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Definition

Down syndrome is the most common cause of mental retardation and malformation in a newborn. It occurs because of the presence of an extra chromosome.

Description

Chromosomes are the units of genetic information that exist within every cell of the body. Twenty-three distinctive pairs, or 46 total chromosomes, are located within the nucleus (central structure) of each cell. When a baby is conceived by the combining of one sperm cell with one egg cell, the baby receives 23 chromosomes from each parent, for a total of 46 chromosomes. Sometimes, an accident in the production of a sperm or egg cell causes that cell to contain 24 chromosomes. This event is referred to as nondisjunction. When this defective cell is involved in the conception of a baby, that baby will have a total of 47 chromosomes. The extra chromosome in Down syndrome is labeled number 21. For this reason, the existence of three such chromosomes is sometimes referred to as Trisomy 21.

In a very rare number of Down syndrome cases (about 1–2%), the original egg and sperm cells are completely normal. The problem occurs sometime shortly after fertilization; during the phase where cells are dividing rapidly. One cell divides abnormally, creating a line of cells with an extra chromosome 21. This form of genetic disorder is called a mosaic. The individual with this type of Down syndrome has two types of cells: those with 46 chromosomes (the normal number), and those with 47 chromosomes (as occurs in Down syndrome). Some researchers have suggested that individuals with this type of mosaic form of Down syndrome have less severe signs and symptoms of the disorder.

Another relatively rare genetic accident which can cause Down syndrome is called translocation. During cell division, the number 21 chromosome somehow breaks. A piece of the 21 chromosome then becomes attached to another chromosome. Each cell still has 46 chromosomes, but the extra piece of chromosome 21 results in the signs and symptoms of Down syndrome. Translocations occur in about 3–4% of cases of Down syndrome.

Down syndrome occurs in about one in every 800–1,000 births. It affects an equal number of boys and girls. Less than 25% of Down syndrome cases occur due to an extra chromosome in the sperm cell. The majority of cases of Down syndrome occur due to an extra chromosome 21 within the egg cell supplied by the mother (nondisjunction). As a woman's age (maternal age) increases, the risk of having a Down syndrome baby increases significantly. For example, at younger ages, the risk is about one in 4,000. By the time the woman is age 35, the risk increases to one in 400; by age 40 the risk increases to one in 110; and by age 45 the risk becomes one in 35. There is no increased risk of either mosaicism or translocation with increased maternal age.

— Kim A. Sharp, M.Ln.

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Dictionary: Down syndrome (doun) pronunciation

or Down's syndrome (dounz)

A congenital disorder, caused by the presence of an extra 21st chromosome, in which the affected person has mild to moderate mental retardation, short stature, and a flattened facial profile. Also called trisomy 21.

[After John Langdon Haydon Down (1828–1896), British physician.]

Sci-Tech Encyclopedia: Down syndrome

A developmental disability due to abnormal chromosome number or structure. It is characterized by physical and behavioral features and has been considered the most common form of genetic aberration. Incidence among the newborn is estimated at 3 in 1000, in the general population approximately 1 in 1000. The difference reflects the early mortality.

The most common type (trisomy 21) is due to a nondisjunction of chromosome 21 during the original cell division, resulting in an extra chromosome 21. These children have a total of 47 chromosomes instead of the usual 46. However, the extra material from chromosome 21 can also be attached to another chromosome through translocation; such children have Down syndrome but only 46 chromosomes. More rarely, the trisomy 21 breaks up, giving some cells with 47 chromosomes and some with 46 (mosaicism).

The characteristic physical features include almond-shaped eyes; a rounded, brachycephalic skull with flattened occipital region; a broad, flattened bridge of the nose; an enlarged fissured tongue; broad hands with stubby fingers; often a single “simian” palmar crease; hypotonic muscle development; thick, everted, and cracked lips; dry, rough skin; subnormal height; and infantile genitalia. Not all of these physical signs are present in every case, and some may be observed in individuals without Down syndrome. However, Down syndrome is diagnosed when most of the anomalies are present.

The degree of mental defect is not directly related to the number or gravity of the physical signs, but rather to a combination of those anomalies and the specific chromosomal defect. Few children with Down syndrome are classified today as severely retarded. Most are moderately to mildly retarded and are often educable and highly trainable. They tend to be curious, observant, skillful at mimicry, and usually, very affectionate. Aggression and hostility are rare; however, they are often stubborn and compulsive and are not easily frustrated. They are excellent candidates for vocational training.

