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Down Syndrome
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What is Down Syndrome?
http://diagnosisdownsyndrome.info/
People with Down syndrome have an extra or irregular chromosome in
some or all of their body's cells. The chromosomal abnormalities
impair physical and mental development. Most people with Down
syndrome have distinctive physical features and mild to moderate
below-normal intelligence.
What causes Down syndrome?
The extra or irregular chromosomes related to Down syndrome result
from abnormal cell division in the egg before or after it is fertilized by
sperm. Less often, the abnormal cell division occurs in sperm before
conception. It is not known why the cells divide abnormally.
What are the signs?
Signs of Down syndrome usually appear at birth or shortly thereafter.
Many children with the condition have a flat face, small ears and
mouth, and broad hands and feet, although these features vary from
person to person. Most young children have a lack of muscle tone
(hypotonia), which generally improves by late childhood.
Often developmental disabilities result from the combination of a lower
intelligence level and physical limitations related to Down syndrome.
Heart defects, intestinal abnormalities, and irregular ear and
respiratory tract structures can also occur and cause additional
symptoms or lead to complications.
How is Down syndrome diagnosed?
Fetal ultrasound and the maternal triple screen test are used to screen
for Down syndrome during pregnancy. A chromosomal study called
karyotyping is done for more accurate diagnosis; karyotyping can be
done during pregnancy using chorionic villus sampling or
amniocentesis. Because there is a slight risk with these procedures,
they usually are recommended only if the mother is over age 35, has
had another child with Down syndrome, has had an abnormal
ultrasound or triple screen test, or has a family history of the
condition. All prenatal testing requires your consent.
Karyotyping can also be done shortly after birth if Down syndrome is
suspected. It may take 2 to 3 weeks to get the complete results of this
test, but your health professional may be able to give you an opinion
about the likelihood that your baby has Down syndrome. This opinion
usually is based on your baby's appearance, the results of a physical
exam, your family history, and results of earlier screening tests (if
done during your pregnancy).
How is Down syndrome treated?
Down syndrome is a life-long condition. Generally, treatment includes
regular medical checkups, speech and language therapy, physical and
occupational therapy, nutritional counseling, and vocational training.
You will work with a team of health professionals to develop a
comprehensive treatment plan tailored to your child's specific needs.
This plan will likely be adjusted as your child grows and develops.
Many people with Down syndrome live into their 50s and some into
their 60s or older.
Identifying and treating health problems are the focus of early
treatment. The long-term treatment goal is to help a child become as
independent as possible, which requires developing physical and social
skills. Giving children with Down syndrome proper medical care,
emotional support, and social opportunities can help them to reach
their full potential.
Trisomy 21: The Story of Down Syndrome
http://www.ds-health.com/trisomy.htm
A Brief History
The formal story began in 1866, when a physician named John Langdon Down
published an essay in England in which he described a set of children with
common features who were distinct from other children with mental retardation.
Down was superintendent of an asylum for children with mental retardation in
Surrey, England when he made the first distinction between children who were
cretins (later to be found to have hypothyroidism) and what he referred to as
"Mongoloids."
In the first part of the twentieth century, there was much speculation of the cause
of Down syndrome. The first people to speculate that it might be due to
chromosomal abnormalities were Waardenburg and Bleyer in the 1930s. But it
wasn't until 1959 that Jerome Lejeune and Patricia Jacobs, working
independently, first determined the cause to be trisomy (triplication) of the 21st
chromosome. Cases of Down syndrome due to translocation and mosaicism (see
definitions of these below) were described over the next three years.
The Chromosomes
Chromosomes are thread-like structures composed of DNA and other proteins.
They are present in every cell of the body and carry the genetic information
needed for that cell to develop. Genes, which are units of information, are
"encoded" in the DNA. Human cells normally have 46 chromosomes which can
be arranged in 23 pairs. Of these 23, 22 are alike in males and females; these
are called the "autosomes." The 23rd pair are the sex chromosomes ('X' and 'Y').
Each member of a pair of chromosomes carries the same information, in that the
same genes are in the same spots on the chromosome. However, variations of
that gene ("alleles") may be present. (Example: the genetic information for eye
color is a "gene;" the variations for blue, green, etc. are the "alleles.")
Human cells divide in two ways. The first is ordinary cell division ("mitosis"), by
which the body grows. In this method, one cell becomes two cells which have the
exact same number and type of chromosomes as the parent cell. The second
method of cell division occurs in the ovaries and testicles ("meiosis") and
consists of one cell splitting into two, with the resulting cells having half the
number of chromosomes of the parent cell. So, normal eggs and sperm cells only
have 23 chromosomes instead of 46.
This is what a normal set of chromosomes looks like. Note the 22 evenly paired
chromosomes plus the sex chromosomes. The XX means that this person is a
female.
The test in which blood or skin samples are checked for the number and type of
chromosomes is called a karyotype, and the results look like this picture
Many errors can occur during cell division. In meiosis, the pairs of chromosomes
are supposed to split up and go to different spots in the dividing cell; this event is
called "disjunction." However, occasionally one pair doesn't divide, and the whole
pair goes to one spot. This means that in the resulting cells, one will have 24
chromosomes and the other will have 22 chromosomes. This accident is called
"nondisjunction." If a sperm or egg with an abnormal number of chromosomes
merges with a normal mate, the resulting fertilized egg will have an abnormal
number of chromosomes. In Down syndrome, 95% of all cases are caused by
this event: one cell has two 21st chromosomes instead of one, so the resulting
fertilized egg has three 21st chromosomes. Hence the scientific name, trisomy
21. Recent research has shown that in these cases, approximately 90% of the
abnormal cells are the eggs. The cause of the nondisjunction error isn't known,
but there is definitely connection with maternal age. Research is currently aimed
at trying to determine the cause and timing of the nondisjunction event.
Three to four percent of all cases of trisomy 21 are due to Robertsonian
Translocation. In this case, two breaks occur in separate chromosomes, usually
the 14th and 21st chromosomes. There is rearrangement of the genetic material
so that some of the 14th chromosome is replaced by extra 21st chromosome. So
while the number of chromosomes remain normal, there is a triplication of the
21st chromosome material. Some of these children may only have triplication of
part of the 21st chromosome instead of the whole chromosome, which is called a
partial trisomy 21. Translocations resulting in trisomy 21 may be inherited, so
it's important to check the chromosomes of the parents in these cases to see if
either may be a "carrier."
The remainder of cases of trisomy 21 are due to mosaicism. These people have
a mixture of cell lines, some of which have a normal set of chromosomes and
others which have trisomy 21. In cellular mosaicism, the mixture is seen in
different cells of the same type. In tissue mosaicism, one set of cells, such as all
blood cells, may have normal chromosomes, and another type, such as all skin
cells, may have trisomy 21.
The 21st Chromosome and Down Syndrome
The chromosomes are holders of the genes, those bits of DNA that direct the production
of a wide array of materials the body needs. This direction by the gene is called the gene's
"expression." In trisomy 21, the presence of an extra set of genes leads to
overexpression of the involved genes, leading to increased production of certain
products. For most genes, their overexpression has little effect due to the body's
regulating mechanisms of genes and their products. But the genes that cause Down
syndrome appear to be exceptions.
Which genes are involved? That's been the question researchers have asked
ever since the third 21st chromosome was found. From years of
research, one popular theory stated that only a small portion of the 21st
chromosome actually needed to be triplicated to get the effects seen in Down
syndrome; this was called the Down Syndrome Critical Region. However, this
region is not one small isolated spot, but most likely several areas that are not
necessarily side by side. The 21st chromosome may actually hold 200 to 250
genes (being the smallest chromosome in the body in terms of total number of
genes); but it's estimated that only a small percentage of those may eventually
be involved in producing the features of Down syndrome. Right now, the question
of which genes do what is highly speculative. However, there are some suspects.
Genes that may have input into Down syndrome include:

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Superoxide Dismutase (SOD1)-- overexpression may cause premature
aging and decreased function of the immune system; its role in Senile
Dementia of the Alzheimer's type or decreased cognition is still
speculative
COL6A1 -- overexpression may be the cause of heart defects
ETS2 -- overexpression may be the cause of skeletal abnormalities
CAF1A -- overexpression may be detrimental to DNA synthesis
Cystathione Beta Synthase (CBS) -- overexpression may disrupt
metabolism and DNA repair
DYRK -- overexpression may be the cause of mental retardation
CRYA1 -- overexpression may be the cause of cataracts
GART -- overexpression may disrupt DNA synthesis and repair
IFNAR -- the gene for expression of Interferon, overexpression may
interfere with the immune system as well as other organ systems
Other genes that are also suspects include APP, GLUR5, S100B, TAM, PFKL,
and a few others. Again, it is important to note that no gene has yet been fully
linked to any feature associated with Down syndrome.
One of the more notable aspects of Down syndrome is the wide variety of
features and characteristics of people with trisomy 21: There is a wide range of
mental retardation and developmental delay noted among children with Down
syndrome. Some babies are born with heart defects and others aren't. Some
children have associated illnesses such as epilepsy, hypothyroidism or celiac
disease, and others don't. The first possible reason is the difference in the genes
that are triplicated. As I mentioned above, genes can come in different alternate
forms, called "alleles." The effect of overexpression of genes may depend on
which allele is present in the person with trisomy 21. The second reason that
might be involved is called "penetrance." If one allele causes a condition to be
present in some people but not others, that is called "variable penetrance," and
that appears to be what happens with trisomy 21: the alleles don't do the same
thing to every person who has it. Both reasons may be why there is such
variation in children and adults with Down
syndrome.
Toward the Next Century
Researchers are busy in their attempts to map out the full structure of the
chromosome, including the Human Genome Database. Because of the small
size of the 21st chromosome and its association with Down syndrome, it is the
second-most heavily mapped human chromosome. Research is focusing on
trying to identify genes and their effects when overexpressed.
However, it would be a mistake to assume that the clinical features of Down
syndrome are only due to a handful of genes being overexpressed. You can think
of the overexpressed gene products interacting with a number of normal gene
products, each product individualized by the person's unique genetic makeup,
and thus being thrown "out of genetic balance." This would then make the person
more susceptible to other genetic and environmental insults, leading to the
features, diseases and conditions associated with Down syndrome. It is this
complex arrangement that scientists will be addressing in the second century of
Down syndrome research.
