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Down syndrome / Syndrome de Down

Down syndrome

Down syndrome
Classification and external resources

Boy with Down syndrome assembling a bookcase

Down syndrome, or Down's syndrome (primarily in the United Kingdom),[1][2] trisomy 21, or trisomy G, is a chromosomal disorder caused by the presence of all or part of an extra 21st chromosome. It is named after John Langdon Down, the British physician who described the syndrome in 1866. The disorder was identified as a chromosome 21 trisomy by Jérôme Lejeune in 1959. The condition is characterized by a combination of major and minor differences in structure. Often Down syndrome is associated with some impairment of cognitive ability and physical growth, and a particular set of facial characteristics. Down syndrome in a fetus can be identified with amniocentesis during pregnancy, or in a baby at birth.

Individuals with Down syndrome tend to have a lower than average cognitive ability, often ranging from mild to moderate developmental disabilities. A small number have severe to profound mental disability. The incidence of Down syndrome is estimated at 1 per 800 to 1,000 births, although it is statistically much more common with older mothers. Other factors may also play a role.

Many of the common physical features of Down syndrome may also appear in people with a standard set of chromosomes, including microgenia (an abnormally small chin)[3], an unusually round face, macroglossia[4] (protruding or oversized tongue), an almond shape to the eyes caused by an epicanthic fold of the eyelid, upslanting palpebral fissures (the separation between the upper and lower eyelids), shorter limbs, a single transverse palmar crease (a single instead of a double crease across one or both palms, also called the Simian crease), poor muscle tone, and a larger than normal space between the big and second toes. Health concerns for individuals with Down syndrome include a higher risk for congenital heart defectsgastroesophageal reflux disease, recurrent ear infectionsobstructive sleep apnea, and thyroid dysfunctions.

Early childhood intervention, screening for common problems, medical treatment where indicated, a conducive family environment, and vocational training can improve the overall development of children with Down syndrome. Although some of the physical genetic limitations of Down syndrome cannot be overcome, education and proper care will improve quality of life.[5]



Individuals with Down syndrome may have some or all of the following physical characteristics: microgenia (abnormally small chin)[3], oblique eye fissures with epicanthic skin folds on the inner corner of the eyes (formerly known as a mongoloid fold[4]), muscle hypotonia (poor muscle tone), a flat nasal bridge, a single palmar fold, a protruding tongue (due to small oral cavity, and an enlarged tongue near the tonsils) or macroglossia[4], a short neck, white spots on the iris known as Brushfield spots,[6] excessive joint laxity including atlanto-axial instability, congenital heart defects, excessive space between large toe and second toe, a single flexion furrow of the fifth finger, and a higher number of ulnar loop dermatoglyphs. Most individuals with Down syndrome have mental retardation in the mild (IQ 50–70) to moderate (IQ 35–50) range,[7] with individuals having Mosaic Down syndrome typically 10–30 points higher.[8] In addition, individuals with Down syndrome can have serious abnormalities affecting any body system. They also may have a broad head and a very round face.

The medical consequences of the extra genetic material in Down syndrome are highly variable and may affect the function of any organ system or bodily process. The health aspects of Down syndrome encompass anticipating and preventing effects of the condition, recognizing complications of the disorder, managing individual symptoms, and assisting the individual and his/her family in coping and thriving with any related disability or illnesses.[7]

Down syndrome can result from several different genetic mechanisms. This results in a wide variability in individual symptoms due to complex gene and environment interactions. Prior to birth, it is not possible to predict the symptoms that an individual with Down syndrome will develop. Some problems are present at birth, such as certain heart malformations. Others become apparent over time, such as epilepsy.

The most common manifestations of Down syndrome are the characteristic facial features, cognitive impairment, congenital heart disease (typically a ventricular septal defect), hearing deficits (maybe due to sensory-neural factors, or chronic serous otitis media, also known as Glue-ear), short stature, thyroid disorders, and Alzheimer's disease. Other less common serious illnesses include leukemiaimmune deficiencies, and epilepsy.

However, health benefits of Down syndrome include greatly reduced incidence of many common malignancies except leukemia and testicular cancer[9] — although it is, as yet, unclear whether the reduced incidence of various fatal cancers among people with Down syndrome is as a direct result of tumor-suppressor genes on chromosome 21,[10] because of reduced exposure to environmental factors that contribute to cancer risk, or some other as-yet unspecified factor. In addition to a reduced risk of most kinds of cancer, people with Down syndrome also have a much lower risk of hardening of the arteries and diabetic retinopathy.[11]

Cognitive development

Cognitive development in children with Down syndrome is quite variable. It is not currently possible at birth to predict the capabilities of any individual reliably, nor are the number or appearance of physical features predictive of future ability. The identification of the best methods of teaching each particular child ideally begins soon after birth through early intervention programs.[12] Since children with Down syndrome have a wide range of abilities, success at school can vary greatly, which underlines the importance of evaluating children individually. The cognitive problems that are found among children with Down syndrome can also be found among typical children. Therefore, parents can use general programs that are offered through the schools or other means.