Pathological research suggests nonspecific, generalized defective brain development. There is a tendency toward thyroid dysfunction and congenital heart defects. There may also be vision problems, but below-average dental caries. Medication has little effect on the physical condition or on the mental retardation. See also Alzheimer's disease; Congenital anomalies.

Although there are some reports of more than one child with Down syndrome in a single family, it is not a classical hereditary disease. Incidence is increased if the mother is under 16 or over 35 years old or the father is of advanced age. Furthermore, the Down syndrome child may result from a late or problem pregnancy or the last of numerous pregnancies. Thyroid deficiency, hypopituitarism, and pathology of the ovary have been observed in the mothers, and the probability of upset in their endocrine balance may increase with age. However, the basic etiology is still very much in doubt.

Prenatal identification of Down syndrome in the fetus is possible through amniocentesis. See also Human genetics; Mental retardation.

Dental Dictionary: Down syndrome

A congenital condition characterized by varying degrees of mental retardation and multiple developmental defects. It is most commonly caused by the presence of an extra chromosome 21. It is also called trisomy 21 and trisomy G syndrome. Mongolism is an archaic and discredited term.

Children's Health Encyclopedia: Down Syndrome

Definition

Down syndrome is the most common cause of mental retardation and malformation in a newborn. A genetic disorder, it occurs because of the presence of an extra chromosome.

Description

Chromosomes are units of genetic information that exist within every cell of the body. Twenty-three distinctive pairs, or 46 total chromosomes, are located within the nucleus (central structure) of each cell. When a baby is conceived by combining one sperm cell with one egg cell, the baby receives 23 chromosomes from each parent, for a total of 46 chromosomes. Sometimes, an accident in the production of a sperm or egg cell causes that cell to contain 24 chromosomes. This event is referred to as nondisjunction. When this defective cell is involved in the conception of a baby, that baby will have a total of 47 chromosomes. The extra chromosome in Down syndrome is labeled number 21. For this reason, the existence of three such chromosomes is sometimes referred to as trisomy 21.

In a very rare number of Down syndrome cases (about 1–2%), the original egg and sperm cells are completely normal. The problem occurs sometime shortly after fertilization; during the phase when cells are dividing rapidly. One cell divides abnormally, creating a line of cells with an extra chromosome 21. This form of genetic disorder is called a mosaic. The individual with this type of Down syndrome has two types of cells: those with 46 chromosomes (the normal number) and those with 47 chromosomes (as occurs in Down syndrome). Some researchers have suggested that individuals with this type of mosaic form of Down syndrome have less severe signs and symptoms of the disorder.

Another relatively rare genetic accident which can cause Down syndrome is called translocation. During cell division, the number 21 chromosome somehow breaks. A piece of the number 21 chromosome then becomes attached to another chromosome. Each cell still has 46 chromosomes, but the extra piece of chromosome 21 results in the signs and symptoms of Down syndrome. Translocations occur in about 3–4 percent of cases of Down syndrome.

Demographics

Down syndrome occurs in about one in every 800 to 1,000 births. It affects an equal number of boys and girls. Less than 25 percent of Down syndrome cases occur due to an extra chromosome in the sperm cell. The majority of cases of Down syndrome occur due to an extra chromosome 21 within the egg cell supplied by the mother (nondisjunction). As a woman's age (maternal age) increases, the risk of having a Down syndrome baby increases significantly. For example, at younger ages, the risk is about one in 4,000. By the time the woman is age 35, the risk increases to one in 400; by age 40 the risk increases to one in 110; and by age 45 the risk becomes one in 35. There is no increased risk of either mosaicism or translocation with increased maternal age.

Causes and Symptoms

While Down syndrome is a chromosomal disorder, a baby is usually identified at birth through observation of a set of common physical characteristics. Babies with Down syndrome tend to be overly quiet; less responsive; with weak, floppy muscles. Furthermore, a number of physical signs may be present. These include:

flat appearing face
small head
flat bridge of the nose
smaller than normal, low-set nose
small mouth, which causes the tongue to stick out and to appear overly large
upward slanting eyes
extra folds of skin located at the inside corner of each eye, near the nose (called epicanthal folds)
rounded cheeks
small, misshapen ears
small, wide hands
an unusual, deep crease across the center of the palm (called a simian crease)
a malformed fifth finger
a wide space between the big and the second toes
unusual creases on the soles of the feet
overly flexible joints (sometimes referred to as being double-jointed)
shorter than normal height

Other types of defects often accompany Down syndrome. About 30 to 50 percent of all children with Down syndrome are found to have heart defects. A number of different heart defects are common in Down syndrome, including abnormal openings (holes) in the walls that separate the heart's chambers (atrial septal defect, ventricular septal defect). These result in abnormal patterns of blood flow within the heart. The abnormal blood flow often means that less oxygen is sent into circulation throughout the body. Another heart defect that occurs in Down syndrome is called tetralogy of Fallot. Tetralogy of Fallot consists of a hole in the heart, along with three other major heart defects.