Table I. Systemic conditions associated with Down
syndrome
Systems
Conditions
Cardiovascular Ventricular septal defects
A/V communis
Patent ductus arteriosus
Mitral valve prolapse.
Hematopoietic Impaired immunity
Defective short-lived neutrophils
Risk of lymphopenia
Risk of eosinopenia
Cell mediated immunity impaired
Irregular serum immunoglobin
patterns
Increased risk of leukemia
Increased risk of hepatitis B carrier
status if previously institutionalized
Musculoskeletal Atlantoaxial Instability
Midface is underdeveloped with
relative prognathism
Narrow and partially obstructed
nasal air passages and thickening
of mucosa.
Mouth breathing
Open mouth with tongue thrust
Nervous
Motor functions delayed; affects
coordination
Dementia analogous to Alzheimer's
disease
Speech
Expressive language is delayed
Phonation distorted as a result of
imbalance of neuromuscular
system
Behavior
Natural spontaneity, genuine
warmth, gentleness, patience and
tolerance
A few patients present anxiety and
stubbornness
http://www.altonweb.com/cs/downsyndrome/index.htm?page=desai.html
Table II. Oral conditions associated with Down
syndrome
Area
Condition
Palate
"Stair palate" with "v" shaped high vault
Soft palate insufficiency
Oral
Angle of the mouth pulled down (result
opening
of hypotonic musculature)
Lower lip everted (result of hypotonic
musculature)
Mouth breathing with drooling
Chapped lower lip
Angular cheilitis
Tongue
Scalloped, fissured
Protrusion and tongue thrusting (result
of hypotonic musculature)
Macroglossia (result of small oral cavity)
Desiccated tongue(result of mouth
breathing)
Dental
Microdontia
Hypodontia
Partial anodontia
Supernumerary teeth
Spacing
Taurodontism
Crown variants
Agenesis
Hypoplasia and hypocalcification
Reduced risk of dental caries
Delayed eruption
Periodontal Increased risk of periodontal disease
Occlusion Malalignment
Frequent malocclusions
Frequent temporomandibular joint
dysfunction
Platybsia
Bruxism
http://www.altonweb.com/cs/downsyndrome/index.htm?page=desai.html
http://kidshealth.org/kid/health_problems/birth_defect/down_syndrome.html
In 1866, an English doctor named John Langdon Haydon Down wrote a
description of people with a certain type of developmental delay.
Because he was the first to write about it, the condition became known
as Down syndrome. But Dr. Down didn't know exactly what caused it.
Nearly 100 years later, a French geneticist (say: juh-neh-tuh-sist)
named Dr. Jerome Lejeune discovered that Down syndrome is caused
by a problem with the number of chromosomes (say: kro-mehsohms) a person has. Chromosomes are thread-like structures in the
middle of a cell that carry the genes.
Keep reading to learn about what Down syndrome is, what causes it,
and more.
What Is Down Syndrome?
Down syndrome (say: sin-drum), or DS, is one of the most common
genetic causes of mental retardation or developmental delay. That
means it is caused by a problem with a person's chromosomes, on
which the genes that make each person unique are located.
People with DS are usually mildly to moderately mentally retarded.
Some are developmentally delayed and some are severely retarded.
Each person with DS is different.
Dr. Down worked in a hospital that had many patients who were
mentally challenged. When Dr. Down wrote about the condition, he
tried to give a description of what the people looked like. He described
people with DS as being born with certain physical traits. However, his
description was not completely correct because not every person with
DS looks the same.
Babies with DS tend to develop more slowly than other babies do.
They may start walking later than other babies. When they are grown,
they tend to be smaller than the other members of their family and
they may be a little stocky or heavy.
Many people with DS have eyelids that may be slanted upward. They
may have small folds of skin at the inside corners of their eyes. Their
noses may be somewhat flat and their ears may be small and shaped
abnormally. They may have a large space between the big toe and the
second toe.
Children who are born with DS are also more likely to have certain
health problems. They are more likely to get infections, such as
respiratory illnesses (problems with lungs and breathing). When they
do get infections, they often last longer. They may have eye or ear
problems or digestion problems like constipation. Some babies with DS
may have problems in their stomachs or intestinal blockage that
prevent them from digesting food properly.
About half are born with heart defects, which means there is
something different with the way their heart developed. Some develop
leukemia, a type of cancer. But each person with DS is different and
may have one, several, or all of these problems.
What Causes Down Syndrome?
Down syndrome is caused by having an increased number of
chromosomes. Normally, there are 23 pairs of chromosomes. Half of
the pair are from the mother and half are from the father.
Down syndrome is not caused by anything either the mom or dad did
before the child was born. Anyone can have a baby with Down
syndrome. But the older the mother, the greater the risk of having a
baby with Down syndrome.
About one out of every 800 babies born has DS, no matter what race
or nationality the parents are. It is not contagious, so you can't catch
it from someone else. It's impossible to get DS after you are born.
The most common type of Down syndrome is called trisomy 21. About
95% of people with DS have trisomy 21.With this type of DS, the child
is born with an extra chromosome. He has 47 chromosomes instead of
46. Instead of having two number 21 chromosomes, he has three of
them.
Because people with DS are born with an abnormal number of
chromosomes, there is no cure for Down syndrome. It is something
they will have all their lives.
What causes Down syndrome?
Normally in reproduction, the egg cell of the mother and the sperm cell
of the father start out with the usual number of 46 chromosomes. The
egg and sperm cells undergo cell division where the 46 chromosomes
are divided in half and the egg and the sperm cells end up with 23
chromosomes each. When a sperm with 23 chromosomes fertilizes an
egg with 23 chromosomes, the baby ends up with a complete set of 46
chromosomes, half from the father and half from the mother.
Sometimes, an error occurs when the 46 chromosomes are being
divided in half and an egg or sperm cell keeps both copies of the #21
chromosome instead of just one copy. If this egg or sperm is fertilized,
the baby ends up with three copies of the #21 chromosome and this is
called “trisomy 21” or Down syndrome. The features of Down
syndrome result from having an extra copy of chromosome 21 in every
cell in the body.
Ninety-five percent of Down syndrome results from trisomy 21.
Occasionally, the extra chromosome 21 is attached to another
chromosome in the egg or sperm; this may result in what is called
“translocation” Down syndrome (3 to 4 percent of cases). This is the
only form of Down syndrome that can sometimes be inherited from a
parent. Some parents have a rearrangement called a balanced
translocation, where the #21 chromosome is attached to another
chromosome, but it does not affect his/her health. Rarely, a form of
Down syndrome called “mosaic” Down syndrome may occur when an
error in cell division occurs after fertilization (1 to 2
http://www.chkd.org/Genetics/downs.asp
What types of problems do children with Down syndrome
typically have?
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About 40 to 50 percent of babies with Down syndrome have
heart defects. Some defects are minor and may be treated with
medications, while others may require surgery. All babies with
Down syndrome should be examined by a pediatric cardiologist,
a physician who specializes in heart diseases of children, and
have an echocardiogram (a procedure that evaluates the
structure and function of the heart by using sound waves
recorded on an electronic sensor that produce a moving picture
of the heart and heart valves) in the first two months of life, so
that any heart defects can be treated.
About 10 percent of babies with Down syndrome are born with
intestinal malformations that require surgery.
More than 50 percent have some visual or hearing impairment.
Common visual problems include crossed eyes, near- or
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farsightedness, and cataracts. Most visual problems can be
improved with glasses, surgery, or other treatments. A pediatric
ophthalmologist (a physician who specializes in comprehensive
eye care and provides examinations, diagnosis, and treatment
for a variety of eye disorders) should be consulted within the
first year of life.
Children with Down syndrome may have hearing loss due to fluid
in the middle ear, a nerve defect, or both. All children with Down
syndrome should have regular vision and hearing examinations
so any problems can be treated before they hinder development
of language and other skills.
Children with Down syndrome are at increased risk of thyroid
problems and leukemia. They also tend to have many colds, as
well as bronchitis and pneumonia. Children with Down syndrome
should receive regular medical care including childhood
immunizations. The National Down Syndrome Congress
publishes a “Preventative Medicine Checklist” which outlines
which checkups and medical tests are recommended at various
ages.
http://www.chkd.org/Genetics/downs.asp
What Is Life Like for Kids With Down Syndrome?
At one time, most children with DS did not live past childhood. Many
would often become sick from infections. Others would die from their
heart problems or other problems they had at birth.
Today, most of these health problems can be treated and most
children with DS grow into adulthood. Medicines can take care of many
of their infections. Surgery can correct heart, stomach, and intestinal
problems. There are medical treatments for leukemia. Someone with
DS has a good chance of living to be 50 years old or more.
Many kids with DS are in regular classes. Some need special classes to
help them in areas where they have more trouble learning. Their
parents work with teachers and others to come up with a plan for the
best way for each child to learn. The whole idea is to take advantage
of their strengths and help them in the areas where they have
weaknesses.
With this extra help, kids with DS can grow up to do many of the
things kids without DS can do. Some will live in special homes with
other people who sometimes need extra help.
Sometimes, other kids may want to bully someone with DS just
because he's different. But kids with Down syndrome are just like
anybody else. They go to school, play sports, and have friends. They
can feel happy, sad, silly, angry, and lots of other emotions, like other
kids do. When they get teased, it hurts their feelings as it would
anyone else. They want to be accepted just like everyone else does.
A kid with DS is just another kid, but one who might have a few extra
problems to deal with. And sometimes - just like you - what they need
most is a helping hand and a friendly word of encouragement.
A Diagnosis of Down Syndrome
http://www.nichd.nih.gov/publications/pubs/downsyndrome/
down.htm#ADiagnosis
A newborn baby with Down syndrome often has physical features the
attending physician will most likely recognize in the delivery room.
These may include a flat facial profile, an upward slant to the eye, a
short neck, abnormally shaped ears, white spots on the iris of the eye
(called Brushfield spots), and a single, deep transverse crease on the
palm of the hand. However, a child with Down syndrome may not
possess all of these features; some of these features can even be
found in the general population.
To confirm the diagnosis, the doctor will request a blood test called a
chromosomal karyotype. This involves "growing" the cells from the
baby's blood for about two weeks, followed by a microscopic
visualization of the chromosomes to determine if extra material from
chromosome 21 is present.