Language skills show a difference between understanding speech and expressing speech, and commonly individuals with Down syndrome have a speech delay, requiring speech therapy to improve expressive language.[13] Fine motor skills are delayed[14] and often lag behind gross motor skills and can interfere with cognitive development. Effects of the disorder on the development of gross motor skills are quite variable. Some children will begin walking at around 2 years of age, while others will not walk until age 4. Physical therapy, and/or participation in a program of adapted physical education (APE), may promote enhanced development of gross motor skills in Down syndrome children.[15]

Individuals with Down syndrome differ considerably in their language and communication skills. It is routine to screen for middle ear problems and hearing loss; low gain hearing aids or other amplification devices can be useful for language learning. Early communication intervention fosters linguistic skills. Language assessments can help profile strengths and weaknesses; for example, it is common for receptive language skills to exceed expressive skills. Individualized speech therapy can target specific speech errors, increase speech intelligibility, and in some cases encourage advanced language and literacy. Augmentative and alternative communication (AAC) methods, such as pointing, body language, objects, or graphics are often used to aid communication. Relatively little research has focused on the effectiveness of communications intervention strategies.[16]

In education, mainstreaming of children with Down syndrome is becoming less controversial in many countries. For example, there is a presumption of mainstream in many parts of the UK. Mainstreaming is the process whereby students of differing abilities are placed in classes with their chronological peers. Children with Down syndrome may not age emotionally/socially and intellectually at the same rates as children without Down syndrome, so over time the intellectual and emotional gap between children with and without Down syndrome may widen. Complex thinking as required in sciences but also in history, the arts, and other subjects can often be beyond the abilities of some, or achieved much later than in other children. Therefore, children with Down syndrome may benefit from mainstreaming provided that some adjustments are made to the curriculum.[17]

Some European countries such as Germany and Denmark advise a two-teacher system, whereby the second teacher takes over a group of children with disabilities within the class. A popular alternative is cooperation between special schools and mainstream schools. In cooperation, the core subjects are taught in separate classes, which neither slows down the typical students nor neglects the students with disabilities. Social activities, outings, and many sports and arts activities are performed together, as are all breaks and meals.[18]


Fertility amongst both males and females is reduced; males are usually unable to father children, while females demonstrate significantly lower rates of conception relative to unaffected individuals.[citation needed] Approximately half of the offspring of someone with Down syndrome also have the syndrome themselves.[19] There have been only three recorded instances of males with Down syndrome fathering children.[20][21]


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 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[22] and mice. Recently, researchers have created transgenic mice with most of human chromosome 21 (in addition to the normal mouse chromosomes).[23] 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.[24]

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.[25]


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 mosaicDown syndrome (46,XX/47,XX,+21).[26][27] 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.[25]

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 2–3% of observed cases of Down syndrome.[25] 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)).[28] 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.


Ultrasound of fetus with Down syndrome and megacystis

Pregnant women can be screened for various complications during pregnancy. Many standard prenatal screens can discover Down syndrome. Genetic counseling along with genetic testing, such as amniocentesischorionic villus sampling (CVS), or percutaneous umbilical cord 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. In the United States, ACOG guidelines recommend that non-invasive screening and invasive testing be offered to all women, regardless of their age, and most likely all physicians currently follow these guidelines. However, some insurance plans will only reimburse invasive testing if a woman is >34 years old or if she has received a high-risk score from a non-invasive screening test.

Amniocentesis and CVS are considered invasive procedures, in that they involve inserting instruments into the uterus, and therefore carry a small risk of causing fetal injury or miscarriage. The risks of miscarriage for CVS and amniocentesis are often quoted as 1% and 0.5% respectively. There are several common non-invasive screens that can indicate a fetus with Down syndrome. These are normally performed in the late first trimester or early second trimester. Due to the nature of screens, each has a significant chance of a false positive, suggesting a fetus with Down syndrome when, in fact, the fetus does not have this genetic abnormality. Screen positives must be verified before a Down syndrome diagnosis is made. Common screening procedures for Down syndrome are given in Table 1.

Table 1: First and second trimester Down syndrome screens
ScreenWhen performed (weeksgestation)Detection rateFalse positive rateDescription
Quad screen15–2081%[11]5%This test measures the maternal serum alpha feto protein (a fetal liver protein), estriol (a pregnancy hormone), human chorionic gonadotropin (hCG, a pregnancy hormone), and inhibin-Alpha (INHA).[29]
Nuchal translucency/free beta/PAPPA screen (aka "1st Trimester Combined Test")10–13.585%[30]5%Uses ultrasound to measure Nuchal Translucency in addition to the freeBeta hCG and PAPPA (pregnancy-associated plasma protein A). NIH has confirmed that this first trimester test is more accurate than second trimester screening methods.[31] Performing an NT ultrasound requires considerable skill; a Combined test may be less accurate if there is operator error, resulting in a lower-than-advertised sensitivity and higher false-positive rate, possibly in the 5-10% range.
Integrated Test10-13.5 and 15–2095%[32]5%The Integrated test uses measurements from both the 1st Trimester Combined test and the 2nd trimester Quad test to yield a more accurate screening result. Because all of these tests are dependent on accurate calculation of the gestational age of the fetus, the real-world false-positive rate is >5% and maybe be closer to 7.5%.

