You are in: eMedicine Specialties > Radiology > OBSTETRICS/GYNECOLOGY Down Syndrome, Prenatal FindingsArticle Last Updated: May 15, 2007AUTHOR AND EDITOR INFORMATIONSection 1 of 13
  Author: Badar Bin Bilal Shafi, MBBS, MRCP, Specialist Registrar in Clinical Radiology, Royal Liverpool University Hospital, UK Coauthor(s): Musa Kaleem, MBBS, Honorary Lecturer, University of Liverpool; Fellow in Pediatric Radiology, Department of Radiology, Royal Liverpool Children's NHS Trust Hospital, UK; Suhaib Bin Bilal Hafi, MBBS, Foundation 2 House Officer, Department of Psychiatry, University Hospital of Aintree, UK; Rana Haris Bin Bilal, MBBS, Senior House Officer, Department of Orthopedic Surgery, Nuffield Orthopedic Center, UK Editors: Christopher L Sistrom, MD, Associate Chair for Research, Assistant Professor, Department of Radiology, University of Florida School of Medicine; Bernard D Coombs, MB, ChB, PhD, Consulting Staff, Department of Specialist Rehabilitation Services, Hutt Valley District Health Board, New Zealand; Karen L Reuter, MD, FACR, Professor, Department of Radiology, Lahey Clinic Medical Center; Robert M Krasny, MD, Consulting Staff, Department of Radiology, The Angeles Clinic and Research Institute; Eugene C Lin, MD, Consulting Staff, Department of Radiology, Virginia Mason Medical Center Author and Editor Disclosure Synonyms and related keywords: trisomy 21, trisomy-21, Down's syndrome, alpha-fetoprotein, alpha fetoprotein, human chorionic gonadotropin, hCG, HCG, uE3, inhibin A INTRODUCTIONSection 2 of 13
  BackgroundDown syndrome is a congenital disorder caused by the presence of an extra 21st chromosome. Also called trisomy 21, Down syndrome was named after John Langdon Haydon Down (1828-1896), a British physician. Down syndrome is a relatively common birth defect. The chromosomal abnormality affects both the physical and the intellectual development of the affected individual. Overall, people with Down syndrome have mild-to-moderate mental retardation, short stature, and a characteristically flattened facial profile. The characteristic appearances may be subtle when observed alone. However, when found together, they permit a clinical diagnosis of Down syndrome to be made at birth. These signs of Down syndrome include slight flattening of the face, minimal squaring of the top of the ear, a low nasal bridge (lower than the usually flat nasal bridge of healthy newborns), an epicanthal fold (ie, a fold of skin over the top of the inner corner of the eye that is sometimes seen in healthy babies), a ring of tiny, harmless white spots around the iris (Brushfield spots), and slight narrowing of the palate. The minor malformations of Down syndrome are numerous. Down syndrome is also associated with a number of major disorders. For example, Down syndrome is associated with a major risk of heart malformations, some risk of duodenal atresia (ie, part of the small intestines is not developed), and a minor but notable risk of acute leukemia. However, the risk of solid tumors is lower than that in the general population. Approximately 50% of children with Down syndrome are born with a heart defect, most often a hole between the sides of the heart. In addition, Hirschsprung disease (congenital aganglionic megacolon), which can cause intestinal obstruction, occurs more frequently in children with Down syndrome than it does in other children. The intellectual disabilities in persons with Down syndrome are often the most important challenges. These disabilities may not be evident in early infancy but tend to become increasingly noticeable as developmental delays in late infancy and during childhood. In adults with Down syndrome, intellectual disability manifests as mental retardation. Only a few adults with Down syndrome can lead independent lives, because of mental retardation. It was once thought that nearly all adults with Down syndrome developed Alzheimer disease (dementia); therefore, most people with Down syndrome were expected to have premature senility in addition to a mental disability. However, data now suggest that perhaps only 20-25% of adults with Down syndrome develop dementia. PathophysiologyOf the inborn differences that affect intellectual capacity, Down syndrome is the most prevalent and the best studied. Down syndrome encompasses a number of genetic disorders, of which trisomy 21 is the most common (95%). Discovered by the Parisian physician Jerome Lejeune in 1959, trisomy 21 is the presence of a third copy of chromosome 21 in cells throughout the body. Other disorders in Down syndrome are based on duplication of the same subset of genes (various translocations of chromosome 21). Nondisjunction is the most common(95%). In rare cases, trisomy 21 is present in some but not all cell lines because of anomalous, early cell division in the zygote. Evidence suggests that this variant, called mosaic Down syndrome, may produce less developmental delay than does full trisomy 21. Trisomy 21 results in overexpression of genes located on chromosome 21. One of these genes is the superoxide