Down syndrome is an anomaly of chromosome 21 that can cause intellectual disability, microcephaly, short stature, and characteristic facies. Diagnosis is suggested by physical anomalies and abnormal development and confirmed by cytogenetic analysis. Management depends on specific manifestations and anomalies.
(See also Overview of Chromosomal Anomalies.)
Overall incidence among live births is about 1/700, and the risk increases gradually with increasing maternal age. At 20 years of maternal age, the risk is 1/2000 births; at 35, it is 1/365; and at 40, it is 1/100. However, because most births occur among younger women, the majority of children with Down syndrome are born to women < 35 years; only about 20% of infants with Down syndrome are born to mothers > 35 years.
Etiology of Down Syndrome
In about 95% of cases, there is an extra separate chromosome 21 (trisomy 21), which is typically maternally derived. Such people have 47 chromosomes instead of the normal 46.
About 3% of people with Down syndrome have the normal count of 46 chromosomes but have an extra chromosome 21 translocated to another chromosome (the resulting abnormal chromosome is still counted only as 1).
The most common translocation is t(14;21), in which a piece of an additional chromosome 21 is attached to chromosome 14. 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), although phenotypically normal, 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 risk is lower (about 1:10). If the father is the carrier, the risk is only 1:20.
The next most common translocation is t(21;22). In these cases, carrier mothers have about a 1:10 risk of having a child with Down syndrome; the risk is smaller for carrier fathers.
A 21q21q translocation chromosome, which occurs when the extra chromosome 21 is attached to another chromosome 21, is much less common. It is particularly important to determine whether a parent is a carrier of, or mosaic for, translocation 21q21q (such mosaics have some normal cells and some 45 chromosome cells with the 21q21q translocation). In such cases, each offspring of a carrier of the translocation will either have Down syndrome or monosomy 21 (the latter is not typically compatible with life). If the parent is mosaic, the risk is similar, although these people may also have offspring with normal chromosomes.
Down syndrome mosaicism presumably results from nondisjunction (when chromosomes fail to pass to separate cells) during cell division in the embryo. People with mosaic Down syndrome have two cell lines, one with the normal 46 chromosomes and another with 47 chromosomes, including an extra chromosome 21. The prognosis for intelligence and risk of medical complications probably depends on the proportion of trisomy 21 cells in each different tissue, including the brain. However, in practice, risk cannot be predicted because it is not feasible to determine the karyotype in every single cell in the body. Some people with mosaic Down syndrome have very subtle clinical signs and may have normal intelligence; however, even people with no detectable mosaicism can have very variable findings. If a parent has germline mosaicism for trisomy 21, an increased risk, above the maternal age-based risk, exists for a second affected child.
Pathophysiology of Down Syndrome
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.
Some Complications of Down Syndrome*
Congenital heart disease, most often ventricular septal defect and atrioventricular canal defect
Central nervous system
Cognitive impairment (mild to severe)
Motor and language delay
Duodenal atresia or stenosis
Eyes, ears, nose, and throat
Increased incidence of otitis media
Transient myelodysplastic disorder
Acute megakaryoblastic leukemia
Atlantoaxial and atlanto-occipital instability
* Not all complications are present in a given patient, but incidence is increased compared with unaffected population.
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.
About 50% of affected neonates have congenital heart disease; ventricular septal defect and atrioventricular canal (endocardial cushion) defect are most common.
About 5% of affected people have gastrointestinal anomalies, particularly duodenal atresia, sometimes along with annular pancreas. Hirschsprung disease and celiac disease also are more common. 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. About 60% of people have eye problems, including congenital cataracts, glaucoma, strabismus, and refractive errors. Most people have hearing loss, and ear infections are very common.
The aging process seems to be accelerated. In recent decades, the median life expectancy has increased to about 60 years, and some affected people live into their 80s. Comorbidities contributing to decreased life expectancy include heart disease, increased susceptibility to infections, and acute myelogenous 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. The results of recent research indicate that blacks with Down syndrome have a substantially shorter life span than whites. This finding may be the result of poor access to medical, educational, and other support services.
Affected women have a 50% chance of having a fetus that also has Down syndrome; however, many pregnancies are spontaneously lost. Men with Down syndrome are infertile, except for those with mosaicism.
Symptoms and Signs of Down Syndrome
Affected neonates tend to be placid, rarely cry, and have hypotonia. Most have a flat facial profile (particularly flattening of the bridge of the nose), but some do not have obviously unusual physical characteristics at birth and then develop more noticeable characteristic facial features during infancy. A flattened occiput, microcephaly, and extra skin around the back of the neck are common. The eyes are slanted upward, and epicanthal folds at the inner corners usually are present. Brushfield spots (gray to white spots resembling grains of salt around the periphery of the iris) may be visible. The mouth is often held open with a protruding, furrowed tongue that may lack the central fissure. The ears are often small and rounded.
The hands are often short and broad and often have a single transverse palmar crease. The fingers are often short, with clinodactyly (incurving) of the 5th digit, which often has only 2 phalanges. The feet may have a wide gap between the 1st and 2nd toes (sandal-gap toes), and a plantar furrow often extends backward on the foot.
Growth and development
As affected children grow, delay of physical and mental development becomes apparent. Stature is often short. The mean IQ is about 50, but this varies widely. Behavior suggestive of attention-deficit/hyperactivity disorder is often present in childhood, and the incidence of autistic behavior is increased (particularly in children with profound intellectual disability). There is an increased risk of depression in children and adults.
Symptoms of heart disease are determined by the type and extent of the cardiac anomaly.