Even with the best non-invasive screens, the detection rate is 90%–95% and the rate of false positive is 2%–5%. Inaccuracies 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 or chorionic villus sampling (CVS). Amniocentesis is an invasive procedure and involves taking amniotic fluid from the amniotic sac and identifying fetal cells. The lab work can take several weeks but will detect over 99.8% of all numerical chromosomal problems with a very low false positive rate.[33]

Ethical issues

A 2002 literature review of elective abortion rates found that 91–93% of pregnancies in the United Kingdom and Europe with a diagnosis of Down syndrome were terminated.[34] Data from the National Down Syndrome Cytogenetic Register in the United Kingdom indicates that from 1989 to 2006 the proportion of women choosing to terminate a pregnancy following prenatal diagnosis of Down Syndrome has remained constant at around 92%.[35][36] Some physicians and ethicists are concerned about the ethical ramifications of this.[37] Conservative commentator George Will called it "eugenics by abortion".[38] British peer Lord Rix stated that "alas, the birth of a child with Down's syndrome is still considered by many to be an utter tragedy" and that the "ghost of the biologist Sir Francis Galton, who founded the eugenics movement in 1885, still stalks the corridors of many a teaching hospital".[39] Doctor David Mortimer has argued in Ethics & Medicine that "Down's syndrome infants have long been disparaged by some doctors and government bean counters."[40] Some 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."[41]

Medical ethicist Ronald Green argues that parents have an obligation to avoid 'genetic harm' to their offspring,[42] and Claire Rayner, then a patron of the Down's Syndrome Association, defended testing and abortion saying "The hard facts are that it is costly in terms of human effort, compassion, energy, and finite resources such as money, to care for individuals with handicaps... People who are not yet parents should ask themselves if they have the right to inflict such burdens on others, however willing they are themselves to take their share of the burden in the beginning."[43] Peter Singer argued that "neither haemophilia nor Down's syndrome is so crippling as to make life not worth living, from the inner perspective of the person with the condition. To abort a fetus with one of these disabilities, intending to have another child who will not be disabled, is to treat fetuses as interchangeable or replaceable. If the mother has previously decided to have a certain number of children, say two, then what she is doing, in effect, is rejecting one potential child in favour of another. She could, in defence of her actions, say: the loss of life of the aborted fetus is outweighed by the gain of a better life for the normal child who will be conceived only if the disabled one dies."[44]


Treatment of individuals with Down Syndrome depends on the particular manifestations of the disorder. For instance, individuals with congenital heart disease may need to undergo major corrective surgery soon after birth. Other individuals may have relatively minor health problems requiring no therapy.

Plastic surgery

Plastic surgery has sometimes been advocated and performed on children with Down syndrome, based on the assumption that surgery can reduce the facial features associated with Down syndrome, therefore decreasing social stigma, and leading to a better quality of life.[45] Plastic surgery on children with Down syndrome is uncommon,[46] and continues to be controversial. Researchers have found that for facial reconstruction, "...although most patients reported improvements in their child's speech and appearance, independent raters could not readily discern improvement...."[47] For partial glossectomy (tongue reduction), one researcher found that 1 out of 3 patients "achieved oral competence," with 2 out of 3 showing speech improvement.[48] Len Leshin, physician and author of the ds-health website, has stated, "Despite being in use for over twenty years, there is still not a lot of solid evidence in favor of the use of plastic surgery in children with Down syndrome."[49] The National Down Syndrome Societyhas issued a "Position Statement on Cosmetic Surgery for Children with Down Syndrome"[50] which states that "The goal of inclusion and acceptance is mutual respect based on who we are as individuals, not how we look."

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,[51] and is considered alternative medicine.


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.[52]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.[53]


Graph showing probability of Down syndrome as a function of maternal age.

The incidence of Down syndrome is estimated at one per 800 to one per 1000 births.[54] In 2006, the Centers for Disease Control and Prevention estimated the rate as one per 733 live births in the United States (5429 new cases per year).[55] Approximately 95% of these are trisomy 21. Down syndrome occurs in all ethnic groups and among all economic classes.

Maternal age influences the chances of conceiving a baby with Down syndrome. At maternal age 20 to 24, the probability is one in 1562; at age 35 to 39 the probability is one in 214, and above age 45 the probability is one in 19.[56] Although the probability increases with maternal age, 80% of children with Down syndrome are born to women under the age of 35,[57] reflecting the overall fertility of that age group. Recent data also suggest that paternal age, especially beyond 42,[58] also increases the risk of Down syndrome manifesting.[59]

Current research (as of 2008) has shown that Down syndrome is due to a random event during the formation of sex cells or pregnancy. There has been no evidence that it is due to parental behavior (other than age) or environmental factors.


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.[60] 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.[61] 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.[62]

With the discovery of karyotype techniques in the 1950s, it became possible to identify abnormalities of chromosomal number or shape. In 1959, Jérôme Lejeune discovered that Down syndrome resulted from an extra chromosome.[63][64] 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.[65] 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.[66] 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 [1].

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."[67] Although 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; Down's syndrome is still used in the United Kingdom and other areas.[68]

Society and culture

Advocates for people with Down syndrome point to various factors, such as additional educational support and parental support groups to improve parenting knowledge and skills. There are also strides being made in education, housing, and social settings to create environments which are accessible and supportive to people with Down syndrome. In most developed countries, since the early twentieth century many people with Down syndrome were housed in institutions or colonies and excluded from society. However, since the early 1960s parents and their organizations, educators and other professionals have generally advocated a policy of inclusion,[69] bringing people with any form of mental or physical disability into general society as much as possible. Such organizations included the National Association for Down Syndrome, the first known organization advocating for Down Syndrome individuals in the United States founded by Kathryn McGee in 1960 [2]; MENCAP advocating for all with mental disabilities, which was founded in the U.K. in 1946 by Judy Fryd [3]; and the National Down Syndrome Congress, the first truly national organization in the U.S. advocating for Down Syndrome families, founded in 1973 by Kathryn McGee and others [4]Kathryn McGee. In many countries, people with Down syndrome are educated in the normal school system; there are increasingly higher-quality opportunities to move from special (segregated) education to regular education settings.