Malformations of the gastrointestinal tract are present in about 5–7 percent of children with Down syndrome. The most common malformation is a narrowed, obstructed duodenum (the part of the intestine into which the stomach empties). This disorder, called duodenal atresia, interferes with the baby's milk or formula leaving the stomach and entering the intestine for digestion. The baby often vomits forcibly after feeding and cannot gain weight appropriately until the defect is repaired.

Other medical conditions that occur in patients with Down syndrome include an increased chance of developing infections, especially ear infections and pneumonia; certain kidney disorders; thyroid disease (especially low or hypothyroid); hearing loss; vision impairment that requires corrective lenses; and a 20-times greater chance of developing leukemia (a blood disorder).

Development in a baby and child with Down syndrome occurs at a much slower than normal rate. Because of weak, floppy muscles (hypotonia), babies learn to sit up, crawl, and walk much later than their normal peers. Talking is also quite delayed. The level of mental retardation is considered to be mild-to-moderate in Down syndrome. The actual IQ range of Down syndrome children is quite varied, but the majority of such children are in what is sometimes known as the trainable range. This means that most people with Down syndrome can be trained to do regular self-care tasks, function in a socially appropriate manner in a normal home environment, and even hold simple jobs.

As people with Down syndrome age, they face an increased chance of developing the brain disease called Alzheimer's (sometimes referred to dementia or senility). Most people have a six in 100 risk of developing Alzheimer's, but people with Down syndrome have a one-in-four chance of the disease. Alzheimer's disease causes the brain to shrink and to break down. The number of brain cells decreases, and abnormal deposits and structural arrangements occur. This process results in loss of brain function. People with Alzheimer's have strikingly faulty memories. Over time, people with Alzheimer's disease lapse into an increasingly unresponsive state. Some researchers have shown that even Down syndrome patients who do not appear to have Alzheimer's disease have the same changes occurring to the structures and cells of their brains.

As people with Down syndrome age, they also have an increased chance of developing a number of other medical difficulties, including cataracts, thyroid problems, diabetes, and seizure disorders.

Diagnosis

Diagnosis is usually suspected at birth, when the characteristic physical signs of Down syndrome are noted. Once this suspicion has been raised, genetic testing (chromosome analysis) can be undertaken in order to verify the presence of the disorder. This testing is usually done on a blood sample, although chromosome analysis can also be done on other types of tissue, including skin. The cells to be studied are prepared in a laboratory. Chemical stain is added to make the characteristics of the cells and the chromosomes stand out. Chemicals are added to prompt the cells to go through normal development, up to the point where the chromosomes are most visible, prior to cell division. At this point, they are examined under a microscope and photographed. The photograph is used to sort the different sizes and shapes of chromosomes into pairs. In most cases of Down syndrome, one extra chromosome 21 will be revealed. The final result of such testing, with the photographed chromosomes paired and organized by shape and size, is called the individual's karyotype.

Treatment

As of 2004 no treatment is available to cure Down syndrome. Treatment is directed at addressing the individual concerns of a particular patient. For example, heart defects often times require surgical repair, as will duodenal atresia. Many Down syndrome patients need to wear glasses to correct vision. Patients with hearing impairment benefit from hearing aids.

In the mid 1900s, all Down syndrome children were quickly placed into institutions for lifelong care. Research shows, however, that the best outlook for children with Down syndrome is family life in their own home. This arrangement requires careful support and education of the parents and the siblings. Parents and other siblings face a life-changing event in receiving a new baby who has a permanent condition that will affect essentially all aspects of his or her development. Some community groups are committed to helping families deal with the emotional effects of this new situation. Schools are required to provide services for children with Down syndrome, sometimes in separate special education classrooms and sometimes in regular classrooms, a practiced called mainstreaming or inclusion.