dismutase (SOD) gene. Some, but not all, studies have shown that the activity of SOD is increased in Down syndrome. SOD protein converts oxygen radicals to hydrogen peroxide and water. Oxygen radicals produced in cells can damage cellular structures—hence, the important role of SOD. However, the current hypothesis is that after SOD activity increases disproportionately to the enzymes responsible for removing hydrogen peroxide (eg, glutathione peroxidase), the cells undergo peroxide damage. Some scientists believe that the treatment of neurons with free-radical scavengers can substantially prevent neuronal degeneration in Down syndrome. Oxidative damage to neurons results in rapid brain aging similar to that of Alzheimer disease. Another gene on chromosome 21 that may predispose individuals with Down syndrome to Alzheimer pathology is the gene that encodes for the precursor of the amyloid protein. Neurofibrillary tangles and amyloid plaques are commonly found in both patients with Down syndrome and patients with Alzheimer disease. Layer II of the entorhinal cortex and the subiculum are critical for memory consolidation, and both areas are among the first affected by the damage, with the number of nerve cells throughout the cortex gradually decreasing. Researchers at Johns Hopkins University created a genetically engineered mouse called Ts65Dn (segmental trisomy 16 mouse), which is an excellent model for studying Down syndrome. Ts65Dn mouse has genes on chromosomes 16 that are similar to human genes on chromosome 21. With this animal model, the exact causes of the neurologic symptoms of Down syndrome may soon be elucidated. Ts65Dn research is also likely to highly benefit Alzheimer disease research. FrequencyUnited StatesDown syndrome occurs in 1 in 150 conceptions. In a 40-year-old mother, the risk is about 6 times greater than that of the general population (1 in 110). For most babies with Down syndrome, the mothers are younger than 40 years. Egan et al studied the rate of Down syndrome in the United States from 1989 through 2001 and found that despite an expected 1.32-fold increase, the rate of Down syndrome actually declined. There was an expected increase because of delayed or extended childbearing, but instead, the number of live births with Down syndrome decreased from 3962 in 1989 to 3654 in 2001. Maternal age-specific live births from 1989-2001 were recorded by using birth-certificate data and were stratified for women aged 15-34 years and women aged 35-49 years. Live births were estimated from 1989 to 2001, with an assumption of no terminations. The rate of Down syndrome in 1989 was 15% lower than expected, and the rate decreased to 51% by 1998. In 2001, affected pregnancies decreased by 45% in women aged 15-34 years and by 53% in women aged 35-49 years.1 Also see Age, below. InternationalDown syndrome affects 1 in 650 births worldwide. For mothers aged 20-29 years, the prevalence is 1 in 1000. As maternal age increases, the prevalence increases to 1 in 30 mothers older than 45 years.2 Down syndrome accounts for approximately 8% of all reported congenital anomalies in Europe, affecting more than 7000 pregnancies in the 15 member states of the European Union each year. Since 1980, the rate of affected births in mothers aged 35 years or older has risen from 8% to 14% in the European Union as a whole, with even greater increases some areas. The total prevalence of Down syndrome is 1-3 per 1000 births. The rise in the mean maternal age in Europe has brought with it an increase in the number of pregnancies affected by Down syndrome. In most regions, the widespread practice of prenatal screening and terminating pregnancies has counteracted the effect of rising maternal age and its effect on live-birth prevalence.3 Mortality/MorbidityDown syndrome is the most frequently identified cause of mental retardation, but information about mortality and comorbidity in people with Down syndrome is limited.
RaceMaternal age patterns for Down syndrome are reported to differ by race.
SexThe male-to-female ratio for persons with Down sydrome is 1.15.8 AgeStudies of parity as a risk factor for Down syndrome have been hindered by inadequate control for maternal age and/or the failure to account for differences in prenatal diagnosis and pregnancy termination between low-parity women and high-parity women.9
Clinical DetailsHistory Maternal and paternal ages are important, and any family history of Down syndrome should be elicited. Problems occurring during pregnancy and details of the birth should be recorded, as should antenatal sonographic results. Prenatal screening, diagnostic tests, and their results should be noted. Physical findings If not prenatally diagnosed, Down syndrome is usually recognized at birth owing to its characteristic physical findings. Common neonatal findings include the following:
Depending on the etiology, impairment may range from mild to severe. Certain life-threatening disorders and other conditions may be diagnosed in newborn with Down syndrome. These are listed below.