THE GENETIC VARIATIONS THAT CAN CAUSE DOWN SYNDROME
Three genetic variations can cause Down syndrome. In most cases,
approximately 92% of the time, Down syndrome is caused by the
presence of an extra chromosome 21 in all cells of the individual. In
such cases, the extra chromosome originates in the development of
either the egg or the sperm. Consequently, when the egg and sperm
unite to form the fertilized egg, three--rather than two--chromosomes
21 are present. As the embryo develops, the extra chromosome is
repeated in every cell. This condition, in which three copies of
chromosome 21 are present in all cells of the individual, is called
trisomy 21.
In approximately 2-4% of cases, Down syndrome is due to mosaic
trisomy 21. This situation is similar to simple trisomy 21, but, in this
instance, the extra chromosome 21 is present in some, but not all,
cells of the individual. For example, the fertilized egg may have the
right number of chromosomes, but, due to an error in chromosome
division early in embryonic development, some cells acquire an extra
chromosome 21. Thus, an individual with Down syndrome due to
mosaic trisomy 21 will typically have 46 chromosomes in some cells,
but will have 47 chromosomes (including an extra chromosome 21) in
others. In this situation, the range of the physical problems may vary,
depending on the proportion of cells that carry the additional
chromosome 21.
CHROMOSOME 21
In trisomy 21 and mosaic trisomy 21, Down syndrome occurs because
some or all of the cells have 47 chromosomes, including three
chromosomes 21. However, approximately 3-4% of individuals with
Down syndrome have cells containing 46 chromosomes, but still have
the features associated with Down syndrome. How can this be? In
such cases, material from one chromosome 21 gets stuck or
translocated onto another chromosome, either prior to or at
conception. In such situations, cells from individuals with Down
syndrome have two normal chromosomes 21, but also have additional
chromosome 21 material on the translocated chromosome. Thus, there
is still too much material from chromosome 21, resulting in the
features associated with Down syndrome. In such
Prenatal Screening for Down Syndrome
Prenatal screening for Down syndrome is available. There is a
relatively simple, noninvasive screening test that examines a drop of
the mother's blood to determine if there is an increased likelihood for
Down syndrome. This blood test measures the levels of three markers
for Down syndrome: serum alpha feto-protein (MSAFP), chorionic
Table 1. The major numerical abnormalities that survive to term
gonadotropin (hCG), and unconjugated estriol (uE3). While these
measurements are not a definitive test for Down syndrome, a lower
MSAFP value, a lower uE3 level, and an elevated hCG level, on
average, suggests an increased likelihood of a Down syndrome fetus,
and additional diagnostic testing may be desired.
DIAGNOSTIC TESTS FOR DOWN SYNDROME
AMNIOCENTESIS
The removal and analysis of a small sample of fetal cells from the
amniotic fluid.
Cannot be done until the 14-18th week of pregnancy
Lower risk of miscarriage than chorionic villus sampling
CHORIONIC VILLUS SAMPLING (CVS)
Extraction of a tiny amount of fetal tissue at 9 to 11 weeks of
pregnancy
The tissue is tested for the presence of extra material from
chromosome 21
Carries a 1-2% risk of miscarriage
PERCUTANEOUS UMBILICAL BLOOD SAMPLING
(PUBS)
Most accurate method used to confirm the results of CVS or
amniocentesis.The tissue is tested for the presence of extra material
from chromosome 21
PUBS cannot be done until the 18-22nd week
Syndrome
Abnormality
Incidence per
10 000 births
Lifespan (years)
Down
Trisomy 21
15
40
Edward's
Trisomy 18
3
<1
Patau's
Trisomy 13
2
<1
Table 1. The major numerical abnormalities that survive to term
Incidence per
Syndrome
Abnormality
Lifespan (years)
10 000 births
Down
Trisomy 21
15
40
Edward's
Trisomy 18
3
<1
Patau's
Trisomy 13
2
<1
Turner’s
Monosomy X
2 (female births)
30-40
Klinefelter’s
XXY
10 (male births)
Normal
XXX
XXX
10 (female births)
Normal
XXY
XYY
10 (male births)
Normal
Table 2. Unbalanced structural abnormalities
p = short arm, q = long arm
Syndrome
Abnormality
Incidence
Wolf-Hirschhorn
Deletion, tip of
4p
1 in 50
000
Cri-du-chat
Deletion, tip of
5p
1 in 50
000
WAGR
Microdeletion,
11p
PraderWilli/Angelman
Microdeletion,
15p
DiGeorge
Microdeletion,
22q
http://www.wellcome.ac.uk/en/genome/genesandbody/hg06b012.html
The Effects of Trisomy 21 – Symptoms of Down
Syndrome 21.
http://www.emedicinehealth.com/articles/50095-3.asp
This extra material means that there are more genes expressed than
normal. For most genes, this overexpression has little effect because
the body regulates genes and their products. But the genes that cause
Down syndrome appear to be exceptions.
Scientists have been trying to determine exactly which genes are
involved in Down syndrome ever since the third 21st chromosome
(trisomy 21) was found. Current research has led to a theory that only
certain areas of chromosome 21 need to be tripled to get the effect of
Down syndrome. These regions are called the Down syndrome critical
region. Exactly which genes cause Down syndrome when tripled is not
known, but some genes are suspected.
Genes that may have input into Down syndrome include:

SOD1 (superoxide dismutase 1 gene) overexpression may cause
premature aging and decreased function of the immune system.

COL6A1 (alpha-1 collagen VI gene) overexpression may be the
cause of heart defects.

ETS2 (ETS2 oncogene) overexpression may be the cause of
skeletal abnormalities.

CAF1A (chromatin assembly factor 1, p60 subunit)
overexpression may cause problems with DNA synthesis.

CBS (cystathione beta synthase) overexpression may disrupt
metabolism and DNA repair.

DYRK1A (dual-specificity tyrosine phosphorylation-regulated
kinase 1A) overexpression may be the cause of mental
retardation.

CRYA1 (alpha-1 crystallin) overexpression may be the cause of
cataracts.

GART (glycinamide ribonucleotide synthetase) overexpression
may disrupt DNA synthesis and repair.

IFNAR (interferon alpha receptor) overexpression may interfere
with the immune system as well as other organ systems.
Remember that no gene has yet been fully linked to any feature
associated with Down syndrome.
Figuring out which genes may be associated with Down syndrome is
difficult because, although there are certain characteristics associated
with Down syndrome, people with Down syndrome have a wide variety
of features and a wide range of mental retardation and developmental
delay is possible. Some babies are born with heart defects and others
aren't. Some children have associated illnesses such as
hypothyroidism, and others don't. There are some possible
explanations for this variability.
Genes come in different versions (alleles). For example, one allele for
eye color produces blue eyes and one allele produces brown eyes. The
variety of features in Down syndrome may be related to which version
(allele) of a gene is present in triplicate. Also, some alleles cause a
condition in some people but not in others, which is called reduced or
incomplete penetrance. Reduced penetrance appears to occur with
trisomy 21: the extra alleles don't do the same thing to every person
who has them. Both the type of allele and the penetrance of the allele
may be why there is such variation In trisomy 21, there is extra
genetic material from chromosome in children and adults with Down
syndrome
What are the maternal age risks for Down syndrome?
As women get older, the chance for having a baby with any
chromosome problm, including Down Syndrome increases
.
Maternal Age
Risk at birth
15 to 24 years
1 out of 1300
25 to 29 years
1 out of 1100
35 years
1 out of 350
40 years
1 out of 100
45 (and older)
1 out of 25
http://www.chkd.org/Genetics/downs.asp
Medical research
http://cc.msnscache.com/cache.aspx?q=1761956072761&lang=enUS&FORM=CVRE2
Of the inborn disorders that affect intellectual capacity, Down
syndrome is the most prevalent and best studied. Down syndrome is a
term used to encompass a number of genetic disorders of which
trisomy 21 is the most frequent (95% of cases). Trisomy 21 is the
existence of the third copy of the chromosome 21 in cells throughout
the body of the affected person. Other Down syndrome disorders are
based on the duplication of the same subset of genes (e.g., various
translocations of chromosome 21). Depending on the actual etiology,
the learning disability may range from mild to severe.
Trisomy 21 results in over-expression of genes located on
chromosome 21. One of these is the superoxide dismutase gene.
Some (but not all) studies have shown that the activity of the
superoxide dismutase enzyme (SOD) is elevated in Down syndrome.
SOD converts oxygen radicals to hydrogen peroxide and water.
Oxygen radicals produced in cells can be damaging to cellular
structures, hence the important role of SOD. However, the hypothesis
says that once SOD activity increases disproportionately to enzymes
responsible for removal of hydrogen peroxide (e.g., glutathione
peroxidase), the cells will suffer from a peroxide damage. Some
scientists believe that the treatment of Down syndrome neurons with
free radical scavengers can substantially prevent neuronal
degeneration. Oxidative damage to neurons results in rapid brain
aging similar to that of Alzheimer's disease.
Another chromosome 21 gene that might predispose Down syndrome
individuals to develop Alzheimer's pathology is the gene that encodes
the precursor of the amyloid protein. Neurofibrillary tangles and
amyloid plaques are commonly found in both Down syndrome and
Alzheimer's individuals. Layer II of the entorhinal cortex and the
subiculum, both critical for memory consolidation, are among the first
affected by the damage. A gradual decrease in the number of nerve
cells throughout the cortex follows. A few years ago, Johns Hopkins
scientists created a genetically engineered mouse called Ts65Dn
(segmental trisomy 16 mouse) as an excellent model for studying the
Down syndrome. Ts65Dn mouse has genes on chromosomes 16 that
are very similar to the human chromosome 21 genes. With this animal
model, the exact causes of Down syndrome neurological symptoms
may soon be elucidated. Naturally, Ts65Dn research is also likely to
highly benefit Alzheimer's research.
While there are a number of commercially promoted dietary
supplements on the market, especially in the USA, mainly involving
various combinations of vitamins and minerals, none of these have
been medically approved for use in the UK for the mass treatment of
people with Down syndrome and none appear to lead to any proven
lasting benefits, and all remain highly controversial.
