Mosaic Trisomy 21 at CVS With a Normal Amniocentesis
A 36-year-old G2P1 woman undergoes chorionic villus sampling at 12 weeks for advanced maternal age. The direct cytogenetic preparation shows 47,XX,+21[6]/46,XX[14]; long-term culture confirms mosaicism. Ultrasound at 13 weeks is normal, nuchal translucency 1.4 mm, nasal bone present. At 16 weeks, amniocentesis is performed; FISH on uncultured amniocytes is normal, and 25 cultured amniotic fluid cells show 46,XX. Maternal serum quad screen at 16 weeks: AFP 1.0 MoM, hCG 1.8 MoM, uE3 0.7 MoM, inhibin 1.2 MoM. The couple asks whether the baby has Down syndrome and whether the CVS result can be ignored. They also ask about “UPD testing” they read about online.
1. Interpret the discordance and estimate the residual risk of true fetal mosaicism.
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The CVS result demonstrates trisomy 21 mosaicism in the placenta. With a normal early ultrasound, this is most likely confined placental mosaicism (CPM), which occurs in roughly 1–2% of CVS samples. A normal amniocentesis is strongly reassuring but does not entirely exclude low-level fetal mosaicism. If the true fetal mosaic fraction were 10%, the chance of finding no trisomic cell in 25 cells is (0.9)^25 ≈ 7%; for a 20% mosaic fraction it is (0.8)^25 ≈ 0.4%. Thus low-level mosaicism remains possible. The quad screen is not interpretable for Down syndrome risk in this setting; the elevated hCG and low uE3 may reflect the trisomic placenta rather than a trisomic fetus. UPD testing is not indicated for chromosome 21, because there is no established imprinting phenotype; UPD studies are relevant for CPM involving chromosomes 6, 7, 11, 14, 15, 16, or 20.
2. What additional testing, if any, would you offer, and is UPD testing indicated?
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I would offer additional reassurance rather than immediate repeat invasive testing. Options include counting more cultured amniocytes or performing FISH on 50–100 uncultured amniocytes to increase sensitivity for low-level mosaicism. A detailed anatomy scan at 18–20 weeks and a fetal echocardiogram at 20–24 weeks are appropriate because trisomy 21 can cause cardiac defects. If anatomy is normal and additional cell counts are normal, the residual risk is low. No test can exclude every low-level mosaic fraction. UPD testing is not indicated for chromosome 21. If the CPM had involved an imprinted chromosome, UPD testing would be considered because of risks such as Silver–Russell syndrome or Prader–Willi syndrome.
3. How would you counsel the couple and plan delivery?
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Counsel that the CVS finding most likely represents placental mosaicism and that the normal amniocentesis is very reassuring, but a small residual risk of fetal mosaicism remains. Explain that the serum screen cannot be used to revise the Down syndrome risk in this situation. Offer the additional FISH or cell counts and the detailed ultrasound/fetal echo. If these are normal, continue routine prenatal care with a low-risk mindset, while noting that postnatal examination and, if any features are present, a newborn karyotype can provide final reassurance. Delivery should occur at a center prepared for neonatal evaluation, but no cesarean or specialized delivery is required solely for this finding. Document the counseling and the couple’s decision.