Genetic Markers Overview by Dr. Emanuel Gaziano MD

Absent Nasal Bone

Absent Nasal Bone

Some commentary and selected images courtesy Jane J.K. Burns, A.S., R.T., RDMS

Page Links:Ultrasound Markers for Fetal Aneuploidy, Nuchal Translucency (NT), NT Measurement, Nuchal Fold, NF Measurement, Fetal Nasal Bone, Choroid Plexus Cysts, CPC Measurement, Echogenic Intracardiac Focus, Ultrasound Findings, Renal Pyelectasis (RP), RP Measurement, Shortened Long Bones, Long Bone Measurement, Echogenic Bowel, Ultrasound Findings, Ventriculomegaly, Ventricular Measurement, References

Ultrasound Markers for Fetal Aneuploidy

During the second trimester, ultrasound findings consistent with genetic abnormalities include nuchal fold (NF), short femur and humerus, echogenic cardiac focus, pyelectasis, hyperechoic bowel, ventriculomegaly, aberrant right subclavian artery, and any major abnormality. Based upon advanced maternal age and serum screen risk, the absence of any marker reduces the a priori risk of Down syndrome by 60% to 80%, while a detection rate of at least 75% is possible by modifying the baseline risk as a result of the ultrasound findings. [1] Markers are present in women with and without fetuses with aneuploidy. When assessed during the second trimester, markers for aneuploidy are seen in 17% of women greater than 35 years of age. [2]

Ultrasound Markers for Fetal Aneuploidy

Nuchal Translucency (NT)

NT measurement during the first trimester is the most effective sonogrpahic marker for trisomy 21 and other chromosomal defects [3], while the results of second trimester markers are viewed within the context of the first trimester results to achieve the greatest diagnostic accuracy. [4] In addition, the advent of high-frequency (5 to 9 MHz) and high-resolution (5 to 12 MHz) transvaginal probes permits the early detection of fetal malformations. [5]

NT Measurement

The measurement of NT in the correct mid-sagittal plane is necessary for accuracy and reliability. The head and chest must be in a neutral position without flexion or extension. An image is obtained with the fetus away from the amnion. A high-resolution transducer (6 MHz or higher) should be used with calipers (+) that measure structures to within .001 mm. The image should be magnified so that the fetal head and chest occupy two-thirds of the image. The measurement calipers should be placed on the inner borders of the fluid-filled space, and perpendicular to the long axis of the fetus.

NT is gestational age-dependent, and the 95th percentile will vary with the fetal crown-rump-length (CRL) measurement. NT is abnormal if it is greater than the 95th percentile for assigned gestational age by CRL. Recommended follow-up includes genetic counseling, and detailed anatomy scan including the heart.


Up to 45% of infants with Down syndrome demonstrate an increased NF (≥ 6 mm) during the second trimester. [6] The sensitivity of this marker ranges from 18% to 39%, while the likelihood ratio (LR) ranges from 10 to 53.4 based upon a number of studies.

[7] In a meta-analysis of second-trimester markers for trisomy 21, the pooled estimates suggest a detection rate of 26% with a false positive rate of 1.1% for trisomy 21.

NF Measurement

NF measurement should be taken at the back of the neck at the level of the transcerebellar measurement, or occipital fossa view. Adjusting the transducer so it is perpendicular to the back of the fetal head will increase the accuracy of the measurement. The cut-off for NF will vary with gestational age. From 15 to 18 weeks, an NF > 5.0 mm is abnormal, and from 18 to 21 weeks, an NF > 6.0 mm is abnormal.

Fetal NB

The detection rate is 57% for fetal aneuploidies for an absent or hypoplastic NB and the false positive rate is 0.5%. [9] In a meta-analysis of second-trimester markers for trisomy 21, the pooled detection rate was 59.8% with a false positive rate of 2.8%.

[10] Combining NB observations, maternal age, beta hCG, and PAPP-A with NT yielded a detection rate for trisomy 21 of 95% with a false positive rate of 2.9%. [11]

NB Measurement

The optimal time for NB assessment is between 12 and 13.5 weeks of gestation. [12] The NB should be evaluated in a mid-sagittal plane with an angle of insonation close to 45 degrees. The head should be in a neutral position, not hyperflexed or hyperextended. The NB is actually a pair of bones, usually of equal size. Scan through the mid-face to identify the greatest NB length. The NB should appear as a linear echogenic structure beneath and separate from the fetal skin. The fetal NB increases linearly with advancing gestational age. Some ethnic groups may normally have shorter NBs, specifically the Asian population.

Choroid Plexus Cysts (CPCs)

Choroid Plexus Cysts (CPCs)

CPCs have been identified in 0.4% to 3.6% of pregnancies and are usually an insignificant finding that resolves spontaneously. CPCs have been associated with trisomy 18. If choroid plexus cysts are identified, a targeted sonogram to search for additional anomalies should be performed.