Maternal Blood Screening for Down Syndrome
and Neural Tube Defects
http://www.marchofdimes.com/professionals/681_1166.asp
Health care providers offer their pregnant patients a screening test
that identifies pregnancies at higher-than-average risk of certain
serious birth defects, including neural tube defects such as spina bifida
(sometimes called open spine) and some chromosomal
disorders (Down syndrome and trisomy 18). This blood test, which can
provide valuable information about a developing fetus, has a number
of names including maternal serum (blood) screening test, multiple
marker screening test, triple screen, quad screen and others. It’s
important to understand that, in most cases, an abnormal test result
shows an increased risk, but not a definite problem with the baby.
Further testing usually rules out the suspected problem.
What does this test measure?
This test currently measures the levels of three or four substances in
the mother’s blood.
When maternal blood testing first began in the early 1980s, the test
measured only alpha-fetoprotein (AFP), a substance produced by the
liver of the fetus. Some of this protein is excreted into the amniotic
fluid surrounding the fetus. AFP also passes into the mother’s
bloodstream, where its concentration rises gradually until late in
pregnancy.
Along with maternal serum alpha-fetoprotein (MSAFP) levels, the test
now also measures the levels of two pregnancy hormones called estriol
and human chorionic gonadotropin (hCG). When the test measures the
levels of these three substances, it is often called the triple screen.
Many laboratories in the U.S. measure the level of a fourth substance
in the mother’s blood called inhibin-A. The addition of inhibin appears
to make the test more accurate in detecting pregnancies at risk of
Down syndrome. The test is called the quadruple screen when it
measures the four substances in the mother’s blood. Researchers
continue to study other substances in the mother’s blood, which
eventually may be added to the blood test to improve its ability to
detect birth defects.
The laboratory calculates a woman’s individual risk of neural tube
defects (NTDs), Down syndrome and trisomy 18 based upon the levels
of the three or four substances plus the woman’s age, weight, race,
and whether she has diabetes requiring insulin treatment. These last
three factors influence MSAFP levels.
When during pregnancy is the maternal serum screening test
done?
This blood test most often is done between 15 and 18 weeks after the
last menstrual period. The results usually are available within one
week. Researchers also are exploring approaches for earlier screening.
Does an abnormal test result mean the baby has a birth defect?
No. This test cannot diagnose a birth defect, it only can indicate an
increased risk. An abnormal screening test result simply means that
additional testing is needed. Out of every 100 women who take a
maternal serum screening test, about 5 to 7 will have an abnormal
result. However, only about 1 to 2 percent of women whose test
results show an increased risk of Down syndrome will actually have a
baby with Down syndrome. Similarly, only a very small number of
women whose test results show an increased risk of spina bifida and
related birth defects will actually have an affected baby (a woman’s
doctor can give her a better estimate of the risk to her baby, based on
her test results).
For many of the rest, the abnormal test result simply indicates that the
fetus is either a few weeks older or younger than originally thought.
Because the range of normal results varies with the weeks of
pregnancy, it is very important to know the accurate gestational age of
the fetus. The gestational age of the fetus should be confirmed by
ultrasound if there is any question about it. Another common cause of
an abnormal test result is a multiple pregnancy (twins, triplets, etc.).
It’s important to remember that follow-up (diagnostic) tests usually
show that a baby does not have Down syndrome, trisomy 18 or an
NTD. Pregnant women who do not understand that most women with
abnormal test results have healthy babies may experience much
unnecessary anxiety.
What fetal problems can cause abnormal maternal serum
screening test results?
Neural tube defects (NTDs). High levels of one of the measured
substances, MSAFP, suggest an increased risk of NTDs. The neural
tube is the embryonic structure that develops into the brain and spinal
cord. If the neural tube does not close properly during the fourth week
after conception, birth defects such as spina bifida and anencephaly
will result. About 2,500 babies are born in this country each year with
these birth defects.
Spina bifida, often called open spine, affects the backbone and,
sometimes, the spinal cord. Children with the severe form of spina
bifida have varying degrees of leg paralysis and bladder and bowel
control problems. Anencephaly is a fatal condition in which a baby is
born with a severely underdeveloped brain and skull.
The causes of NTDs are not thoroughly understood. Scientists believe
that genetic and environmental factors act together to cause these
malformations. About 90 to 95 percent of babies with NTDs are born to
couples with no family history of these abnormalities.
Studies show that, if all women consumed the recommended amount
of the B vitamin folic acid before and during early pregnancy, up to 70
percent of NTDs could be prevented. The March of Dimes recommends
that all women of childbearing age take a multivitamin containing 400
micrograms of folic acid daily, and eat a healthy diet including foods
rich in folic acid. Foods that contain folic acid include: fortified
breakfast cereals, beans, green leafy vegetables, orange juice and
peanuts. (Any woman with a history of nut allergies should avoid
eating peanuts or peanut products at all times, not just when pregnant
or breastfeeding.)
Abdominal defects. Certain uncommon birth defects of the
abdominal wall also can raise MSAFP levels, as can certain rare kidney
and bowel defects. In rare instances, the MSAFP level is elevated
because the fetus is dying or dead.
Down syndrome. Low levels of MSAFP and estriol, along with high
levels of human chorionic gonadotropin (hCG) suggest an increased
risk of Down syndrome. About 1 in 800 babies is born with Down
syndrome, which is caused by an extra copy of chromosome 21.
Affected children have characteristic facial features, mental retardation
and, often, heart defects and other problems.
Trisomy 18 (Edward syndrome). Low levels of MSAFP, estriol and
hCG suggest an increased risk of this less common chromosomal
abnormality, which affects about 1 in 3,000 babies. Affected babies,
who have an extra copy of chromosome 18, have severe mental
retardation, heart defects and numerous other birth defects. Most die
in the first year of life.
The risk of Down syndrome, trisomy 18 and other chromosomal
problems increases with a woman’s age. Pregnant women who are 35
years of age and older generally are offered prenatal testing with
amniocentesis or chorionic villus sampling (CVS) to diagnose or, far
more likely, rule out these disorders. If the maternal serum screening
test shows that a woman under age 35 has a risk that equals that of a
35-year-old woman (about 1 in 270), she also will be offered follow-up
tests.
What tests are recommended following an abnormal maternal
serum screening test?
After an abnormal test result, the next step usually is an ultrasound
examination. This test uses sound waves to take a picture of the fetus.
Ultrasound can help determine the gestational age of the fetus and
show if a woman is carrying twins. If either of these factors accounts
for the abnormal test result, no further testing is needed. Ultrasound
also can detect some serious birth defects.
If the ultrasound does not provide an explanation for an abnormal test
result, additional diagnostic testing is recommended. If the maternal
serum screening test shows that a woman is at increased risk of Down
syndrome or trisomy 18, her health care provider will offer her
amniocentesis. In this test, the doctor inserts a thin needle through
the abdominal wall and into the uterus to withdraw a few teaspoons of
amniotic fluid. Fetal cells contained in the amniotic fluid will be tested
for Down syndrome and other chromosomal abnormalities.
Amniocentesis is more than 99 percent accurate in diagnosing or, far
more likely, ruling out Down syndrome.
If the maternal serum screening test shows that a woman is at
increased risk of having a baby with an NTD, her provider may
recommend a detailed ultrasound examination (sometimes referred to
as a targeted, comprehensive or level II exam), amniocentesis or
both. A targeted ultrasound examination of the fetal skull, spine and
other organs can quite accurately detect or rule out serious NTDs. It
also may help predict the severity of NTDs. If this type of ultrasound
examination is not available, or if more information is needed after an
ultrasound examination, amniocentesis often is recommended to
measure the level of AFP and another substance called
acetylcholinesterase in the amniotic fluid. When amniocentesis is done
to help detect NTDs, cells from the fetus usually are tested for
chromosomal abnormalities because they sometimes can accompany
an NTD or an abdominal wall defect.
The maternal serum screening test leads to the prenatal diagnosis of
about 95 percent of cases of anencephaly, 85 percent of cases of
serious spina bifida, as well as 65 percent of cases of Down syndrome
(about 75 percent of Down syndrome cases if the quadruple screen is
used).
What are the benefits of the maternal serum screening test?
For the great majority of women, the screening test provides
reassurance that their fetus does not appear to have certain serious
birth defects. Test results also can help a woman manage her
pregnancy more effectively. For example, finding the correct
gestational age helps determine whether the fetus is growing at a
normal rate. And detecting a multiple pregnancy allows for special
care.
When an NTD or other problems are diagnosed or suspected, a couple
can discuss all their options with their health care provider. They can
plan for delivery in a specially equipped medical center so that the
baby can have any surgery or treatment required soon after birth.
In a 1991 study supported by the March of Dimes, David B. Shurtleff,
MD, and others at the University of Washington in Seattle, found that
cesarean delivery before the onset of labor appeared to reduce the
severity of paralysis in babies with spina bifida. If a baby is prenatally
diagnosed with spina bifida, a woman can discuss with her health care
provider the possibility of a planned cesarean.
In some cases, there is no clear-cut explanation for an abnormal test
result. Abnormal results have been linked with pregnancy problems
such as placental abruption (in which the placenta peels away from the
uterine wall before delivery), preeclampsia (pregnancy-related high
blood pressure), preterm labor, low birthweight, and fetal or infant
death. If a woman has an unexplained abnormal maternal serum
screening test result, her health care provider may monitor her
carefully in the last trimester of pregnancy. She may need more
frequent prenatal visits and various tests of fetal well-being, such as
ultrasound.
Some women over age 35 may choose the maternal serum screening
test to provide more information on their risk of having a baby with
Down syndrome before deciding whether or not to proceed with
amniocentesis. Because amniocentesis poses a small risk of
miscarriage, some women choose to avoid the procedure. If the
screening test shows that a woman is at low risk of Down syndrome,
she may choose not to have amniocentesis. However, it is important to
note that this approach does not guarantee that the baby will be free
of chromosomal defects. Additionally, amniocentesis and CVS can
diagnose or rule out many other chromosomal defects besides Down
syndrome and trisomy 18. The screening test does not test for these
additional chromosomal disorders, nor can it definitively diagnose or
rule out Down syndrome or trisomy 18, as amniocentesis and CVS can.
Can maternal blood screening be done in the first trimester?
