Down Syndrome

Definition and Facts About Down Syndrome

  • The earliest known depiction of a person with Down syndrome is an angel in a Flemish painting dated 1515.
  • In 1866, Doctor John Langdon Down first described Down syndrome as a disorder, but he misunderstood how Down syndrome arises. The cause of Down syndrome was discovered rather recently in 1959.
  • Down syndrome is a genetic disorder and the most common cause of cognitive impairment. All individuals with Down syndrome have mild to moderate learning disabilities, distinctive facial features, and low muscle tone (hypotonia) in early infancy.
  • Down syndrome is also often associated with heart defects, leukemia, and early-onset Alzheimer's disease. The degree to which an individual is affected by these characteristics varies from mild to severe.
  • Due to recent advances in medical care and social inclusion, life expectancy has increased dramatically for individuals with Down syndrome.
  • A majority of infants with Down syndrome survive 1 year, and half of people with Down syndrome live longer than 50 years. The average life span is greater than 55 years.

What Is Down Syndrome (the Genetics)?

Down syndrome is a genetic disorder caused by the presence of an extra chromosome 21. Chromosomes contain the genes that carry all the information necessary to properly develop and maintain our bodies.

Human cells normally contain 46 chromosomes that can be arranged in 23 pairs. One set of 23 chromosomes comes from the mother (egg cell or ovum) and the other half of the 23 pairs comes from the father (sperm cell). In most cases of Down syndrome, the person inherits two chromosomes 21 from the mother (instead of one) and one chromosome 21 from the father, resulting in three copies of chromosome 21 instead of two (hence Down syndrome is also known as trisomy 21). In Down syndrome, the additional copy of chromosome 21 results in the increased expression of genes located on this chromosome. It is believed that the activity of these extra genes leads to many of the features that characterize Down syndrome.

Down Syndrome - Trisomy 21

Individuals who inherit an entire extra chromosome 21 make up approximately 95% of Down syndrome cases. As mentioned above, this usually happens when the individual inherits two copies of chromosome 21 (instead of one) from the mother's egg during fertilization. In rare cases, the individual inherits the extra chromosome 21 through the father's sperm. In either case, it leads to a fertilized egg with three copies of chromosome 21 instead of two. To date, it is not known what causes the inheritance of the extra chromosome 21. The only known risk factor for Down syndrome is the mother's age at conception; the older the mother, the higher the risk of conceiving a baby with Down syndrome.

Robertsonian Translocation and Partial/Segmental Trisomy

In some people, parts of chromosome 21 fuse with another chromosome (usually chromosome 14). This is called a Robertsonian translocation. The person has a normal set of chromosomes, but one chromosome contains extra genes from chromosome 21. When a person with a Robertsonian translocation has a child, the extra genetic material from chromosome 21 is inherited and the child will have Down syndrome. Robertsonian translocations occur in a small percentage of Down syndrome cases.

In extremely rare cases, very small pieces of chromosome 21 are incorporated into other chromosomes. This is known as partial or segmental trisomy 21.

Mosaic Down Syndrome

Another small percentage of Down syndrome cases are mosaic. In mosaic Down syndrome, some cells in the body have three copies of chromosome 21 and the rest of the cells are unaffected. For example, a person might have skin cells with trisomy 21, while all other cell types are normal. Mosaic Down syndrome can sometimes go undetected, because a person with mosaic Down syndrome does not necessarily have all the characteristic physical features and often is less cognitively impaired than a person with trisomy 21. A person with mosaic Down syndrome may also be misdiagnosed as having trisomy 21.

Down Syndrome Risk Factors

Advanced maternal age is the only known risk factor for Down syndrome. The older the woman is when she delivers the infant, the higher the chances of having a child with Down syndrome.

