Down Syndrome

Down syndrome was first described in 1866. The cause of Down syndrome (trisomy 21) was discovered in 1959. Down syndrome is relatively well known, with distinctive characteristics such as mental retardation, distinguishing facial features, and other traits. In the United States, Down syndrome occurs in 1 in 800 live births, and approximately 6000 children are born with Down syndrome each year. About 85% of infants with Down syndrome survive 1 year, and 50% of people with Down syndrome live longer than 50 years.

Down syndrome is a genetic disorder caused by extra genetic material (DNA) (ie, presence of an extra 21st chromosome). Chromosomes, which are microscopic thread-like structures that are present in every cell of the body except red blood cells, carry genes. Genes are necessary for development. Human cells normally have 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).

Trisomy 21

In Down syndrome, 95% of all cases are caused by either the sperm or the egg cell having two 21st chromosomes instead of one, so the resulting fertilized egg has three 21st chromosomes. Hence the scientific name, trisomy 21. Recent research has shown that in these cases, approximately 90% of the time the abnormal cells are the eggs. The cause of the extra chromosome isn't known, but there is definitely connection with the mother's age.

Robertsonian translocation and partial trisomy 21

A different kind of genetic error occurs in 3-4% of cases of Down syndrome. In this case, the genetic material (genes carried on chromosomes) is rearranged so that some of the 13th, 14th, or 15th chromosome is replaced by an extra copy of genetic material from the 21st chromosome. The overall number of chromosomes remains normal (46 chromosomes in 23 pairs), but there are 3 copies of the 21st chromosome material. Sometimes the extra genetic material only comes from part of the long arm of the 21st chromosome (21q), and this is called partial trisomy 21.

Mosaicism and trisomy 21

Mosaicism causes the remaining cases of Down syndrome. In these cases, people have a mixture of cells (cell lines). Some cells have a normal set of chromosomes, and other cells have trisomy 21. In cellular mosaicism, the mixture is seen in different cells of the same type. In tissue mosaicism, one set of cells, such as all blood cells, may have normal chromosomes, and another type, such as all skin cells, may have trisomy 21.

In trisomy 21, there is extra genetic material from chromosome 21. This extra material means that there are more genes expressed than normal. For most genes, this overexpression has little effect because the body regulates genes and their products. But the genes that cause Down syndrome appear to be exceptions.

Scientists have been trying to determine exactly which genes are involved in Down syndrome ever since the third 21st chromosome (trisomy 21) was found. Current research has led to a theory that only certain areas of chromosome 21 need to be tripled to get the effect of Down syndrome. These regions are called the Down syndrome critical region. Exactly which genes cause Down syndrome when tripled is not known, but some genes are suspected.

Genes that may have input into Down syndrome include:

• SOD1 (superoxide dismutase 1 gene) overexpression may cause premature aging and decreased function of the immune system.
  
  
• COL6A1 (alpha-1 collagen VI gene) overexpression may be the cause of heart defects.
  
  
• ETS2 (ETS2 oncogene) overexpression may be the cause of skeletal abnormalities.
  
  
• CAF1A (chromatin assembly factor 1, p60 subunit) overexpression may cause problems with DNA synthesis.
  
  
• CBS (cystathione beta synthase) overexpression may disrupt metabolism and DNA repair.
  
  
• DYRK1A (dual-specificity tyrosine phosphorylation-regulated kinase 1A) overexpression may be the cause of mental retardation.
  
  
• CRYA1 (alpha-1 crystallin) overexpression may be the cause of cataracts.
  
  
• GART (glycinamide ribonucleotide synthetase) overexpression may disrupt DNA synthesis and repair.
  
  
• IFNAR (interferon alpha receptor) overexpression may interfere with the immune system as well as other organ systems.

Remember that no gene has yet been fully linked to any feature associated with Down syndrome.

Figuring out which genes may be associated with Down syndrome is difficult because, although there are certain characteristics associated with Down syndrome, people with Down syndrome have a wide variety of features and a wide range of mental retardation and developmental delay is possible. Some babies are born with heart defects and others aren't. Some children have associated illnesses such as hypothyroidism, and others don't. There are some possible explanations for this variability.

Genes come in different versions (alleles). For example, one allele for eye color produces blue eyes and one allele produces brown eyes. The variety of features in Down syndrome may be related to which version (allele) of a gene is present in triplicate. Also, some alleles cause a condition in some people but not in others, which is called reduced or incomplete penetrance. Reduced penetrance appears to occur with trisomy 21: the extra alleles don't do the same thing to every person who has them. Both the type of allele and the penetrance of the allele may be why there is such variation in children and adults with Down syndrome.

Despite the variability in Down syndrome, children with Down syndrome have a widely recognized characteristic appearance. The head may be smaller than normal (microcephaly) and abnormally shaped. Typical facial features include a flattened nose, protruding tongue, and upward slanting eyes. The inner corner of the eyes may have a rounded fold of skin (epicanthal fold) rather than coming to a point. The hands are short and broad with short fingers, and they often have a single crease in the palm. Normal growth and development is usually retarded, and most affected children never reach average adult height.

Heart defects present from birth are often present in people with Down syndrome. Early death is often caused by cardiac abnormalities. Gastrointestinal abnormalities (such as obstruction of the esophagus, called esophageal atresia, and obstruction of the duodenum, called duodenal atresia) are also relatively common. Obstruction of the gastrointestinal tract may require major surgery shortly after birth. Acute lymphocytic leukemia is also more common in children with Down syndrome.

There is no specific treatment for Down syndrome. Early intervention programs, such as physical therapy, occupational therapy, and speech therapy, are helpful. Special education and training is offered in most communities for mentally handicapped children. Because the risk of vision problems, hearing loss, infection, and hypothyroidism (low thyroid hormone) is increased, screening and treatment may be necessary.

