genetic sonogram and soft tissue markers

Genetic sonogram

&

Soft tissue markers

Dr. Mohit Satodia

GMCH 32

Chadigarh

Introduction to Genetic sonogram •It’s a specific targeted examination for fetal aneuploidy,

most specific for Downs syndrome, that searches for the

presence of

1)Fetal structural anomalies

2)Aneuploidy markers and

3)Abnormal biometry. (Callen’s 5th)

• These aneuploidy markers are called as “soft” markers

and these are variations in normal anatomy that, except for

their relationship to aneuploidy, are unlikely to be

clinically significant. (Callen’s 5th)

• soft markers are often transient and nonspecific findings

which can also occur frequently in euploid fetuses.

Genetic Sonogram

•Sensitivity of genetic sonogram ranges from 84%

among women with advanced maternal age to 90%

among women younger than 35 years with abnormal

triple test.

• Performed between 18 to 20 weeks of gestation.

• Major advantage is, it reduces the invasive testing rate

and can optimize the selection of candidate for invasive

testing in order to minimize the procedure related losses

of normal fetuses without significantly decreasing

detection rate.

(Callen’s 5th)

Candidate for Genetic sonogram

Low risk vs. high risk population• Inappropriate for LOW RISK population

1)High false positive rate of 12 to 15% in high risk population (which is probably more in low risk).

2)Each marker by itself has only low to moderate sensitivity for Downs, when found in isolation it not necessarily increase the risk but increases cost and anxiety in LOW RISK.

3) In LOW RISK patient the prior risk may be so low that

Presence of one marker will not qualify a patient for Amniocentesis.

4) Further the accuracy of soft markers has only been studied in HIGH RISK population and generalizing the result in low risk is not appropriate.

Prenatal sonographic features of trisomy 21

(Callen’s 5th)

Prenatal sonographic

features of trisomy 18

(Callen’s 5th)

Prenatal sonographic

features of trisomy 13

(Callen’s 5th)

Most investigated “Six Soft markers” of downs syndrome with

likelihood ratio

( Williams 23rd edi)

Second Trimester Ultrasound Markers Practice

Guidelines

Normal Ultrasound (No marker present)

Low RiskIncluding

1)Age < 35 and

2)serum screen negative

High RiskIncluding Age

1) Age≥ 35years

or 2) Serum screen positive

or Both

No testing required Downs syndrome risk

adjustment (80% reduction in a

priori risk)From (Callen’s 5th)

Second Trimester Ultrasound Markers Practice

Guidelines

ONE ISOLATED SOFT MARKER PRESENT ( Except Nuchal

Fold or Absent nasal bone)

Low RiskIncluding

1)Age < 35 and

2)serum screen negative

High RiskIncluding Age

1) Age≥ 35years

or 2) Serum screen positive

or Both

No testing required Offer Genetic Amniocentesis

From (Callen’s 5th)

Second Trimester Ultrasound Markers Practice

Guidelines

≥ 2 SOFT MARKERS PRESENT OR Thick Nuchal fold OR

Absent nasal bone OR structural anomaly

Low RiskIncluding

1)Age < 35 and

2)serum screen negative

High RiskIncluding Age

1) Age≥ 35years

or 2) Serum screen positive

or Both

Offer Genetic AmniocentesisOffer Genetic Amniocentesis

From (Callen’s 5th)

Individual soft markers

Nuchal fold

• Most sensitive and specific single midtrimester marker

of downs syndrome.

Also seen in 1) trisomy 18

2) trisomy 13

3) Turners syndrome.

• Nuchal skin folds is excess soft tissue in posterior neck

area.

• Sensitivity of Downs detection in range of 42 to 43%

with cut off as 6mm, sensitivity increases to 77.8% with

5mm as cut off (with slight increase in false positive rate)

• Best obtained in trans axial plane through head, angled

posteriorly to include cerebellum and occipital bone.

Trans axial plane for

taking nuchal fold

It should include

following internal

structures.

1)cerebellum,

2)occipital bone

3)cavum septum

pellucidum

• The nuchal fold is

measured with

placement of calipers

from the outer edge of

occipital bone to the

outer edge of the skin

Nuchal fold

Increased Nuchal fold on USG

Significance of Nuchal fold

• Most sensitive and specific with likelihood ratio of 11

for down syndrome even as isolated marker.

• In low risk patients also its helpful in detecting cases.

•Amniocentesis is advised even in low risk patients with

abnormal nuchal fold thickness.

Nasal Bone

• Common feature of downs syndrome facies is flat face with

small nose, again there were evidences of absent, hypoplastic ,

short and agenesis of nasal bone in radiographs of downs

syndrome fetuses—this formed the basis of incorporating absent

nasal bone as soft marker.

• Ideal method for evaluating the facial profile for Nasal bone

include—midsagittal plane with angle of insonation close to 45º

or 135º.

As with angle <45º or >135º the nasal bone may appear

absent, further with angle approaching 90º it may appear large.