Despite these changes, the additional support needs of people with Down syndrome can still pose a challenge to parents and families. Although living with family is preferable to institutionalization, people with Down syndrome often encounter patronizing attitudes and discrimination in the wider community.

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 European Down Syndrome Association during their European congress in Palma de Mallorca (febr. 2005). In the United States, the National Down Syndrome Society observes Down Syndrome Month every October as "a forum for dispelling stereotypes, providing accurate information, and raising awareness of the potential of individuals with Down syndrome."[70]In South Africa, Down Syndrome Awareness Day is held every October 20.[71] Organizations such as Special Olympics Hawaii provide year-round sports training for individuals with intellectual disabilities such as down syndrome.

Notable individuals

Scottish award-winning film and TV actress Paula Sage receives her BAFTA award with Brian Cox.

Portrayal in fiction


Down syndrome is “a developmental abnormality characterized by trisomy of human chromosome 21" (Nelson 619). The extra copy of chromosome-21 leads to an over expression of certain genes located on chromosome-21.

Research by Arron et al. shows that some of the phenotypes associated with Down syndrome can be related to the disregulation of transcription factors (596), and in particular, NFAT. NFAT is controlled in part by two proteins, DSCR1 and DYRK1A; these genes are located on chromosome-21 (Epstein 582). In people with Down syndrome, these proteins have 1.5 times greater concentration than normal (Arron et al. 597). The elevated levels of DSCR1 and DYRK1A keep NFAT primarily located in the cytoplasm rather than in thenucleus, preventing NFATc from activating the transcription of target genes and thus the production of certain proteins (Epstein 583).

This dysregulation was discovered by testing in transgenic mice that had segments of their chromosomes duplicated to simulate a human chromosome-21 trisomy (Arron et al. 597). A test involving grip strength showed that the genetically modified mice had a significantly weaker grip, much like the characteristically poor muscle tone of an individual with Down syndrome (Arron et al. 596). The mice squeezed a probe with a paw and displayed a .2 newton weaker grip (Arron et al. 596). Down syndrome is also characterized by increased socialization. When modified and unmodified mice were observed for social interaction, the modified mice showed as much as 25% more interactions as compared to the unmodified mice (Arron et al. 596).

The genes that may be responsible for the phenotypes associated may be located proximal to 21q22.3. Testing by Olson et al. in transgenic mice show the duplicated genes presumed to cause the phenotypes are not enough to cause the exact features. While the mice had sections of multiple genes duplicated to approximate a human chromosome-21 triplication, they only showed slight craniofacial abnormalities (688-690). The transgenic mice were compared to mice that had no gene duplication by measuring distances on various points on their skeletal structure and comparing them to the normal mice (Olson et al. 687). The exact characteristics of Down syndrome were not observed, so more genes involved for Down Syndrome phenotypes have to be located elsewhere.

Reeves et al., using 250 clones of chromosome-21 and specific gene markers, were able to map the gene in mutated bacteria. The testing had 99.7% coverage of the gene with 99.9995% accuracy due to multiple redundancies in the mapping techniques. In the study 225 genes were identified (311-313).

The search for major genes that may be involved in Down syndrome symptoms is normally in the region 21q21–21q22.3. However, studies by Reeves et al. show that 41% of the genes on chromosome-21 have no functional purpose, and only 54% of functional genes have a known protein sequence. Functionality of genes was determined by a computer using exon prediction analysis (312). Exon sequence was obtained by the same procedures of the chromosome-21 mapping.

Research has led to an understanding that two genes located on chromosome-21, that code for proteins that control gene regulators, DSCR1 and DYRK1A can be responsible for some of the phenotypes associated with Down syndrome. DSCR1 and DYRK1A cannot be blamed outright for the symptoms; there are a lot of genes that have no known purpose. Much more research would be needed to produce any appropriate or ethically acceptable treatment options.

Recent use of transgenic mice to study specific genes in the Down syndrome critical region has yielded some results. APP[82] is an Amyloid beta A4 precursor protein. It is suspected to have a major role in cognitive difficulties.[83] Another gene, ETS2[84] is Avian Erythroblastosis Virus E26 Oncogene Homolog 2. Researchers have "demonstrated that over-expression of ETS2 results in apoptosis. Transgenic mice over-expressing ETS2 developed a smaller thymus and lymphocyte abnormalities, similar to features observed in Down syndrome."[84]

Human chromosome 21 contains five microRNA genes: miR-99alet-7c, miR-125b-2, miR-155,and miR-802. MiR-155 and miR-802 regulate the expression of the methyl-CpG-binding protein (MeCP2). It has been suggested that the underexpression of MeCP2, secondary to trisomic overexpression of Human chromosome 21 derived miRNAs, may result in aberrant expression of the transcription factors of CREB1 and MEF2C . This in turn may lead to abnormal brain development through anomalous neuronal gene expression during the critical period of synaptic maturation by alterating neurogenesis, neuronal differentiation, myelination, and synaptogenesis.[85]

Vitamin supplements, in particular supplemental antioxidants and folinic acid, have been shown to be ineffective in the treatment of Down syndrome.[86]

External links


Syndrome de Down

Garçon trisomique assemblant une bibliothèque

Le syndrome de Down, aussi appelé trisomie 21, est une maladie chromosomique congénitale provoquée par la présence d'un chromosome surnuméraire pour la 21e paire. Ses signes cliniques sont très nets, on observe un retard cognitif, associé à des modifications morphologiques particulières.

