Article: Down syndrome

Down syndrome (also Down's syndrome) or trisomy 21 is a genetic condition resulting from the presence of all or part of an extra 21st chromosome. Down syndrome is characterized by a combination of major and minor abnormalities of body structure and function. Among features present in nearly all cases are impairment of learning and physical growth, and a recognizable facial appearance usually identified at birth. It is named after John Langdon Down, the British doctor who first described it in 1866.

Children with Down syndrome have lower than average cognitive ability, normally ranging from mild to moderate retardation. The common physical features of Down syndrome also appear in people with a standard set of chromosomes. They include simian crease (a single crease across one or both palms), almond shaped eyes, shorter limbs, speech impairment, and enlarged tongue. In addition, health concerns for children with Down syndrome include a higher risk for congenital heart defects, gastroesophageal reflux disease, recurrent ear infections, obstructive sleep apnea, and thyroid disfunctions.

Early childhood intervention, screening for common problems, such as thyroid functioning, medical treatment where indicated, a conducive family environment, vocational training, etc., can improve the overall development of children with Down syndrome. Experience with children with Down syndrome shows that while some genetic limitations cannot be overcome, education and proper care can produce progress whatever the starting point.

Characteristics

Individuals with Down syndrome may have some or all of the following physical characteristics:^[1] oblique eye fissures with small skin folds on the inner corner of the eyes, muscle hypotonia, flat nasal bridge, simian crease, large and protruding tongue, short neck, white spots on the iris, excessive flexibility in joints, congenital heart defect, excessive space between large and second toe, and fifth finger with one flexion furrow instead of two. In additional to observable physical characteristics, individuals with Down syndrome may have some medical concerns, discussed later.

Most children with Down syndrome have mental retardation in the mild (IQ 50–70) to moderate range (IQ 35–50),^[2] with scores for children with Mosaic Down syndrome some 10–30 points higher.^[3] Emotional and social abilities follow a more normal path, moderated by whatever cognitive disability the child may have.

History

English physician John Langdon Down first characterized Down syndrome as a distinct form of mental retardation in 1862, and in a more widely published report in 1866 entitled "Observations on an ethnic classification of idiots".^[4] 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 terms mongolism and mongolian idiocy.^[5] Idiocy was a medical term used at that time to refer to a severe degree of intellectual impairment.

By the 20^th century, "mongolian idiocy" had become the most recognizable form of mental retardation. Most people with it 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, a number of states (33 of the 48 United States) and countries began programs of involuntary sterilization of individuals with Down syndrome and comparable degrees of disability. The ultimate expression of this type of public policy was the German euthanasia program "Aktion T-4" begun in 1940. Court challenges and public revulsion at the nature of these programs led to discontinuation or repeal of such programs during the decades after World War II. Even voluntary institutionalization of children with Down syndrome has become rare in Western countries.

Until the middle of the 20th century, the cause of Down syndrome remained unknown, although 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 due to a combination of inheritable factors which had not been identified. There was some expert opinion that it might result from trauma occurring during pregnancy.^[6]

With the discovery of karyotype techniques in the 1950s it became possible to identify the obvious abnormalities of chromosomal number or shape. In 1959, Professor Jérôme Lejeune discovered that Down's syndrome resulted from an extra chromosome.^[7] The extra chromosome was subsequently labeled as the 21st, and the condition as trisomy 21. The labeling of chromosome 21 represented an unintentional deviation from the genetic convention by which the 22 pairs of autosomes comprising the human karyotype were numbered from largest to smallest (excluding the sex chromosomes). Lejeune identified the extra chromosome in mongolism as the second smallest, hence 21. Although it was later determined that chromosome 22 is actually slightly larger than 21, it was deemed too confusing to change either the numbering of the two chromosomes or name of the trisomy.

In 1961, a group of nineteen geneticists wrote to the editor of The Lancet suggesting that mongolian idiocy had "misleading connotations," had become "an embarrassing term" and should be changed.^[8] 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.^[9]

In 1975, the United States National Institute 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."^[10] While both the possessive and non-possessive forms are used in the general population, Down syndrome is the accepted term among professionals in the USA, Canada and other countries, while Down's syndrome continues to be used in the United Kingdom and other areas.^[11]

Genetics

Main article: Genetic origins of Down syndrome

Karyotype for trisomy Down syndrome. Notice the three copies of chromosome 21.