Preferred ExaminationPrenatal screeningPrenatal screening tests are noninvasive and painless, and they are used to help clinicians and parents decide if additional diagnostic tests are needed. Screening tests are performed to estimate the risk of a fetus having Down syndrome. Screening tests are noninvasive and generally painless. These tests do not give a definitive answer as to whether a baby has Down syndrome, but they are used to help parents and clinicians decide whether diagnostic tests are warranted. Screening tests include nuchal translucency testing, tests of several serum markers, and detailed ultrasonography. Nuchal translucency testing A sonolucent area in the nuchal region (back of the neck) of the fetus is typically observed in the first trimester. Screening for nuchal translucency provides the parents with an individualized, specific risk of their having a child with Down syndrome, trisomy 13, or trisomy 18. This test, performed between 11 and 14 weeks of pregnancy, involves the use of ultrasonography to measure the clear space in the folds of tissue behind a developing baby's neck. In babies with Down syndrome and other chromosomal abnormalities, fluid tends to accumulate here, making the space appear enlarged. Increased nuchal translucency refers to a measurement greater than 3 mm. This finding does not mean that the fetus has a chromosomal abnormality but, rather, indicates that the risks of some genetic disorders and birth defects, including Down syndrome, are increased. This measurement, taken together with the mother's age and the baby's gestational age, can be used to calculate the odds that the baby has Down syndrome. With nuchal translucency testing, Down syndrome is correctly detected in about 80% of cases. When performed with a maternal blood test, its accuracy may be improved. Tests of serum markers Quantities of various markers in the mother's blood can be measured. The resultant levels, considered along with the woman's age, can be used to estimate the likelihood of the fetus having Down syndrome. The tests are typically offered between 15 and 20 weeks of pregnancy. Double (alpha-fetoprotein [AFP], human chorionic gonadotropin [hCG]), triple (AFP, hCG, unconjugated estriol [uE3]), or quadruple (AFP, hCG, uE3, inhibin A) testing may be performed to screen for Down syndrome. The first antenatal diagnosis of Down syndrome was made in 1968. Later, it was found that low maternal serum AFP levels, increased maternal serum hCG levels, and low uE3 levels were associated with Down syndrome. In 1988, the 3 biochemical markers were used together, along with maternal age, as a method of screening. At 15-22 weeks' gestation, the principal markers are AFP, hCG or its individual subunits (free alpha-hCG and free beta-hCG), uE3, and inhibin A. Screening performance varies according to the choice of markers and according to whether sonography is used to estimate gestational age. When a sonogram is used to estimate gestational age, detection rates—given a 5% false-positive rate and in combination with maternal age—are estimated to be 59% for the double test (AFP, hCG), 69% for the triple test (AFP, hCG, uE3), and 76% for the quadruple test (AFP, hCG, uE3, inhibin A). Other factors that can be useful in screening are maternal weight and ethnic origin, multiple pregnancies, the presence of insulin-dependent diabetes mellitus, previous pregnancy with Down syndrome, and the use of serum marker testing as an initial screen or as a repeat test during pregnancy. Factors such as parity and smoking are less well established than the others. In demonstration projects of such screening, uptake was about 80%. Rates of positive findings were about 5-6%. About 80% of women with positive results underwent an invasive diagnostic test. Of those found to have a pregnancy with Down syndrome, about 90% chose to terminate the pregnancy. Ultrasonography Detailed ultrasonography is often performed in conjunction with blood tests, and it is done to check the fetus for physical traits associated with Down syndrome. However, screening sonography is only about 60% accurate and often leads to false-positive or false-negative readings. Evidence now suggests that the careful combination of accurately performed noninvasive ultrasonography and maternal blood testing, eventually followed by a quantitative fluorescent polymerase chain reaction (QF-PCR), should reduce the need for conventional chromosomal analysis, which is relatively time consuming. Diagnostic testsDiagnostic tests are performed to confirm the presence of Down syndrome. Diagnostic tests are about 99% accurate in detecting Down syndrome and other chromosomal abnormalities. However, because they are performed inside the uterus, they are associated with a risk of miscarriage and other complications. For this reason, they are generally recommended only for women