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Down Syndrome

(Trisomy 21; Trisomy G)

by Nina N. Powell-Hamilton, MD, FAAP, FACMG

Down syndrome is an anomaly of chromosome 21 that causes intellectual disability, 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 the risk increases with increasing maternal age. 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, the majority of children with Down syndrome are born to women < 35 yr; only about 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. Such people have 47 chromosomes.

The remaining 5% 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 46 chromosomes and one with 47 chromosomes. 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 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 Some Complications of Down Syndrome*). Not all defects are present in each person.

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)

Motor and language delay

Autistic behavior

Alzheimer disease

GI

Duodenal atresia or stenosis

Hirschsprung disease

Celiac disease

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

Thrombocytopenia

Neonatal polycythemia

Transient leukemia

Acute megakaryoblastic leukemia

Acute lymphoblastic leukemia

Musculoskeletal

Atlantoaxial and atlanto-occipital instability

Joint laxity

*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 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, more recently, some affected people have been living into their 70s. Life expectancy is decreased primarily by heart disease and, to a lesser degree, by increased susceptibility to infections and acute myelocytic 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 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 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 children with profound intellectual disability). Depression is common among children and adults.

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 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 chorionic villus sampling and/or amniocentesis with karyotype analysis

  • Neonatal karyotype analysis (when indicated)

  • Free fetal DNA analysis of maternal blood sample

Diagnosis may be suspected prenatally based on physical anomalies detected by fetal ultrasonography (eg, increased 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. Confirmatory methods include chorionic villus sampling and/or amniocentesis with karyotyping. More recently, free fetal DNA obtained from a maternal blood sample has been used for prenatal diagnosis of trisomy 21. In these cases, neonatal karyotyping is recommended primarily to rule out an associated translocation for appropriate genetic counseling regarding recurrence risk. 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 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) :

  • Echocardiogram—at prenatal visit or at birth

  • Thyroid screening (thyroid-stimulating hormone [TSH], or thyroxine [T 4 ] with TSH follow-up)—at birth, 6 mo, 12 mo, and annually thereafter

  • Hearing evaluations—at birth, every 6 mo thereafter until normal hearing established (about age 4 yr), then annually

  • Ophthalmology evaluation—by 6 mo, then annually until age 5; then every 2 yr until age 13 and every 3 yr until age 21 (more frequently as indicated)

  • Growth—height, weight, and head circumference plotted at each health supervision visit using a Down syndrome growth chart

  • Evaluation for obstructive sleep apnea completed by age 4

Routine screening for atlantoaxial instability and celiac disease is no longer recommended. Children are tested based on clinical suspicion, and 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

The underlying disorder cannot be treated. Management depends on specific manifestations. 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 (ID)).

Key Points

  • Down syndrome involves an extra chromosome 21, either a whole chromosome or a translocation onto another chromosome.

  • Diagnosis should be established prenatally by free fetal DNA analysis (from maternal blood) confirmed by karyotyping from chorionic villus sampling or amniocentesis.

  • Life expectancy is decreased primarily by heart disease and, to a lesser degree, by increased susceptibility to infections and acute myelocytic leukemia.

  • 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.

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