Face profile with angle of insonation as 45º showing Nasal Bone

Nasal Bone

• Sensitivity for absent nasal bone have ranged from 28 to 66%, with likelihood ratio of 83 for Downs.

(this approximates that of nuchal fold thickening).

•After addition of absent nasal bone as soft marker, the sensitivity of genetic sonogram has increased from 87% to 92.8% without increasing false +ve rate.

• Short or hypoplastic nasal bone as soft marker requires sonographic normograms which are specific to local population and based on it cutoff are decided for better results.

•Further BPD/NBL ratio >10 can also be used, with 81% sensitivity for downs syndrome.

Echogenic Intracardiac Focus (EIF)

• Echogenic cardiac foci (EIF) is commonly seen on 2nd trimester USG –in 3 to 4% of normal fetuses.

• EIF-its discrete brightly echogenic spot with brightness similar to bone, due to reflection from coarse intra myocardial calcification of papillary muscles and chordae tendinae surrounded by myocardial fibrosis.

• Best visualized in apical 4 chamber view with apex towards or away from transducer.

• Resolves by 3rd trimester

•Most frequently seen in the left ventricle, but also can be seen in right ventricle or bilaterally.

•Likelihood ratio of EIF for Downs syndrome ranges between 1.8 to 4.2.

Echogenic Intracardiac Focus

Significance of EIF

• EIF is associated with aneuploidy trisomy 21 and 13.

• In high risk populations EIF increases the risk of

downs syndrome, but in low risk EIF is considered a

normal variant with absence of other major or minor

USG anomalies.

• M/C in left ventricle but right side or bilateral EIF-

higher risk of aneuploidy.

• Multiple(67%) and large in size-higher risk of

aneuploidy.

• Right vs. Left EIF-higher risk of aneuploidy in right

side EIF.

Echogenic Intracardiac Focus

Choroid plexus Cysts (CPCs)

• Lateral ventricles contain sonolucent CSF and with in this

lies brightly echogenic choroid plexus that normally fills the

atrium and may contains cyst.

• Prevalence among normal is variable from 0.3% to 3.6%.

• CPCs seen between 16 to 21 weeks of GA and are transient,

by 23rd weeks undergo resolutions and uncommon after 25 to

26 weeks.

• CPCs can be unilateral/bilateral/ unilocular or multilocular.

•Commonly they are multilocular and range from 0.5 to 2cm,

occasionally large as to fill almost entire lateral ventricle.

Significance of Choroid plexus Cysts•CPCs always resolve, Larger cysts may take longer time.

•CPCs are associated with fetal aneuploidy- Trisomy 18.

•Prevalence of CPCs in trisomy 18 is 53% when other soft tissue marker is also present, isolated CPCs are not associated with trisomy 18.

• Larger cyst (>1cm) compared to smaller increases the risk of trisomy 18.

• Isolated presence of CPCs in low risk patient is not considered clinically significant, does not change risk category.

• CPCs in absence of other minor or major soft markers & in absence of other risk factors considered to be a “normal variant” and no further evaluation is needed.

• Recommendations are if CPCs is present detailed USG for other soft markers to be done, and if isolated and they always resolve repeat scan add no value to decision making.

Choroid plexus Cysts

Choroid plexus cyst single

unilateral with normal

chromosomes

Choroid plexus Cysts

Multiple Unilateral Cysts

with normal

chromosomes

Choroid plexus Cysts

Bilateral cysts with

trisomy 18

Hyper echogenic bowel

• Non specific and can be seen in normal fetuses (0.5%).

• Normally in 2nd trimester bowel is homogenous with

same echogenicity as rest of abdomen, if it has

echogenicity similar to iliac bones-

HYPERECHOGENIC.

• Hyper echogenic bowel is seen with increased

frequency in trisomy 21, it increases risk by six to

sevenfold ( with other risk factors like age, other soft

markers).

•Risk of trisomy 21 with isolated Hyper echogenic bowel

is 1.4%.

Significance of Hyper echogenic bowel

• Other conditions were Hyper echogenic bowel is seen

1) congenital infections- Cytomegalovirus, herpes

simplex, parvo virus.

2) meconium ileus (due to cystic fibrosis).

3) Bowel obstructions/ Atresia / malformations.

4) Prenatal vaginal bleeding and fetal swallowing

of blood from inatraamniotic hemorrhage.

• There is also increases risk of fetal demise, IUGR and

placenta related complications.

• Risk of both cystic fibrosis and aneuploidy increases

with degree of echogenicity.

Hyper echogenic bowel

Recommendations-

1)consider maternal

studies for congenital

infection, cystic

fibrosis carrier status.

2)invasive testing for

fetal karyotype.

3)serial scan for

IUGR and to rule out

bowel malformations

( evident mostly in

3rd trimester).

Short Long Bones

•Somatic and visceral growth profiles of midtrimester trisomy 21 fetuses have shown short limbs which are discordant with head circumference (HC).

• Short Femur length – BPD/Femur length ratio or observed to expected FL ratio—associated with downs syndrome.