Prognosis

The prognosis in Down syndrome is quite variable, depending on the types of complications (heart defects, susceptibility to infections, development of leukemia) of each individual baby. The severity of the retardation can also vary significantly. Without the presence of heart defects, about 90 percent of children with Down syndrome live into their teens. People with Down syndrome appear to go through the normal physical changes of aging more rapidly, however. The average age at death for an individual with Down syndrome is about 50 to 55 years.

Still, in the early 2000s, the prognosis for a baby born with Down syndrome is better than ever before. Because of modern medical treatments, including antibiotics to treat infections and surgery to treat heart defects and duodenal atresia, life expectancy has greatly increased. Community and family support allows people with Down syndrome to have rich, meaningful relationships and in some cases to hold jobs.

Men with Down syndrome appear to be uniformly sterile (meaning that they are unable to have offspring). Women with Down syndrome, however, are fully capable of having babies. About 50 percent of these babies, however, will also be born with Down syndrome.

Prevention

Efforts at prevention of Down syndrome are aimed at genetic counseling of couples who are preparing to have babies. A counselor needs to inform a woman that her risk of having a baby with Down syndrome increases with her increasing age. Two types of testing is available during a pregnancy to determine if the baby being carried has Down syndrome.

Screening tests are used to estimate the chance that an individual woman will have a baby with Down syndrome. At 14–17 weeks of pregnancy, measurements of a substance called AFP (alpha-fetoprotein) can be performed. AFP is normally found circulating in the blood of a pregnant woman but may be unusually high or low with certain disorders. Carrying a baby with Down syndrome often causes AFP to be lower than normal. This information alone, or along with measurements of two other hormones, is considered along with the mother's age to calculate the risk of the baby being born with Down syndrome. These results are only predictions and are only correct about 60 percent of the time. Other screening tests measure and compare the levels of other markers present in the mother's blood. A specialized ultrasound exam measures the thickness of the back of the fetus's neck (called nuchal lucency). Thicker measurements correlate with the possibility of Down syndrome or other chromosomal abnormalities.

All of these screening tests are used to decide which mothers will be offered other, more definitive testing to ascertain whether the baby has Down syndrome. These more definitive tests each carry a risk of miscarriage, which is why screening tests are an important first step. The only way to definitively establish (with about 98–99% accuracy) the presence or absence of Down syndrome in a developing baby is to test tissue from the pregnancy itself. This is usually done either by amniocentesis or chorionic villus sampling (CVS). In amniocentesis, a small amount of the fluid in which the baby is floating is withdrawn with a long, thin needle. In chorionic villus sampling, a tiny tube is inserted into the opening of the uterus to retrieve a small sample of the placenta (the organ that attaches the growing baby to the mother via the umbilical cord, and provides oxygen and nutrition). Both amniocentesis and CVS allow the baby's own karyotype to be determined. A couple must then decide whether to use this information in order to begin to prepare for the arrival of a baby with Down syndrome or to terminate the pregnancy.

Once a couple has had one baby with Down syndrome, they are often concerned about the likelihood of future offspring also being born with the disorder. Most research indicates that this chance remains the same as for any other woman at a similar age. However, when the baby with Down syndrome has the type that results from a translocation, it is possible that one of the two parents is a carrier of that defect. (A carrier carries the genetic defect but does not actually have the disorder.) When one parent is a carrier of a translocation, the chance of future offspring having Down syndrome is greatly increased. The specific risk will have to be calculated by a genetic counselor.

Parental Concerns

Parenting a child with Down syndrome can be both challenging and rewarding. Children with Down syndrome have a wide range of potential outcomes. Early intervention programs have been proven to be of great help in assisting these children in achieving the highest level of functioning possible. There are many support groups available for parents and siblings of Down syndrome children.

Resources

Books

Hall, Judith G. "Chromosomal Clinical Abnormalities." In Nelson Textbook of Pediatrics. Edited by Richard E. Behrman et al. Philadelphia: Saunders, 2004.

Simpson, Joe Leigh. "Genetic Counseling and Prenatal Diagnosis." In Obstetrics: Normal and Problem Pregnancies. Edited by Steven G. Gabbe. London: Churchill Livingstone, 2002.

Tierney, Lawrence, et al. Current Medical Diagnosis and Treatment. Los Altos, CA: Lange Medical Publications, 2001.Periodicals

Canick, J. A. "Prenatal screening for Down syndrome: current and future methods." Clinical Laboratory Medicine 86 (June 2003): 395–411.

Roizen, N. J. "Medical care and monitoring for the adolescent with Down syndrome." Adolescent Medicine 13 (June 2002): 345–58.

