DOWN SYNDROME

INTRODUCTION
Down syndrome (also called Trisomy 21) is a genetic disorder that occurs in
approximately 1 of 800 live births. It is the leading cause of cognitive impairment. Down
syndrome is associated with mild to moderate learning disabilities, developmental delays,
characteristic facial features, and low muscle tone in early infancy. Many individuals with
Down syndrome also have heart defects, leukemia, early-onset Alzheimer's disease,
gastro-intestinal problems, and other health issues. The symptoms of Down syndrome
range from mild to severe.
Life expectancy for individuals with Down syndrome has dramatically increased
over the past few decades as medical care and social inclusion have improved. A person
with Down syndrome in good health will on average live to age 55 or beyond.
Down syndrome is named after Doctor Langdon Down, who in 1866 first
described the syndrome as a disorder. Although Doctor Down made some important
observations about Down syndrome, he did not correctly identify what causes the
disorder. It wasn't until 1959 that scientists discovered the genetic origin of Down
syndrome.

HISTORY
English physician John Langdon Down first characterized Down syndrome as a
distinct form of mental disability in 1862, and in a more widely published report in 1866.
Due to his perception that children with Down syndrome shared physical facial
similarities (epicanthal folds) with those of Blumenbach's Mongolian race, Down used
the term mongoloid, derived from prevailing ethnic theory. Attitudes about Down
syndrome were very much tied to racism and colonialism until as recently as the 1970s.

By the 20th century, Down syndrome had become the most recognizable form of
mental disability. Most individuals with Down syndrome were institutionalized, few of
the associated medical problems were treated, and most died in infancy or early adult life.
With the rise of the eugenics movement, 33 of the (then) 48 U.S. states and several
countries began programs of forced sterilization of individuals with Down syndrome and
comparable degrees of disability. The ultimate expression of this type of public policy
was "Action T4" in Nazi Germany, a program of systematic murder. Court challenges,
scientific advances and public revulsion led to discontinuation or repeal of such
sterilization programs during the decades after World War II.
Until the middle of the 20th century, the cause of Down syndrome remained
unknown. However, the presence in all races, the association with older maternal age, and
the rarity of recurrence had been noticed. Standard medical texts assumed it was caused
by a combination of inheritable factors which had not been identified. Other theories
focused on injuries sustained during birth.
With the discovery of karyotype techniques in the 1950s, it became possible to
identify abnormalities of chromosomal number or shape. In 1959, Jrme Lejeune
discovered that Down syndrome resulted from an extra chromosome. The extra
chromosome was subsequently labeled as the 21st, and the condition as trisomy 21.
In 1961, eighteen geneticists wrote to the editor of The Lancet suggesting that
Mongolian idiocy had "misleading connotations," had become "an embarrassing term,"
and should be changed. The Lancet supported Down's Syndrome. The World Health
Organization (WHO) officially dropped references to mongolism in 1965 after a request
by the Mongolian delegate. However, almost 40 years later, the term mongolism still
appears in leading medical texts such as General and Systematic Pathology, 4th Edition,
2004, edited by Professor Sir James Underwood. Advocacy groups adapted and parents
groups welcomed the elimination of the Mongoloid label that had been a burden to their
children. The first parents group in the United States, the Mongoloid Development
Council, changed its name to the National Association for Down Syndrome in 1972

In 1975, the United States National Institutes of Health convened a conference to

standardize the nomenclature of malformations. They recommended eliminating the
possessive form: "The possessive use of an eponym should be discontinued, since the
author neither had nor owned the disorder." Although both the possessive and nonpossessive forms are used in the general population, Down syndrome is the accepted term
among professionals in the USA, Canada and other countries; Down's syndrome is still
used in the United Kingdom and other areas.

The chromosome basics of Down syndrome

Genes on an extra copy of chromosome 21 are responsible for all characteristics
associated with Down syndrome. Normally, each human cell contains 23 pairs of
different chromosomes. Each chromosome carries genes, which are needed for proper
development and maintenance of our bodies. At conception, an individual inherits 23
chromosomes from the mother (through the egg cell) and 23 chromosomes from the
father (through the sperm cell).
However, sometimes a person inherits an extra chromosome from one of the
parents. In Down syndrome, an individual most often inherits two copies of chromosome
21 from the mother and one chromosome 21 from the father for a total of three
chromosomes 21. Because Down syndrome is caused by the inheritance of three
chromosomes 21, the disorder is also called trisomy 21. About 95% of individuals with
Down syndrome inherit an entire extra chromosome 21.
Approximately 3% to 4% of individuals with Down syndrome do not inherit an
entire extra chromosome 21, but just some extra chromosome 21 genes, which are
attached to another chromosome (usually chromosome 14). This is called a translocation.
Most of the time, translocations are random events during conception. In some instances
however, a parent is a balanced carrier of a translocation: The parent has exactly two
copies of chromosome 21, but some of the genes are distributed to another chromosome.
If a baby inherits the chromosome with the extra genes from chromosome 21, then the

child will have Down syndrome (two chromosomes 21 plus extra chromosome 21 genes
attached to another chromosome).
About 2% to 4% of people with Down syndrome inherit additional genes from
chromosome 21, but not in every cell of the body. This is known as mosaic Down
syndrome. These individuals may, for example, have inherited extra genes from
chromosome 21 in their muscle cells, but not in any other type of cell. Because the
percentage of cells with extra genes from chromosome 21 varies in people with mosaic
Down syndrome, they often don't have all the typical physical characteristics and may not
be as severely intellectually impaired as people with full trisomy 21. Sometimes, mosaic
Down syndrome is so mild that it will go undetected. On the other hand, mosaic Down
syndrome can also be misdiagnosed as trisomy 21, if no genetic testing has been done.

