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Down Syndrome

NORD is very grateful to the National Down Syndrome Society for assistance in the preparation of this report.

Synonyms of Down Syndrome

  • chromosome 21, mosaic Down syndrome
  • chromosome 21, translocation Down syndrome
  • trisomy 21

Disorder Subdivisions

  • No subdivisions found.

General Discussion

Down syndrome is a chromosomal condition in which all or a portion of chromosome 21 appears three times (trisomy) rather than twice in cells of the body. In some individuals with this condition, only a percentage of cells may contain the chromosomal condition (mosaicism).

Symptoms and findings may vary greatly in range and degree, depending on the specific length and location of the duplicated (trisomic) portion of chromosome 21 as well as the percentage of cells containing the condition. However, in many individuals with this condition, such characteristics may include low muscle tone (hypotonia); a tendency to keep the mouth open with protrusion of the tongue; and distinctive facial characteristics including a short, small head (microbrachycephaly), upwardly slanting eyelid folds (palpebral fissures), a depressed nasal bridge, a small nose, and a relatively flat facial profile. Individuals with Down syndrome may also have unusually small, misshapen (dysplastic) ears; a narrow roof of the mouth (palate); vertical skin folds covering the inner corners of the eyes (epicanthal folds); dental abnormalities; and excessive skin on the back of the neck. Other characteristics include unusually short arms and legs; short fingers; and unusual skin ridge patterns (dermatoglyphics) on the fingers, palms, and toes. Individuals with Down syndrome may also have short stature, poor coordination, mild to severe intellectual disability, and hearing impairment.

In some cases, Down syndrome may also be characterized by structural malformations of the heart at birth (congenital heart defects). In addition, those with the condition may have an increased susceptibility to respiratory disease (e.g., pneumonia), other infectious diseases, and malignancies in which there is an increased proliferation of certain white blood cells (leukemia). Rarely do these conditions lead to potentially life-threatening complications.

Symptoms

The symptoms and findings associated with Down syndrome may be extremely variable. In addition, if only a percentage of cells contain the chromosomal condition (mosaicism), associated symptoms may tend to be less severe. However, the presence of certain co-existing conditions at or shortly after birth (neonatal period) is considered characteristic of Down syndrome. Such findings may include diminished muscle tone (hypotonia) and a poor startle (Moro) reflex; excessive flexibility of the joints; improper development (dysplasia) of the middle bone (phalanx) of the fifth fingers; the presence of a single crease across the palms; and improper development of the pelvis. Additional characteristic symptoms include distinctive characteristics of the head and facial (craniofacial) area, such as a flat facial profile; upwardly slanting eyelid folds (palpebral fissures); malformed (dysplastic) ears; and excessive skin on the back of the neck.

Some affected individuals may have additional craniofacial conditions, such as a short, small head (microbrachycephaly) with a relatively flat back region (occiput); a small nose with a depressed nasal bridge; vertical skin folds covering the eyes' inner corners (epicanthal folds); and a short, narrow roof of the mouth (palate). Individuals with Down syndrome may also have wide, dry lips; a tendency to keep the mouth open; a protruding tongue that may appear relatively large; and dental abnormalities, including delayed eruption, irregular alignment, malformation, and/or absence of certain teeth. Most affected individuals also have hearing impairment due to malformations of the outer and middle ears (conductive hearing loss).

In some cases, eye abnormalities may also be present. These may include nearsightedness (myopia); small white spots on the outer edges of the colored regions of the eyes (Brushfield spots); loss of transparency (opacities) of the lenses (cataracts); abnormal deviation of one eye in relation to the other (strabismus); and/or involuntary rapid eye movements (nystagmus).

Down syndrome is also often associated with growth delays before and after birth (prenatal and postnatal growth retardation), short stature, and delayed bone maturation. Individuals may also have short, broad hands and short fingers (brachydactyly), particularly the "pinkies," which typically bend inward (clinodactyly). There may also be unusually wide gaps between the great and second toes.

Individuals with Down syndrome may also have genital abnormalities. For example, males with Down syndrome may have an unusually small penis and failure of the testes to descend into the scrotum (cryptorchidism). In rare cases, fertility has been reported in some females with Down syndrome, however the reproductive potential of individuals with Down syndrome has probably not been fully realized due to socially limiting circumstances. Only in rare cases have males with the condition reproduced.

