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  • 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 ...

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