Abstract
Trisomy 21 (Down syndrome) is the most common autosomal trisomy in newborns, and is strongly associated with increasing maternal age. Trisomy 21 results most commonly from maternal meiotic nondisjunction. Unbalanced translocation accounts for up to 4% of cases. Trisomy 21 has a distinct clinical phenotype and varying degrees of cognitive impairment. The majority of cases are detected prenatally, usually with a combination of maternal genetic screening and prenatal ultrasound. The most common structural abnormalities in trisomy 21 are increased nuchal translucency, cardiac defects, and duodenal atresia. Other possible ultrasound findings include thick nuchal fold, ventriculomegaly, absent or hypoplastic nasal bone, echogenic intracardiac focus, echogenic bowel, pyelectasis, and short limbs.
Keywords
cardiac malformation, duodenal atresia, echogenic intracardiac focus, nuchal fold
Introduction
Trisomy 21 (Down syndrome) is the most common trisomy in live-born infants and in spontaneous abortions. British physician John Langdon Down first described the syndrome in 1866. The chromosomal abnormality was discovered in 1959 by French geneticist Jerome Lejeune, and in 1961, the name Down syndrome was proposed by the editors of The Lancet .
Disorder
Definition
Trisomy 21, also called Down syndrome, results from three copies of chromosome 21, either the entire chromosome or the critical region. The syndrome has a distinctive phenotype.
Prevalence and Epidemiology
Trisomy 21 is the most common inherited cause of intellectual disability. About 0.45% of human conceptuses have trisomy 21. The incidence of Down syndrome in live births is between 1 : 319 and 1 : 1000, depending on the population. The risk of trisomy 21 increases with increasing maternal age and decreases with advancing gestation (because of pregnancy loss). Controversy exists about whether the incidence increases with advancing paternal age. Table 151.1 presents maternal and gestational age risks, demonstrating these changes.
| Maternal Age (y) | GESTATIONAL AGE (WK) | |||||
|---|---|---|---|---|---|---|
| 10 | 12 | 14 | 16 | 20 | 40 | |
| 20 | 1 : 983 | 1 : 1068 | 1 : 1140 | 1 : 1200 | 1 : 1295 | 1 : 1527 |
| 25 | 1 : 870 | 1 : 946 | 1 : 1009 | 1 : 1062 | 1 : 1147 | 1 : 1342 |
| 30 | 1 : 576 | 1 : 626 | 1 : 668 | 1 : 703 | 1 : 759 | 1 : 895 |
| 31 | 1 : 500 | 1 : 543 | 1 : 580 | 1 : 610 | 1 : 658 | 1 : 776 |
| 32 | 1 : 424 | 1 : 461 | 1 : 492 | 1 : 518 | 1 : 559 | 1 : 659 |
| 33 | 1 : 352 | 1 : 383 | 1 : 409 | 1 : 430 | 1 : 464 | 1 : 547 |
| 34 | 1 : 287 | 1 : 312 | 1 : 333 | 1 : 350 | 1 : 378 | 1 : 446 |
| 35 | 1 : 229 | 1 : 249 | 1 : 266 | 1 : 280 | 1 : 302 | 1 : 356 |
| 36 | 1 : 180 | 1 : 196 | 1 : 209 | 1 : 220 | 1 : 238 | 1 : 280 |
| 37 | 1 : 140 | 1 : 152 | 1 : 163 | 1 : 171 | 1 : 185 | 1 : 218 |
| 38 | 1 : 108 | 1 : 117 | 1 : 125 | 1 : 131 | 1 : 142 | 1 : 167 |
| 39 | 1 : 82 | 1 : 89 | 1 : 95 | 1 : 100 | 1: 108 | 1 : 128 |
| 40 | 1 : 62 | 1 : 68 | 1 : 72 | 1 : 76 | 1 : 82 | 1 : 97 |
| 41 | 1 : 47 | 1 : 51 | 1 : 54 | 1 : 57 | 1 : 62 | 1 : 73 |
| 42 | 1 : 35 | 1 : 38 | 1 : 41 | 1 : 43 | 1 : 46 | 1 : 55 |
| 43 | 1 : 26 | 1 : 29 | 1 : 30 | 1 : 32 | 1 : 35 | 1 : 41 |
| 44 | 1 : 20 | 1 : 21 | 1 : 23 | 1 : 24 | 1 : 26 | 1 :30 |
| 45 | 1 : 15 | 1 : 16 | 1 : 17 | 1 : 18 | 1 : 19 | 1 : 23 |
Etiology and Pathophysiology
Most cases of trisomy 21 are due to meiotic nondisjunction (95%), usually in the ovum. In the remaining 5% of cases, unbalanced translocation accounts for 3% to 4%, and mosaicism accounts for 1%. The additional copy of chromosome 21 presumably causes increased expression of many genes on the chromosome, and the imbalance in expression is thought to cause the various phenotypic expressions of the disorder.