aged 35 years and older, those with a family history of genetic defects, or those who have had an abnormal result on a screening test. Diagnostic tests include amniocentesis, chorionic villus sampling (CVS), and percutaneous umbilical blood sampling (PUBS). Amniocentesis, performed between 16 and 20 weeks of pregnancy, involves the removal of a small amount of amniotic fluid through a needle inserted into the mother's abdomen. The collected cells can then be analyzed for chromosomal abnormalities. Amniocentesis poses a small risk of complications, such as preterm labor and miscarriage. CVS involves taking a tiny sample of the placenta through a needle inserted into the mother's abdomen. The advantage of this test is that it can be performed earlier than amniocentesis, at between 8 and 12 weeks. The disadvantage is that it poses a slightly increased risk of miscarriage and other complications. PUBS is usually performed after 20 weeks. A needle is used to retrieve a small sample of blood from the umbilical cord. It poses risks similar to those associated with amniocentesis. After a baby is born, Down syndrome can usually be diagnosed by looking at the baby. If the physician suspects Down syndrome, a karyotype (ie, a blood or tissue sample stained to show chromosomes grouped by size, number, and shape) can be obtained to verify the diagnosis. Limitations of TechniquesThe current inhibin-A assay is unacceptable as a screening tool because of its poor performance. First- and second-trimester screening for Down syndrome First-trimester screening enables efficient risk assessment for Down syndrome, with a detection rate of 84% (95% CI, 80-87%), which is clinically comparable to that of second-trimester quadruple screening, with a fixed false-positive rate of 5%. There is sufficient evidence to support implementing first-trimester risk assessment for Down syndrome in obstetric practice in the United States, provided that certain requirements are met. These requirements include training and quality-control standards for first-trimester nuchal translucency measurement and laboratory assays, access to CVS, and appropriate counseling regarding screening options. First-trimester combined screening at 11 weeks' gestation is better than second-trimester quadruple screening. However, at 13 weeks, the results are similar to those of second-trimester quadruple screening. Rates of detecting Down syndrome are high with both stepwise, sequential screening and fully integrated screening, with low rates of false-positive results. Safety and cost-effectiveness of first- and second-trimester screening The choice of screening strategy should be between the integrated test, first-trimester combined test, quadruple test, and nuchal translucency measurement, depending on how much service providers are willing to pay, the total budget available, and values on safety. Screening based on maternal age, the second-trimester double test, and the first-trimester serum test is less effective, less safe, and more costly than the integrated test, first-trimester combined test, quadruple test, and nuchal translucency measurement. One study shows that integrated serum screening was the most cost-effective screening strategy for Down syndrome. First-trimester combined screening is the most cost-effective strategy if the cost of nuchal translucency is less than 57 dollars or if a genetic sonogram is included in the second-trimester strategies. The following scoring system has been proposed in one study. Nuchal fold = 2, major structural defect = 2, and short femur, short humerus, and pyelectasis = 1 each. Future screening techniques Future screening techniques may involve the detection of maternal urinary markers and fetal cells in maternal blood. Urinary levels of beta-core hCG, total estriol, and free beta-hCG are increased in women with fetuses with Down syndrome and are being intensively researched. Their measurement may be of value in screening for or diagnosing Down syndrome in the future. Available new techniques have not shown improved performance, simplicity, or economy necessary to replace existing methods. DIFFERENTIALSSection 3 of 13
Other Problems to Be ConsideredTrisomy 18 RADIOGRAPHSection 4 of 13
FindingsRadiography has no defined role in the antenatal diagnosis of Down syndrome. CT SCANSection 5 of 13
FindingsCT has no defined role in the antenatal diagnosis of Down syndrome. MRISection 6 of 13
FindingsMRI is not routinely used for screening or diagnosing Down syndrome. However, anatomic markers of Down syndrome, such as nuchal thickening and choroid plexus cysts, show well on fetal MRI. ULTRASOUNDSection 7 of 13
