that people get this information early when
they still have all their career and family choices open to them.
I've met pregnant women who are just finding out that they
are carriers, and they are very stressed deciding what to
do."
The Future for Fragile X Children
Research is now providing important clues to explain the mental,
emotional and physiologic features of the fragile X syndrome,
according to Randi J. Hagerman, M.D., FAAP, professor of
pediatrics, University of Colorado Health Sciences Center and
Child Development Unit, Children's Hospital, Denver, who
described some of the basic and clinical research underway.
The FMR1 protein appears to be important for maturation of
synapses, particularly for pruning excess synaptic connections in
the developing brain. Electrodermal response studies show
patients habituate poorly to repeated stimuli, indicating
inability to screen out unimportant sensory data. These
observations help to explain the problems fragile X patients have
with sensory overload and with paying selective attention.
About 15% of fragile X children show signs of autism and many
have more severe sensory process deficits. Anxiety,
obsessive-compulsive behaviors, and extreme shyness are common.
Serotonin system functioning appears deficient in these patients,
an observation that can guide medication selection.
Imaging studies are pinpointing areas of underactivity and
overactivity in the brains of fragile X children that help to
explain the variety of learning and behavior problems seen. These
sorts of observations, Dr Hagerman said, may aid in finding
optimal drug combinations for controlling behavioral and
attention problems. Further in the future, perhaps 10-15 years,
FMR1 protein replacement therapies may be developed.
Katie Clapp and her family focus on the advances made in the
field of fragile X research and in their own child's struggle
with his handicap. "There are good days and bad days. Andy
is just completely with it some days, and the teachers say so.
I'm fairly optimistic for the future, that research is going
to reveal what's happening with the connections in the brain
and what can be done about it,. Then Andy can have more and more
of those good days."
Resources for Physicians and Families
The National Fragile X Foundation
1441 York Street, Suite 303
Denver, CO 80206
800-688-8765
natlfx@sprintmail.com
http://www.nfxf.org
FRAXA Research Foundation
PO Box 935
West Newbury, MA 01985
978-462-1866
fraxa@seacoast.com
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