PATOFISIOLOGY
Down syndrome is a chromosomal abnormality characterized by the presence of
an extra copy of genetic material on the 21st chromosome, either in whole (trisomy 21) or
part (such as due to translocations). The effects of the extra copy vary greatly among
people, depending on the extent of the extra copy, genetic history, and pure chance. Down
syndrome occurs in all human populations, and analogous effects have been found in
other species such as chimpanzees and mice. Recently, researchers have created
transgenic mice with most of human chromosome 21 (in addition to the normal mouse
chromosomes). The extra chromosomal material can come about in several distinct ways.
A typical human karyotype is designated as 46,XX or 46,XY, indicating 46 chromosomes
with an XX arrangement typical of females and 46 chromosomes with an XY
arrangement typical of males.

Trisomy 21
Trisomy 21 (47,XX,+21) is caused by a meiotic nondisjunction event. With
nondisjunction, a gamete (i.e., a sperm or egg cell) is produced with an extra copy of
chromosome 21; the gamete thus has 24 chromosomes. When combined with a normal

gamete from the other parent, the embryo now has 47 chromosomes, with three copies of
chromosome 21. Trisomy 21 is the cause of approximately 95% of observed Down
syndromes, with 88% coming from nondisjunction in the maternal gamete and 8%
coming from nondisjunction in the paternal gamete.

Mosaicism
Trisomy 21 is usually caused by nondisjunction in the gametes prior to
conception, and all cells in the body are affected. However, when some of the cells in the
body are normal and other cells have trisomy 21, it is called mosaic Down syndrome
(46,XX/47,XX,+21). This can occur in one of two ways: a nondisjunction event during
an early cell division in a normal embryo leads to a fraction of the cells with trisomy 21;
or a Down syndrome embryo undergoes nondisjunction and some of the cells in the
embryo revert to the normal chromosomal arrangement. There is considerable variability
in the fraction of trisomy 21, both as a whole and among tissues. This is the cause of 1
2% of the observed Down syndromes.

Robertsonian translocation
The extra chromosome 21 material that causes Down syndrome may be due to a
Robertsonian translocation in the karyotype of one of the parents. In this case, the long
arm of chromosome 21 is attached to another chromosome, often chromosome 14
[45,XX,der(14;21)(q10;q10)]. A person with such a translocation is phenotypically
normal. During reproduction, normal disjunctions leading to gametes have a significant
chance of creating a gamete with an extra chromosome 21, producing a child with Down
syndrome. Translocation Down syndrome is often referred to as familial Down syndrome.
It is the cause of 23% of observed cases of Down syndrome. It does not show the
maternal age effect, and is just as likely to have come from fathers as mothers.

Duplication of a portion of chromosome 21

Rarely, a region of chromosome 21 will undergo a duplication event. This will lead to
extra copies of some, but not all, of the genes on chromosome 21 (46,XX, dup(21q)). If
the duplicated region has genes that are responsible for Down syndrome physical and
mental characteristics, such individuals will show those characteristics. This cause is very
rare and no rate estimates are available.

Characteristic Features and Symptoms of Down Syndrome

Although the severity of Down syndrome ranges from mild to severe, most individuals
with Down syndrome have widely recognizable physical characteristics. These include:

a flattened face and nose, a short neck, a small mouth sometimes with a large,
protruding tongue, small ears, upward slanting eyes that may have small skin
folds at the inner corner (epicanthal fold);

white spots (also known as Brushfield spots) may be present on the colored part
of the eye (iris);

the hands are short and broad with short fingers, and with a single crease in the
palm;

poor muscle tone and loose ligaments are also common; and

development and growth is usually delayed and often average height and
developmental milestones are not reached.

Risk factors for conceiving a child with Down syndrome

The only well known risk factor for conceiving a child with Down syndrome is advanced
maternal age. The older the woman is at conception, the greater the risk of having a child
with Down syndrome.
Mother's age at conception Risk of Down syndrome

25 years 1 in 1,250

30 years 1 in 1,000

35 years 1 in 400

40 years 1 in 100

45 years 1 in 30

Parents who have conceived a child with Down syndrome have a 1% increased risk of
conceiving another child with Down syndrome. If a parent is a carrier of a chromosome
21 translocation, the risk can be as high as 100%. Women with Down syndrome have a
50% risk of conceiving a child with Down syndrome. If the father has Down syndrome,
the risk of conceiving a child with Down syndrome is also increased.

