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. Treatment depends on specific manifestations and anomalies.
Overall incidence among live births is about 1/700, 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).
Pathophysiology
As with most conditions that result from chromosome imbalance, Down syndrome affects multiple systems and causes both structural and functional defects. 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. 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 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 average life expectancy is about 55 yr; however, more recently, some affected people have been living into their 70s and 80s. Life expectancy is decreased primarily by heart disease and, to a lesser degree, by 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 affected fetuses abort spontaneously. Men with Down syndrome are infertile, except for those with mosaicism.
Symptoms and Signs
• General appearance
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 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 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, and a plantar furrow often extends backward on the foot. Hands and feet show characteristic dermatoglyphics.
Growth and development
As affected children grow, delay 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.
Cardiac manifestations
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 initially. 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.
GI manifestations
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 and/or chromosomal microarray analysis
• Neonatal karyotype analysis (if prenatal karyotype analysis not done)
Diagnosis of Down syndrome 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 alpha-fetoprotein, beta-hCG (human chorionic gonadotropin), unconjugated estriol, and inhibin in early 2nd trimester (15 to 16 wk 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.
If Down syndrome was suspected based on maternal serum screening tests or ultrasonography, fetal or neonatal confirmatory testing is recommended. Confirmatory methods include chorionic villus sampling and/or amniocentesis with testing by karyotype analysis and/or chromosomal microarray analysis (CMA). Confirmatory testing is done particularly in cases where the screening result is indeterminate or unclear; in younger women, in whom the positive predictive value of NIPS is lower; and to diagnose other fetal chromosomal disorders. Management decisions, including termination of pregnancy, should not be made based on NIPS testing alone. Karyotyping can also be used to diagnose an associated translocation so parents can receive appropriate genetic counseling regarding recurrence risk.
Maternal serum 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.
The American College of Obstetricians and Gynecologists Committee on Genetics and the Society for Maternal–Fetal Medicine committee opinion advises that cell-free fetal DNA testing be offered to patients at increased risk of aneuploidy. At-risk patients include women ≥ 35 yr 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:
Echocardiography: At prenatal visit or at birth
Thyroid screening (thyroid-stimulating hormone [TSH] levels): 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 yr
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
• Specific manifestations treated
• Genetic counseling
The underlying disorder cannot be cured. 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.
Key Points
• 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) 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.
• Diagnosis should be confirmed by karyotype analysis, or chromosomal microarray analysis (CMA) from chorionic villus sampling in the 1st trimester or amniocentesis in the 2nd trimester, or postnatally by cytogenetic testing of 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.
• 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.
CLINICAL VIGNETTES
A baby is born with a flat facial profile, prominent epicanthal folds, and simian crease. She vomits when fed, and upper GI studies demonstrate a “double bubble” in the upper abdomen. Which of the following cardiovascular abnormalities might this child also have?
A. Atrial septal defect
B. Berry aneurysm
C. Coarctation of the aorta
D. Endocardial cushion defect
E. Tetralogy of Fallot
The correct answer is D. The disease is Down syndrome (trisomy 21). In addition to mental retardation and the characteristic physical findings described in the question stem, duodenal atresia is fairly common, as evidenced by the “double bubble” sign on x-ray. These children are also likely to have various cardiac anomalies; endocardial cushion defect is the most common.
Atrial septal defect (choice A) is one of the most common genetic defects in the general population, but is less common than endocardial cushion defect in patients with Down syndrome.
Berry aneurysms (choice B), also known as saccular aneurysms, are typically located in the circle of Willis on the ventral surface of the brain. They occur more frequently in patients with adult polycystic disease. Rupture can produce subarachnoid hemorrhage.
Coarctation of the aorta (choice C) occurs more commonly in females with a 45, XO genotype (Turner syndrome).
Tetralogy of Fallot (choice E) is the most common cause of early cyanosis, consisting of a ventricular septal defect, right ventricular outflow tract obstruction, an overriding aorta, and right ventricular hypertrophy.
A 45-year-old woman with polyhydramnios delivers a full-term male infant with a birth weight of 6 lb 12 oz (3.06 kg). The infant’s physical examination is pertinent for hypotonia, upward and slanted palpebral fissures and epicanthic folds, a simian crease, and a short fifth finger. A few hours after birth, the infant begins to vomit bile-stained fluid. On physical examination, the abdomen is not distended. Radiographs of the chest and abdomen were obtained, and the results revealed a “double-bubble” sign. Which of the following is the most likely diagnosis?
A) Congenital pyloric stenosis
B) Duodenal atresia
C) An intussusception
D) A diaphragmatic hernia
E) A perforated viscus
The answer is B. The patient in this question has trisomy 21, or Down syndrome, which is characterized by hypotonia, a simian crease, a short fifth finger, and upward and slanted palpebral fissures and epicanthic folds. These patients will also have differing degrees of mental and growth retardation. Duodenal atresia (choice B) is often associated with Down syndrome and appears in the first day of life as bilious vomiting after feedings without abdominal distention. Plain abdominal radiographs typically show the “double-bubble” sign, caused by a distended and gas-filled stomach and proximal duodenum. The initial treatment for patients with duodenal atresia is nasogastric or orogastric decompression and intravenous fluid replacement. The definitive treatment is duodenojejunostomy.
Pyloric stenosis (choice A) appears at 2–3 weeks of age with nonbilious vomiting. Bile-stained emesis may be seen in the later phase of intussusception (choice C); however, it is rare under 3 months of age. It is associated with colicky abdominal pain, a sausage-shaped mass, and currant-jelly stool. If a diaphragmatic hernia (choice D) presents at birth, the infant usually has a scaphoid abdomen and respiratory distress due to herniation of the abdominal contents into the chest that compresses the lungs. Bowel sounds can be auscultated in the chest, and the presence of abdominal contents in the thorax can be visualized on chest roentgenogram. A perforated viscus (choice E) will cause free air in the abdomen that is evident on plain abdominal radiographs as air under the diaphragm.
A 34-year-old primiparous woman is seeing you because she is considering a second pregnancy. She tells you she is afraid to get pregnant given the outcome of her first pregnancy. At 32 years of age, she delivered a term infant with Down syndrome. During that gestation, a serum screen for aneuploidy was not performed. Had a second-trimester multiple marker screen been performed, which of the following results would have been helpful?
A) Low MSAFP, low estriol, low hCG, low inhibin A
B) Low MSAFP, high estriol, low hCG, high inhibin A
C) Low MSAFP, low estriol, high hCG, high inhibin A
D) High MSAFP, high estriol, low hCG, low inhibin A
E) High MSAFP, low estriol, low hCG, low inhibin A
The answer is C. Trisomy 21 is associated with low MSAFP, low estriol, high hCG, and high inhibin A. It is a screening test that can identify up to 80% of pregnancies with Down syndrome. Multiple marker screens with high MSAFP are associated with neural tube defects.
A 39-year-old man with Down syndrome has exhibited increasing forgetfulness and angry outbursts over the past several months. He has become neglectful of personal hygiene and has trouble finding items in his room. Which of the following conditions is the most likely cause of these problems?
A) Alzheimer disease
B) Cerebrovascular disease
C) Intracranial neoplasm
D) HIV
E) Thiamine deficiency
The answer is A. The symptoms are very suggestive of dementia, with impairment in memory and other cognitive processes. Alzheimer disease causes 55% of cases of dementia. It is usually seen in older individuals, but individuals with Down syndrome are very likely to develop this disease by age 40 years.