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Down syndrome is an anomaly of chromosome 21 that causes mental retardation, microcephaly, short stature, and characteristic facies. Diagnosis is suggested by physical anomalies and abnormal development and confirmed by karyotype analysis. Treatment depends on specific manifestations and anomalies.

Overall incidence among live births is about 1/800 but increases as maternal age increases. At 20 yr 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, just 20% of infants with Down syndrome are born to mothers > 35 yr.

Etiology

In about 95% of cases, there is an extra whole chromosome 21 (trisomy 21), which is almost always maternally derived. Some people with Down syndrome have the normal 46 chromosomes, but a piece of an additional chromosome 21 has been translocated to another chromosome. 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 the cases, 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.

Down syndrome mosaicism presumably results from nondisjunction (when chromosomes fail to pass to separate cells) during cell division in the embryo. Most affected people have two cell lines, one with 46 and one with 47 chromosomes. The prognosis for intelligence probably depends on the proportion of trisomy 21 cells in the brain. A few people with mosaic Down syndrome have barely recognizable clinical signs and normal intelligence. If a parent has germ-line mosaicism for trisomy 21, an increased risk exists for a second affected child.

Pathophysiology

As with most conditions that result from chromosome imbalance, Down syndrome affects multiple systems and causes both structural and functional defects (see Table 1: Chromosomal Anomalies: Some Complications of Down Syndrome*). Not all defects are present in each person.

Table 1
Some Complications of Down Syndrome* System Deficit Cardiac Congenital heart disease, most often VSD and AV canal; increased risk of mitral valve prolapse and aortic regurgitation CNS Cognitive impairment (mild to severe) Gross motor and language delay Autistic behavior Alzheimer's disease GI Duodenal atresia or stenosis Hirschsprung's disease Celiac sprue Endocrine Hypothyroidism Diabetes EENT Ophthalmic disorders (eg, congenital cataracts, glaucoma, strabismus, refractive errors) Hearing loss Increased incidence of otitis media Growth Short stature Obesity Hematologic Hematologic disorders (neonatal polycythemia, transient leukemia, acute megakaryoblastic leukemia, acute lymphoblastic leukemia) Musculoskeletal Atlantoaxial and atlanto-occipital instability * Not all are present in a given patient, but incidence is increased compared with unaffected population. AV = atrioventricular; EENT = eyes, ears, nose, and throat; VSD = ventricular septal defect.

Most 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 significantly reduced, and the person has an increased risk of obesity. About 40 to 50% of affected neonates have congenital heart disease; ventricular septal defect and atrioventricular canal (endocardial cushion) defect are most common. About 5% of people have GI anomalies, particularly duodenal atresia, sometimes along with annular pancreas. Hirschsprung's 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. The median age at death is 49; however, many reach their 50s or 60s. Life expectancy is decreased primarily by heart disease and, to a lesser degree, by increased susceptibility to infections and acute myelocytic leukemia. Many people develop clinical signs of Alzheimer's 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 substantially shorter life spans 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 affected fetuses abort spontaneously. Men with Down syndrome are infertile, except for those with mosaicism.

Symptoms and Signs

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), although some appear normal at birth and then develop characteristic facial features during infancy. A flattened occiput, microcephaly, and extra skin around the back of the neck are common. The outer sides of the eyes are slanted upward, and epicanthal folds at the inner corners usually are present. Brushfield's spots (gray to white spots resembling grains of salt around the periphery of the iris) may be visible. The mouth is often held open because of a large, protruding, furrowed tongue that lacks the central fissure. The ears are often small and rounded. The hands are short and broad and often have a simian crease (a single, palmar crease). The fingers are 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, and a plantar furrow often extends backward on the foot. Hands and feet show characteristic dermatoglyphics.

As affected children grow, retardation of physical and mental development quickly becomes apparent. Stature is short, and the mean IQ is about 50. Behavior suggestive of attention-deficit/hyperactivity disorder is often present in childhood, and the incidence of autistic behavior is increased (particularly in those with profound intellectual disability). Depression is common among children and adults.

Down Syndrome

Symptoms of heart disease are determined by the type and extent of the cardiac anomaly. Infants with ventricular septal defects can either be asymptomatic or show signs of heart failure (eg, labored breathing, fast respiratory rate, difficulty with feeding, sweating, poor weight gain). A high-frequency, 2/6 or louder, systolic murmur may be present depending on the size of the defect. Infants with atrioventricular canal defects can show signs of heart failure or be asymptomatic. Characteristic heart sounds include a wide fixed splitting of the second sound. Murmurs may not be appreciated; however, a number of different murmurs are possible.

Infants with Hirschsprung's disease usually have delay in passage of meconium for 48 h after birth. 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.

Diagnosis

• Prenatal amniocentesis with karyotype analysis
• Sometimes neonatal karyotype analysis (if prenatal diagnosis not done)

Diagnosis may be suspected prenatally based on physical anomalies detected by fetal ultrasound (eg, nuchal translucency) or based on abnormal levels of plasma protein A in late 1st trimester and α-fetoprotein, β-hCG (human chorionic gonadotropin), unconjugated estriol, and inhibin in early 2nd trimester (15 to 16 wk gestation) on maternal serum screening. The diagnosis is confirmed by amniocentesis with karyotyping. Screening and diagnostic testing for Down syndrome are recommended for all women who present for prenatal care before 20 wk gestation regardless of maternal age. If diagnosis is not made prenatally, then neonatal diagnosis is based on physical anomalies and confirmed by karyotype analysis.

Concomitant medical conditions: Certain routine testing helps identify conditions associated with Down syndrome:

• Echocardiogram—at prenatal visit or at birth
• Thyroid screening (TSH [thyroid-stimulating hormone], or T4 [thyroxine] with TSH follow-up)—newborn, 6 mo, 12 mo, and annually thereafter
• Hearing evaluations—at birth, every 6 mo thereafter until 3 yr, then annually
• Ophthalmology evaluation—by 6 mo, then annually or more frequently as indicated
• X-ray screening for atlantoaxial instability—once between 3 and 5 yr, then as needed for sports (eg, Special Olympics) participation
• Celiac sprue screening—at 2 to 3 yr using anti-tissue transglutaminase antibodies and IgA anti-endomysial antibodies
• Growth—height and weight plotted at each health supervision visit using a Down syndrome growth chart

Treatment

The underlying disorder cannot be treated. Treatment depends on specific manifestations. Some congenital cardiac anomalies are repaired surgically. Hypothyroidism is treated with thyroid hormone replacement. Treatment should also include genetic counseling for the family, social support, and educational programming appropriate for the level of intellectual functioning (see Learning and Developmental Disorders: Intellectual Disability (ID)).

Last full review/revision December 2008 by Gregory S. Liptak, MD, MPH

Content last modified December 2008