  • At age 25: the risk is 1 in 1,250
  • At age 30: the risk is 1 in 1000
  • At age 35: the risk is 1 in 400
  • At age 40: risk is 1 in 100
  • At age 45: the risk is 1 in 30

Couples who have had one child with Down syndrome are at a slightly increased risk (about 1%) for having another affected child. The risk of having a baby with Down syndrome is increased, if one of the parents has a translocation involving chromosome 21. The recurrence risk is as high as 100% if the carrier parent has a translocation in which two chromosomes 21 are fused.

People with Down syndrome rarely reproduce. About 15% to 30% of women with trisomy 21 are fertile, and they have a 50% risk of having an affected child. Men with Down syndrome are even less fertile, but at least one case is known, in which a man with Down syndrome fathered a child.

Down Syndrome Symptoms (the Effects of Trisomy 21)

It is now well known that the extra genes on the additional chromosome 21 are the cause of Down syndrome. Scientists are trying to determine which of the genes on chromosome 21 cause different characteristics of the disorder when present in three copies. Some genes may be more active and others less active due to the extra copy, and some of the genes may have a stronger influence on the characteristics of Down syndrome than others. Currently, about 400 genes on chromosome 21 have been identified, but the function of most remains unknown.

Until recently, scientists hypothesized that the most important genes involved in Down syndrome were located in an area on chromosome 21 called the Down syndrome critical region. However, scientists have found that genes outside this region are also important in Down syndrome.

Down Syndrome Characteristic Features

Despite the variability in Down syndrome, individuals with Down syndrome have a widely recognized characteristic appearance. Typical facial features include a flattened nose, small mouth, protruding tongue, small ears, and upward slanting eyes. The inner corner of the eyes may have a rounded fold of skin (epicanthal fold). The hands are short and broad with short fingers, and may have a single palmar crease. White spots on the colored part of the eye called Brushfield spots may be present. Babies with Down syndrome often have decreased muscle tone at birth. Normal growth and development is usually delayed and often individuals with Down syndrome don't reach the average height or developmental milestones of unaffected individuals.

Down Syndrome and Cognitive Impairment

Down syndrome is the leading cause for impaired cognition. Cognitive development is usually delayed and learning difficulties persist throughout life. Scientists are trying to determine what causes this dysfunction. The average brain volume of a person with Down syndrome is small and certain brain structures such as the hippocampus and the cerebellum do not function properly. The hippocampus in particular, is important for learning and memory. Through human studies and mouse models of Down syndrome, scientists are trying to find out which genes on the extra chromosome 21 affect cognition in Down syndrome.

Medical Conditions Associated with Down Syndrome

  • Up to half of people with Down syndrome are born with a heart defect. The atrioventricular septal defect is the most common heart defect found in newborns with Down syndrome. Other heart defects include ventricular septal defect, atrial septal defect, tetralogy of Fallot, and patent ductus arteriosus. Some newborns with these types of heart defects will require surgery shortly after birth.
  • Gastrointestinal abnormalities also occur quite frequently in Down syndrome. Esophageal atresia, tracheoesophageal fistula, duodenal atresia or stenosis, Hirschsprung's disease, and imperforate anus are some of the more common conditions. Approximately some people with Down syndrome develop celiac disease. Surgery may be necessary for some of these gastrointestinal conditions.
  • Children with Down syndrome are also at an increased risk of developing acute lymphoblastic leukemia, myeloid leukemia, and testicular cancer; however, the risk of developing most solid tumors is reduced in individuals with Down syndrome.
  • Other medical conditions include, infantile spasms, frequent ear infections (otitis media), hearing loss, visual impairment, sleep apnea, underactive thyroid (hypothyroidism), cervical spine-instability, constipation, obesity, seizures, dementia, and early-onset Alzheimer's disease.
  • Coexisting psychiatric and behavior disorders occur in a significant percentage of individuals with Down syndrome. These include attention deficit hyperactivity disorder (ADHD), autism spectrum disorders, stereotypical movement disorders, obsessive compulsive disorder (OCD), and depression.