Tyler, C. "Down syndrome, Turner syndrome, and Klinefelter syndrome: primary care throughout the life span." Primary Care 31 (September 2004): 627.

Organization

National Down Syndrome Congress. 1370 Center Drive, Suite 102 Atlanta, GA 30338 (800) 232-6372. Web site: www.ndsccenter.org

National Down Syndrome Society. 666 Broadway, 8th Floor, New York, NY 10012-2317. Web site: www.ndss.org.

[Article by: Kim A. Sharp, M.Ln. Rosalyn Carson-DeWitt, MD]

Genetics Encyclopedia: Down Syndrome

Down syndrome, also called trisomy 21, is the single most common genetic cause of moderate mental retardation. It occurs in about one of every eight hundred live births. It is caused by the inheritance of an extra copy of chromosome 21. The condition was named after an English physician, J. Langdon Down, who in 1866 published the first report describing patients with similar facial features and mental retardation. The chromosomal basis of Down syndrome was not determined until nearly a century later.

Clinical Features

Down syndrome is associated with a characteristic physical appearance, mental retardation, and specific birth defects or health conditions. The facial features, in addition to low muscle tone (called hypotonia), are often the first signs that alert a physician to a potential diagnosis of Down syndrome. These features include an up-slant of the outer corners of the eyes, small skin folds over the inner corners of the eyes, a small nose with a flat nasal bridge, a flat profile, and a large, grooved tongue that often protrudes from the mouth. Other physical characteristics can include a short neck, excess skin on the back of the neck, short hands with a single palmar crease, a wide gap between the first and second toes, and short stature. There are many individuals without Down syndrome who may have one or more of these features. It is only when the features occur together and the appropriate genetic test (chromosome studies) confirms clinical suspicion that a diagnosis of Down syndrome is made.

All individuals with Down syndrome have mental retardation, usually mild to moderate. The degree of learning disability may not be immediately apparent, since social ability generally exceeds scholastic ability. Early intervention programs are important for giving people with Down syndrome the best chance to maximize their learning potential.

Certain birth defects and health conditions are more common in individuals with Down syndrome. The most common birth defect is a congenital heart defect, affecting 40 percent to 50 percent of newborns with the condition. Although many can be repaired with surgery, congenital heart defects remain the major cause of early death among affected persons. Individuals with Down syndrome have an increased chance of experiencing hearing loss, vision problems, and thyroid disease, as well as an increased susceptibility to infections. Because of such concerns, specific guidelines for the health care of individuals with Down syndrome have been developed.

Chromosomal Basis of Down Syndrome

In 1959 French geneticist Jerome Lejeune recognized that individuals with Down syndrome have forty-seven chromosomes instead of the usual forty-six. Later, it was determined that it is an extra copy of chromosome 21 that causes the condition. It is not yet clear how the extra chromosome causes the clinical features, although it is believed that an "extra dose" of one or more of the genes on the chromosome is responsible.

There are three types of Down syndrome: trisomy 21, mosaic Down syndrome, and translocation Down syndrome. In 94 percent of cases, the extra copy of chromosome 21 stands alone (is not attached to any other chromosomes) and is present in every cell of the body. This is called trisomy 21, trisomy meaning three.

Trisomy 21 occurs due to a chromosome packaging error. Usually when the body makes its sex cells (egg or sperm cells) during meiosis, it packages up one chromosome from each pair. However, sometimes an error (nondisjunction) occurs, causing both chromosomes from a pair to get packaged together. If the sex cell with the extra chromosome is fertilized by a sex cell with the usual chromosome number, the resulting embryo will have a trisomy. If the extra chromosome is chromosome 21, the embryo will have Down syndrome. About 75 percent of embryos with trisomy 21 abort spontaneously before birth. Nondisjunction occurs by chance in the making of both egg and sperm cells, but it happens more often in egg cells as women get older. Thus, the chance of having a baby with Down syndrome increases with increasing maternal age.

Translocation Down syndrome, which accounts for 3 percent to 4 percent of cases, occurs when the extra copy of chromosome 21 is attached to another chromosome. In about one-fourth of the cases where a person has translocation Down syndrome, he or she inherited the translocation from a parent. Therefore it is important to test the parents' chromosomes in these cases, for purposes of future family planning.

The third type of Down syndrome is the mosaic type, which occurs in 2 percent to 3 percent of cases. In mosaic Down syndrome, a person has some cells with an extra copy of chromosome 21 and some cells with the usual two copies. People with mosaic Down syndrome may or may not have milder symptoms than people with "full" trisomy 21.