Several studies recently reported that a screening test done between
10 and 14 weeks of pregnancy may be as accurate as the maternal
serum screening test done in the second trimester. The first-trimester
blood test measures the levels of hCG and a substance called
pregnancy-associated plasma protein A. An ultrasound examination of
the fetal neck was done along with the blood test. This approach
detected about 75 percent of fetuses with Down syndrome. When both
the first- and second-trimester screening tests were done, more than
90 percent of affected fetuses were detected. Although promising,
first-trimester screening is not yet the standard of care nor is it widely
available in most parts of the country.
Women who receive abnormal results on a first-trimester screening
test may be offered a prenatal test called chorionic villus sampling
(CVS), which is done between 10 and 12 weeks of pregnancy. In this
test, the health care provider inserts a thin tube through the vagina
and cervix or through a needle in the abdomen to take a tiny tissue
sample from outside the sac where the baby grows. Like
amniocentesis, CVS is highly accurate in diagnosing or, far more likely,
ruling out Down syndrome and other chromosomal birth defects.
How are genetic conditions and genes named?
http://www.ghr.nlm.nih.gov/info=mutations_and_disorders/show/naming
Naming genetic conditions
Genetic conditions are not named in one standard way (unlike genes,
which are given an official name and symbol by a formal committee).
Doctors who treat families with a particular disorder are often the first
to propose a name for the condition. Expert working groups may later
revise the name to improve its usefulness. Naming is important
because it allows accurate and effective communication about
particular conditions, which will ultimately help researchers find new
approaches to treatment.
Disorder names are often derived from one or a combination of
sources:






The basic genetic or biochemical defect that causes the condition
(for example, alpha-1 antitrypsin deficiency);
One or more major signs or symptoms of the disorder (for
example, sickle cell anemia);
The parts of the body affected by the condition (for example,
retinoblastoma);
The name of a physician or researcher, often the first person to
describe the disorder (for example, Marfan syndrome, which was
named after Dr. Antoine Bernard-Jean Marfan);
A geographic area (for example, familial Mediterranean fever,
which occurs mainly in populations bordering the Mediterranean
Sea); or
The name of a patient or family with the condition (for example,
amyotrophic lateral sclerosis, which is also called Lou Gehrig
disease after a famous baseball player who had the condition).
Disorders named after a specific person or place are called eponyms.
There is debate as to whether the possessive form (e.g., Alzheimer’s
disease) or the nonpossessive form (Alzheimer disease) of eponyms is
preferred. As a rule, medical geneticists use the nonpossessive form,
and this form may become the standard for doctors in all fields of
medicine. Genetics Home Reference uses the nonpossessive form of
eponyms.
Genetics Home Reference consults with experts in the field of medical
genetics to provide the current, most accurate name for each disorder.
Alternate names are included as synonyms.
Naming genes
The HUGO Gene Nomenclature Committee (HGNC) designates an
official name and symbol (an abbreviation of the name) for each
known human gene. Some official gene names include additional
information in parentheses, such as related genetic conditions,
subtypes of a condition, or inheritance pattern. The HGNC is a nonprofit organization funded by the U.K. Medical Research Council and
the U.S. National Institutes of Health. The Committee has named more
than 13,000 of the estimated 20,000 to 25,000 genes in the human
genome.
During the research process, genes often acquire several alternate
names and symbols. Different researchers investigating the same gene
may each give the gene a different name, which can cause confusion.
The HGNC assigns a unique name and symbol to each human gene,
which allows effective organization of genes in large databanks, aiding
the advancement of research. To access the HGNC's guidelines for
naming human genes, click on “Guidelines” from the HGNC home
page .
Genetics Home Reference describes genes using the HGNC’s official
gene names and gene symbols. Genetics Home Reference frequently
presents the symbol and name separated with a colon (for example,
FGFR4: Fibroblast growth factor receptor 4).
Screening for Down Syndrome
http://cpmcnet.columbia.edu/texts/gcps/gcps0051.html
Accuracy of Screening Tests
Down syndrome is diagnosed prenatally by determining karyotype in
fetal cell samples obtained by amniocentesis or chorionic villus
sampling (CVS). Because of their invasiveness, risks, and cost, these
procedures are generally reserved for women identified as high-risk
either by history (i.e., advanced maternal age, prior affected
pregnancy, known chromosome rearrangement) or by screening
maneuvers (e.g., serum markers, ultrasound). Chromosome analysis
of fetal cells obtained by second-trimester amniocentesis has been
demonstrated to be accurate and reliable for prenatal diagnosis of
Down syndrome in a randomized controlled trial and several cohort
studies.16-19 CVS, a technique for obtaining trophoblastic tissue, is an
alternative to amniocentesis for detecting chromosome anomalies. The
advantages of this procedure include the ability to perform karyotyping
as early as 10-12 weeks and more rapid cytogenetic analysis. Potential
disadvantages of CVS include apparent discrepancies between the
karyotype of villi and the fetus due to maternal cell contamination or
placental mosaicism, and failure to obtain an adequate specimen,
resulting in a repeat procedure (usually amniocentesis) in up to 5% of
tested women.20-22 In randomized controlled trials20-22 and cohort
studies23-29 comparing CVS to amniocentesis, accurate prenatal
diagnosis has been obtained in over 99% of high-risk women when
CVS is accompanied by both direct and culture methods of cytogenetic
examination and when amniocentesis is provided to clarify CVS
diagnoses of mosaicism or unusual aneuploidy. Transabdominal CVS
has been reported to have comparable accuracy to transcervical CVS
in randomized controlled trials.20,30,31 First-trimester amniocentesis
(at 10-13 weeks) has been compared to CVS in one randomized
controlled trial.32 Success rates were the same for the two procedures
(97.5%); early amniocentesis failures were primarily due to failed
culture. First- and second-trimester amniocentesis have not been
directly compared in controlled trials.
For low-risk women, the risks associated with prenatal diagnostic
testing (see Adverse Effects of Screening and Early Detection, below)
are generally considered to outweigh the potential benefits because of
the low likelihood of diagnosing a Down syndrome gestation. If
screening tests, such as measurement of maternal serum markers or
ultrasound imaging, can identify women who are at high risk for
carrying a Down syndrome fetus, the relative benefit of prenatal
diagnostic testing increases, potentially justifying the more invasive
diagnostic procedures. Reduced levels of maternal serum a-fetoprotein
(MSAFP) and unconjugated estriol, and elevated levels of human
chorionic gonadotropin (hCG), have each been associated with Down
syndrome gestations. Intervention studies of screening have not been
carried out with unconjugated estriol alone, while cohort intervention
studies evaluating MSAFP and hCG have found them to have relatively
poor discriminatory power as individual tests.33-36 Multiple-marker
screening uses results from two or three individual maternal serum
marker tests, combined with maternal age, to calculate the risk of
Down syndrome in the current gestation.37,38 Amniocentesis and
diagnostic chromosome studies are then offered to women whose
screening test results suggest a high risk of Down syndrome, with high
risk often defined as having the same or greater risk of an affected
pregnancy that a 35-year-old woman has (i.e., 1 in 270).
Six interventional cohort studies that analyzed low-risk women
younger than 35 years,39-41 36 years,42 37 years,43 or 38 years,44
and six that included women of any age desiring screening (90-95%
Û35 years),45-50 have evaluated the proportion of Down syndrome
pregnancies identified through double-marker (hCG and either MSAFP
or estriol) or triple-marker screening in the midtrimester compared to
the total number of such pregnancies identified. Interpretation of
sensitivity is affected by incomplete ascertainment of karyotype and
incomplete diagnosis at birth in these studies, although most had
active surveillance systems for Down syndrome cases born to screened
women. The reported sensitivity of multiple-marker screening for
Down syndrome ranged from 48 to 91% (median 64.5%) and the
false-positive rate (after revision of dates by ultrasound) ranged from
3% to 10%. The likelihood of Down syndrome given a positive
screening test result was 1.2-3.8%, depending on the threshold for
high risk used to define a positive test result. In these studies, the
threshold chosen ranged from a 1 in 125 to a 1 in 380 chance of
having an affected pregnancy given a positive test result. A young
woman with a prescreen risk of about 1 in 1,000 who tested positive
would have a postscreen risk similar to the risk in women of advanced
age who are currently offered prenatal diagnosis.
Multiple-marker screening has also been evaluated in women 35 years
of age or older, for whom prenatal diagnosis using amniocentesis or
CVS is routinely recommended because of their increased risk of Down
syndrome. Studies suggest that multiple-marker screening in these
women might reduce the need for more invasive diagnostic tests. In a
cohort study of 5,385 women Ú35 years of age with no other risk
factors, all of whom were undergoing routine amniocentesis and
chromosome studies (thus allowing complete ascertainment of
chromosome abnormalities), estimates of the individual risk of Down
syndrome were calculated based on maternal age in combination with
the results of multiple-marker screening using MSAFP, hCG, and
unconjugated estriol.51 If amniocentesis were performed only on older
women with at least a 1 in 200 risk of carrying a fetus with Down
syndrome based on triple-marker screening, 89% of affected fetuses
would have been detected, 25% of women with unaffected fetuses
would have been identified by screening as needing amniocentesis. A
threshold of 1 in 300 (similar to risk based on age Ú35 years alone)
did not add sensitivity but did increase the screen-positive rate to
34%. Thus, triple-marker screening could have avoided 75% of
amniocenteses in older women, with their attendant risk of fetal loss,
at a cost of missing 11% of cases of Down syndrome. In this study,
performing amniocenteses only on women with postscreen risks of at
least 1 in 200 for Down syndrome would also have detected 47% of
fetuses with other autosomal trisomies, 44% of fetuses with sex
aneuploidy, and 11% with miscellaneous chromosome abnormalities.
In previously cited interventional cohort studies of double- or triplemarker screening that reported separate results for older women, the
Down syndrome detection rate was reported as 80-100% for women
Ú35 years43,46,47,50 and 100% for women Ú36 years,42,45 with
false-positive screening results of 19-27%. Incomplete case
ascertainment was possible, however, since screen-negative women
rarely had diagnostic chromosome studies.
