Down Syndrome (Trisomy 21)

In approximately 95% of cases, Down syndrome is caused by nondisjunction resulting in an extra chromosome 21 (trisomy 21), which is typically maternally derived (1). Nondisjunction refers to the failure of homologous chromosomes or sister chromatids to separate properly during gamete meiosis. Affected people have 47 chromosomes instead of the normal 46.

Down Syndrome Karyotype

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Down syndrome is characterized by trisomy 21, which is an extra chromosome 21 (see arrow).

L. WILLATT, EAST ANGLIAN REGIONAL GENETICS SERVICE/SCIENCE PHOTO LIBRARY

Approximately 4% of Down syndrome cases are due to a genetic translocation (2). In a balanced translocation, genetic material is exchanged with material from another nonhomologous chromosome, and the chromosome count is maintained at 46. In an unbalanced translocation, there is either a gain or loss of genetic material, creating a genetic imbalance and subsequent clinical abnormalities.

The most common translocation is t(14;21), in which chromosome 21 is attached to chromosome 14; this is an unbalanced translocation, resulting in a chromosome count of 45. In about half of people with the t(14;21) translocation, both parents have normal karyotypes, indicating a de novo translocation. In the other half, one parent (almost always the mother), who does not have Down syndrome, has only 45 chromosomes, one of which is t(14;21). Theoretically, the chance that a carrier mother will have a child with Down syndrome is 1:3, but the actual chance is lower (approximately 1:10). If the father is the carrier, the chance is only 1:20.

The next most common translocation is t(21;22). In these cases, carrier mothers have approximately a 1:10 chance of having a child with Down syndrome; the likelihood is even smaller for carrier fathers.

Translocation 21q;21q, which occurs when the extra chromosome 21 is attached to another chromosome 21, is much less common. Determining whether a parent is a carrier or mosaic for translocation 21q;21q is important for understanding the risks to their children. A carrier parent (ie, one who has a balanced translocation) has a 100% chance of having a child with Down syndrome because all viable offspring would have either Down syndrome or monosomy 21. Monosomy 21 is typically incompatible with life.

Down syndrome mosaicism presumably results from nondisjunction during cell division in the embryo. People with Down syndrome mosaicism have 2 cell lines: one with the normal 46 chromosomes and one with 47 chromosomes, including an extra chromosome 21, or a different number of chromosomes, depending on the translocation. Although their risk of having a child with Down syndrome is markedly increased, the parent may also have children with normal chromosomes. In people with Down syndrome mosaicism, the prognosis for intelligence and risk of medical complications probably depends on the proportion of abnormal (eg, trisomy 21) cells in each different tissue, including the brain. However, in practice, this risk cannot be predicted because it is not feasible to determine the karyotype in every single cell in the body. Some people with Down syndrome mosaicism have very subtle clinical signs and may have normal intelligence; however, even people with Down syndrome without mosaicism can have variable clinical findings. This is also true for affected people who are not mosaic.

As with most conditions that result from chromosome imbalance, Down syndrome affects multiple systems and causes both structural and functional defects (see table Some Complications of Down Syndrome). Not all defects are present in each person.

Most affected people have some degree of cognitive impairment, ranging from severe (IQ 20 to 35) to mild (IQ 50 to 75). Gross motor and language delays also are evident early in life. Height is often reduced, and there is an increased risk of obesity.

Approximately 50% of affected neonates have congenital heart disease; ventricular septal defect and atrioventricular septal defect (also called endocardial cushion defect or atrioventricular canal defect) are most common (1, 2).

Approximately 6% of affected people have gastrointestinal anomalies, particularly duodenal atresia, sometimes along with annular pancreas. Hirschsprung disease and celiac disease are also more common (3).

Many people develop endocrinopathies, including thyroid disease (most often hypothyroidism) and diabetes.

Atlanto-occipital and atlantoaxial hypermobility, as well as bony anomalies of the cervical spine, can cause atlanto-occipital and cervical instability; weakness and paralysis may result.

Approximately 60% of people have eye problems, including congenital cataracts, glaucoma, strabismus, and refractive errors (4); however, this prevalence may vary among different populations (5).

Most people have hearing loss, and ear infections are very common.