Testing for Down Syndrome

Cytogenetic analysis looks at the number and structure of a person's chromosomes. This test, which can be performed on a blood sample, is the test used to definitively determine if an individual has Down syndrome.

Table 1

Maternal Age	Risk of Down Syndrome	Total Risk for all Chromosomal Abnormalities
20	1/1667	1/526
21	1/1667	1/526
22	1/1429	1/500
23	1/1429	1/500
24	1/1250	1/476
25	1/1250	1/476
26	1/1176	1/476
27	1/1111	1/455
28	1/1053	1/435
29	1/1000	1/417
30	1/952	1/385
31	1/909	1/385
32	1/769	1/322
33	1/602	1/286
34	1/485	1/238
35	1/378	1/192
36	1/289	1/156
37	1/224	1/127
38	1/173	1/102
39	1/136	1/83
40	1/106	1/66
41	1/82	1/53
42	1/63	1/42
43	1/49	1/33
44	1/38	1/26
45	1/38	1/21
46	1/23	1/16
47	1/18	1/13
48	1/14	1/10
49	1/11	1/8

Prenatal diagnosis for Down syndrome (testing for the condition during pregnancy) is possible. Chromosome studies can be performed on fetal cells collected via chorionic villus sampling (CVS) at ten to twelve weeks of pregnancy or by amniocentesis at fifteen to twenty weeks of pregnancy. Because of the link between the mother's age and the chance of Down syndrome, prenatal diagnosis for Down syndrome and other chromosome conditions is routinely offered to women thirty-five and older. Whether to pursue prenatal diagnosis is a personal decision that can only be made by the parents.

Bibliography

Evans, Mark I., et al. Fetal Diagnosis and Therapy: Science, Ethics, and the Law. Philadelphia, PA: JB Lippincott Co., 1989.

Gardner, R., J. McKinlay, and Grant R. Sutherland. Chromosome Abnormalities and Genetic Counseling, 2nd ed. New York: Oxford University Press, 1996.

Nussbaum, Robert L., Roderick R. McInnes, and Huntington F. Willard, eds. Thompson & Thompson Genetics in Medicine, 6th ed. Philadelphia, PA: W. B. Saunders, 2001.

Pueschel, Siegfried M., ed. A Parent's Guide to Down Syndrome: Toward a Brighter Future, 2nd ed. Baltimore, MD: Paul H. Brooks Publishing, 2001.

Internet Resource

Cohen, William I., ed. "Health Care Guidelines for Individuals with Down Syndrome: 1999 Revision." Down Syndrome Quarterly 4, no. 3 (1999): 1-15. http://www.denison.edu/dsq/health99.shtml.

—Angela Trepanier and Gerald L. Feldman

Britannica Concise Encyclopedia: Down syndrome

Congenital disorder caused by an extra chromosome (trisomy) on the chromosome 21 pair. Those with the syndrome may have broad, flat faces; up-slanted eyes, sometimes with epicanthal folds (whence its former name, mongolism); intellectual disability (usually moderate); heart or kidney malformations; and abnormal fingerprint patterns. Many persons with Down syndrome can live and work independently or in a sheltered environment, but they age prematurely and have a short (55-year) life expectancy. The risk of bearing a child with the disorder increases with the mother's age; it can be detected in the fetus by amniocentesis.

For more information on Down syndrome, visit Britannica.com.

Columbia Encyclopedia: Down syndrome,

congenital disorder characterized by mild to severe mental retardation, slow physical development, and characteristic physical features. Down syndrome affects about 1 in every 730 live births and occurs in all populations equally. It was first described in 1866 by an English physician, J. Langdon Down. In 1959 a French physician, Jerome Lejeune, discovered that the syndrome was caused by an extra chromosome. It was later discovered that this extra chromosome appears as a third chromosome attached to the 21st of the 23 pairs of chromosomes normally present in the human genome. This third chromosome gives rise to the alternate name trisomy 21.

The extra genetic material is responsible for the physical characteristics of the syndrome: low muscle tone, flattish facial features, an upward slant to the eyes and epicanthal folds (which were the basis for the former name, mongolism), a single crease across the palm, hyperflexibility of the joints, and a displastic middle phalanx on the fifth finger. People with Down syndrome have an increased incidence of infection, childhood leukemia, congenital heart defects, and respiratory problems, but modern medical treatment has improved the life expectancy from 9 (in 1910) to 55 (in 1995).