FindingsUltrasonography is the mainstay of prenatal screening and diagnosis of Down syndrome, and it is often used in combination with biochemical tests. Second-trimester ultrasonography helps detect 60-91% cases of Down syndrome, depending on the criteria used. The addition of color Doppler imaging to gray-scale sonography increases the sensitivity for detection of cardiac malformations, which include atrioventricular septal defect (AVSD), abnormalities of the outflow tract, mitral and tricuspid regurgitation, and right-to-left disproportion of the cardiac chamber. General sonographic markers Sonographic markers include thickness of the nuchal fold (75% sensitive), cardiac abnormalities, duodenal atresia, shortened femur, shortened humerus, renal pyelectasis, absence of the nasal bone (58% sensitive), a hyperechogenic bowel, and a choroid plexus cyst. An echogenic intracardiac focus has also been identified as a soft marker. None of these markers are specific, and false-positive rates have been reported. To date, 11 prospective studies, including about 125,000 patients, have been conducted to assess the measurement of nuchal translucency in a general population. Global sensitivity of this screening was 70%, with a false-positive rate of 5%. When the risk was adjusted for maternal age, the detection rate increased to 77%. Although nuchal translucency measurement is a potentially useful early-screening tool, uncertainties remain about its reproducibility in the general population. To correctly measure nuchal translucency, clinicians must receive training to guarantee the adequacy and reproducibility of their measurements. The absence of a nasal bone is a powerful marker for Down syndrome. A short nasal bone is associated with an increased likelihood of fetal Down syndrome in a high-risk population. Pelvic and cerebral diameters Although the diameters of the pelvis and the cerebrum are individually statistically significant as markers of trisomy 21, the combination of transcerebellar diameter (TCD) and frontothalamic distance (FTD) measurements may be superior to the measurement of either parameter alone. Patients with Down syndrome have a large mean iliac angle and a shortened mean iliac length. The most pronounced differences are at the middle sacral level. This observation suggests that the middle sacral level may be the optimal level for measuring the iliac angle and length during prenatal sonography. The iliac angle is significantly greater in second-trimester fetuses with trisomy 21 than in euploid fetuses. The iliac angle varies with the axial level, with the widest angle being at the most superior level. Evidence supports the measurement of the iliac angle at the most superior level as a potential marker for Down syndrome on prenatal ultrasonography. Measurements of the axial iliac angle on standardized 3-dimensional multiplanar views of the pelvis are reliable and can be used to identify some fetuses at increased risk for trisomy 21. In the second trimester, the nasal bones are present in most fetuses with trisomy 21. These fetuses have a characteristic midfacial anthropometry. Best sonographic markers to detect trisomy 21 in the second trimester Structural anomalies, cardiac abnormalities, a nuchal fold 6 mm or thicker, bowel echogenicity, choroid plexus cysts, and renal pyelectasis have been studied. With the exception of bowel echogenicity and choroid plexus cysts, the sonographic markers were more common in fetuses with trisomy 21 than in euploid fetuses. Cardiac anomalies, other structural anomalies, and a nuchal fold 6 mm or thicker were the only independent predictors of trisomy 21 with a significant 95% CI and OR. When any of the sonographic markers significant in univariate analysis are considered, the false-positive rate and sensitivity are reported to be 5.3% (48 of 898) and 59.1% (13 of 22), respectively. When any of the predictors from multivariate analysis are present, the false-positive rate and sensitivity are 3.1% (28 of 898) and 54.5% (12 of 22), respectively, . Because of the considerable overlap of sonographic markers in fetuses with trisomy 21, use of markers that are not independent predictors increases the false-positive rate without a gain in sensitivity. NUCLEAR MEDICINESection 8 of 13
FindingsNuclear medicine study has no defined role in the antenatal diagnosis of Down syndrome. ANGIOGRAPHYSection 9 of 13
FindingsAngiography has no defined role in antenatal diagnosis. INTERVENTIONSection 10 of 13
Ultrasonographically guided transabdominal or transvaginal interventions include amniocentesis with CVS, PUBS, and termination of pregnancy. Medical/Legal Pitfalls
Special Concerns
ACKNOWLEDGMENTSection 11 of 13
The authors extend their sincere thanks to Mrs Helen Lee, ultrasonographer, Liverpool Women's NHS Trust and Royal Liverpool Children's NHS Trust, for her help in compiling prenatal sonograms for this article. MULTIMEDIASection 12 of 13
REFERENCESSection 13 of 13
Down Syndrome, Prenatal Findings excerpt Article Last Updated: May 15, 2007 | ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