• Fetal ultrasound

• Maternal serum screening

• Noninvasive prenatal screening (NIPS)

• Prenatal chorionic villus sampling and/or amniocentesis with karyotyping

• Percutaneous umbilical blood sampling (cordocentesis) with karyotyping

• Postnatal karyotyping

(See also Next-generation sequencing technologies.)

Fetal ultrasound and material serum testing, as well as NIPS, are offered to all pregnant people in high-resource settings as screening tests for chromosome abnormalities including Down syndrome.

Fetal ultrasound can detect anomalies including increased nuchal translucency, atrioventricular septal defect, and duodenal atresia, but they may not be present in all fetuses with trisomy 21.

Maternal serum testing may show abnormal levels of plasma protein A in late first trimester and alpha-fetoprotein, beta-hCG (human chorionic gonadotropin), unconjugated estriol, and inhibin in early second trimester (15 to 16 weeks gestation). may show abnormal levels of plasma protein A in late first trimester and alpha-fetoprotein, beta-hCG (human chorionic gonadotropin), unconjugated estriol, and inhibin in early second trimester (15 to 16 weeks gestation).

NIPS, in which cell-free fetal DNA obtained from the maternal circulation is tested for aneuploidy, is now the screening option of choice for trisomy 21 in high-resource settings because it has good sensitivity and specificity (1).

If Down syndrome is suspected based on maternal serum screening tests, ultrasound, or NIPS, fetal or postnatal diagnostic confirmatory testing is recommended. Fetal confirmatory methods include chorionic villus sampling and/or amniocentesis with testing by karyotype analysis as the test of choice, but confirmation can also be made by FISH and chromosomal microarray analysis.

Percutaneous umbilical blood sampling (PUBS), also known as cordocentesis, is an invasive procedure that is used to obtain fetal blood directly from the umbilical cord, allowing for rapid karyotyping and confirmation of trisomy 21. PUBS is typically reserved for situations where other diagnostic methods are inconclusive or when rapid results are required, but it has a higher risk profile and is generally performed later in gestation (after 18 weeks).

Karyotyping is the test of choice to rule out an associated translocation so that parents can receive appropriate genetic counseling regarding recurrence risk. The option of prenatal confirmatory testing is offered to all patients with an abnormal, indeterminate, or unclear NIPS result. Management decisions, should not be based only on the NIPS result.

Chromosomal microarray analysis is able to detect deletions and duplications on a submicroscopic level and has replaced conventional karyotyping in many countries (2); however, karyotyping is still the test of choice when aneuploidy is suspected.

In high-resource settings, maternal serum screening and diagnostic testing for Down syndrome are usually available to all patients who present for prenatal care before 20 weeks gestation regardless of maternal age.

The American College of Obstetricians and Gynecologists Committee on Practice Bulletins advises that cell-free fetal DNA analysis be offered to all pregnant patients regardless of age or additional risk factors (3).

If diagnosis is not made prenatally, then neonatal diagnosis is based on physical anomalies and confirmed by cytogenetic testing, preferably karyotyping.

• Treatment of specific manifestations

• Screening for complications and associated diseases

• Genetic counseling

The underlying genetic abnormality cannot be cured. Treatment approaches that are focused on management of specific manifestations and surveillance for complications or associated diseases are fairly uniform for all children (see Concomitant medical conditions).

Some congenital cardiac or gastrointestinal anomalies are repaired surgically. Other diseases (eg, hypothyroidism, celiac disease, leukemia) are treated as appropriate.

Care of children with Down syndrome and their families should also include genetic counseling for the family, social support, and educational programming appropriate for the level of intellectual functioning (see Intellectual Disability).

The aging process may be accelerated (1). In recent decades, and according to studies of people who live in high-resource settings, the median life expectancy has increased to about 60 years, and some affected people have been known to live into their 80s (2). Comorbidities contributing to decreased life expectancy include heart disease, increased susceptibility to infections, and leukemia. There is an increased risk of Alzheimer disease at an early age, and, at autopsy, brains of adults with Down syndrome show typical microscopic findings (eg, cerebral amyloid angiopathy) (3). Research indicates that Black people with Down syndrome have a substantially shorter life span than White people (4, 5). This finding may be the result of social determinants of health, including the impacts of decreased health care access, quality, and utilization.

Affected women have an approximately 50% chance of having a fetus that also has Down syndrome; however, there appears to be an increased risk of spontaneous abortion. Men with Down syndrome are typically infertile because of impaired spermatogenesis, except for those with mosaicism.