Ultrasound to detect abnormal imprinting in fetus

Ultrasound as detecting the fetal phenotype produced by abnormal imprinting

1. Prader-Willi syndrome: the strongest standalone ultrasound phenotype
PWS is the imprinting disorder among these three that can produce a reasonably recognizable prenatal functional phenotype.
Pattern:
↓ fetal movement
+
polyhydramnios
+
FGR or asymmetric FGR
+
often normal UA Doppler
+
breech/malpresentation

In one series of molecularly confirmed PWS, decreased fetal movements occurred in 88-91%, SGA in about 65%, breech presentation in 64%, and polyhydramnios in about 34%. Importantly, most evaluated UA Dopplers were normal.

FGR + polyhydramnios + reduced fetal movements + normal placental Dopplers Reported fetuses also show flexed wrists, clenched hands and dorsiflexed feet, presumably reflecting reduced fetal activity/hypotonia.

The prenatal phenotype is fetal hypotonia/reduced swallowing and abnormal neuromuscular activity rather than a structural malformation.
PWS: Imprinting defect at 15q11-q13
→ abnormal neuronal/neuromuscular function
→ ↓ fetal movement and swallowing
→ polyhydramnios
→ sometimes secondary abnormal limb positioning/malpresentation
→ FGR may coexist.

2. Silver-Russell syndrome: think "growth phenotype", not malformation
very early, disproportionate growth restriction, especially with relative macrocephaly and asymmetry.
early-onset FGR
• head relatively preserved
• small AC and/or long-bone restriction
• body/limb asymmetry
• often normal anatomy
• Dopplers may initially be normal.

A recent series of 23 molecularly confirmed SRS cases found that IUGR was the major prenatal presentation; in the prenatal group, many were recognized because of IUGR, and some were initially detected after an NIPT result suggesting trisomy 7 A published first-trimester case is particularly instructive: the fetus already showed disproportionate growth restriction at the first scan, described as "head too big for the body", progressing to severe restriction of AC and femur with no structural abnormalities and normal Dopplers at 20 weeks. Molecular testing subsequently showed 11p15 loss of methylation.

There is also evidence that SRS-related growth restriction tends to appear earlier and more severely than FGR caused by conventional placental insufficiency

Early severe FGR
→ disproportion preserved HC
→ short femur / small body
→ asymmetry
→ apparently normal anatomy
→ Dopplers not necessarily explaining the degree of growth restriction

SRS versus placental FGR
A fetus with: EFW <3rd percentile + severe AC restriction + very short femur
but: normal UA Doppler + relatively preserved HC
is not automatically "placental insufficiency."
The newer prenatal data specifically support early and severe FGR as a clue to SRS.

3. Angelman syndrome: ultrasound is much weaker
The characteristic clinical phenotype generally emerges after birth, with developmental delay, severe speech impairment, ataxia, seizures, microcephaly developing over time, etc. The distinctive clinical picture is generally not established prenatally.

Pattern A
Polyhydramnios
+
reduced fetal movements
+
FGR
+
normal UA Doppler
→ PWS rises high on the differential
Must exclude other fetal neuromuscular conditions, CNS disease, upper GI obstruction, aneuploidy and other causes of polyhydramnios/reduced swallowing.
Reduced fetal movement itself is a strong marker of a genetic disorder in pregnancies with polyhydramnios, but it is not specific to PWS.

Pattern B
FGR begins early
+
HC relatively preserved
+
AC disproportionately small
+
short limbs
+
asymmetry
+
normal or relatively nondiagnostic Dopplers
+
no major structural anomaly
→ SRS becomes an important consideration
Especially: very early FGR + relative macrocephaly + body asymmetry

Growth excess phenotype
Macrosomia + macroglossia + omphalocele ± placentomegaly → think BWS / 11p15

Growth restriction + asymmetry phenotype
early severe FGR + relative macrocephaly + asymmetry → think SRS

Hypotonia/swallowing phenotype
↓ movements + polyhydramnios + breech ± FGR → think PWS

Neurodevelopmental imprinting disorder without a fetal structural phenotype
essentially normal prenatal USG → Angelman remains possible

That is a much more useful way to think about prenatal imprinting disorders than asking whether "ultrasound can diagnose imprinting."

PWS
→ functional abnormality first
→ ↓ movement / ↓ swallowing
→ polyhydramnios
→ sometimes FGR
→ Doppler may remain normal.

SRS
→ growth abnormality first
→ early disproportionate FGR
→ relative macrocephaly
→ body asymmetry
→ often no major malformation.

Polyhydramnios + fetal akinesia/hypotonia phenotype → PWS.
Very early disproportionate FGR + relative macrocephaly/asymmetry → SRS.
Normal fetal phenotype → cannot meaningfully exclude Angelman.