Mental retardation varies widely, from minimal to severe. The great majority of those who have the disorder attend public schools and as adults can live independently or in group homes. After age 35 individuals with the syndrome develop the neurological changes of Alzheimer's disease, and many develop the dementia that accompanies them.

Eighty percent of children with Down syndrome are born to women under 35 years of age, but the incidence of Down syndrome births does increase with age. Approximately 5% of cases are transmitted by the sperm. Amniocentesis or chorionic villus sampling can be used to detect the disorder in the fetus. Children born to women with Down syndrome have a 50% chance of having the disorder.

Health Dictionary: Down's syndrome

A congenital condition, caused by an abnormality in the chromosomes, marked by moderate to severe mental retardation and changes in certain physical features.

Wikipedia: Down syndrome

Image:Padlock-silver-medium.svg

**Down syndrome**
*Classification & external resources*

Boy with Down syndrome assembling a bookcase
ICD-10	Q 90.
ICD-9	758.0
OMIM	190685
DiseasesDB	3898
MedlinePlus	000997
eMedicine	ped/615
MeSH	D004314

Down syndrome or trisomy 21 (usually Down's Syndrome in British English^[1]) is a genetic disorder caused by the presence of all or part of an extra 21st chromosome. It is named after John Langdon Down, the British doctor who described it 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 as well as facial appearance. Down syndrome can be identified during pregnancy or at birth.

Individuals with Down syndrome can have a lower than average cognitive ability, often ranging from mild to moderate learning disabilities. Developmental disabilities often manifest as a tendency toward concrete thinking or naïveté. A small number have severe to profound mental disability. The incidence of Down syndrome is estimated at 1 per 800 to 1,000 births.

Many of the common physical features of Down syndrome also appear in people with a standard set of chromosomes. They may include a single transverse palmar crease (a single instead of a double crease across one or both palms), an almond shape to the eyes caused by an epicanthic fold of the eyelid, upslanting palpebral fissures, shorter limbs, poor muscle tone, a larger than normal space between the big and second toes, and protruding tongue. Health concerns for individuals with Down syndrome include a higher risk for congenital heart defects, gastroesophageal reflux disease, recurrent ear infections, obstructive 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.^[2]

Characteristics

Example of white spots on the iris known as Brushfield spots

Individuals with Down syndrome may have some or all of the following physical characteristics: oblique eye fissures with epicanthic skin folds on the inner corner of the eyes, 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), a short neck, white spots on the iris known as Brushfield spots,^[3] 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,^[4] with scores of children having Mosaic Down syndrome (explained below) typically 10–30 points higher.^[5] In addition, individuals with Down syndrome can have serious abnormalities affecting any body system.

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 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^[6] and mice. Recently, researchers have created transgenic mice with most of human chromosome 21 (in addition to the normal mouse chromosomes).^[7] 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.^[8]

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.^[9]

Mosaicism

Trisomy 21 is caused 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).^[10] 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.^[9]

Robertsonian translocation

The extra chromosome 21 material that causes Down syndrome may be due to a Robertsonian translocation. In this case, 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 disjunctions 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 observed cases of Down syndrome.^[9] It does not show the maternal age effect, and is just as likely to have come from fathers as mothers.^{[citations needed]}

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)).^[11] 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.

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.^[12] In 2006, the Center for Disease Control estimated the rate as 1 per 733 live births in the United States (5429 new cases per year).^[13] 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 1/1490; at age 40 the probability is 1/60, and at age 49 the probability is 1/11.^[14] Although the probability increases with maternal age, 80% of children with Down syndrome are born to women under the age of 35,^[15] reflecting the overall fertility of that age group. Recent data also suggest that paternal age also increases the risk of Down Syndrome manifesting in pregnancies in older mothers.^[16]

Prenatal screening

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 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.

