Commentary Published on May 23, 2022

 

Soft Markers of Down Syndrome

Rinshi Abid Elayedatta, Vivek Krishnana

a. Division of Fetal Medicine & Perinatology, Amrita Institute of Medical Sciences & Research Centre, Kochi, Kerala

 

Abstract

Down syndrome is the most common congenital cause for mental disability. It is an aneuploidy that is potentially detectable in the prenatal period by biochemical and ultrasound markers. The ultrasound findings (soft markers) are not structural anomalies per se and are usually clinically insignificant except for their association with aneuploidy. However, these soft markers are particularly important in screening for trisomy 21 fetuses as majority of them will not have any major congenital anomalies detectable on ultrasound.

 

Down syndrome (DS) is the most frequent survivable autosomal aneuploidy characterised by multiple clinical features including intellectual disability due to the presence of a supernumerary chromosome 21. The 21st chromosome has more than 200 protein-coding genes which are responsible for the direct and indirect effects on the homeostasis in cells, tissues, organs and systems.1 Thus, fetuses with DS may present with nonspecific, often transient, sonographically detectable features that are collectively called “soft markers”. These soft markers may be seen in normal fetuses; however, they have an increased incidence in fetuses with chromosomal abnormalities.2 Despite not being pathologic themselves, these markers are used to screen for, or adjust the a-priori risk for Down syndrome and other aneuploidies including trisomy 13, 18, monosomy X, and triploidy.3,4 As approximately 75% of DS fetuses will not have any major congenital anomalies on second trimester morphological ultrasound, detection of these markers is important in their screening.5

First Trimester Markers of Aneuploidy

The screening for DS was started using maternal age in the mid 1960’s, followed by the addition of maternal serum biomarkers including free β-hCG and PAPP-A. This resulted in a detection rate (DR) of about 65% cases of DS for a false-positive rate (FPR) of 5%.6 Further, sonographic parameters were added to the above, to increase the DR. The most important sonographic parameter in the first-trimester is the Nuchal translucency (NT),2 which is a fluid collection behind the fetal neck. It is measured between a fetal crown rump length (CRL) of 45-84mm at 11-13 weeks +6 days of gestation. An increased NT measurement even when isolated can detect about 80% of fetuses with DS and other major aneuploides for a FPR of 5%. Combining the NT with maternal serum free β-hCG and PAPP-A improves the detection rate to 90% at the same FPR of 5%.2,6 Evidence shows that the use of other highly sensitive and specific first-trimester sonographic markers of DS including the nasal bone, ductus venosus flow and tricuspid flow increase DR to about 95% with a reduction in the FPR by 3%.7 The absence of nasal bone, reversed a-wave in the ductus venosus (DV) and the presence of tricuspid regurgitation (TR) was observed in about 60, 66 and 55% of fetuses with DS and in 2.5, 3.0 and 1.0%, respectively, of euploid fetuses.2 Additionally, increased flow in the fetal hepatic artery has also been described as a first trimester marker for aneuploidy.8,2 The reliability of measurement of NT, DV and TR depends to a great extent on the appropriate training of the operators, and the adherence to a standard protocol in measurement.9

The Second Trimester Genetic Sonogram

The prenatal ultrasound examination in the second trimester can screen for morphologic features or soft markers of aneuploidy and is therefore referred to as a “genetic sonogram”. This ultrasound examination is done at 18 to 22 weeks and can help detect 50% - 70% of fetuses with DS, 70% - 100% trisomy 18, and 90% - 100% trisomy 13.2,6 Major abnormalities are seen in only 25% of the abnormal fetuses while one or more soft markers may be observed in at least 50% of the cases.2

The various second trimester soft markers of Down syndrome are increased nuchal fold thickness (NFT) of 6mm or more, lateral cerebral ventriculomegaly (if the diameter of the lateral cerebral ventricle is 10 mm or more), absent or hypoplastic nasal bone, aberrant right subclavian artery (ARSA), rhizomelic limb shortening9 (<2.5 centile for GA,10 mild renal pelviectasis (anteroposterior diameter of renal pelvis of more than 4mm), echogenic bowel (when the bowel echogenicity equals the echogenicity of bone) and echogenic intracardiac focus. The presence of these aneuploidy markers increases, and their absence decreases, the risk of DS.7 A positive likelihood ratio (LR) indicates the number of times the presence of the marker increases the likelihood of DS while a negative LR denotes the number of times its absence decreases the likelihood of DS. The absence of soft markers on a second trimester scan automatically results in a 60-80% reduction in the prior maternal age based and serum- based aneuploidy screen risk (LR 0.13 = 7.7 fold risk reduction) while the presence of a soft marker will raise the baseline risk of DS by a factor equal to its positive LR. This approach identifies approximately 75% of fetuses with DS by modifying the patient’s baseline risk according to the ultrasound finding.11The presence of most isolated markers results in only a small effect on modifying the pre-test odds for DS, but the presence of markers like ventriculomegaly, NFT and ARSA results in a 3–4-fold increase in risk while with hypoplastic nasal bone, the risk increases 6–7-fold. The overall Likelihood Ratio (LR) for DS is derived by multiplying the positive LR for the soft marker that is present on ultrasound examination, by the negative LR of each of the other markers that are absent. For example, in the presence of two markers - mild renal pelviectasis and ventriculomegaly, (the positive LRs for which are 7.63 and 27.52, respectively), the combined positive LR is 209.98 (7.63 × 27.52). This is multiplied by the combined negative LR of all the other markers (0.80 × 0.80 × 0.90 × 0.80 × 0.71 × 0.46 = 0.15) to derive a aggregate LR of (209.98 × 0.15) = 31.50. There are calculators available online to do this computation.9 The final risk for DS is then derived by multiplying the a priori risk (from the results of previous screening) by the aggregate LR obtained by the above method.9

The hypoplastic or absent nasal bone (NB) is the single most predictive sonographic marker of DS in the second trimester12 and this correlates to the un-ossification of the nasal bone, secondary to abnormalities in bone growth and development observed in DS.7Increased NFT is another important ultrasound marker caused by the redundant soft tissue in the posterior part of the fetal neck, a characteristic feature in DS babies.2 The shorter stature seen in individuals with DS due to abnormally short long bones has been used as a marker for aneuploidy and EICF are discrete areas of echogenicity in the region of papillary muscle comparable to bone in either cardiac ventricle.2 The presence of each of the soft markers mandates a different management approach. However, there are a few generalizations. Firstly, the detection of a soft marker of aneuploidy should prompt an immediate detailed ultrasound evaluation of the fetus by an experienced and trained sonographer. When the maternal age is above 38 years, a multi marker aneuploidy screen is abnormal or multiple soft markers and/or anomalies are noted on scan, an amniocentesis should be recommended.

Conclusion

Prenatal ultrasonographic examination is not a modality to diagnose or exclude aneuploidy. It is a non-invasive means to adjust the a priori risk based on multiple soft markers.  More prospective studies are needed to confirm the value of isolated “soft markers” in low-risk women.

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