Description
- Trisomy 21 - commonest autosomal trisomy compatible with survival
- Dysmorphism: brachycephaly, flat facial profile, upslanting palpebral fissures, epicanthic folds, Brushfield spots, small ears, single palmar crease, sandal gap toe, hypotonia
- Clinical diagnosis, confirmed by karyotype
Epidemiology
- ~1 in 700-1000 live births
- Risk rises steeply with maternal age
- ~1:1500 at age 20 -> ~1:100 at age 40 -> ~1:30 at age 45
- Commonest genetic cause of intellectual disability
Aetiopathogenesis
- Full trisomy 21 (~95%) - meiotic non-disjunction
- Maternal meiosis I error most common - risk tied to maternal age
- Robertsonian translocation (~4%)
- ~1/3 de novo, ~2/3 inherited from balanced-translocation carrier parent
- Not age-related - triggers parental karyotype + genetic counselling for recurrence risk
- Mosaicism (~1-2%)
- Post-zygotic mitotic error -> milder, variable phenotype
Diagnosis
Antenatal
- Combined first-trimester screening (11-13+6 wks): NT + PAPP-A + beta-hCG
- cfDNA (NIPT) - high sensitivity/specificity for T21, but remains a screening test, not diagnostic
- Positive screen -> offer diagnostic test
- Diagnostic: CVS (from ~11 wks) or amniocentesis (from ~15 wks) -> karyotype/QF-PCR/microarray
Postnatal
- Clinical suspicion -> karyotype confirms and identifies mechanism (trisomy/translocation/mosaic)
- Mechanism determines recurrence risk counselling
Management
At diagnosis
- Echocardiogram - identify CHD regardless of clinical exam
- FBE - exclude transient abnormal myelopoiesis / congenital leukaemia
- TFTs, hearing screen, ophthalmology review
Ongoing surveillance (MDT, structured schedule)
- Thyroid - annual TSH (acquired hypothyroidism common)
- Vision/hearing - regular screening (cataracts, refractive error, OSA-related and conductive loss)
- Coeliac screen - if symptomatic (weight faltering, GI symptoms)
- Atlantoaxial instability - assess clinically (neck pain, gait change, new UMN signs); routine screening cervical spine X-ray no longer recommended in asymptomatic children
- OSA - low threshold for sleep study
- Developmental/early intervention support, cardiology and GI follow-up as needed
Associations
- Cardiac (~40-50%) - AVSD most characteristic, also VSD, ASD, TOF
- GI - duodenal atresia, Hirschsprung disease, TOF/oesophageal atresia
- Endocrine - autoimmune hypothyroidism, T1DM
- Haematological - transient abnormal myelopoiesis (neonatal), AML (megakaryoblastic) and ALL risk inc ~10-20x
- Coeliac disease - inc prevalence
- Atlantoaxial instability, epilepsy, cataracts/refractive error, conductive + sensorineural hearing loss
- OSA - very common, often under-recognised
Natural history & complications
- Life expectancy now ~60 yrs, transformed by cardiac surgery and MDT care
- Early-onset Alzheimer disease - APP gene triple dose (chr21)
- Neuropathology near-universal by 40yrs; clinical dementia in a majority by 60-70
- Childhood leukaemia risk elevated but overall solid-tumour risk reduced vs general population
- Fertility: males near-universally infertile; females fertile with own inc risk of T21 offspring
7 of 7 sections written · drafted 2026-09-13