CPC Measurement

CPCs are seen within the choroid plexus of the fetal ventricular system and are easily recognized in axial views as thin-walled, hypoechoic cystic structures, which may be unilateral or bilateral and of varying size. The maximum diameters of the cysts should be recorded.

Echogenic Intracardiac Focus (EIF)

An EIF is a common finding identified in about 5% of fetuses. [13] Although generally considered to be a normal variant, it has also been associated with trisomy 21 and trisomy 13. In a meta-analysis of second trimester markers for trisomy 21 the pooled detection rate for trisomy 21 is 24.4% with a false positive rate of 3.9% and a positive LR of 5.83. [14]

Ultrasound Findings

In most instances, the EIF will be located in the left ventricle which may be less significant than when identified in the right ventricle or seen bilaterally. The EIF can be identified in the four-chamber view of the heart, with the apex towards the transducer, and should have a similar echogenicity to that of fetal bone.

Genetic Markers: Renal Pyelectasis (RP)

Genetic Markers: Renal Pyelectasis (RP)

The detection rate is 17% to 25% for fetal aneuploidies for mild RP and the false positive rate is 2% to 3%. [15]

RP Measurement

The detection rate is 17% to 25% for fetal aneuploidies for mild RP and the false positive rate is 2 to 3%. [16] Normal values are pyelectasis ≥ 4 mm up to 20 weeks of gestation and ≥ 7 mm at 32 weeks gestation.

Shortened Long Bones

The detection rate is 40% to 50% for fetal aneuploidies for femoral length and the false positive rate is 7%. [17] In a meta-analysis of second-trimester markers for trisomy 21 the pooled detection rate for short femur is 27.7% with a false positive rate of 6.4%, and a positive LR of 3.7%.[18]

The detection rate is 50% to 54% for fetal aneuploidies for humeral length and the false positive rate is 5% to 6%. [19] In a meta-analysis of second-trimester markers for trisomy 21 the pooled detection rate for short humerus is 30.3% with a false positive rate of 4.6% and a positive LR of 4.81. [20]

Long Bone Measurement

Fetuses with Down syndrome tend to have slightly shorter long bones than those of normal fetuses. The sonographic criteria for a mildly shortened femur or humerus (< .9 FL/ BPD ratio) overlaps with the range observed in unaffected fetuses, making it necessary for laboratories to establish criteria based on their own populations. [21]

Long bones, when measuring at < 5th percentile, are associated with early onset intrauterine growth restriction (IUGR) or skeletal dysplasia.

Echogenic Bowel

The detection rate is 3.7% to 27% for fetal aneuploidies for echogenic bowel and the false positive rate is 1%. [22] In a meta-analysis of second trimester markers for trisomy 21 the pooled detection rate for echogenic bowel is 16.7% with a false positive rate of 1.1% and a positive LR of 11.44. [23]

Ultrasound Findings

Echogenic bowel is a term used for hyperechoic bowel that is the same as or brighter than the surrounding bone. Echogenic bowel may be an isolated finding with no significance, but has been associated with aneuploidy (most commonly trisomy 21), cystic fibrosis, intrauterine infections and intestinal obstructions. [24]

In addition, it has been identified with pregnancies affected by IUGR, placental insufficiency, perinatal death, and a history of bleeding during pregnancy.


In a meta-analysis of second trimester markers for trisomy 21 the pooled detection rate for ventriculomegaly is 7.5%% with a false positive rate of 0.2% and a positive LR of 27.5. [25]

Ventricular Measurement

Measurement is taken in the axial plane at the level of the atria of the lateral ventricle. Values of ≥ 10 mm are considered abnormal.

Follow-up Soft Markers

Recent recommendations are as follows [26]:

1. The association between soft markers and aneuploidy risk is not relevant among women who have undergone successful CVS, amniocentesis, or
cfDNA testing of maternal blood.

2. CPC and EIF are not considered significant markers in the absence of a prior increased risk for aneuploidy.

3. In the presence of EIF, pyelectasis, short humerus length, short femur length, perform cfDNA testing or quad screen.

4. If low-risk result from cfDNA testing or quad screen, no further risk assessment is recommended.

5. If more than one marker, genetic counseling is recommended.
6. A targeted ultrasound and the following is recommended for these soft markers:

A. If pyelactasis criteria are met, perform 32 week renal ultrasosund follow-up and then perform postnatal ultrasound.

B. If short humerus length and/or short femur length, consider third-trimester growth ultrasound.

C. In the presence of NT, or absent/hpoplastic NB, genetic counseling is recommended.

Gain more valuable information on Genetic Markers Overview and additional OB topics:

Gallery 1: trisomy 21

Gallery 2: trisomy 21

Fetal Heart

Fetal Chest




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