Although no controlled trials have directly compared double-marker to
triple-marker screening, several cohort studies of triple-marker
screening have reported the detection rates for double-marker
screening with hCG and MSAFP only. Three markers appear to be
somewhat more sensitive than two for detection of Down syndrome;
the net difference in sensitivity ranged from - 2 to +18% in these
studies, depending on the false-positive rate and risk cut-off
used.43,48,50,51
Ultrasonography is another potential screening test for Down
syndrome. Abnormalities associated with Down syndrome (including
intrauterine growth retardation, cardiac anomalies, hydrops, duodenal
and esophageal atresia) and differences in long-bone length and
nuchal fold thickness between Down syndrome and normal
pregnancies observable on midtrimester ultrasound have been
reviewed.52 In prospective cohort studies of midtrimester ultrasound
screening in high-risk women who were undergoing amniocenteses for
chromosome studies, nuchal fold thickening identified 75% of Down
syndrome fetuses; shortened humerus or femur length detected 31%;
and an index based on thickened nuchal fold, major structural defect,
and certain other abnormalities identified 69%.53-55 The likelihood of
Down syndrome given a positive result was 7-25% in these high-risk
samples, but would be substantially lower in low-risk women. No
published cohort studies have evaluated the accuracy of ultrasound
screening for detection of chromosome abnormalities in low-risk
women, nor have interventional cohort studies evaluated its efficacy as
a screening tool in high-risk women. The use of ultrasound as a
screening test for Down syndrome is limited by the technical difficulty
of producing a reliable sonographic image of critical fetal
structures.56,57 Incorrect positioning of the transducer, for example,
can produce artifactual images resembling a thickened nuchal skin fold
in a normal fetus.58 Sonographic indices are therefore subject to
considerable variation. Imaging techniques require further
standardization before routine screening by ultrasound for Down
syndrome can be considered for the general population.56,59,60 In
addition, results obtained by well-trained and well-equipped operators
in a research context may not generalize to widespread use. In a
multicenter cohort study in high-risk women that involved a large
number of ultrasonographers of varying ability, the sensitivity of
nuchal fold thickening for Down syndrome was only 38%.59 The falsepsitive rate in this study was 8.5%, many times higher than that
reported in studies involving expert ultrasonographers.55,61
Effectiveness of Early Detection
The detection of Down syndrome and other chromosome anomalies in
utero provides as its principal benefit the opportunity to inform
prospective parents of the likelihood of giving birth to an affected
child. Parents may be counseled about the consequences of the
abnormality and can make more informed decisions about optimal care
for their newborn or about elective abortion. No controlled trials have
been performed to assess clinical outcomes for those using screening
or prenatal diagnosis for Down syndrome compared to those who do
not. Therefore, the usefulness of this information depends to a large
extent on the personal preferences and abilities of the parents.62
Whether or not parents choose to use prenatal screening or diagnosis
is related both to their views on the acceptability of induced abortion
and their perceived risk of the fetus being abnormal.63 The perception
of the harm or nature of the disability may play a greater role in the
decision than the actual probability of its occurrence.64-67
Induced abortion is currently sought by the majority of women whose
prenatal diagnostic studies (i.e., karyotyping) reveal fetuses with
Down syndrome.33-35,39,40,45,48,68 Estimates of the reduction in
birth prevalence of Down syndrome associated with offering prenatal
diagnosis to women 35 years and older range from 7.3% to 29% in
the U.S. and other developed countries.2,69-73 The effect of this
approach on the total number of Down syndrome births is limited
because older women have low birth rates and therefore account for a
relatively small proportion of affected pregnancies despite their
exponentially increased risk for having an affected pregnancy.74
Limited data are available to estimate the impact of serum-marker
screening in younger women on Down syndrome birth prevalence. In
England and Wales, the proportion of all cytogenetically diagnosed
Down syndrome cases detected prenatally (thus potentially
preventable) increased from 31% to 46% after the introduction of
screening by maternal serum analysis and ultrasound for low-risk
women.68 In cohort studies evaluating double- or triple-marker
screening, when the proportions of screen-positive women who
decided not to undergo amniocentesis or induced abortion were taken
into account, the proportion of Down syndrome births to screened
women that were actually prevented ranged from 36% to
62%.39,40,45,48 Up to 25% of screen-positive women declined
prenatal diagnosis by amniocentesis in these studies. The effectiveness
of screening in preventing Down syndrome births may be further
reduced by incomplete uptake of screening. In antenatal screening
programs in which double- or triple-marker screening was offered to
all women and amniocentesis or CVS was offered to women over 35
years of age, nearly 60% of all Down syndrome births were potentially
preventable, the remainder either being missed by screening (1423%) or occurring in women who were not screened (17-27%).47,49
Neither study evaluated acceptance of induced abortion, however. In
another population, offering ouble-marker screening to all women
prevented 59% of all Down syndrome births.45 This population had
high rates of screening (89%), largely due to the fact that pregnant
women had to specifically ask to be excluded. There was also high
acceptance of amniocentesis in screen-positive women (89%), and of
induced abortion of cytogenetically confirmed cases (91%). The birth
prevalence of Down syndrome decreased from approximately
1.1/1,000 to 0.4/1,000 after initiation of prenatal screening in this
population.
Other potential effects of prenatal detection of Down syndrome have
not been adequately explored. In families at high risk of Down
syndrome births, such as those with advanced maternal age, a
previous affected pregnancy, or known carriage of translocations, the
availability of prenatal diagnosis may reduce the induced abortion rate
by identifying normal pregnancies that might otherwise be electively
aborted. This benefit has been reported with screening for cystic
fibrosis,75 but it has not been evaluated for Down syndrome. The
diagnosis of a chromosome abnormality may spare unsuspecting
parents some of the trauma associated with delivering an abnormal
infant, and may help parents to prepare emotionally. Studies
evaluating these potential psychological benefits have not been
reported, however. Prenatal diagnosis may also enable clinicians to
better prepare for the delivery and care of the baby. Studies are
lacking regarding the impact of these measures on neonatal morbidity
and mortality.
The prominent epicanthal fold of a child with Down syndrome is shown here. The pupil
also demonstrate a light smudgy opacity called a Brushfield spot.
This baby demonstrates the typical features of Down syndrome with downslanting
palpebral fissures and a slightly protruding tongue.
http://medgen.genetics.utah.edu/photographs/pages/down_syndrome.htm
Down's Syndrome Screening procedures
http://www.nelh.nhs.uk/screening/dssp/procedures.htm
There are two methods of initial screening for Down’s syndrome:
1. serum screening, the most common method being biochemical;
2. ultrasound screening.
For both methods, it is necessary to use software to estimate the risk
of a woman having a Down’s syndrome pregnancy from the results.
Biochemical screening
Different methods of serum screening have been developed. The most
common method of serum screening is biochemical. A blood sample is
taken from the pregnant woman at between 10 and 20 weeks’
gestation and tested for various proteins and hormones, usually in
combination.
The most common combination used in the second trimester is
alphafetoprotein (AFP) and free beta-human chorionic gonadotrophin
(beta-hCG); a combination used less frequently is that of
unconjugated eostriol (UE3) and Inhibin A. The National Screening
Committee is awaiting the outcome of a feasibility study before fully
recommending the use of Inhibin A. It is expected that this will report
at the end of 2004.
Biochemical screening can also be undertaken during the first
trimester of pregnancy between 10 and 14 weeks’ gestation, when the
combination used is free beta-hCG and placenta associated plasma
protein A (PAPP-A).
Ultrasound
There have been significant developments in using ultrasound
techniques as a screening tool for Down’s syndrome. During the first
trimester of the majority of pregnancies, it is possible to measure the
size of the fluid area at the back of the fetus’s neck, known as the
nuchal translucency or NT (see glossary entry). The increasing size of
the NT indicates a greater risk of the fetus having Down’s syndrome1.
--------->
An ultrasound image of a fetus showing the nuchal translucency
Both biochemical and ultrasound screening methods can be combined
to give a better detection rate. This is the suggested way forward for
screening in England where sufficient resources have been identified.
NT is the only marker that should be used. Measurement of other
markers, including the nasal bone, should be done only in the context
of an ethically approved research project.
Interpretation of results from initial screening procedures
What are the causes of Down Syndrome?
Most of the time, the occurrence of Down syndrome is due to a
random event that occurred during formation of the reproductive cells,
the ovum or sperm. As far as we know, Down syndrome is not
attributable to any behavioral activity of the parents or environmental
factors. The probability that another child with Down syndrome will be
born in a subsequent pregnancy is about 1 percent, regardless of
maternal age.
The incidence of Down syndrome rises with increasing maternal
age.
For parents of a child with Down syndrome due to translocation
trisomy 21, there may be an increased likelihood of Down syndrome in
future pregnancies. This is because one of the two parents may be a
balanced carrier of the translocation. The translocation occurs when a
piece of chromosome 21 becomes attached to another chromosome,
often number 14, during cell division. If the resulting sperm or ovum
receives a chromosome 14 (or another chromosome), with a piece of
chromosome 21 attached and retains the chromosome 21 that lost a
section due to translocation, then the reproductive cells contain the
normal or balanced amount of chromosome 21. While there will be no
Down syndrome associated characteristics exhibited, the individual
who develops from this fertilized egg will be a carrier of Down
syndrome. Genetic counseling can be sought to find the origin of the
translocation.
However, it is important to realize that not all parents of individuals
with translocation trisomy 21 are themselves balanced carriers. In
such situations, there is no increased risk for Down syndrome in future
pregnancies.
Researchers have extensively studied the defects in chromosome 21
that cause Down syndrome. In 88% of cases, the extra copy of
chromosome 21 is derived from the mother. In 8% of the cases, the
father provided the extra copy of chromosome 21. In the remaining
2% of the cases, Down syndrome is due to mitotic errors, an error in
cell division which occurs after fertilization when the sperm and ovum
are joined.
Down Syndrome And Maternal Age
Researchers have established that the likelihood that a reproductive
cell will contain an extra copy of chromosome 21 increases
dramatically as a woman ages. Therefore, an older mother is more
likely than a younger mother to have a baby with Down syndrome.
However, of the total population, older mothers have fewer babies;
about 75% of babies with Down syndrome are born to younger women
because more younger women than older women have babies. Only
about nine percent of total pregnancies occur in women 35 years or
older each year, but about 25% of babies with Down syndrome are
born to women in this age group.
The incidence of Down syndrome rises with increasing maternal age.