C'est l'une des maladies transmises génétiquement les plus communes, avec une prévalence de 9,2 pour 10 000 naissances vivantes, aux USA1. L’incidence est d'environ 1 pour 800 naissances, toutes grossesses confondues et varie en fonction de l'âge de la mère : environ 1/1500 à 20 ans, 1/900 à 30 ans et 1/100 à 40 ans2.

L'un des traits les plus notables est le déficit du développement cognitif, mais aussi un ensemble varié d'autres malformations congénitales comme des cardiopathies3. Le QI des enfants atteints de syndrome de Down est extrêmement variable.

Près de 30 % des patients souffrent de complications dites « orthopédiques » imposant l'hospitalisation4 et le pourcentage (hanches) devrait croître au prorata de l'allongement de l'espérance de vie de tous. Les anomalies musculo-squelettiques sont volontiers source de complications, luxations, dysplasie acétabulaire, instabilité articulaire.



John Langdon Haydon Down

Le médecin britannique John Langdon Down (1828-1896) publie en 1866 un article intitulé Observations sur une classification ethnique des idiots dans lequel il classe les idiots selon des caractéristiques physiques et ethniques et dans lequel il donne une description clinique détaillée de la maladie qu’il appelle « idiotie mongoloïde »5 : « Un très grand nombre d'idiots congénitaux sont typiquement mongols [...] Les cheveux ne sont pas noirs, comme chez les vrais Mongols, mais de couleur brune, raides et étriqués. La face est plate et large, et dénuée de proéminence. Les joues sont rondes et élargies latéralement. Les yeux sont placés en oblique, et les canthi internes sont anormalement distants l'un de l'autre. La fissure palpébrale est très étroite. Le front est plissé transversalement [...] Les lèvres sont larges et épaisses avec des fissures transversales. La langue est longue, épaisse, et râpeuse. Le nez est petit. La peau à une teinte légèrement jaunâtre, déficiente en élasticité, donnant l'apparence d'être trop large pour le corps [...] il ne peut y avoir aucun doute que ces caractéristiques ethniques sont le résultats d'une dégénérescence [...] Le type mongolien d'idiotie représente plus de 10 pour cent des cas qui se sont présentés à moi. Ce sont toujours des idiots congénitaux, et jamais la conséquence d'accidents après la vie intra-utérine [...] Ils ont une capacité considérable d'imitation [...] Ils sont comiques [...] Ils sont habituellement capables de parler; le langage est simplet et indistinct, mais peut être amélioré grandement par une méthode bien dirigée de gymnastique de la langue. La faculté de coordination est anormale, mais pas si défectueuse qu'elle ne puisse être grandement renforcée. »

Les médecins français Marthe Gautier, Raymond Turpin et Jérôme Lejeune publient en 1959 un article6 dans lequel ils décrivent que la maladie est causée par la présence d'un chromosome supplémentaire, il y a trois chromosomes 21 au lieu de deux. C'est la première anomalie génétique décrite chez l'homme, et c'est la première maladie pour laquelle est mise en évidence la relation entre le génotype et le phénotype. Elle est renommée par Lejeune, « trisomie 21 », « tri » voulant dire « trois » et « some » voulant dire « chromosome », c’est-à-dire « trois chromosomes 21 ».

Traits cliniques


  • Faciès rond,
    • Fentes palpébrales (des paupières) obliques en haut en dehors et étroites
    • Repli de l'angle cutané interne des paupières (épicanthus, proéminent).
    • Langue épaisse.
  • Enfant qui tend à être de petite taille
  • Sont également volontiers notés :
    • Nuque Large.
    • Oreilles implantées bas, mal ourlées.
    • Mâchoire étroite, entraînant, en l'absence d'opération, une gêne considérable (langue épaisse) et l'amenant, surtout chez l'enfant, à la sortir fréquemment de la bouche (protrusion de la langue).
    • Mains barrées d'un seul pli palmaire très marqué, doigts courts.
  • L'hyperlaxité ligamentaire est généralisée.
  • La croissance et le développement sont retardés avec le début de la marche habituellement observé seulement à l'âge de 2 ou 3 ans.

Des malformations d'organes

Très fréquentes et devront être recherchées dès le diagnostic de certitude posé (par le caryotype, voir plus bas) : canal atrio-ventriculaire, atrésie digestive, anomalies urinaires, oculaires, ostéo-articulaires.


  • Le retard mental est hétérogène : QI est généralement situé entre 20 et 60 alors qu'un QI moyen est de 100. Le QI peut être supérieur, notamment par acquisition (stimulations adaptées), mais en ce cas, on ne parle plus de retard mental au-dessus de 69.
  • Les acquisitions sont retardées (marche vers 2 ans, langage)
  • Le développement des aptitudes sociales et affectives est, dans la grande majorité des cas, normal.