Manifestations of Disease
Clinical Presentation
Clinical presentation of trisomy 21 may vary, but most cases have distinct ultrasound (US) features including major structural anomalies and minor (“soft”) markers of aneuploidy. Nearly half of fetuses with trisomy 21 have a cardiac defect (for example, ventricular septal defects, atrioventricular septal defects, and tetralogy of Fallot). Other major anomalies include duodenal atresia and tracheoesophageal fistula/esophageal atresia. Findings may include increased nuchal fold, cerebral ventriculomegaly, echogenic intracardiac focus, pyelectasis, echogenic bowel, enlarged cisterna magna, pericardial effusion, liver calcification, and digit anomalies (polydactyly, clinodactyly, sandal gap, and clubfoot). Hepatosplenomegaly and fetal hydrops may occur secondary to a leukemoid reaction.
Imaging Technique and Findings
Ultrasound.
US screening is one component of currently available screening strategies for trisomy 21, which also includes serum biochemistry screening and cell-free DNA screening (cfDNA). Definitive diagnosis depends on direct fetal testing, typically by chorionic villus sampling or amniocentesis.
The multicenter Biochemistry, Ultrasound, Nuchal translucency (BUN) trial demonstrated that the combination of maternal age, first-trimester serum biochemistry, and nuchal translucency combined had a trisomy 21 detection rate of 85% at a 5% false-positive rate. A study that was part of the F irst- a nd s econd- t rimester e valuation of r isk (FASTER) trial showed that at a 5% false-positive rate, detection of Down syndrome was 95% with stepwise sequential screening and 96% with fully integrated screening (nuchal translucency measurement performed at 11 to 14 weeks’ gestation, with greater detection earlier). Using both measurement of nuchal translucency and serum markers in the first trimester was more effective for trisomy 21 screening than using either screening modality alone.
Another FASTER trial study confirmed that genetic US evaluation to assess for both major and minor markers of aneuploidy increases detection rates of trisomy 21 after first-trimester screening and second-trimester biochemistry screening. At a 5% false-positive rate, genetic US evaluation increases the detection rate from 81% to 90% after combined or quadruple marker screening. Detection was improved, albeit to a lesser degree, after integrated (from 93%–98%), stepwise (from 97%–98%), or contingent (from 95%–97%) screening.
The absence of any marker on a second-trimester US scan conveys a 60% to 80% reduction in Down syndrome risk based on advanced maternal age or serum screen. In other words, the likelihood ratio (LR) of trisomy 21 after a normal genetic US scan is 0.2 to 0.4 times the prior risk.
Introduced into clinical practice in 2011, cfDNA screening has high sensitivity and specificity, and low negative predictive values for the detection of trisomy 21. In the general obstetric population, the positive predictive value cfDNA screening for trisomy 21 has been reported to be 45.5%, compared with 4.2% for standard serum biochemistry screening, although the true positive predictive value will depend on the baseline risk in the patient population and may be different in clinical practice.
In the FASTER trial, major structural malformations were seen in 8.5% of second-trimester fetuses with trisomy 21 in an unselected population. Older studies (from the 1990s) showed a higher prevalence of major malformation (17%), although these data were collected before first-trimester screening, which presumably detects many cases earlier than the second trimester, so some of the fetuses were terminated before the second-trimester US scan to detect anomalies.
The two most common major malformations associated with trisomy 21 are cardiac defects and duodenal atresia. Nearly half of fetuses with Down syndrome have heart defects; most common are atrioventricular septal defects (atrioventricular canal), ventricular septal defects, and atrial septal defects. Tetralogy of Fallot, although less common, is also associated with trisomy 21. Atrioventricular septal defects are very strongly associated with Down syndrome. In a large population-based study of congenital heart defects in Down syndrome, 45% of infants with Down syndrome had atrioventricular septal defects, and 35% had ventricular septal defects.
Duodenal atresia ( Chapter 26 ) is the most common gastrointestinal anomaly, seen in 30% of fetuses with Down syndrome, making it a strong and classic marker. It is seen on US as a double bubble sign comprising the fluid-filled stomach and the proximal duodenum on either side of the fetal abdomen. Even with normal biochemical markers and in the absence of other US markers, the presence of isolated duodenal atresia confers an LR of 30 for Down syndrome.
Minor markers are seen more commonly than major malformations in an unselected population ( Table 151.2 ). One of the FASTER trial studies found increased nuchal fold to be the most statistically significant minor marker (LR 49). Other statistically significant findings were short femur, short humerus, echogenic intracardiac focus, pyelectasis, echogenic bowel, and ventriculomegaly. The risk of trisomy 21 is higher with an increasing number of US markers. US identification of a minor marker should prompt a referral for perinatal and genetics counseling. Specific markers are described subsequently. For the presence of minor markers in the setting of a negative cfDNA screen, some experts advocate that additional diagnostic testing may not be necessary due to the high negative predictive value of these screening tests, although patients should be counseled that the detection rate of cfDNA is significantly lower than standard karyotype or microarray analysis. However, some patients may find this to be an acceptable alternative to invasive testing modalities.
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