Many specialists recommend that women who become pregnant at age
35 or older undergo prenatal testing for Down syndrome. The
likelihood that a woman under 30 who becomes pregnant will have a
baby with Down syndrome is less than 1 in 1,000, but the chance of
having a baby with Down syndrome increases to 1 in 400 for women
who become pregnant at age 35. The likelihood of Down syndrome
continues to increase as a woman ages, so that by age 42, the chance
is 1 in 60 that a pregnant woman will have a baby with Down
syndrome, and by age 49, the chance is 1 in 12. But using maternal
age alone will not detect over 75% of pregnancies that will result in
Down syndrome.
http://pediatrics.about.com/od/birthdefects/f/down_syn_cau
ses.htm
The results of one or both initial screening procedures are entered into
a software programme which calculates the risk for a woman of having
a child with Down’s syndrome at her present age. This risk is
calculated in relation to that of the population covered by the
programme. The levels of risk associated with having a Down’s
syndrome pregnancy in relation to a woman’s age are shown in the
table below:.
Levels of risk of having a Down’s syndrome pregnancy in relation to a
woman’s age
Woman’s age
(years)
Risk as a ratio
%Risk
20
1:1500
0.066
30
1:800
0.125
35
1:270
0.37
40
1:100
1.0
45 and over
1:50 and greater
2.0
If the risk is greater than 1 in 250, it is judged to be within the higher
risk category. In such cases, it is necessary to offer the woman a
further procedure to establish the diagnosis.
About 5% of all pregnant women undergoing screening will have a
high-risk result, and need to be offered a follow-on diagnostic
procedure such as amniocentesis or chorionic villus sampling (see
glossary entry). However, the percentage of women who undergo such
procedures is slightly lower than 5% because not all women who have
a high-risk result want to be subjected to an invasive procedure.
It is one of the aims of the programme to lower the number of women
who are offered an invasive diagnostic test by improving the specificity
of the screening tests.
To ensure that interpretation of the results from the initial screening
procedures is as accurate as possible, it is essential to establish the
date of the pregnancy. This need for accuracy underlines the
importance of women having an early ultrasound scan to date the
pregnancy.
Age
20
21
22
23
24
25
26
27
28
29
30
31
32
Risk:
1 in
1529
1508
1481
1447
1404
1351
1286
1209
1119
1019
910
797
683
Age
33
34
35
36
37
38
39
40
41
42
43
44
45
Risk:
1 in
575
474
384
307
242
189
146
112
86
65
49
37
28
http://www.leeds.ac.uk/lass/screening%20for%20Down's.htm
Down syndrome - the risks?
Age
Risk
20
25
30
35
36
37
38
39
40
42
44
46
48
49
1:1,340
1:1,500
1:900
1:400
1:300
1:230
1:180
1:135
1:105
1:60
1:35
1:20
1:16
1:12
http://www.mothers35plus.co.uk/down.htm
Follow-on diagnostic procedures
If the pregnancy is beyond 15 weeks’ gestation, the follow-on
diagnostic procedure is amniocentesis; if the pregnancy is of less than
13 weeks’ gestation, the follow-on diagnostic procedure is chorionic
villus sampling (CVS).
Amniocentesis
This test is performed usually between 15 - 20 weeks of pregnancy,
although this may vary.
Amniocentesis is quite a common procedure and is undertaken for
many reasons. Normally it is performed to establish the structure and
number of the chromosomes or to establish any genetic problems that
may affect the baby.
Before undergoing this test it is important that the pregnant woman is
fully counselled regarding the reason to have it done, the risks to the
baby and the consequences of finding any information related to this
test. This includes the findings of any other opportunist information
that may occur. No other testing should be carried out without the
pregnant woman's consent.
A needle is inserted through the abdomen or through the vaginal
canal. It is recommended, by the Royal College of Obstetricians and
Gynaecologists that this is performed constantly under the guidance of
ultrasound. A small amount of fluid is removed and sent to the genetic
laboratory for investigation
.
This picture shows a woman having amniocentesis
This test has a 1% risk of miscarriage for the baby and a pregnant
woman should be fully aware of this prior to the procedure so that she
and her partner can make a fully informed decision.
Chorionic Villus Sampling (CVS)
This is normally performed between 11 - 13 weeks of pregnancy. It is
known that performing this test before 9 weeks will increase the
possibility of limb abnormalities.
Again it is recommended that this procedure is performed under
ultrasound guidance. A needle is inserted through the abdomen or
through the vagina. The aim is to remove a small piece of placenta
(afterbirth). The placenta originates alongside the same cells as the
baby and consequently should have the same type of chromosomal
and genetic makeup.
This also has a risk of miscarriage for the baby and is quoted at
between 0.5 - 2%. This is dependant upon the experience of the
clinician performing the procedure. Both of these diagnostic
procedures carry a risk of miscarriage, quoted as 2% for CVS and 1%
for amniocentesis by most hospitals3
.
During CVS, samples of the cells that line the placenta, known
as chorionic villi cells, are removed and tested for genetic
abnormalities in the laboratory
Cytogenetic techniques
The sample from amniocentesis or CVS is sent to a cytogenetics
laboratory to be cultured. Cytogenetics is the name given for looking
at chromosomes in a laboratory. The techniques assesses their
number and structure. This is necessary in cases such as Down
syndrome to obtain a definite diagnosis.
The process develops the chromosome to a stage where it can be
looked at under a microscope, and produces a karyotype (see glossary
entry) of the baby. It can take up to 3 weeks before the results of the
follow-on diagnostic procedure are available. See
http://www.kumc.edu/gec/prof/cytogene.html for more information.
This picture shows a view of chromosomes through a microscope,
producing the karyotype (chromosomal make-up) of a person
In a normal human cell there are 46 chromosomes, including one pair
of sex chromosomes. In Down syndrome there are 47 chromosomes.
Fluorescent In Situ Hybridisation techniques and Quantitative
fluorescent polymerase chain reaction
Quantitative fluorescent polymerase chain reaction or QFPCR (see
glossary entry), and fluorescent in situ hybridisation or FISH (see
glossary entry), are techniques which allow rapid diagnosis of the
sample, usually within 48 hours.
FISH is a type of hybridisation in which a ‘probe’ DNA is labelled with a
fluorescent molecule so that it can be seen with a microscope.
QFPCR is the amplification and quantification of specific genomic DNA
regions from an amniotic or CVS sample.
The DNA fragments are analysed in a sequencer
1:1 ratio (normal fetus)
2:1 ratio: (Down's Syndrome)
The results are displayed graphically on a computer screen as a series of
peaks (below)
For more information about the performance of FISH, Q-PCR tests and
karyotyping, see this HTA report:
Health Technology Assessment (HTA) 2003, Volume 7, number 10. Evaluation of
molecular tests for prenatal diagnosis of chromosome abnormalities (Grimshaw).
Termination of pregnancy
From the results of published studies, it would appear that 90% of women who
have a definitive diagnosis of Down’s syndrome in their fetus choose to terminate
their pregnancy (see glossary entry). Termination can occur late in the pregnancy
(at 24 weeks’ gestation) if the initial screening procedure was undertaken at
about 20 weeks’ gestation2.
However, whenever possible women would be encouraged to undergo screening
and diagnosis as early as possible to avoid late decision-making.
Pathways through the screening process
An overview of the various routes a pregnant woman could take through the
Down's Syndrome screening process is shown in this flow diagram (pdf
document). However, this diagram is only a guide; practice may vary from hospital to
hospital due to differences in policies and protocols.
DOWN'S SYNDROME
http://www.leeds.ac.uk/lass/down's.htm
The level of each marker is typically either increased or reduced on average
in a Down's syndrome pregnancy. The table shows a typical profile for the
most important markers found so far.
Marker
nuchal translucency (NT)
+++
human chorionic gonadotropin (hCG)
++
inhibin-A
++
free-beta hCG
++
alpha hCG
+
alpha-fetoprotein (AFP)
–
unconjugated estriol (uE3)
–
pregnancy associated plasma protein A
(PAPP-A)
†
Profile†
–––
the number of + and - signs gives the increase or decrease in a typical
affected pregnancy.
All are blood markers except for nuchal translucency, which is a temporary
swelling of the fetal neck measurable by ultrasound.
The average levels for each of the markers change with gestational age. To
quantify the extent of increase or decrease in marker level they are
expressed as multiples of the normal median (MoMs) for the gestation. For
example, 2.0 MoM means that the level is double that expected for the
gestational age of the pregnancy. Although, on average, a Down’s syndrome
pregnancy follows a typical profile there is a lot of variability and many are
atypical. Equally, some unaffected pregnancies have a profile similar to
Down's syndrome. When someone is screened we use a computer program
to calculate how close their profile is to that of an affected pregnancy.
Taking the maternal age, family history and profile together our program
calculates the risk of the pregnancy ending in the birth of a baby with Down's
syndrome. If the risk exceeds 1 in 250 the result is regarded as screen
positive, otherwise it is screen negative. We also report the actual risk which
could be as low as 1 in 50,000 or as high as 1 in 10.
CHOICE OF TESTS
Various combinations of markers can be used in a screening test. We offer a number
of tests, using combinations with the highest detection rates. These are the Primark,
Biomark and Beta triple tests. When choosing which test to have the most important
factors to consider are the gestational range over which it is effective, whether
additional disorders can be detected, and if there are twins.
In general we recommend that a test is performed as early in pregnancy as possible,
to allow plenty of time for further decision making. If screening is required for NTDs
and AWDs, testing should be delayed until 15 weeks’ gestation. However, a separate
AFP test may be routinely offered at the local hospital. Additionally a detailed
ultrasound ‘anomaly’ scan may be offered at 18-20 weeks gestation and this detects
most NTDs and AWDs.
In twins, tests involving NT are more accurate than those based on blood markers
alone. This is because the NT treats each fetus separately whereas maternal blood
marker levels are influenced by both an affected twin and its normal co-twin.
PRIMARK TEST
A first trimester screening test, incorporating biochemical testing
and ultrasound.
Markers measured:
AFP, uE3, free beta hCG and PAPP-A are the biochemical markers; nuchal
translucency is the ultrasound marker.
Gestational range: 10 -12 weeks (biochemistry) and 11-13 weeks (NT scan)
Anomalies detected: Down’s syndrome and Edwards’ syndrome.
