Clinical overview
Down syndrome (trisomy 21) is the commonest autosomal aneuploidy compatible with survival to term and the leading genetic cause of intellectual disability. For the registrar, the examinable challenge is rarely the karyotype itself — it is the counselling: how to offer screening so that a woman makes an informed, autonomous choice; how to interpret a screening result as a probability rather than a verdict; how to discuss diagnostic testing and its procedure-related risks; and how to do all of this in a way that is non-directive, unhurried, and free of any pressure toward a particular reproductive decision. This is a HOTS objective precisely because the knowledge (the tests, the numbers) is the easy part — the higher-order skill is weaving probability, choice, and emotionally loaded information into a conversation the woman controls.
The clinical pathway is a funnel. Every woman is offered (never required) a risk-assessment screen. Those with a higher-chance result are offered diagnostic testing, which is the only way to confirm or exclude the diagnosis. At each gate the woman may decline and step off. The counsellor's job is to keep the gates open and the woman in the driving seat, not to push her through. In South Africa this happens across a steep resource gradient: a first-trimester combined screen needs an accredited nuchal-translucency sonographer and a biochemistry assay that many district facilities do not have, so the realistic offer at primary level is often maternal-age risk plus a second-trimester anomaly scan, with referral upward for formal screening and any diagnostic procedure. Honest counselling names what is actually available locally rather than reciting an idealised menu.
Core knowledge
Cytogenetics and recurrence
Down syndrome results from three mechanisms, and the distinction matters for recurrence counselling:
- Free trisomy 21 (~94%) — meiotic non-disjunction, usually maternal. Strongly age-related. Recurrence after an affected pregnancy is modestly raised above the age-specific background (standard teaching is roughly an extra ~0.5–1% above the woman's age risk, though figures vary with the source — quote it cautiously).
- Robertsonian translocation (~4%) — e.g. der(14;21) or der(21;21). Here the parents must be karyotyped, because a balanced carrier parent carries a high, age-independent recurrence risk. A parent carrying an isochromosome 21q [t(21;21)] has effectively a 100% recurrence risk and warrants explicit discussion of donor gametes or pre-implantation genetic testing.
- Mosaicism (~2%) — post-zygotic non-disjunction; phenotype is variable and may be milder.
The age relationship is the single most counselled fact: maternal-age risk of trisomy 21 rises slowly through the twenties and steeply after the mid-thirties. Standard teaching quotes the term risk at age 35 as roughly 1 in 350 and at age 40 as roughly 1 in 100, but the exact figures differ between reference tables and between gestations (the live-birth risk is lower than the first-trimester risk because of fetal loss), so present them as orders of magnitude, not precise quotes.
Figure K2.1 — Cytogenetic mechanisms of Down syndrome and how each changes recurrence counselling, including maternal-age risk anchors.
What screening actually estimates
Screening does not diagnose. It converts a woman's prior risk (chiefly her age) into a posterior, individualised chance by combining markers. The combined first-trimester screen pairs ultrasound nuchal translucency (NT) with two maternal serum analytes — free β-hCG (raised in affected pregnancies) and PAPP-A (lowered) — performed in the 11+0 to 13+6 week window where a crown– rump length of roughly 45–84 mm allows reliable NT measurement. The result is a ratio (e.g. "1 in 1500" = lower chance; "1 in 50" = higher chance) against a chosen cut-off. The combined test detects in the order of ~85–90% of affected pregnancies for a ~5% screen-positive (false-positive) rate — quote these as approximate performance figures, as they vary by laboratory and cohort.