Adults with Down Syndrome

Adults with Down syndrome age prematurely. This leads to an increased risk for memory loss, dementia, late-onset seizures (tonic-clonic seizures in particular), and hypothyroidism. Many individuals will show signs of dementia and develop early-onset Alzheimer's disease by age 40. By the age of 60, a majority of adults with Down syndrome will develop Alzheimer's disease. Since individuals with Down syndrome are already cognitively impaired, it is challenging to diagnose dementia in this population.

Down Syndrome Treatment

There is currently no treatment for Down syndrome. Although the genetic cause of Down syndrome is known, scientists are only just beginning to understand which extra genes are responsible for which aspect of Down syndrome. A large part of current research focuses on understanding how cognition is impaired in Down syndrome and on finding therapies that might improve cognition. With the help of Down syndrome mouse models, some progress has been made toward finding potential drugs that might improve cognition, but it is too early for human studies.

Some individuals with cardiac and gastrointestinal anomalies will need corrective surgery soon after birth. Regular screening for vision problems, hearing loss, ear infections, hypothyroidism, and other medical conditions should be performed.

Early intervention programs, such as physical therapy, occupational therapy, and speech therapy, are helpful. Special education and training for children with intellectual and developmental disabilities is offered in most communities.

Adolescents and young adults should receive proper education regarding sexual development and contraception.

Inclusion in family and community life is very important for the well-being of people with Down syndrome.

Outlook for a Person with Down Syndrome

The overall outlook for individuals with Down syndrome has improved dramatically in recent years due to better medical treatment and social inclusion. However, life expectancy is still reduced compared to the normal population.

Congenital heart disease is the major cause for early death.

Many people with Down syndrome show signs of dementia and symptoms of Alzheimer's disease by age 40 years.

Down Syndrome Screening

Diagnosis of Down syndrome before birth can be very useful. Parents can learn about Down syndrome before the arrival of their baby and prepare accordingly; particularly to assess immediate medical needs such as heart and gastrointestinal conditions.

Prenatal Screening

  • Expanded alpha-fetoprotein screening (AFP) is the most widely used test to screen for Down syndrome. A small blood sample is taken from the mother between 15 and 20 weeks of pregnancy. The levels of AFP as well as three hormones called unconjugated estriol, human chorionic gonadotropin, and inhibin-A are measured in the blood sample. Altered levels of AFP and the three hormones can indicate Down syndrome. A normal test result does not exclude Down syndrome.
  • The nuchal translucency test measures the thickness of the neck fold via ultrasound. Combined with the mother's age, it identifies about 80% of Down syndrome fetuses.
  • Shortened humerus (arm bone) or femur (leg bone) length measured via ultrasound, detects about 31% of Down syndrome cases.

Prenatal Diagnosis

Several invasive diagnostic tests reliably detect Down syndrome. Most of these procedures carry a small risk of pregnancy loss.

  • Amniocentesis is usually performed between 16 and 20 weeks of pregnancy. A needle is inserted through the abdominal wall and a small sample of amniotic fluid is collected for analysis.
  • Chorionic villus sampling (VCS) is another reliable test to detect chromosomal abnormalities such as Down syndrome. The main advantage over amniocentesis is that it can be done earlier, usually between 11 and 12 weeks of pregnancy.
  • In percutaneous umbilical blood sampling, fetal blood is collected from the umbilical cord and examined for chromosomal abnormalities such as Down syndrome. It is performed after 17 weeks of pregnancy.
  • Fluorescent in situ hybridization (FISH analysis) can be done quickly to determine how many copies of a particular chromosome are present. This test is usually performed on the same sample taken from blood, during amniocentesis, or during CVS.
Reviewed on 9/11/2017


Mundakel, G.T. "Down Syndrome." Medscape. Updated: Jan 17, 2017.

Korbel, J., et al. Proceedings of the National Academy of Sciences, July 2009; vol 106 no.29: pp 12031-12036.

Sheridan, R., et al. Journal of Medical Genetics, May 1989; vol 26: pp 294-298.

Wiseman, F., et al. Human Molecular Genetics, April 2009; vol 18: pp R75-R83.

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