La taille définitive est le plus souvent inférieure à la moyenne.

L’adolescence et la puberté, vont entraîner comme chez les autres jeunes, des comportements sexuels et affectifs qui demanderont à être accompagnés, expliqués par les adultes. Des groupes de parole avec un professionnel peuvent leur permettre d’avancer dans la construction de leur identité d’adolescent et d’adulte.

Une femme trisomique 21 a une probabilité de 50 % d'avoir un enfant atteint. Le vieillissement est accéléré.

Trisomie 21

Caryotype d'un garçon trisomique

La présence d'un troisième chromosome 21 est la cause de la pathologie. Le mécanisme de la présence du chromosome supplémentaire est important à connaître pour le conseil génétique. La réalisation du caryotype permet de connaître le mécanisme.

Trisomie 21 libre

La formule chromosomique de la personne atteinte de trisomie 21 est donc 47, 21+. Le chromosome 21 supplémentaire vient presque toujours de la mère. L'origine de cette maladie génétique se situe lors de la gamétogénèse, et plus précisément à la mauvaise répartition des chromosomes homologues au cours de la première métaphase de la méiose. Un des gamètes ainsi formé comportera deux chromosomes de la 21e paire, au lieu d'un seul, ce qui, aprèsfécondation de ce gamète par un autre « normal » formera une cellule œuf dont la 21e paire possède 3 chromosomes.

Trisomie 21 par translocation

Translocation d'un bras du chromosome 21 sur le chromosome 14

Il s'agit de la fusion de deux chromosomes 21 par le mécanisme dit de translocation. Il s'agit donc d'un chromosome apparent ayant le contenu génétique de deux chromosomes. La formule chromosomique de la personne atteinte de cette forme de trisomie 21 est donc 45,XY der(21)t(21;21) ou 45,XX der(21)t(21;21).

La trisomie 21 par translocation est toujours héritée de l'un des parents. Il faut dans ce cas pratiquer un caryotype chez les parents si l'on veut identifier le porteur de l'anomalie.

Évaluation anténatale du risque de trisomie 21

La trisomie 21 est la cause la plus fréquente de retard mental responsable de 25 % des handicaps mentaux chez les enfants d’âge scolaire 7. Il s’agit, parmi les anomalies chromosomiques observées en cours de grossesse, de celle dont l’incidence est la plus élevée : aux alentours de 1/770 naissances soit 1,3/1000 naissances. Actuellement, avec l'utilisation des techniques modernes de dépistage la proportion a été repoussée à 1/2000 naissances. En France on relève de 65 000 à 70 000 individus porteurs de la trisomie 21.

Le principe de l'évaluation consiste donc à évaluer le risque de trisomie 21 afin de pouvoir décider si le risque de la ponction est tolérable. Le but de l'évaluation du risque est, lorsque le risque est élevé, de permettre aux futurs parents de décider ou non de pratiquer une amniocentèse afin de faire le diagnostic. Le seuil de tolérance est un choix arbitraire, il est en effet difficile de comparer le risque de tuer un fœtus sain avec celui de permettre la naissance d'un enfant trisomique.

Le but des examens de dépistage est en fonction d’un ou de plusieurs paramètres cliniques ou para-cliniques, de séparer les femmes enceintes en deux sous populations :

  • Une population dont le risque est jugé bas et pour laquelle on va s’abstenir de réaliser tout prélèvement invasif en lui expliquant néanmoins que le risque nul n’existe pas et qu’elle doit donc ne pas méconnaître le fait qu’un risque minime persiste.
  • Une population estimée à haut risque pour laquelle un examen invasif va être proposé au couple après information concernant le risque lié à la méthode de diagnostic employée.

L'évaluation d'un risque fait appel à des méthodes statistiques et de probabilités suivantes :

  • Avoir des signes pertinents, c'est-à-dire connaître la sensibilité, la spécificité, la valeur prédictive positive et négative et enfin la prévalence du signe.
  • Pouvoir calculer la probabilité individuelle qu'a un patient d'avoir une pathologie donnée après passage d'un test de dépistage et en partant d'un risque initial déterminé dans la population à laquelle appartient ce patient : utilisation du théorème de Bayes.

En pratique, le calcul du risque de trisomie 21

Le calcul du risque est basé sur le risque a priori qui est fonction de l'âge gestationnel et l'âge de la mère. En effet, le risque de trisomie 21 diminue durant la grossesse car environ 30% des fœtus atteints de trisomie 21 décèdent in utero.

Évolution du nombre de grossesses total pour une naissance avec trisomie 21, en fonction de l'âge maternel et du terme de la grossesse
Âge maternelTerme de la grossesse en semaines

Avant le test, une femme a un risque d'avoir un fœtus atteint de trisomie 21 : c'est le risque pré-test. Après le test, une femme a un risque d'avoir un fœtus atteint de trisomie 21 : c'est le risque post-test. Le rapport de vraisemblance ou likehood ratio est le nombre multiplicateur qui permet de passer du risque pré-test au risque post-test.

