Etiology and Pathogenesis

Although trisomy 21 is responsible for 1 : 150 first-trimester spontaneous abortions, the live-born incidence is approximately 1 : 800-1 : 1000, and its incidence is highly correlated with advanced maternal age. The additional copy of chromosome 21 usually occurs from meiosis I nondisjunction, when the pair of homologous chromosomes 21 fail to separate. Errors that occur during meiosis are nearly always maternal in origin, and the incidence increases with advancing maternal age. This is likely attributable to the years from oocyte formation during maternal embryogenesis to the time of fertilization that the oocyte spends suspended in meiosis I.

Although trisomy of chromosome 21 (e.g., 47,XY, +21) in which a complete extra copy of chromosome 21 is present, causes approximately 94% of cases, other causes are also seen. Approximately 2% to 3% of cases of trisomy 21 can present with mosaicism (e.g., 47,XY, +21 [50%] or 46,XY[50%]) in which there is a mixture of trisomic cells and normal cells. This can lead to an attenuated phenotype, but it depends on the relative mosaicism of different tissues. Finally, approximately 3% to 4% of cases are caused by a Robertsonian translocation, in which the q arm of chromosome 21 is translocated onto another chromosome. This results in a fetus with 46 chromosomes but three copies of the long arm of chromosome 21, which carries all of the functional genes of this chromosome (e.g., 46,XY,der(15 : 21)(q10;q10), +21; Figure 117-1). Although most Robertsonian translocations are new mutations and occur regardless of maternal age, it is important to distinguish the cause and rule out a translocation carrier parent, which substantially increases the risk of recurrence.

The risk of recurrence for parents of children with Down syndrome varies according to maternal age at the time of birth of the affected infant. Mothers who were of advanced maternal age maintain their age-related risk, but mothers younger than 30 years old have a sixfold increased risk compared with their age-related peers. The reason for this increased risk is not entirely clear, although it may be related to a lower rate of spontaneous abortion of affected fetuses or an increased risk of nondisjunction that is unrelated to age. Furthermore, some evidence suggests a higher incidence of early pregnancy losses in mothers of children with Down syndrome, although, second- and third-degree relatives of individuals with trisomy 21 are not at an elevated risk of having children with Down syndrome. Parents of children with de novo translocations are not at increased risk of having another affected child; however, a man carrying balanced Robertsonian translocation has a 3% to 5% risk, but a woman has a 10% to 15% risk for recurrence. Of note, parents carrying a balanced 21;21 translocation have a 100% recurrence risk.

Clinical Presentation and Differential Diagnois

The diagnosis of trisomy 21 is often made by prenatal screening. When no prenatal diagnosis has been made, Down syndrome is usually recognized from the characteristic phenotype present in the newborn. The diagnosis is confirmed with a karyotype.