In about 4% of all patients with trisomy 21, the extra chromosomal material is present as a translocation of the long arm of chromosome 21 to chromosome 22 or 14. Such cases frequently (but not always) are familial, and the translocated chromosome is inherited from one of the parents, who typically is a carrier of a Robertsonian translocation. Approximately 1% of patients with trisomy 21 are mosaics, usually having a mixture of 46-and 47-chromosome cells. These cases result from mitotic nondisjunction of chromosome 21 during an early stage of embryogenesis. Clinical manifestations in such cases are variable and milder, depending on the proportion of abnormal cells.
The diagnostic clinical features of this condition—flat facial profile, oblique palpebral fissures, and epicanthic folds (
Fig. 7.15 )—are usually readily evident, even at birth. Down syndrome is a leading cause of severe mental retardation; approximately 80% of those afflicted have an IQ of 25 to 50. By contrast, some mosaics with Down syndrome have mild phenotypic changes and normal or near-normal intelligence. In addition to the phenotypic abnormalities and the mental retardation already noted, some other clinical features are worthy of mention:
Approximately 40% of the patients have congenital heart disease, most commonly defects of the endocardial cushion, including atrial septal defects, atrioventricular valve malformations, and ventricular septal defects (Chapter 11). Cardiac problems are responsible for a majority of the deaths in infancy and early childhood. Several other congenital malformations, including atresias of the esophagus and small bowel, also are common.
Children with trisomy 21 have a tenfold-to twentyfold increased risk of developing acute leukemia. Both acute lymphoblastic leukemias and acute myeloid leukemias occur (Chapter 12).
Virtually all patients with trisomy 21 older than age 40 develop neuropathologic changes characteristic of Alzheimer disease, a degenerative disorder of the brain (Chapter 23).
Patients with Down syndrome demonstrate abnormal immune responses that predispose them to serious infections, particularly of the lungs, and to thyroid autoimmunity (Chapter 20). Although several abnormalities, affecting mainly T cell functions, have been reported, the basis for the immunologic disturbances is not clear.
Despite all of these problems, improved medical care has increased the longevity of persons with trisomy 21. Currently the median age at death is 60 years (up from 25 years in 1983). Although the karyotype of Down syndrome has been known for decades, the molecular basis for this disease remains elusive. Studies of humans with partial trisomy of chromosome 21 and mouse models of trisomy have identified the critical region of human chromosome 21 that is involved in the pathogenesis. Based on these studies, several gene clusters, each of which is predicted to participate in the same biologic pathway, have been implicated. For example, 16 genes are involved in the mitochondrial energy pathway, several are likely to influence CNS development, and one group is involved in folate metabolism. It is not known how each of these groups of genes is related to Down syndrome. Adding complexity is the fact that several miRNA genes reside on chromosome 21 that can shut down translation of genes that map elsewhere in the genome.