Trisomy 21 is an abnormality due to the presence of an extra copy of chromosome 21 (Figure 131-1). Individuals with the clinical characteristics of what we now know as Down syndrome were first described by Dr. John Langdon Down in 1866. Dr. Down was a physician at the Earlswood asylum in Surrey, England. His erroneous ideas about a racial cause for Down syndrome, along with a superficial similarity in facial appearance to persons of mongoloid origin, led to the term mongolism (Cooley and Graham, 1991). Interestingly, Dr. Down eventually had a grandson who was also named John Langdon Down, and he had Down syndrome (Patterson and Costa, 2005).

The association between the clinical entity Down syndrome and an extra copy of chromosome 21 was noted simultaneously in 1959 by Drs. Jerome Lejeune in France and Patricia Jacobs in Scotland. Ninety-five percent of individuals with Down syndrome have three copies of chromosome 21, which results from meiotic nondisjunction of the pair of number 21 chromosomes in the formation of an egg or sperm prior to fertilization (Sherman et al., 2005). Ninety-four percent of the time, the extra copy of the chromosome 21 is maternal in origin (Antonarakis, 1991). Approximately 3% to 4% of cases of Down syndrome are due to an unbalanced translocation involving chromosome 21. Fifty percent of the translocation cases occur spontaneously (de novo) and 50% are inherited from a parent with a balanced translocation. One percent of cases of Down syndrome are due to mosaicism, beginning as a trisomic conceptus with selective loss of one copy of chromosome 21 (“disomic rescue”) or as mitotic nondisjunction occurring after fertilization in a specific cell line or lines.

A full extra copy of chromosome 21 is not needed to cause the symptoms of Down syndrome. The phenotype of Down syndrome is thought to be due to triplication of the genes expressed in a relatively small region of chromosome 21, band 21q22. However, recent gene expression studies using cell-free fetal RNA in amniotic fluid of second trimester affected fetuses suggests that the fetal phenotype is due to differential regulation of many genes that are not on chromosome 21 (Slonim et al., 2009). Furthermore, second trimester fetuses with Down syndrome experience significant oxidative stress.

Currently, there is much interest in the noninvasive detection of Down syndrome, by first and second trimester serum screening and nuchal translucency measurement (Nicolaides et al., 1992a) (see Chapters 2 and 3). The analysis of cell-free fetal nucleic acids in maternal blood may eventually have a role in the noninvasive prenatal diagnosis of Down syndrome (Maron and Bianchi, 2007; Lo, 2009).

The incidence of trisomy 21 is 1 in 920 livebirths (Krivchenia et al., 1993). The frequency of Down syndrome increases with advanced maternal age. The incidence of Down syndrome is somewhat similar in all ethnic and racial groups, although population-based data from the United States National Birth Defects Prevention Network suggest that there is a higher incidence in Hispanics and a lower incidence in blacks compared to non-Hispanic white women (Canfield et al., 2006).

Cuckle et al. (1991) estimated the “natural birth prevalence” of Down syndrome, which they defined as the birth prevalence that would be expected in the absence of prenatal diagnosis or induced abortion. In their study, performed in England and Wales from 1974 to 1987, the natural birth prevalence of Down syndrome increased from 12.2 in 10,000 to 13.2 in 10,000—an average of 12.6 in 10,000 births. Fourteen percent of cases of Down syndrome were avoided by prenatal diagnosis and termination of affected pregnancies. The actual birth prevalence, which reflected the utilization of prenatal diagnosis, was 10.8 in 10,000 births in this population (Cuckle et al., 1991). In a more recent U.S. population-based study, the prevalence of Down syndrome was 13.65per 10,000 livebirths (Canfield et al., 2006).

The major sonographic findings seen in fetuses with trisomy 21 are listed in Table 131-1. Many of these findings are discussed in individual chapters and in Chapters 2 and 3. The frequency of major internal congenital malformations is less than with trisomies 13 or 18 (Hill, 1996). In general, in cases of trisomy 21, sonographic defects tend to be more subtle than in cases of Trisomies 13 or 18, such as flattening of the facial profile (Figure 131-2). These “soft” markers include nuchal edema, hydronephrosis, clinodactyly, sandal gap (wide space between first and second toes), macroglossia (Nicolaides et al., 1992b), as well as absent or shortened nasal bone (Sonek and Nicolaides, 2002) and increased frontomaxillary facial angle (Sonek et al.,2007).

Relatively long differential diagnoses exist for each individual sonographic finding that has been reported to be associated with Down syndrome. A karyotype that demonstrates the presence of an extra chromosome 21 is diagnostic and highly accurate. Once the chromosomes have been studied, there is no longer a need for a differential diagnosis. Postnatally, however, findings such as muscular hypotonia in the newborn may suggest a diagnosis of congenital muscular dystrophy. Furthermore, abnormalities in the facial profile may suggest a diagnosis of Zellweger syndrome.

The incidence of Down syndrome in clinically recognized pregnancies is reported to be as high as 1 in 225 (Hecht and Hecht, 1987). The difference between the incidence of Down syndrome in conceptuses and livebirths indicates the strong selection pressure against this chromosomal abnormality.

Fetuses with Down syndrome have a higher rate of spontaneous abortion or stillbirth than normal fetuses (Figure 131-3). This has been studied extensively by (Hook et al. 1989, 1995). This group reported the results of an ongoing survey of rates of spontaneous death of fetuses with trisomy 21 that were detected at second trimester amniocentesis in which the mother did not elect termination of pregnancy. The loss rates were ~50% for fetuses ascertained at 15 to 17 weeks, 43% at 18 weeks, 31% at 19 weeks, 25% at 20 weeks, and 21% to 25% at 21 to 28 weeks (Hook et al., 1995). This was adjusted for the likelihood that spontaneous fetal death would occur in a fetus with a normal karyotype in a population of women with advanced maternal age.