Approximately 50 percent of individuals with Down syndrome also have congenital heart defects. In many cases, there may be abnormal persistence of an opening between the upper heart chambers (atria) due to failed fusion of certain regions of the heart during embryonic development (i.e., endocardial cushion defects). Additional heart defects may also be present, including an abnormal opening in the fibrous partition (septum) that divides the lower chambers of the heart (ventricular septal defects) or abnormal persistence of the fetal channel that joins the main artery of the body (aorta) and the pulmonary artery (patent ductus arteriosus). In some cases, Down syndrome may also be associated with other congenital heart defects.

Some individuals may also have gastrointestinal abnormalities, such as Hirschsprung disease, a condition characterized by absence of groups of nerve cell bodies in the muscular wall of the small intestine. Due to absence of these nerve groups, there is impairment of the rhythmic contractions that propel food through the digestive tract (peristalsis). Additional findings may include an abnormal passage (fistula) between the esophagus and the windpipe (tracheoesophageal fistula); narrowing of the ring-shaped muscle at the outlet of the stomach (pyloric stenosis), obstructing the passage of food into the upper region of the small intestine (duodenum); or partial or complete closure of the anal opening (imperforate anus).

Individuals may also have defects of the immune system (immunodeficiency). Immunodeficiency in those with Down syndrome may be associated with an increased susceptibility to certain infections, including inflammation of the lungs (pneumonia) or other respiratory illnesses. In addition, individuals may have an increased risk of developing certain malignancies, particularly leukemia, which is a group of diseases characterized by an increased proliferation of certain white blood cells. In children with Down syndrome, reports indicate that leukemia mainly occurs in those who are younger than age of six, occurring in about 1 out of every 100 children with Down syndrome. In addition, a general population study has confirmed the increased frequency of leukemia in children with Down syndrome, particularly acute myeloid leukemia (AML). (AML is characterized by uncontrolled proliferation of primitive cells [myelocytes] in the bone marrow that normally develop into white blood cells known as granulocytes.) Although the numbers were not considered significant, the study also reported a somewhat higher than expected frequency of other malignancies (i.e., ovarian cancers, testicular cancers, retinoblastomas). However, the study also suggested that there is a decreased frequency of certain solid tumors in all age groups among those with Down syndrome.

Celiac disease and hypothyroidism may present in Down syndrome patients without symptoms. Celiac disease is triggered by the ingestion of wheat, rye, or barley gluten. Greater than 15% of Down syndrome patients have hypothyroidism (low thyroid function).

The condition is also typically associated with intellectual disabilities that may range from mild to severe. Affected individuals may experience delays in the acquisition of skills requiring the coordination of mental and physical abilities (psychomotor delays), have poor physical coordination, and have difficulties articulating speech. In addition, according to reports in the medical literature, older individuals with Down syndrome may tend to develop symptoms of Alzheimer's disease. These symptoms typically become apparent at an earlier age than in those without trisomy 21. Alzheimer's disease is a progressive condition in which degenerative changes of nerve cells in the brain lead to deterioration of cognitive functioning (dementia). Symptoms associated with dementia may include increasing confusion and disorientation, impairment of memory control, personality disintegration, agitation, restlessness, and other findings.

Causes

In individuals with Down syndrome, all or a critical portion of chromosome 21 is present three times (trisomy) rather than twice in cells of the body. In approximately one to two percent of cases, only a percentage of cells may contain the extra 21st chromosome (mosaicism).

Chromosomes are found in the nucleus of all body cells. They carry the genetic characteristics of each individual. Pairs of human chromosomes are numbered from 1 through 22, with an unequal 23rd pair of X and Y chromosomes for males and two X chromosomes for females. Each chromosome has a short arm designated as "p" and a long arm identified by the letter "q". Chromosomes are further subdivided into bands that are numbered.

Trisomy of a certain region or regions of chromosome 21 is responsible for the symptoms and findings that characterize the condition. The degree and range of symptoms may depend on the length and location of the duplicated portion of the chromosome as well as the percentage of cells that contain the abnormality.

Analysis of DNA samples from individuals with a partial trisomy of chromosome 21 has suggested that a minimal critical region associated with Down syndrome is in chromosome 21q22. (DNA or deoxyribonucleic acid, found in chromosomes, is the principal carrier of genetic information.) Researchers have also identified a number of genes within this region that appear to play a role in causing certain features potentially associated with the syndrome (e.g., intellectual disability, cardiac defects).