Si un signe est présent dans 50% des fœtus atteints de trisomie et 5% chez les fœtus non atteints, le rapport de vraisemblance est de 10 c'est-à-dire que le risque est multiplié par 10. Le rapport de vraisemblance est aussi vrai dans l'autre sens. Si un signe est présent dans 20% des fœtus atteints de trisomie et 40% chez les fœtus non atteints, le rapport de vraisemblance est de 0,5 c'est-à-dire que le risque est divisé par 2.

Il faut aussi être sur que les signes utilisés ne soient pas liés entre eux c'est-à-dire que l'un ne dépend de l'autre. Il faut que les signes soit statistiquement indépendants.

Le risque intégré effectué par certains obstétriciens c’est-à-dire le risque donné par la mesure de la clarté nucale et le risque donné par les dosages de l'H.C.G et de l'alpha-fœto-protéine (la prise de sang proposée en France à toutes les femmes enceintes) est l'intégration de tous les rapports de vraisemblance. Il nécessite l'utilisation de logiciel qui élimine le risque maternel dans un des deux calculs.

  • Le risque à partir duquel on réalise un caryotype dépend des pays ; il est de 1/300 en Angleterre et de 1/250 en France.

Les différents signes

  • Disposer de signe pertinent: ce tableau inspiré de l'article paru dans le British Medical Journal résume l'ensemble des signes disponibles dans le cadre d'un dépistage du syndrome de Down. Les marqueurs en italique sont en cours d'évaluation8.
Différents marqueurs pour le dépistage de la trisomie 21
MarqueursFacteur de risque
Âge maternelAugmente avec l'âge (Age est utilisé dans l'algorithme du calcul intégré)
Marqueurs sériques
HCG totalAugmente au second trimestre
Beta HCG libreAugmente au premier trimestre
Alpha foetoprotéineDiminue au second trimestre
Estriol libreDiminue au second trimestre
PAPP-ADiminue au premier trimestre
InhibineAugmente au second trimestre
ADAM12Diminue au premier trimestre
Marqueurs échographiques
Clarté nucaleAugmentation
Os propre du nezAbsence
Doppler du ductus venosusAnormale, augmentation de l'index de pulsatilité
Régurgitation au niveau de la valve tricuspidePrésence

Les signes du premier trimestre

  • Cette technique d'évaluation de la trisomie 21 (et des autres aneuploïdies) doit beaucoup au Professeur K. Nicolaides de la Fetal Medicine Foundation de Londres.
  • Le marqueur échographique utilisé est la clarté nucale. La technique de mesure doit répondre à des critères stricts.
  • Il existe un autre marqueur échographique mais de mesure plus délicate : l'os propre du nez.
Méga vessie chez un embryon de 11 semaines porteur d'une trisomie 21
Vessie normale chez un embryon de 12 semaines
  • Les substances utilisées sont l'HCG libre et la PAPP-A (pregnancy-associated plasma protein A)

Les signes du second trimestre


Aucun signe échographique n'est symptomatique de la trisomie 21. Toutefois, on peut quelquefois mettre en évidence un certain nombre d'anomalies mineures ou majeures qui se rencontrent plus fréquemment dans cette maladie chromosomique.

  • Anomalies mineures :
    • hypoplasie ou absence des os propres du nez,
    • fémur court, inférieur au 5e centile pour l'âge,
    • épaisseur de nuque supérieure à 6 mm à 20 semaines,
    • écartement important entre le premier et le deuxième orteil,
    • brièveté de la deuxième phalange du cinquième doigt (brachymésophalangie),
    • langue protruse...
  • Anomalies majeures :
    • des malformations cardiaques (canal atrio-ventriculaire et en particulier) (dans 40% des cas),
    • des sténoses digestives (dans 10 à 18 % des cas) (image en « double bulle » de sténose duodénale).

L'évaluation se fait entre 14+0 semaines d'aménorrhée et 17+6 semaines d'aménorrhée. Les marqueurs utilisés sont l'alpha-fœtoprotéine et l'HCG libre. Certains laboratoires ajoutent l'estriol plasmatiques mais l'ajout de ce troisième marqueur n'augmente la sensibilité et est de fait peu employé. Cette technique d'évaluation par trois marqueurs sériques se nomme le triple test. Certains laboratoires pondèrent le résultat en fonction du poids de la patiente et/ou du nombre de cigarettes fumées par jour.


Le diagnostic ne peut se faire que par la mise en évidence du chromosome 21 supplémentaire par le caryotype. Au premier trimestre par un prélèvement de trophoblaste qui est fait à partir de 11 semaines jusqu'à 14 semaines. Au-delà, le risque d'avortement iatrogène augmente de façon importante. Avant il est de 1% comme pour l'amniocentèse. Après il faut une ponction de liquide amniotique pour examiner les cellules du fœtus. Lorsque la date d'accouchement est proche, il faut effectuer une ponction de sang fœtal en ponctionnant lecordon ombilical car la réalisation du caryotype ne demande que quelques jours alors qu'il faut plusieurs semaines par l'amniocentèse.

Conseil génétique


Plusieurs études conduites aux États-Unis ou au Royaume-Uni ont montré que 90 à 93 % des grossesses ayant donné lieu au diagnostic du syndrome de Down ont été interrompues9. Ces chiffres donnent parfois lieu à des accusations d'eugénisme10. Certaines associations de défense des personnes handicapées font valoir que ces avortements envoient un message très dévalorisant aux personnes affectées : « il est préférable de ne pas exister que d'avoir un handicap » 11.

