ESSENTIALS OF DIAGNOSIS
Typical craniofacial features (flat occiput, epicanthal folds, large tongue).
Congenital heart disease (eg, atrioventricular canal defects) in 50% of patients.
Alzheimer dementia in early-to-mid adulthood.
Three copies of chromosome 21 (trisomy 21) or a chromosome rearrangement that results in three copies of a region of the long arm of chromosome 21.
Nearly 0.5% of all human conceptions are trisomic for chromosome 21. Because of increased fetal mortality, birth incidence of Down syndrome is 1 per 700 but varies from 1 per 1000 in young mothers to more than three times as frequent in women of advanced maternal age. The presence of a fetus with Down syndrome can be detected in many pregnancies in the first or early second trimester through screening maternal serum for alpha-fetoprotein and other biomarkers (“multiple marker screening”) and by detecting increased nuchal thickness and underdevelopment of the nasal bone on ultrasonography. Prenatal diagnosis with high sensitivity and specificity can be achieved by assaying fetal DNA that is circulating in maternal blood. The chance of bearing a child with Down syndrome increases exponentially with the age of the mother at conception and begins a marked rise after age 35. By age 45 years, the odds of having an affected child are as high as 1 in 40. The risk of other conditions associated with trisomy also increases, because of the predisposition of older oocytes to nondisjunction during meiosis. There is little risk of trisomy associated with increased paternal age. However, older men do have an increased risk of fathering a child with a new autosomal dominant condition. Because there are so many distinct conditions, though, the chance of fathering an offspring with any given one is extremely small.
Down syndrome is usually diagnosed at birth on the basis of the typical craniofacial features, hypotonia, and single palmar crease. Several serious problems that may be evident at birth or may develop early in childhood include duodenal atresia, congenital heart disease (especially atrioventricular canal defects), and hematologic malignancy. The intestinal and cardiac anomalies usually respond to surgery. A transient neonatal leukemia generally responds to conservative management. The incidences of both acute lymphoblastic and myeloid leukemias are increased in childhood. Intelligence varies across a wide spectrum. Many people with Down syndrome do well in sheltered workshops and group homes, but few achieve full independence in adulthood. Other frequent complications include atlanto-axial instability, celiac disease, frequent infections due to immune deficiency, and hypothyroidism. An Alzheimer-like dementia usually becomes evident in the fourth or fifth decade. Patients with Down syndrome who survive childhood and who develop dementia have a reduced life expectancy; on average, they live to about age 55 years.
Cytogenomic analysis should always be performed—even though most patients will have simple trisomy ...