Most cases of Down syndrome result from errors during the division of reproductive cells in one of the parents (e.g., nondisjunction during meiosis). The genetic errors are not caused by any actions from the parents. The risk of such errors may increase with advanced maternal age. In other cases (e.g., mosaicism), errors may also occur during cellular division after fertilization (mitosis). In addition, in approximately four to five percent of affected individuals, the disorder results from a translocation involving chromosome 21 and another chromosome. Translocations occur when portions of certain chromosomes break off and are rearranged, resulting in shifting of genetic material and an altered set of chromosomes. Such translocations may occur spontaneously for unknown reasons (de novo) or be transmitted by a parent who is a carrier of a "balanced" translocation. (If a chromosomal rearrangement consists of an altered but balanced set of chromosomes, it is usually harmless to the carrier. However, balanced translocations may be associated with an increased risk of abnormal chromosomal development in the carrier's offspring. Chromosomal testing may determine whether a parent has a balanced translocation.)

Affected Populations

Down syndrome occurs in approximately one in 691 live births. It is considered the most common chromosomal syndrome. The incidence of Down syndrome increases with advancing maternal age.

Related Disorders

There are a number of other disorders, including other chromosomal syndromes, that may be characterized by certain symptoms and findings similar to those associated with Down syndrome. Chromosomal testing is necessary to confirm whether a specific chromosomal abnormality is present.

Standard Therapies

Diagnosis
A diagnosis of Down syndrome may be suggested before birth (prenatally) based upon specialized testing, such as fetal ultrasonography, certain blood studies, amniocentesis, and/or chorionic villus sampling (CVS).

During fetal ultrasonography, reflected sound waves create an image of the developing fetus, potentially revealing findings that may suggest a chromosomal condition or other abnormalities. (As an example, increased nuchal [neck] translucency may be considered suggestive of Down syndrome in some cases. Nuchal translucency refers to a temporary collection of fluid under the skin behind the neck of the fetus that can be measured during ultrasound.)

Blood screening tests may also be conducted that, together with age, may help to estimate a woman's chance of having a baby with Down syndrome. Such tests measure the levels of specific substances in the mother's blood, including alpha-fetoprotein (AFP); human chorionic gonadotropin (hCG); unconjugated estriol; or other markers. If such screening studies reveal abnormal levels of these markers, additional testing may be recommended, such as amniocentesis with chromosome analysis.

Prenatal diagnostics tests, such as amniocentesis or CVS, are now being offered to all pregnant women regardless of age. During amniocentesis, a sample of fluid that surrounds the developing fetus is removed and analyzed, while CVS involves the removal of tissue samples from a portion of the placenta. Chromosomal analysis performed on the fluid or tissue samples may confirm the presence of trisomy 21.

The diagnosis of Down syndrome may also be made or confirmed after birth (postnatally) based upon a thorough clinical evaluation, detection of characteristic physical findings, and chromosomal analysis. For those with the condition, careful monitoring and specialized testing may be conducted to ensure early detection and prompt, appropriate treatment of certain conditions that may be associated with Down syndrome.

Treatment
The treatment of Down syndrome is directed toward the specific symptoms that are apparent in each individual. Such treatment may require the coordinated efforts of a team of medical professionals who may need to systematically and comprehensively plan a child's treatment. These professionals may include pediatricians, physicians who diagnose and treat heart abnormalities (cardiologists), specialists who assess and treat hearing impairment (audiologists), physical therapists, and/or other health care professionals.

In some cases, recommended treatment may include surgical repair of certain craniofacial, cardiac, gastrointestinal, and/or other abnormalities associated with the disorder. The surgical procedures performed will depend upon the nature and severity of the anatomical abnormalities, their associated symptoms, and other factors.

Treatment may also include measures to help prevent or aggressively treat infections. In those who develop leukemia or other malignancies, treatment may include therapy with certain anticancer drugs or other appropriate measures.

Early intervention may be important in ensuring that children with Down syndrome reach their potential. Special services that may be beneficial include special education, speech therapy, physical therapy, and other medical, social, and/or vocational services. Genetic counseling will also be of benefit for families of children. Other treatment for this disorder is symptomatic and supportive.

Investigational Therapies

Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. Government funding, and some supported by private industry, are posted on this government web site.

For information about clinical trials being conducted at the NIH Clinical Center in Bethesda, MD, contact the NIH Patient Recruitment Office:

Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: prpl@cc.nih.gov

For information about clinical trials sponsored by private sources, contact:
www.centerwatch.com

Organizations related to Down Syndrome

References

TEXTBOOKS
Jones KL. Smith's Recognizable Patterns of Human Malformation. 5th ed. Philadelphia, PA: W.B. Saunders Company; 1997:8-13, 80.