Infants with congenital heart defects, the most common of which are ventricular septal defects and atrioventricular canal defects, can either be asymptomatic or show signs of heart failure (eg, labored breathing, fast respiratory rate, difficulty with feeding, sweating, poor weight gain).
Murmurs may not be appreciated; however, a number of different murmurs are possible.
Infants with Hirschsprung disease usually have delay in passage of meconium. Severely affected infants may have signs of intestinal obstruction (eg, bilious vomiting, failure to pass stool, abdominal distention).
Duodenal atresia or stenosis can manifest with bilious vomiting or with no symptoms, depending on the extent of the stenosis. These defects may be detected by prenatal ultrasonography (double-bubble sign).
Diagnosis of Down Syndrome
- Prenatal chorionic villus sampling and/or amniocentesis with karyotyping
- Postnatal karyotyping (if prenatal karyotyping not done)
(See also Next-generation sequencing technologies.)
Diagnosis of Down syndrome may be suspected prenatally based on physical anomalies detected by fetal ultrasonography (eg, increased nuchal translucency, atrioventricular canal defect, duodenal atresia) or based on abnormal levels of plasma protein A in late 1st trimester and alpha-fetoprotein, beta-hCG (human chorionic gonadotropin), unconjugated estriol, and inhibin in early 2nd trimester (15 to 16 weeks gestation) on maternal serum screening. More recently, noninvasive prenatal screening (NIPS), in which fetal DNA obtained from the maternal circulation is tested, has become a screening option for trisomy 21 because it has good sensitivity and specificity.
If Down syndrome was suspected based on maternal serum screening tests or ultrasonography, fetal or postnatal confirmatory testing is recommended. Fetal confirmatory methods include chorionic villus sampling and/or amniocentesis with testing by karyotype analysis. 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, including termination of pregnancy, should not be made based on NIPS alone.
Maternal serum screening and diagnostic testing for Down syndrome are options for all women who present for prenatal care before 20 weeks gestation regardless of maternal age.
The American College of Obstetricians and Gynecologists Committee on Genetics and the Society for Maternal–Fetal Medicine practice bulletin advises that cell-free fetal DNA testing be offered to patients at increased risk of aneuploidy. At-risk patients include women ≥ 35 years and in cases where fetal ultrasonographic findings indicate an increased risk. The committee advises that cell-free fetal DNA does not replace the accuracy and diagnostic precision of prenatal diagnosis with chorionic villus sampling or amniocentesis.
If diagnosis is not made prenatally, then neonatal diagnosis is based on physical anomalies and confirmed by cytogenetic testing.
Concomitant medical conditions
Certain age-specific routine screening helps identify conditions associated with Down syndrome (see the 2011 American Academy of Pediatrics Guidelines Health Supervision for Children with Down Syndrome):
- Echocardiography: At prenatal visit or at birth
- Thyroid screening (thyroid-stimulating hormone [TSH] levels): At birth, 6 months, 12 months, and annually thereafter
- Hearing evaluations: At birth, every 6 months thereafter until normal hearing established (about age 4 years), then annually (more frequently if indicated)
- Ophthalmology evaluation: By 6 months, then annually until age 5; then every 2 years until age 13 and every 3 years until age 21 (more frequently if indicated)
- Growth: Height, weight, and head circumference plotted at each health supervision visit using a Down syndrome growth chart
- Sleep study for obstructive sleep apnea: Completed by age 4 years
Routine screening for atlantoaxial instability and celiac disease is no longer recommended; children are tested based on clinical suspicion. It is recommended that patients with a history of neck pain, radicular pain, weakness, or any other neurologic symptoms that suggest myelopathy have x-rays of the cervical spine in the neutral position; if no suspicious abnormalities are seen, they should have x-rays done in flexion and extension positions.
Treatment of Down Syndrome
- Specific manifestations treated
- Genetic counseling
The underlying disorder cannot be cured. Management depends on specific manifestations, but surveillance is fairly uniform for all children. Some congenital cardiac anomalies are repaired surgically. Hypothyroidism is treated with thyroid hormone replacement.
Care should also include genetic counseling for the family, social support, and educational programming appropriate for the level of intellectual functioning (see Intellectual Disability).
- Down syndrome involves an extra chromosome 21, either a separate chromosome or a translocation onto another chromosome.
- Diagnosis may be suspected prenatally based on anomalies detected by fetal ultrasonography (eg, increased nuchal translucency, heart defect, duodenal atresia) or based on cell-free fetal DNA analysis of maternal blood or maternal multiple marker screening for levels of plasma protein A in late 1st trimester and levels of alpha-fetoprotein, beta-human chorionic gonadotropin (beta-hCG), unconjugated estriol, and inhibin in early 2nd trimester.
- Karyotype analysis is the confirmatory test of choice and can be done prenatally by chorionic villus sampling in the 1st trimester or amniocentesis in the 2nd trimester, or postnatally on a blood sample.
- Life expectancy is decreased primarily by heart disease and, to a lesser degree, by increased susceptibility to infections, acute myelocytic leukemia, and early-onset Alzheimer disease; however, it has increased remarkably in recent decades, and some people live into their 80s.
- Do routine age-specific screening to detect associated medical conditions (eg, cardiac anomalies, hypothyroidism).
- Treat specific manifestations, and provide social and educational support and genetic counseling.
The following are some English-language resources that may be useful. Please note that THE MANUAL is not responsible for the content of these resources.
- American College of Obstetricians and Gynecologists Committee on Genetics and the Society for Maternal-Fetal Medicine Publications Committee: Practice bulletin on screening for fetal aneuploidy
- American Academy of Pediatrics: Guidelines on health supervision for children with Down syndrome