La vie sociale du sujet atteint

Les personnes atteintes du syndrome ont une vie un peu plus difficile que la moyenne : elles sont bien sûr victimes de leur retard physique et intellectuel, mais plus souvent encore du regard inquiet ou hostile que certains portent sur leur anomalie qui n'est pourtant pas contagieuse et qui est plus familière et moins désespérante pour les familles que bien des affections congénitales.

Les trisomiques ont besoin de développer une vie affective et sociable, comme tout un chacun. Il est nécessaire pour les familles de prendre le conseil de spécialistes qui les aideront à susciter et à encourager les progrès intellectuels et physiques (rééducation musculaire,activités physiques adaptées) du sujet.

Entre autres règles de communication, il est recommandé de s'exprimer par des phrases claires et concises, de répondre aux questions avec pertinence et avec un délai court.

On a longtemps caché dans des lieux spécialisés les enfants atteints du syndrome de Down. Leur existence était alors terrible et très brève, leur espérance de vie moyenne ne dépassait pas l'adolescence. Autant que possible il est conseillé de ne pas cantonner les enfants trisomiques à la fréquentation d'un milieu spécialisé : de nombreuses études montrent que le contact de l'école et d'enfants ordinaires a une influence extrêmement positive sur le développement général et sur le quotient intellectuel du sujet atteint de trisomie (QI allant de 20 à 80 environ, selon divers paramètres, notamment les stimulations intellectuelles offertes par l'environnement). Avec une prise en compte de leurs insuffisances physiologiques et en les traitant comme les êtres pensants et aimants qu'ils sont, la médecine parvient aujourd'hui à leur donner une espérance de vie presque normale et il n'est pas rare qu'ils prennent une place dans la vie active.

L'OMS qualifie un Qi entre 50 et 69 de retard léger : ces personnes connaissant des difficultés scolaires, sont cependant capables de s'intégrer à la société de façon autonome à l'âge adulte. Les personnes stimulées et correctement traitées atteignant un nombre supérieur sont donc considérées a contrario comme "normales" sur le plan intellectuel.

Trisomiques 21 célèbres

Place de la chirurgie orthopédique

  • Les soucis « orthopédiques » sont en grande partie liés à la laxité ligamentaire et à ses conséquences au niveau
    • de la colonne vertébrale,
    • des hanches,
    • des genoux, et
    • des pieds.

Instabilité atlanto-axiale

Instabilité au niveau des articulations du membre inférieur

Anomalies des hanches

  • Près de 7.9% de sujets atteints de syndrome de Down présentent une anomalie de hanche (Shaw ED and Beals RK., 1992), dont
    • dysplasie,
    • luxation,
    • nécrose avasculaire, ou
    • épiphysiolyse
  • La luxation de hanche du sujet atteint de syndrome de Down est
    • rarement douloureuse au début, mais
    • peut le devenir à la longue.
    • Le traitement est difficile, car la luxation se reproduit de manière non exceptionnelle.
    • L'orthèse de contention non chirurgicale est rarement efficace, tandis que le plâtre pelvicrural peut permettre à la hanche de se stabiliser en position de réduction.
    • La réduction par abord direct avec capsuloraphie d'une capsule volontiers tenue et les ostéotomies fémorale et pelvienne peuvent assurer la stabilité de la hanche (Bennet GC, Rang M, Roye DP and Aprin H., 1982).
  • L'épiphysiolyse de hanche est aussi connue en association avec le syndrome de Down.
    • L'hypothyroïdie peut être un facteur prédisposant, et la fonction de la thyroïde serait volontiers étudiée chez l'enfant atteint de syndrome Down et d'épiphysiolyse.
    • Le traitement est la fixation (vis) in situ, avec son risque de faillite du matériel.
  • Les indications de prothèse de hanche encore rares font clairement ici la preuve de leur intérêt.
    • Le vieillissement général de la population (espérance de vie) devrait en voir multiplier les indications ici chez des sujets encore « jeunes » (dysplasie).
    • Le risque septique paraît très raisonnable, voire identique au reste de la population, même si d'exceptionnelles et redoutables complications post-opératoires peuvent en faire le lit (pneumopathie, ventilation assistée, fistule de hanche).

Instabilité de rotule

Pieds plats


Trisomie 21 et mémoire

Les personnes porteurs de la trisomie 21 auraient une moindre activité du gyrus denté de l'hippocampe. Ceci serait l'une des explications de la déficience variable de la mémoire de ces sujets.

Des gènes surexprimés seraient en cause et notamment ceux de la cystathionine beta synthase (CBS) et DYRK1A. Des travaux pour mettre au point des inhibiteurs de la CBS et DYRK1A sont en cours.

Trisomie 21 et tumeurs

La trisomie 21 diminuerait le risque de développer des tumeurs solides12. Cela serait (au moins pour les cancers intestinaux) la surexpression d’un gène présent en trois exemplaires (du moins dans un modèle expérimental de souris de laboratoire caractérisée par une centaine de gènes orthologues du chromosome humain 21), qui réprime (de 44 % chez cette souris) la croissance tumorale dans les cancers intestinaux. Le gène Ets2, déjà identifié comme oncogène semble en cause (quand il est inactivé chez des souris mutées, le nombre de tumeurs devient inversement proportionnel au nombre de copies de Ets2 fonctionnelles, et à la quantité de ses ARN messagers)13.