Epidemiology of trisomy 21: A review and theoretical analysis

In 1969, Abe Lilienfeld published a monograph entitled, Epidemiology of Mongolism [l]. His work was a comprehensive and timely review of what had been learned about this birth defect up to that time, He chose to refer to the birth defect as mongolism; however, he did note that many investigators were voicing the opinion that the term mongolism had been based on racial hypotheses no longer considered tenable. After 1969, the term Down’s syndrome became common. More recently, the term Trisomy 21 is being used, reflecting an accurate and well-known description of the chromosome abnormality that is nearly always associated with this birth defect. We have elected to use the term Trisomy 21 (T21) in the present review. However, some studies have not been based on uniform cytogenetic classification and small proportions of other cytogenetic abnormalities are sometimes grouped under the clinical diagnosis of T2 1. T21 was first described by J. Langdon Down in 1867 [2]. There was considerable speculation about the etiology of T21 until 1959, when the cytogenetic basis for the disease was proven [3] after having been theorized to exist by a number of investigators. These included Penrose [4], who did much to describe the early epidemiology of this disorder. When Lilienfeld’s review was published in 1969, T21 was receiving considerable attention because it is the most common birth defect known to be associated with a specific chromosome disorder. As cytogenetic techniques became more common, more detailed, and more accurate, this disorder was studied increasingly. It was also of special interest because of the strong association between maternal age and the risk of delivering a child with this disorder. In addition, a great deal of epidemiological attention was given to T21 because of its linkage with other diseases, especially with congenital heart disease [5]. Growing interest in the genetic basis for cancer also led many investigators to pay special attention to the high risk of leukemia in individuals with T21 [6]. Linkages between T21 and other diseases remain of fundamental interest because they offer the opportunity to better understand the etiology of genetically linked disorders. Space constraints require that this be a selective update of the epidemiology of T21. We will not attempt to restate the critically important information organized and presented in Lilienfeld’s monograph. In general, however, this review will follow the organizational structure of that monograph, summarizing Lilienfeld’s work briefly and adding new information where it is available. We will give the greatest attention to new developments in the field: recently reported changes in incidence rates; disease linkage, especially to Alzheimer’s disease; and new questions since the time of Lilienfeld’s monograph, such as potential risks due to oral contraceptive and spermicide use. Cytogenetic banding techniques, an important new development in the field, have been reviewed elsewhere [7]. It should be noted that, although an extra chromosome 21 is the most common cytogenetic abnormality associated with T21, a small proportion (approximately 4%) [8] of T21 cases may have a mosaic (normal and abnormal) cytogenetic configuration in their