The salient clinical features of Down syndrome include several minor malformations or dysmorphic features, which, while not all are invariably present, together constitute the distinctive physical phenotype of the syndrome. Mental retardation and hypotonia are virtually always present, and congenital heart disease (particularly endocardial cushion defects) occurs in about 40 percent of affected individuals. Gastrointestinal anomalies (especially duodenal atresia and Hirschsprung disease) are found in about 5 percent.

There is a wide range of ultimate intellectual attainment and rate of psychomotor development, which, to some extent, may be influenced by both environmental and genetic factors. No pharmacologic therapy as yet has been shown to have a beneficial effect. The specific causes of mental retardation have not been elucidated, although decreased nerve cell densities, changes in phospholipid composition, and alterations in certain electrophysiologic properties of the brain and isolated neurons have been demonstrated. The pathologic, metabolic, and neurochemical changes of Alzheimer disease are present after the third decade in the brains of all individuals with Down syndrome, who also have a progressive loss in cognitive functions. Many develop a frank dementia.

There is a fifteen- to twentyfold increase in the incidence of leukemia in children with Down syndrome, with acute megakaryoblastic leukemia being particularly frequent among cases of acute nonlymphocytic leukemia. Leukemoid reactions or transient leukemia occurs in infants, as does macrocytosis and increased hematocrit. The activities of several erythrocyte and granulocyte enzymes not coded for by genes on chromosome 21 are increased, and hyperuricemia may be present.

Males with Down syndrome are almost invariably infertile, whereas females, while decreased in fertility, are often capable of reproduction. Longitudinal growth is impaired, and there is an increased frequency of thyroid dysfunction in newborns and of thyroid autoantibodies throughout life. A variety of cellular abnormalities are present, including enhanced responses to interferon and β-adrenergic agonists, and possibly small increases in sensitivity to radiation, mutagenic and carcinogenic chemicals, and viruses.

The principal causes of death in Down syndrome are infection, congenital heart disease, and malignancy. Longevity has been steadily increasing in recent years, and the life expectancy for individuals without congenital heart disease may be greater than 60 years. The increased susceptibility to infection appears to be the result of abnormalities of the immune system, particularly in the maturation and function of T lymphocytes.

In most instances, Down syndrome results from trisomy 21, the presence of an extra chromosome 21 either free or as part of a robertsonian fusion chromosome or isochromosome. Occasional cases result from triplication of just the distal part of the long arm of chromosome 21, or from the presence of trisomy 21/diploid mosaicism. Depending on the frequency and distribution of trisomic cells, mosaic individuals may range from being normal to having the typical phenotypic features of Down syndrome. There is a very strong effect of maternal age, but not of paternal age, on the incidence of trisomy 21. The nondisjunction event leading to the trisomy occurs in the mother about 86 percent of the time, with the maternal error being predominantly (75 percent) in meiosis I. Meiosis I errors are associated with a decreased rate of chromosome 21 recombination; meiosis II errors are associated with an increased rate. No environmental factor has been found to correlate with the occurrence of nondisjunction.

The risk for recurrence of nondisjunction is increased in younger mothers (≤30 to 35 years) of children with Down syndrome, and the risk of aneuploid offspring is much higher in mothers who are carriers of balanced robertsonian translocations than in carrier fathers. Prenatal diagnosis by amniocentesis or chorionic villus sampling is capable of detecting fetuses with Down syndrome, and maternal serum triple-marker screening and fetal ultrasonography can each identify a proportion of pregnancies in which a fetus with Down syndrome is present. Fetal cells in maternal blood can be used for the detection of known mutations.

Aneuploid phenotypes, while often variable in their expression, are differentiable from one another and are, in terms of overall pattern, specific. Nonspecific effects, while they may occur, are not major determinants of aneuploid phenotypes. Phenotypic variability may result from a combination of genetic, stochastic, and environmental factors. Individual features of aneuploid phenotypes can often be assigned to specific regions of the genome. The existence of a trisomic state results in the production of 50 percent more of the products of genes present on the unbalanced chromosome segment, and these gene dosage effects are, in turn, responsible for the abnormalities of development and function that constitute the aneuploid phenotype.

Chromosome 21 is the smallest of the human autosomes, and comprises about 1–1.5 percent of the haploid genome. The long arm is 33.7 megabase pairs in length and contains 225 known and predicted genes. Loss of the short arm, which contains ribosomal RNA genes and other highly repeated DNA sequences, does not impair normal function or development. The physical phenotype of Down syndrome is thought to be produced principally by imbalance of the region which comprises bands distal q22.1 to proximal q22.3, but imbalance of other regions may also contribute to the phenotype.

Gene dosage effects have been demonstrated for several loci on chromosome 21, and work is presently underway to determine whether the increases in gene product activity or concentration have secondary effects on the functions of these gene products. In particular, studies are being done to assess the roles of increased CuZn-superoxide dismutase activity and of increased, and possibly dysregulated, synthesis of the amyloid precursor protein in the pathogenesis of Alzheimer disease.

Several mouse models have been developed to facilitate studies of the mechanisms of the pathogenesis of Down syndrome. These include several strains of mice segmentally trisomic for chromosome 16, in which the mouse genome homologous to most of human chromosome 21q is triplicated, the trisomy 16/diploid mouse chimera, which is homologous to human trisomy 21/diploid mosaicism, single gene transgenic mice producing increased quantities of individual chromosome 21 gene products, and YAC transgenic mice with segments of human DNA. Abnormalities of learning and behavior have been demonstrated in the segmentally trisomic and YAC-transgenic mice.