Behrman RE, et al., eds. Nelson Textbook of Pediatrics. 15th ed. Philadelphia, PA: W.B. Saunders Company; 1996:314-15.

Buyse ML. Birth Defects Encyclopedia. Dover, MA: Blackwell Scientific Publications, Inc.; 1990:391-93.

Gorlin RJ, et al., eds. Syndromes of the Head and Neck. 3rd ed. New York, NY: Oxford University Press; 1990:33-40.

JOURNAL ARTICLES
Roizen NJ, Patterson D. Down's syndrome. The Lancet. 2003;361:1281-89.

Audibert F, et al. Screening for Down syndrome using first-trimester ultrasound and second-trimester maternal serum markers in a low-risk population: a prospective longitudinal study. Ultrasound Obstet Gynecol. 2001;18:26-31.

Schuchter K, et al. Sequential screening for trisomy 21 by nuchal translucency measurement in the first trimester and maternal serum biochemistry in the second trimester in a low-risk population. Ultrasound Obstet Gynecol. 2001;18:23-25.

Hasle H, et al. Risks of leukaemia and solid tumours in individuals with Down's syndrome. Lancet. 2000;355:165-69.

Spencer K. Second trimester prenatal screening for Down's syndrome using alpha-fetoprotein and free beta hCG: a seven year review. Br J Obstet Gynaecol. 1999;106:1287-93.

Cole LA, et al. Hyperglycosylated human chorionic gonadotropin (invasive trophoblast antigen) immunoassay: a new basis for gestational Down syndrome screening. Clin Chem. 1999;45:2109-19.

Haddow JE, et al. Screening of maternal serum for fetal Down's syndrome in the first trimester. New Engl J Med. 1998;338:955-61.

Malone FD, et al. Increased nuchal translucency and fetal chromosomal defects. New Engl J Med. 1998;338:1228-29.

Fuentes JJ, et al. Genomic organization, alternative splicing, and expression patterns of the DSCR1 (Down syndrome candidate region 1) gene. Genomics. 1997;44:358-61.

Taipale P, et al. Increased nuchal translucency as a marker for fetal chromosomal effects. New Engl J Med. 1997;337:1654-58.

Nakamura A, et al. Isolation of a novel human gene from the Down syndrome critical region of chromosome 21q22.2. J Biochem (Tokyo). 1997;122:872-77.

Aitken DA, et al. Dimeric inhibin A as a marker for Down's syndrome in early pregnancy. New Engl J Med. 1996;334:1231-36.

Fuentes JJ, et al. A new human gene from the Down syndrome critical region encodes a proline-rich protein highly expressed in fetal brain and heart. Hum Molec Genet. 1995;4:1935-44.

Mazzoni DS, et al. Abnormal pinna type and hearing loss correlations in Down's syndrome. J Intellect Disabil Res. 1994;38:549-60.

Pueschel SM. Clinical aspects of Down syndrome from infancy to adulthood. Am J Med Genet Suppl. 1990;7:52-56.

Korenberg J, et al. Molecular definition of the region of chromosome 21 that causes features of the Down syndrome phenotype. Am J Hum Genet. 1990;47:236-46.

Ashwood ER, et al. Maternal serum alpha-fetoprotein and fetal trisomy-21 in women 35 years and older: implications for alpha-fetoprotein screening programs. Am J Med Genet. 1987;26:531-39.

Wisniewski KE, et al. Occurrence of neuropathological changes and dementia of Alzheimer's disease in Down's syndrome. Ann Neurol. 1985;17:278-82.

INTERNET
Online Mendelian Inheritance in Man (OMIM). The Johns Hopkins University. Down Syndrome. Entry No: 190685. Last Edited August 5, 2011. Available at: http://www.ncbi.nlm.nih.gov/omim/. Accessed March 5, 2012.

The information in NORD’s Rare Disease Database is for educational purposes only. It should never be used for diagnostic or treatment purposes. If you have questions regarding a medical condition, always seek the advice of your physician or other qualified health professional. NORD’s reports provide a brief overview of rare diseases. For more specific information, we encourage you to contact your personal physician or the agencies listed as “Resources” on this report.

Report last updated: 2012/04/09 00:00:00 GMT+0

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