Cognitive impairment in Down syndrome

The most common condition associated with Down syndrome is cognitive
impairment. Cognitive development is often delayed, and all individuals with Down

syndrome have mild to severe learning difficulties that last throughout their lives. How
the extra chromosome 21 leads to cognitive impairment is not entirely clear. The average
brain size of a person with Down syndrome is small and scientists have found alterations
in the structure and function of certain brain areas such as the hippocampus and
cerebellum. Particularly affected is the hippocampus, which is responsible for learning
and memory. Scientists are using human studies and animal models of Down syndrome to
find out which specific genes on the extra chromosome 21 lead to different aspects of
cognitive impairment.

ASSESSMENT
Although the genetic cause of Down syndrome is known, there is currently no
cure. Due to advances in technology, scientists are slowly beginning to understand which
genes when present in three copies are responsible for which Down syndrome
characteristics, but it will take many years to fully grasp the complex interplay between
the different genes. Much research to date is focused on understanding the causes of
impaired cognition in Down syndrome and on finding potential therapies that might
improve learning. Most of these studies are carried out using animal models of Down
syndrome, but some human clinical trials involving potential therapies are also being
conducted.
Corrective surgery for heart defects, gastrointestinal irregularities, and other
health issues is necessary for some individuals. Regular health checkups should be
scheduled to screen for other conditions such as visual impairments, ear infections,
hearing loss, hypothyroidism, obesity, and other medical conditions. Individuals with
Down syndrome should be fully included in family and community life.
It is very important to stimulate, encourage, and educate children with Down
syndrome from infancy. Programs for young children with special needs are offered in
many

communities.

Early intervention

programs,

including

occupational therapy, and speech therapy can be very helpful.

physical

therapy,

Adolescents with Down syndrome undergo the same hormonal changes during
puberty as typically developing children. Girls with Down syndrome have regular
menstrual periods and should receive instructions on hygiene. Although women with
Down syndrome are not very fertile, they can become pregnant. Men with Down
syndrome have low sperm count, but in some cases have fathered children. Proper
education regarding sexual development and contraception is very important.
Individuals with Down syndrome live longer than ever before. Due to full
inclusion in society, many adults with Down syndrome now live semi-independently,
enjoy relationships, work, and contribute to their community.
Adults with Down syndrome also age faster than average. The older they become,
the higher the risk of developing hypothyroidism, late-onset seizures (tonic-clonic
seizures in particular), memory loss, and dementia. By age 40, many individuals with
Down syndrome will show signs of dementia and early-onset Alzheimer's disease. By age
60, 50% to 70% of adults will develop Alzheimer's disease. Why individuals with Down
syndrome age prematurely and why they develop Alzheimer's disease is not entirely clear.
At least one gene (the amyloid precursor protein) on chromosome 21 is thought to be
involved in Alzheimer's disease. Since individuals with Down syndrome have three
copies of this gene, it is likely that this gene contributes to the increased occurrence of
Alzheimer's disease in this population.
Detecting dementia and early signs of Alzheimer's disease is a challenge in individuals
with Down syndrome who are often already cognitively impaired. It is important for
caregivers and doctors to be aware of changes in skills necessary for independence.

PROGNOSIS
These factors can contribute to a shorter life expectancy for people with Down syndrome.
One study, carried out in the United States in 2002, showed an average lifespan of 49
years, with considerable variations between different ethnic and socio-economic groups.
However, in recent decades, the life expectancy among persons with Down syndrome has
increased significantly up from 25 years in 1980. The causes of death have also changed,

with chronic neurodegenerative diseases becoming more common as the population ages.
Most people with Down Syndrome who survive into their 40s and 50s begin to suffer
from an Alzheimer's disease-like dementia.

CONCLUSION

Down syndrome is a genetic disorder and the most common cause of cognitive
impairment.

Individuals with Down syndrome have characteristic physical features that are
widely recognized.

Down syndrome is associated with heart defects, gastrointestinal conditions, and

other health issues.

Individuals with Down syndrome are at a high risk for developing dementia and
early-onset Alzheimer's disease.

The only well known risk factor for conceiving a child with Down syndrome is
advanced maternal age.

Screening for and diagnosis of Down syndrome is possible before birth.

Due to improved medical treatment and social inclusion, the average life span of
an individual with Down syndrome is now more than 55 years.

Individuals with Down syndrome often live very healthy and productive lives.

REFERENCES
Sindrom Down Online http://www.down-syndrome.org
National Institute of Child Health and Human Development. Facts About Down
Syndrome. http://www.nichd.nih.gov/publications/pubs/downsyndrome.cfm
Reddy, U.M., et al. Prenatal Imaging: Ultrasonography and Magnetic Resonance
Imaging. Obstet Gynecol July 2008; vol 112(1): pp 145-157
Wiseman, F., et al. Human Molecular Genetics. Human Molecular Genetics. April 2009;
vol 18: pp R75-R83.