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 varies greatly from individual to individual, depending on the extent of the extra copy, genetic background, environmental factors, and random chance. Down syndrome can occur in all human populations, and analogous effects have been found in other species, such as chimpanzees and mice. Recently, researchers have been able to create transgenic mice with most of human chromosome 21 (in addition to their normal chromosomes).^[12]

The extra chromosomal material can come about in several distinct ways.

Trisomy 21

Trisomy 21 (47,XX,+21) is caused by a meiotic nondisjunction event. With nondisjunction, a gamete is produced with an extra copy of chromosome 21 (the gamete has 24 chromosomes). When combined with a normal gamete from the other parent, the child 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.^[13] Mitotic nondisjunctions after conception would lead to mosaicism, and is discussed later.

Robertsonian translocation

The extra chromosome 21 material that causes Down syndrome may be due to a Robertsonian translocation. The long arm of chromosome 21 is attached to another chromosome, often chromosome 14 (45,XX,t(14;21q)) or itself (called an isochromosome, 45,XX,t(21q;21q)). Normal disjunction leading to gametes have a significant chance of creating a gamete with an extra chromosome 21. Translocation Down syndrome is often referred to as familial Down syndrome. It is the cause of 2-3% of the observed Down syndromes. It does not show the maternal age effect, and is just as likely to have come from fathers as mothers.

Mosaicism

When some of the cells in the body are normal and some cells have trisomy 21, it is called Mosaic Down Syndrome (46,XX/47,XX,+21).^[14] 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 back to the normal chromosomal arrangement. There is considerable variability in the fraction of trisomy 21, both as a whole and tissue-by-tissue. This is the cause of 1–2% of the observed Down syndromes.^[13] There is evidence that mosaic Down syndrome, may produce less developmental delay, on average, than full trisomy 21.^[15] It is likely that all people have an extremely small fraction of their cells that are trisomy 21, with no discernable effects.

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 possible.

Incidence

Graph showing increased chance of Down syndrome compared to maternal age.

The incidence of Down syndrome is estimated at 1 per 800 to 1 per 1000 births.^[16] A recent study from the Center for Disease Control gives the rate as 1 per 733 live births.^[17] Approximately 95% of these are trisomy 21, making it the most common human aneuploidy. Down syndrome occurs in all ethnic groups and among all economic classes.

Maternal age influences the risk of conceiving a baby with Down syndrome. At maternal age 20 to 24, the risk is 1/1490, while at age 40 the risk is 1/106, and at age 49 the risk is 1/11.^[18] Although the risk increases with maternal age, most children with Down syndrome (80%) are born to women under the age of 35,^[19] reflecting the overall fertility of that age group. Other than maternal age, there are no other known risk factors. However, in up to 12% of trisomy 21 cases, the extra chromosome comes from the paternal gamete.^[20] There does not appear to be a paternal age effect.

Many standard prenatal screens can discover Down syndrome. Genetic counseling along with genetic testing, such as amniocentesis, chorionic villus sampling (CVS), or percutaneous umbilical blood sampling (PUBS) are usually offered to families who may have an increased chance of having a child with Down syndrome, or where normal prenatal exams indicate possible problems. Genetic screens are often performed on pregnant women older than 30 or 35.

Prenatal screening

Pregnant women can be screened for various complications in their pregnancy, or due to risk factors such as maternal age. There are several common non-invasive screens that can indicate a Down syndrome fetus, and are normally performed in the late first trimester or early second trimester. Due to the nature of screens, each has a significant chance to indicate a Down syndrome fetus when, in fact, the fetus is normal. Such results are called false positives. Screen positives must be verified before a Down syndrome diagnosis. Common screening procedures for Down syndrome are given in Table 1.

Ultrasound of embryo with Down syndrome and megacystis.

Even with the best non-invasive screens, the detection rate is 90%–95% and the rate of false positive of 2%–5%. False positives can be caused by undetected multiple fetuses (very rare with the ultrasound tests), incorrect date of pregnancy, or normal variation in the proteins.