Timely surgeries for cardiac and gastrointestinal anomalies are necessary to prevent serious complications. Digitalis and diuretics are usually needed for the medical management of cardiac anomalies along with prophylaxis for subacute bacterial endocarditis.

People with Down syndrome should have plenty of opportunities to participate in community life. Children with Down syndrome should participate in social activities, sports, and other aspects of society during the growing years.

Prognosis

• The overall outlook for individuals with Down syndrome has improved dramatically in recent years. Many adult patients are healthier, have more active roles in society, and have increased lifespan. 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 begin to develop progressive loss of mental function similar to Alzheimer disease by age 40 years, and 75% of people with Down syndrome show signs and symptoms of Alzheimer disease (see Dementia and Alzheimer Disease in Individuals with Down Syndrome).

• Prenatal screening and diagnosis
  
  
  • Because Down syndrome is associated with getting pregnant at an older age, older women should generally have screening with amniocentesis. Amniocentesis (routinely performed at 14-16 weeks' gestation) is the most commonly used and most reliable invasive diagnostic test. The procedure is associated with a small risk of pregnancy loss (1 in 200-300). Other invasive diagnostic tests include chorion villi biopsy (CVS) in the first trimester and cordocentesis (collection of fetal blood from the umbilical vein with an ultrasound-guided needle). Fluorescence in situ hybridization (FISH) analysis may be performed to analyze interphase cells (uncultured cells) and metaphase spreads (cultured cells) for speedy results. However, these results should be confirmed with chromosome analysis from cultured fetal cells.
    
    
  • Other screening tests include testing for low maternal serum alpha-fetoprotein (MSAFP), high human chorionic gonadotropin (hCG), and low unconjugated estriol (uE3).
    
    
  • Down syndrome may also be suspected based on prenatal ultrasonography in routine examination or in women at high risk. The prenatal ultrasound markers include the following:
    
    
    • Nuchal (neck) fold thickening - Identifies 75% of Down syndrome fetuses
      
      
    • Shortened humerus or femur (leg bones) length - Detect about 31% of cases
      
      
    • Cystic hygroma (cystic structure in neck region)
      
      
    • Duodenal atresia or stenosis (double bubble sign)
      
      
    • Cardiac defects - The most common defects are endocardial cushion defect with atrial and ventricular septal defects.
      
      
    • Echogenic bowel (the bowel reflects sound waves)
      
      
    • Renal pyelectasis (dilatation of the pelvis of the kidney)
  
  
• Risk for Down syndrome
  
  
  • Advanced maternal age remains the only well-documented risk factor for Down syndrome.
    
    
    • With a maternal age of 35 years, risk is 1 in 385.
      
      
    • With a maternal age of 40 years, risk is 1 in 106.
      
      
    • With a maternal age of 45 years, risk is 1 in 30.
      
      
  • Couples who have had one child with the most common type of Down syndrome are at a slightly increased risk (about 1%) for having another affected child. A carrier parent with a translocation has much higher risk of having a baby with Down syndrome, depending on the type of translocation. The recurrence risk is as high as 100% if the carrier parent has 21q21q translocation (between the two 21st chromosomes) or isochromosome (an abnormal chromosome consisting of two identical long arms of the 21st chromosome due to duplication of the long arm and the loss of the short arm). So prenatal screening and genetic counseling are important. Talk to your doctor.
    
    
  • People with Down syndrome rarely reproduce. From 15-30% of women with trisomy 21 are fertile, and they have a 50% risk of having an affected child. No evidence exists of an affected man fathering a child.

The National Down Syndrome Society
666 Broadway, 8th Floor
New York, NY 10012-2317
Phone: 212-460-9330 or 800-221-4602
Fax: 212-979-2873
E-mail: info@ndss.org

National Down Syndrome Congress
1370 Center Drive, Suite 102
Atlanta, GA 30338
Phone: 770-604-9500 or 800-232-NFSC
E-mail: NDSCcenter@aol.com

National Association for Down Syndrome
PO Box 4542
Oak Brook, IL 60522

International Resource Center for Down Syndrome
Case Western Reserve University School of Medicine
Cleveland, OH 44106-4921
Phone: 216-368-8806 or 800-288-8804

The Arc National Headquarters
PO Box 1047
Arlington, TX 76004

|Web Links|

The National Down Syndrome Society

National Down Syndrome Congress

National Association for Down Syndrome

The Arc National Headquarters

The Down Syndrome World Wide Web page

Down Syndrome: Health Issues

Down Syndrome on the Internet

Down Syndrome Information Network

Down’s syndrome, Down syndrome, mongolism, trisomy 21, mental retardation, mosaicism, mental disability, mental handicap, mentally handicapped, dementia, Alzheimer disease in individuals with Down syndrome, Alzheimer disease, Alzheimer's disease

Author: Harold Chen, MD, MS, FAAP, FACMG, Chief, Professor, Department of Pediatrics, Section of Perinatal Genetics, Louisiana State University Medical Center.

Coauthor(s): Jessica B Johnson, Medical Writer, .com, Inc.

Editors: Robert A Hauser, MD, Director, Parkinson's Disease and Movement Disorders Center, Tampa General Hospital; Professor, Departments of Neurology, Pharmacology, and Experimental Therapeutics, University of South Florida; Mary L Windle, Pharm D, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy; Pharmacy Editor, .com, Inc; Rajesh Pahwa, MD, Professor of Neurology, Director, Parkinson Disease and Movement Disorder Center, Department of Neurology, University of Kansas Medical Center.