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. 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: Common first and second trimester Down syndrome screens
Screen	When performed (weeks gestation)	Detection rate	False positive rate	Description
Triple screen	15–20	75%	8.5%	This test measures the maternal serum alpha feto protein (a fetal liver protein), estriol (a pregnancy hormone), and human chorionic gonadotropin (hCG, a pregnancy hormone).^[17]
Quad screen	15–20	79%	7.5%	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 high inhibin-Alpha (INHA).^[17]
AFP/free beta screen	13–22	80%	2.8%	This test measures the alpha feto protein, produced by the fetus, and free beta hCG, produced by the placenta.
Nuchal translucency/free beta/PAPPA screen	10–13.5	91%^[18]	5%^[18]	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.^[19]

Ultrasound of fetus with Down syndrome and megacystis

Even with the best non-invasive screens, the detection rate is 90%–95% and the rate of false positive is 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 or chorionic villus sampling (CVS). Amniocentesis is an invasive procedure and involves taking amniotic fluid from the mother 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. ^[20]

Due to the low incidence of Down syndrome, a vast majority of early screen positives are false.^[21] Since false positives typically prompt an amniocentesis to confirm the result, and the amniocentesis carries a small risk of inducing miscarriage, there is a slight risk of miscarrying a healthy fetus. (The added miscarriage risk from an amniocentesis is traditionally quoted as 0.5%, but recent studies suggest that it may be considerably smaller (0.06% with a 95% CI of 0 to 0.5%).^[22])

A 2002 literature review of elective abortion rates found that 91–93% of pregnancies with a diagnosis of Down syndrome were terminated.^[23] Physicians and ethicists are concerned about the ethical ramifications,^[24] with some commentators calling it "eugenics by abortion".^[25] 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."^[26]

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.^[27] 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. It is not uncommon for children with Down Syndrome to have a speech delay, although it is common for them to need speech therapy to help with expressive language.^[28] Fine motor skills are delayed^[29] and often lag behind gross motor skills and can interfere with cognitive development. Gross Motor Skills can be affected anywhere from minor to major. Some children will walk at around 2 while others around 4. A physical therapist or APE will help a child with this. ^[30]

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.^[31]

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.^[32]

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.^[33]

Health

Main article: Health aspects of Down syndrome

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.^[34]

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 leukemia, immune deficiencies, and epilepsy. However, health benefits of Down syndrome include greatly reduced incidence of many common malignancies except leukemia and testicular cancer^[35] — 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, because of reduced exposure to environmental factors that contribute to cancer risk, or some other as-yet unspecified factor. 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.

Life expectancy

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.^[36] 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.

Fertility

Fertility amongst both males and females is reduced,^[37] with only three recorded instances of males with Down syndrome fathering children.^[38]^[39]

Genetic research

Main article: Research of Down syndrome-related genes

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 (displayed genetic characteristics), associated with Down Syndrome can be related to the dysregulation of gene-regulating proteins (596). The gene-regulating proteins bind to DNA and initiate certain segments of DNA to be replicated for the production of a certain protein (Arron et al. 596). The gene-regulator in interest is called NFATc. Its activities are controlled 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 mean that most of the NFATc is located in the cytoplasm rather than in the nucleus promoting DNA replication which will produce vital proteins (Epstein 583).

This dysregulation was discovered by testing in transgenic mice. The mice had segments of their chromosomes duplicated to simulate a human chromosme-21 trisomy (Arron et al. 597). A common characteristic of Down Syndrome is poor muscle tone, so a test involving the grip strength of the mice showed that the genetically modified mice had a significantly weaker grip (Arron et al. 596). The mice squeezed a probe with a paw; the modified mice displayed a .2 Newton (measurement of force) weaker grip (Arron et al. 596). Down syndrome is also characterized by increased socialization. Both modified and unmodified mice were observed for social interaction. The modified mice showed as many as 25% more interactions per time period as 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 chromosme-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 of 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^[40] is an Amyloid beta A4 precursor protein. It is suspected to have a major role in cognitive difficulties.^[41] Another gene, ETS2^[42] is Avian Erythroblastosis Virus E26 Oncogene Homolog 2. Researchers have "demonstrated that overexpression of ETS2 results in apoptosis. Transgenic mice overexpressing ETS2 developed a smaller thymus and lymphocyte abnormalities, similar to features observed in Down syndrome."^[43]

Sociological and cultural aspects

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 (such as MENCAP), educators and other professionals have generally advocated a policy of inclusion,^[44] 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; 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 Down Syndrome International.^[45] 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."^[46] In South Africa, Down Syndrome Awareness Day is held every October 20.^[47]

History

Main article: History of Down syndrome

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 entitled "Observations on an ethnic classification of idiots".^[48] Due to his perception that children with Down syndrome shared physical facial similarities (epicanthal folds) with those of Blumenbach's Mongolian race, Down used terms such as mongolism and Mongolian idiocy.^[49] Down wrote that mongolism represented "retrogression," the appearance of Mongoloid traits in the children of allegedly more advanced Caucasian parents.

By the 20^th century, "Mongolian idiocy" 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)