•Assessed between 15 to 23 weeks, but most helpful in detecting trisomy 21 between 17 to 19 weeks.

•Ideal method—FL measured with diaphysis located horizontally in image ( as vertical measurement a/w high false + rate).

Short Long Bones• Different studies showing different sensitivity rates for trisomy

21 detection.

• Most accepted studies out of all is by Lockwood et al showing

sensitivity of 51% with BPD/FL ratio and by Benacerraf et al

showing sensitivity of 68%.

Short Long Bones

• Humeral length--short humeral length also associated

with trisomy 21.

• with measured to expected HL >0.90 as cutoff

sensitivity is 50%.

• Short HL is less useful then FL as screening marker.

Significance of Short Long Bones

• Isolated Short FL is not much sensitive rather

combining it with other USG markers.

•Combining both HL and FL assessments—it carry a 11

fold higher risk of having trisomy 21.

• Gender influences the long bones length, affected

male fetuses had more short FL and HL than affected

female fetuses.

Pyelectasis• Renal pyelectasis ( pelvic dilation) is measured in AP dimension as fluid filled renal pelvis.

• Common finding on USG seen in 2 to 2.8% of normal fetuses.

• Measured in view with kidney and spine are positioned directly toward or away from transducer.

• Cut off is >4mm.

• sensitivity is 25% with cut off > 4mm.

• Isolated pyelectasis carries slightly increased risk but not enough to justify amniocentesis in low risks and to be used with other USG markers.

• When present in high risk as isolated it increased priori risk for fetal trisomy 21.

•

Lliac Wing angle

• Trisomy 21 fetuses have pelvic dysplasia and wider

lateral span of iliac wing as compared to normal thus

causing a widened iliac angle.

• Its measured in transverse view of fetal pelvis, the

iliac angle made by two iliac crests at pivot point of

sacral spine is measured.

•Mean iliac angle in downs is 80± 19.7 ºas compare to

63.1±0.3ºin normal, thus by taking 90º as cut off—

sensitivity is 36.8%.

Significance of Lliac Wing angle

• It is non reproducible due to variation in measurement

of angle.

Depending on 1) actual transverse level

2) intra and interobserver variation.

3) Orientation of spine, axial level

and GA.

• Not a useful marker of trisomy 21.

Ear Length •Abnormally small ears is one of the consistent clinical

finding in newborns and infants with aneuploidy

including downs syndrome.

•Its always found sonographically in cases with trisomy

18 and 13, and in half of the cases of trisomy 21.

•As a result Short ear length on midtrimester USG, is

taken as one of the soft markers of aneuploidy.

• Sensitivity of short ear length (<10th percentile of GA)

in midtrimester is 71%. ( as per Lettieri et al).

• Measured to expected ear length ratio < 0.8 had

sensitivity of 75% for downs and 83.3% for trisomy 18.

(Callens 5th edi)

Ear Length

• Further studies has shown that sensitivity of ear length

for downs syndrome is 41%, for trisomy 18 is 96% and

for trisomy 13 its 100%.

•

Single umbilical artery

• Single Umbilical artery (SUA) is associated with

cytogenetic abnormality – with incidence of 17% with

SUA.

• Trisomy 18 is most common aneuploidy associated

with SUA, then trisomy 13, Turners syndrome and

triploidy, but Downs syndrome is not commonly

associated with SUA.

• In midtrimester USG transverse views of a free loop of

cord with adequate magnification is examined, In SUA

only two vessels one large (vein) and smaller (artery)

will be seen.

Single umbilical artery

• Single Umbilical artery (SUA) is associated with

cytogenetic abnormality – with incidence of 17% with

SUA.

• Trisomy 18 is most common aneuploidy associated

with SUA, then trisomy 13, Turners syndrome and

triploidy, but Downs syndrome is not commonly

associated with SUA.

• In midtrimester USG transverse views of a free loop of

cord with adequate magnification is examined, In SUA

only two vessels one large (vein) and smaller (artery)

will be seen.

Single umbilical artery

• Overall SUA has incidence of 11.3% among

cytogenetically abnormal pregnancies, it can be found in

10 to 50% of trisomy 18 and 13 fetuses.

• It has also been reported to be associated with

1) Congenital anomalies involving various organ

system.(most common system involved-CVS, GIT, CNS).

2) Genetic syndrome ( VATER, Meckel Gruber syndrome)

3) Fetal growth restriction.

4) Prematurity.

5) Increased perinatal mortality rate.

Significance of Single umbilical artery

• In fetuses with isolated SUA there is no increased

incidence for chromosomal abnormality.

• With isolated SUA a detailed sonogram by experience

personnel for other anomalies to be done, once

confirmed isolated and in absence of high risk factors

no need of invasive analysis.

• If other multiple malformations are detected with SUA

Patient should be offered prenatal karyotyping

Sandal Gap

• Sandal gap is separation of great toe from second toe

causing a wide gap between two phalanges.

•

Sandal Gap