Confirmation of screen positive is normally accomplished with amniocentesis. This is an invasive procedure and involves taking amniotic fluid from the mother and identifying fetal cells. The lab work can take a couple of weeks and will detect over 99.8% of all numerical chromosomal problems with a very low false positive rate. The vast majority of early screen positives are false. Since the risk of spontaneous abortion is approximately 1/200 to 1/300, amniocentesis confirmation presents a risk of spontaneously aborting a healthy fetus (from a false positive).

A 2002 review of elective abortion rates found that 91–93% of pregnancies with a diagnosis of Down syndrome were terminated.^[24] Physicians and ethicists are concerned about the ethical ramifications,^[25] with some commentators calling it "eugenics by abortion".^[26] Many members of the disability rights movement "believe that public support for prenatal diagnosis and abortion based on disability contravenes the movement's basic philosophy and goals."^[27]

Cognitive development

Cognitive development in children with Down syndrome is quite variable. Many can be successful in school, while others struggle. Because of this variability in expression of Down syndrome, it is important to evaluate children individually. The cognitive problems that are found among children with Down syndrome are also found among children without Down syndrome. This means that parents can take advantage of general programs that are offered through the schools or other means. Children with Down syndrome have a wide range of abilities. It is not possible at birth to predict their capabilities. The identification of the best methods of teaching each particular child ideally begins soon after birth, through early intervention programs.^[28]

Language skills show a difference between understanding speech and expressing speech. It is common for children with Down syndrome to need speech therapy to help with expressive language.^[29] Fine motor skills are delayed^[30] and often lag behind gross motor skills and can interfere with cognitive development. Occupational therapy can address these issues.^[31]

Mainstreaming of children with Down syndrome is controversial. Mainstreaming is when students of differing abilities are placed in classes with their chronological peers. Children with Down syndrome do not age emotionally/socially and intellectually at the same rates as children without Down syndrome, so eventually the intellectual and emotional gap between children with and without Down syndrome widens. Complex thinking as required in sciences but also in history, the arts, and other subjects is often beyond their abilities, or achieved much later than in most children. Therefore, if they are to benefit from mainstreaming without feeling inferior most of the time, special adjustments must be made to the curriculum.^[32]

A danger in not mainstreaming is underestimating their abilities. This was more common in institutions, where children with Down syndrome often failed to reach their potential despite being capable of much more, but this issue is very real and present in the modern school system as well. Some European countries such as Germany and Denmark advise a two-teacher system, whereby the second teacher takes over a group of disabled children within the class. A popular alternative is cooperation between special education schools and mainstream schools. In cooperation, the core subjects are taught in separate classes, which neither slows down the non-disabled students nor neglects the disabled ones. Social activities, outings, and many sports and arts activities are performed together, as are all breaks and meals.^[33]

Alternative treatment

The Institutes for The Achievement of Human Potential is a non-profit organization which treats children who have, as the IAHP terms it, "some form of brain injury," including children with Down syndrome. The approach of "Psychomotor Patterning" is not proven,^[34] and is considered alternative medicine.

Health

Individuals with Down syndrome are at risk for various medical conditions. There is no way to predict what conditions they will have, if any. In addition, all these medical conditions can be exhibited by individuals without Down syndrome. It is important to keep these medical risks in mind while undergoing wellness checkups.^[35] The American Academy of Pediatrics has issued a policy statement on the health supervision for children with Down syndrome.^[36]

A partial list of risks is given below. Risks run from 80% for hearing deficits to 44% for congenital heart defects^[37] to 20% for hypothyroidism to rare but significantly increased risks for Leukemia.^[16][38]

• Congenital heart defects
• Increased susceptibility to infection
• Muscular/Skeletal abnormalities, including generally poor muscle tone (muscle hypotonia).
• Respiratory problems
• Obstructive sleep apnea
• Gastroesophageal reflux disease
• Obstructed digestive tracts
• Thyroid dysfunctions (hypothyroidism)
• Acute myeloid leukemia, although their survival and relapse rate is much better than average
• Infertility (nearly absolute in males, fertility in females is possible)
• Hearing deficits
• Enlargement of tongue in relationship to size of mouth
• Eye problems (cataracts, strabismus, near and far sightedness)
• Alzheimer's disease

There is some evidence that individuals with Down syndrome have a much lower rate of lung cancer than others, as is expected for cancers caused by tumor suppressor genes (two-hit model).

