Prenatal Imaging Findings in Down Syndrome

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Down syndrome is a relatively common 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. The image below is that of a fetus with Down syndrome.

Down syndrome is associated with a number of major disorders. For example, this condition 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.

Screening tests are noninvasive and generally painless studies performed to estimate the risk of a fetus having Down syndrome. 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. Radiologic screening tests include nuchal translucency testing and detailed ultrasonography. Ultrasonographically guided transabdominal or transvaginal interventions include amniocentesis with chorionic villus sampling (CVS), Percutaneous umbilical blood sampling (PUBS), and termination of pregnancy. ^{[1, 2, 3]}

A sonolucent area in the nuchal region (back of the neck) of the fetus is typically observed in the first trimester. ^{[4, 5]} 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 (see the images below).

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.

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 ultrasonography is only about 60% accurate and often leads to false-positive or false-negative readings. ^[6]

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. ^{[7, 8, 9, 10]}

Some have proposed a “scoring system” for the detection of Down syndrome. ^[11] The importance of the clustering of markers forms the basis of the scoring index, such that individual markers are assigned point values based on their sensitivity and specificity in the detection of Down syndrome. The points acquired by each fetus are tabulated into a final score.

One study proposed the following scoring system: nuchal fold = 2, major structural defect = 2, and short femur, short humerus, and pyelectasis = 1 each. Selecting fetuses with a score of 2 or more identified 26/32 (81%) Down syndrome fetuses, 9/9 (100%) trisomy-18 fetuses, and 2/2 (100%) trisomy-13 fetuses, but only 26/588 (4.4%) normal fetuses were identified by this scoring system. For a 1/250 risk group, using the ultrasonographic score of 2 resulted in a positive predictive value of 6.87% for Down syndrome and 7.25% for all 3 trisomies.

First-trimester combined screening at 11 weeks’ gestation for Down syndrome is better than second-trimester quadruple screening. ^{[12, 13]} 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.

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. ^[14] First-trimester combined screening is the most cost-effective strategy if the cost of nuchal translucency is less than $57 or if a genetic ultrasonogram is included in the second-trimester strategies. ^[15]

Other conditions that should be considered are trisomy 18; trisomy G syndrome; 49,XXXXY chromosome and other high-order multiple X chromosomes; Zellweger syndrome; chromosome 21, mosaic 21 syndrome; and chromosome 21, translocation 21 syndrome.

If diagnostic tests yield positive results and parents decide to continue the pregnancy, fetal echocardiography should be performed at 20 weeks’ gestation to detect serious cardiac malformations. Ultrasonography should be performed at 28-32 weeks’ gestation.

MRI 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.

Ultrasonography 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 ultrasonography 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. ^{[16, 17, 18, 1, 8, 9]}

Ultrasonographic 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 (see the images below). 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.

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 ultrasonography.

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.

Structural anomalies, cardiac abnormalities, a nuchal fold 6 mm or thicker, bowel echogenicity, choroid plexus cysts (see the first image below), and renal pyelectasis (see the second and third images below) have been studied. With the exception of bowel echogenicity and choroid plexus cysts, the ultrasonographic 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.

When any of the ultrasonographic markers significant in univariate analysis are considered, the false-positive rate is reported to be 5.3% (48 of 898) and the sensitivity is reported to be 59.1% (13 of 22). When any of the predictors from multivariate analysis are present, the false-positive rate is 3.1% (28 of 898) and the sensitivity is 54.5% (12 of 22). Because of the considerable overlap of ultrasonographic markers in fetuses with trisomy 21, use of markers that are not independent predictors increases the false-positive rate without a gain in sensitivity.

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Badar Bin Bilal Shafi, MBBS, MRCP, FRCR, CCT, EBIR Consultant Interventional Radiologist, South Mersey Vascular Centre and Countess of Chester Hospital, UK

Badar Bin Bilal Shafi, MBBS, MRCP, FRCR, CCT, EBIR is a member of the following medical societies: Radiological Society of North America, Royal College of Physicians, Royal College of Radiologists, Society of Interventional Radiology, Cardiovascular and Interventional Radiological Society of Europe, British Society of Interventional Radiology

Disclosure: Nothing to disclose.

Musa Kaleem, MBBS, FRCR, MRCP Consultant Pediatric Radiologist, Central Manchester University Hospitals NHS Foundation Trust (Royal Manchester Children’s Hospital); Honorary Lecturer, University of Liverpool Faculty of Medicine, UK

Musa Kaleem, MBBS, FRCR, MRCP is a member of the following medical societies: Radiological Society of North America, Royal College of Radiologists, Royal College of Paediatrics and Child Health

Disclosure: Nothing to disclose.

Suhaib Bin Bilal Hafi, MBBS Core Trainee 1 (CT1) Psychiatry, Greater Manchester West Mental Health NHS Foundation Trust, UK

Disclosure: Nothing to disclose.

R H Bilal, MBBS, MRCS Specialist Registrar in Cardiothoracic Surgery, North West Cardiothoracic Rotation, UK

R H Bilal, MBBS, MRCS is a member of the following medical societies: British Medical Association

Disclosure: Nothing to disclose.

Bernard D Coombs, MB, ChB, PhD Consulting Staff, Department of Specialist Rehabilitation Services, Hutt Valley District Health Board, New Zealand

Disclosure: Nothing to disclose.

Karen L Reuter, MD, FACR Professor, Department of Radiology, Lahey Clinic Medical Center

Karen L Reuter, MD, FACR is a member of the following medical societies: American Association for Women Radiologists, American College of Radiology, American Institute of Ultrasound in Medicine, American Roentgen Ray Society, Radiological Society of North America

Disclosure: Nothing to disclose.

Eugene C Lin, MD Attending Radiologist, Teaching Coordinator for Cardiac Imaging, Radiology Residency Program, Virginia Mason Medical Center; Clinical Assistant Professor of Radiology, University of Washington School of Medicine

Eugene C Lin, MD is a member of the following medical societies: American College of Nuclear Medicine, American College of Radiology, Radiological Society of North America, Society of Nuclear Medicine and Molecular Imaging

Disclosure: Nothing to disclose.

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.

Prenatal Imaging Findings in Down Syndrome

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