Test performance: Overall, the Down's syndrome detection rate is 81% and the
false-positive rate is 2½%. These rates alter with maternal age, as shown in the
graph (which gives the rates for each completed year of age at the estimated date of
delivery).
Take a vertical line from the age and note where it crosses the two curves. For
example a woman aged 30 years would have a detection rate of 76% and a falsepositive rate of 2%.
BIOMARK TEST
Markers measured:
AFP, uE3, free-beta hCG and inhibin.
Gestational range: 13-18 weeks, but will consider testing up to 22
weeks.
Anomalies detected: Down’s syndrome and Edwards’ syndrome. Also
NTDs and AWDs if tested after 15 weeks.
Test performance: Overall, the Down's syndrome detection rate is
72% and the false-positive rate is 5%. These rates alter with maternal
age, as shown in the graph (which gives the rates for each completed
year of age at the estimated date of delivery).
Take a vertical line from the age and note where it crosses the two
curves. For example a woman aged 30 years would have a detection
rate of 63% and a false-positive rate of 4%.
BETA TRIPLE TEST
Markers measured:
AFP, uE3 and free-beta hCG (instead of intact hCG which is used in
the triple test).
Gestational range: 13-18 weeks, but will consider testing up to 22
weeks.
Anomalies detected: Down’s syndrome and Edwards’ syndrome. Also
NTDs and AWDs if tested after
15 weeks.
Test performance: Overall, the Down's syndrome detection rate is
64% and the false-positive rate is
4½%. These rates alter with maternal age, as shown in the graph
(which gives the rates for each completed year of age at the estimated
date of delivery).
Take a vertical line from the age and note where it crosses the two
curves. For example a woman aged 30 years would have a detection
rate of 55% and a false-positive rate of 4%
TWINS
Screening is not as successful as in singletons. The detection rate with
biochemical markers is lower in twins than for singletons. This is
because most affected twin pregnancies have one Down's syndrome
and one unaffected fetus. The normal biochemical marker production
in the latter tends to mask abnormal production in the former. This
does not apply to NT since each fetus is measured seperately.
Therefore it is better to have a PRIMARK test rather than a BIOMARK.
The detection and false-positive rates for the two tests in twins are
shown in the graphs (which give the rates for each completed year of
age at the estimated date of delivery). Take a vertical line from the
age and note where it crosses the curves.
Another problem is that amniocentesis is more hazardous in twins: it
causes twice as many miscarriages than in singleton pregnancies.
Also, if one of the fetuses has Down's syndrome one option is 'fetal
reduction' which allows the pregnancy to continue with the unaffected
fetus. However, the procedure is associated with a more than 10%
fetal loss rate in the unaffected co-twin.
Alpha-Fetoprotein (AFP) Screening
http://www.ucsfhealth.org/childrens/medical_services/preg/prena
tal/afp.html
What is expanded alpha-fetoprotein (AFP) screening?
An expanded AFP screening is a simple blood test. It is recommended
by the state of California for all pregnant women and can detect if they
are carrying a fetus with certain genetic abnormalities such as:
Open neural tube defects (ONTD), such as
spina bifida
Down syndrome
Chromosomal abnormalities, such as trisomy 18
Defects in the abdominal wall of the fetus
AFP is a substance made by the yolk sac of a fetus that enters the
amniotic fluid and crosses the placenta into the mother's bloodstream.
Altered AFP levels, those that are either too high or low compared to
normal amounts, can indicate whether a woman is carrying a baby
with a chromosome problem or certain birth defects. A pregnant
woman's AFP levels decrease soon after birth.
How is the screening performed?
AFP screening is performed between 15 and 20 weeks of pregnancy. A
woman will undergo a simple blood test and the blood sample will be
sent off to the laboratory for analysis. In addition to checking the AFP
levels, the laboratory also measures the amount of the hormones
unconjugated estriol, human chorionic gonadotropin (HCG) and
inhibin-A. The amount of these hormones can be altered in a woman's
blood when she is carrying a baby with a chromosome problem or
certain birth defects. Results are usually available within one to two
weeks or less.
Nuchal Translucency Screening (NT)
UCSF Medical Center is one of the few centers nationwide to offer
nuchal translucency screening (NT) screening, a new, non-invasive
test performed early in pregnancy to identify women at increased
risk for Down syndrome and other birth defects. NT screening is
performed between 11 and 14 weeks of pregnancy. It is offered to
women of all ages. The screening is done via a high-resolution
ultrasound exam of the nuchal area - a fold of skin at the back of
the neck of the fetus. The results are combined with the mother's
age to determine an adjusted risk for Down syndrome. The rate of
detection for Down syndrome is about 80 percent. Based on the
results, a woman has the option of undergoing CVS or
amniocentesis for diagnosis.
NT is a screening test only and cannot determine with certainty if
the fetus does or does not have Down syndrome, only if your
risk seems to be high or low. While this test has been developed
for Down syndrome screening, other chromosomal abnormalities
can sometimes be detected. In addition, fetuses with an
increased area of nuchal translucency are at risk for other birth
defects. An additional ultrasound and fetal echocardiogram, an
ultrasound of the fetal heart, can be performed at 18 to 20
weeks of gestation to look for these abnormalities, if indicated.
If the screening indicates that your fetus is at an increased risk
of Down syndrome, a genetic counselor or physician will discuss
the specific risk. The counselor also will discuss further
diagnostic testing available, including chorionic villus sampling
(CVS) or amniocentesis
There are three types of Down syndrome:
Trisomy 21 -- An estimated 95 percent of people with Down
syndrome have Trisomy 21, meaning an individual has three
instead of two number 21 chromosomes. We normally have 23
pairs of chromosomes, each made up of genes. During the
formation of the egg or the sperm a woman's or a man's pair of
chromosomes normally split so that only one chromosome is in
each egg or sperm. In Trisomy 21, the 21st chromosome pair does
not split and a double-dose goes to the egg or sperm. An estimated
95 percent to 97percent of the extra chromosome is of maternal
origin.
Translocation -- This occurs in about 3 percent to 4 percent of
people with Down syndrome. In this type, an extra part of the 21st
chromosome gets stuck onto another chromosome. In about half of
these situations, one parent carries the extra 21st chromosome
material in a "balanced" or hidden form.
Mosaicism -- In mosaicism, the person with Down syndrome has
an extra 21st chromosome in only some of the cells but not all of
them. The other cells have the usual pair of 21st chromosomes.
About 1 percent to 2 percent of people with Down syndrome have
this type.
http://www.ucsfhealth.org/childrens/medical_services/preg/
prenatal/conditions/down/signs.html
Common prenatal tests
http://www.mayoclinic.com/invoke.cfm?objectid=4F298766746D-4EA9-922DB76BFA0B4497
What it is When it's How it's What the Possible
done
done results may safety
tell you
concerns
Triple test
A maternal
blood test
looks for
three
substances
normally
produced
by the fetus
or placenta.
Between
the 15th
and 22nd
weeks of
pregnanc
y.
A blood Screens for
sample
Down
is taken syndrome,
from the
other
mother's chromosom
arm.
al disorders,
spina bifida.
Amniocente
sis
A sample of
the
amniotic
fluid is
checked
for:
1. Specific
genetic
problems.
2. Maturity
of baby's
lungs.
After the
15th
week, for
a genetic
test.
Near the
time of
delivery
for
maturity
test.
Ultrasou Can identify
One in
nd helps
specific
200
the
genetic
chance of
doctor problems or miscarriag
avoid
determine
e.
the baby the maturity
when
of the
placing a
baby's
thin
lungs.
needle
into the
mother's
abdomen
.
Chorionic
villus
sampling
A sample of Between
A thin
Can identify
One in
the
the 9th needle is
specific
100
placenta is and 14th inserted
genetic
chance of
tested for
weeks.
into the
problems, miscarriag
genetic
mother's earlier than
e.
None.
(CVS)
abnormaliti
es.
Percutaneo
us umbilical
blood
sampling
(PUBS)
Blood is
After the Ultrasou
taken from
18th
nd helps
the baby
week.
locate
and then
Prior to
the
tested for that, the umbilical
genetic
umbilical
cord
problems or vein is
vein, so
infections.
too
blood
fragile.
can be
drawn
from it,
through
a long
needle in
mother's
abdomen
.
abdomen amniocentes
OR a
is.
thin tube
is
threaded
through
the
cervix.
Can test for
sickle cell
anemia,
hemophilia,
anemia and
Rh disease.
Two in
100 risk
of fetal
death.
Maternal Serum Screening
The mother's blood is checked for three items: alpha-fetoprotein
(AFP), unconjugated estriol (uE3) and human chorionic gonadotropin
(hCG). These three are independent measurements, and when taken
along with the maternal age (discussed below), can calculate the risk
of having a baby with Down syndrome.

Alpha-fetoprotein is made in the part of the womb called the
yolk sac and in the fetal liver, and some amount of AFP gets into
the mother's blood. In neural tube defects, the skin of the fetus
is not intact and so larger amounts of AFP is measured in the
mother's blood. In Down syndrome, the AFP is decreased in the
mother's blood, presumably because the yolk sac and fetus are
smaller than usual.


Estriol is a hormone produced by the placenta, using
ingredients made by the fetal liver and adrenal gland. Estriol is
decreased in the Down syndrome pregnancy. This test may not
be included in all screens, depending on the laboratory.
Human chorionic gonadotropin hormone is produced by the
placenta, and is used to test for the presence of pregnancy. A
specific smaller part of the hormone, called the beta subunit, is
increased in Down syndrome pregnancies.
A very important consideration in the screening test is the age of the
fetus (gestational age). The correct analysis of the different
components depends on knowing the gestational age precisely. The
best way to determine that is by ultrasound.
Once the blood test results are determined, a risk factor is calculated
based on the "normal" blood tests for the testing laboratory. The
average of normals is called the "population median." Test results are
sometimes reported to doctors as "Multiples of the Median (MoM)."
The "average" value is therefore called 1.0 MoM. Down syndrome
pregnancies have lower levels of AFP and estriol, so their levels would
be below the average, and therefore less than 1.0 MOM. Likewise, hCG
in a Down syndrome pregnancy would be greater than 1.0 MoM. In the
serum screening, the lab reports all results in either this way or as a
total risk factor calculated by a software program.
http://www.ds-health.com/prenatal.htm