As with all risks, this does not mean that everyone with Down syndrome will get these diseases, nor that an individual will get any of them. The concentration on wellness in individuals with Down syndrome and increased medical technology has vastly improved the length and quality of life. Current estimates give life expectancy in the United States as 55 years, compared to 77 years for the population in general.^[39] This life expectancy is a tremendous increase in recent years.

Plastic surgery

Plastic surgery has sometimes been advocated and performed on children with Down Syndrome, based on the idea that surgery can create a more normal facial appearance, which will decrease social stigma, and thus lead to a better quality of life. The National Down Syndrome Society has issued a "Position Statement on Cosmetic Surgery for Children with Down Syndrome" ^[40] which states that "The goal of inclusion and acceptance is mutual respect based on who we are as individuals, not how we look." Plastic surgery on children with Down Syndrome is uncommon.^[41]

Genetic research

Down syndrome disorders are based on having too many copies of the genes located on chromosome 21. In general, this leads to an overexpression of the genes.^{[42] [43]} Understanding the genes involved may help to target medical treatment to individuals with Down syndrome. It is estimated that chromosome 21 contains 200 to 250 genes.^[44] Recent research has identified a region of the chromosome that contains the main genes responsible for the pathogenesis of Down syndrome,^[45] located proximal to 21q22.3. The search for major genes involved in Down syndrome characteristics is normally in the region 21q21–21q22.3.

Some suspected genes involved in features of Down syndrome are given in the Table 2:

To date, "no gene has yet been fully linked to any feature associated with Down syndrome."^[44]

Sociological and cultural aspects

Advocates for people with Down syndrome point to various factors, such as special education and parental support groups, that make life easier for parents. There are also great strides being made in education, housing, and social settings to create "Down-friendly" environments. In most developed countries, since the early 20th century many people with Down syndrome were housed in institutions or colonies and excluded from society. However, in the 21st century there is a change among parents, educators and other professionals generally advocating a policy of "inclusion"^[50], bringing people with any form of mental or physical disability into general society as much as possible. In many countries, people with Down syndrome are educated in the normal school system and there are increasingly higher quality opportunities to mix "special" education with regular education settings.

Despite this change, the reduced abilities of people with Down syndrome pose a challenge to their parents and families. While living with their parents is preferable to institutionalization for most adults with Down syndrome, they often encounter patronising attitudes and discrimination in the wider community.

World Down Syndrome Day

The first World Down Syndrome Day was held on 21 March 2006. The day and month were chosen to correspond with 21 and trisomy respectively. It was proclaimed by Down Syndrome International.^[51]

Notable individuals

Chris Burke (far right) was an actor on Life Goes On

Notable people with Down syndrome include:

• Chris Burke, actor (Life Goes On) and autobiographer
• Anne de Gaulle (1928-1948), daughter of Charles de Gaulle
• Pascal Duquenne, actor (Le Huitième Jour aka The Eighth Day, Toto le héros aka Toto the Hero)
• Stephane Ginnsz, actor (Duo (film)) First actor with Down syndrome in the lead part of a motion picture.
• Joey Moss, Edmonton Oilers Locker room attendant
• Judith Scott, artist
• Miguel Tomasin, singer with Argentinian avant-rock band Reynols

The Down Syndrome Association of Los Angeles has a more complete list of individuals with Down syndrome in roles in TV and movies.

Portrayal in fiction

• Bret Lott: Jewel
• Morris West: The Clowns of God
• Bernice Rubens: A Solitary Grief
• Emily Perl Kingsley: Welcome to Holland
• The Kingdom and its American counterpart, Kingdom Hospital
• Elizabeth Laird: Red Sky in the Morning
• Stephen King: Dreamcatcher
• Dean Koontz: The Bad Place
• Flannery O'Connor: The Violent Bear It Away
• William Faulkner: Benjamin Compson in The Sound and the Fury