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Medical Genetics & Pediatrics & Family Medicine

Trisomy 21 (Down syndrome)

Trisomy 21 - known as Down's syndrome (after the British physician John Langdon Down, who described its clinical features in 1866) - is the most common chromosomal anomaly in live births + with an incidence of 1 in 700 to 1,000 births in Canada + and the leading genetic cause of intellectual disability. In 95 % of cases, it results from meiotic non-disjunction - an error in the separation of chromosome 21 during meiosis I or II (most often of maternal origin - 95 % of meiotic non-disjunctions) - leading to the presence of an extra chromosome 21 in all the body's cells (karyotype 47,XX+21 or 47,XY+21) → triplosomy of chromosome 21 genes → overexpression of hundreds of genes → multisystemic pleiotropic effects. In 4 % of cases, trisomy 21 results from a Robertsonian translocation (additional chromosome 21 fused to another acrocentric chromosome - most often chromosome 14 - apparent karyotype 46 chromosomes with one translocated chromosome 14;21) → requires a search for balanced translocation parental carriage (recurrence risk of up to 10-15 % if the mother is a carrier). In 1 % of cases: mosaicism (post-zygotic non-disjunction → coexistence of normal and trisomic cells → phenotype often more attenuated). The risk of trisomy 21 increases progressively with maternal age: 1/1,500 at age 20 + 1/400 at age 35 + 1/100 at age 40 + 1/30 at age 45 - which justifies the universal prenatal screening offered to all pregnant women in Quebec. Life expectancy for people with trisomy 21 has increased considerably - now exceeding 60 years in developed countries - thanks to advances in pediatric cardiology + preventive care + and social inclusion.

Prenatal screening and diagnosis

  • Combined 1st trimester screening (11-14 SA) - universally available in Quebec : nuchal translucency measurement (NT - fetal neck thickening on ultrasound) + maternal serum markers (low PAPP-A + high + or total free hCG) + maternal age → combined risk calculation → sensitivity 85-90 % + false positive rate 5 %
  • Non-invasive prenatal test (NIPT - plasma free fetal DNA - cfDNA) : analysis of free fetal DNA circulating in maternal blood → sensitivity > 99 % + specificity > 99.9 % for trisomy 21 → screening test + non-diagnostic (confirm by amniocentesis if positive) + offered to women at intermediate or high risk for combined screening + or on request → result in 10-14 days
  • Amniocentesis (diagnosis) : amniotic fluid sample → fetal karyotype + or FISH + or CGH-array → definitive result → indication: positive screening + positive NIPT + history of trisomy 21 + parental carriage of a translocation + or patient's wish → risk of miscarriage: 0.1-0.5 %
  • Trophoblast biopsy (CVS - 11-14 SA) : earlier result than amniocentesis + comparable risk of miscarriage

Clinical features and associated malformations

System Common manifestations Frequency
General morphology Neonatal hypotonia + relative microcephaly + flat face + flattened occiput + short neck 100 %
Facies Upward-slanting palpebral slits + epicanthal fold + flat nose + small, low-set ears + relative macroglossia + protruding tongue 90-100 %
Hands and feet Single transverse palmar crease (simian crease) + brachydactyly + clinodactyly of 5th finger + sandgap (widened space between 1st and 2nd toes) 50-70 %
Congenital heart disease Atrioventricular canal (AVC - 40 %) + IVC + AIC + patent ductus arteriosus + tetralogy of Fallot → systematic neonatal cardiac ultrasound 40-50 %
Digestive Duodenal atresia («double bubble» on prenatal ultrasound - pathognomonic) + Hirschsprung's disease + esophageal atresia + pyloric stenosis 5-12 %
Audition Deafness (mixed or conductive) due to repeated infections + morphology of the auditory canal + fluid in the middle ear 70-75 %
Vision Strabismus + congenital cataract + glaucoma + refractive errors + Brushfield's spots (iris) 60-70 %
Thyroid Hypothyroidism (autoimmune or congenital) → annual TSH screening 15-20 % in adulthood
Orthopedics Atlantoaxial instability (laxity of the transverse ligament of C1-C2 - risk of spinal cord compression) → cervical x-ray 10-15 %
Hematology Acute leukemia (risk × 10-20 vs. general population - AML and ALL) + neonatal transient myeloproliferative disorder (TMT) 1-2 %
Neurological and cognitive Mild to moderate intellectual disability + psychomotor developmental delay + epilepsy (5-10 %) + early-onset Alzheimer's disease (from age 40 - very high risk linked to the APP gene on chromosome 21) 100 % (intellectual disability)

Medical monitoring - systematic preventive surveillance

  • Neonatal period : cardiac echocardiography (cardiac malformations in 40-50 %) + thyroid workup (TSH + T4) + audiology + CBC (leukemia + transient myeloproliferative disorder) + cervical X-ray (atlantoaxial instability) + ENT evaluation (choana atresia) + genetic consultation + karyotype if not done prenatally.
  • Infants and children: TSH annually + audiology every 6 months until age 3, then annually + ophthalmology annually + cardiological follow-up if heart disease + physiotherapy + occupational therapy + speech therapy (hypotonia + language delay) + development follow-up + school integration (adapted program).
  • Adolescents and adults : Annual TSH + audiology + ophthalmology + screening for celiac disease (anti-tTG IgA antibodies - prevalence 5-12 %) + cervical radiography before practising high-risk sports (martial arts + gymnastics + contact sports) + annual cognitive assessment (screening for early-onset dementia from age 40) + cardiovascular screening + mental health (anxiety + depression + behavioural disorders).
ℙ️ The APP (Amyloid Precursor Protein) gene responsible for the production of the β-amyloid protein involved in Alzheimer's disease is located on chromosome 21 - triplication of this gene in trisomy 21 results in overproduction of β-amyloid from birth → early cerebral amyloid deposits → almost all trisomic individuals present neuropathological lesions of Alzheimer's disease after age 40 + and 50-70 % develop clinical dementia after age 65. This high risk of early dementia calls for basal cognitive assessment at around 30-35 + and annual monitoring from age 40 onwards.
Medical consultation recommended

Consult a doctor or pediatrician promptly if an infant or child with known trisomy 21 shows a sudden change in behavior + a regression in acquired skills + fatigue + weight gain + constipation + or coldness (signs of hypothyroidism) + or neck pain + difficulty walking + or limb weakness (atlantoaxial instability). For structured preventive medical follow-up of people with trisomy 21 (TSH + audiology + ophthalmology + celiac screening), Clinique Omicron offers medical consultations at its points of service in Quebec and via telemedicine. To book an appointment, visit cliniqueomicron.ca.

Consult at Clinique Omicron

Clinique Omicron's specialized physicians and nurse practitioners (IPS) provide structured preventive medical follow-up for people with trisomy 21 according to Canadian guidelines (annual TSH + audiology + ophthalmology + celiac screening + cognitive evaluation from age 40), coordinate with specialized teams (cardiology + ENT + genetics + neuropsychology), prescribe combined 1st trimester prenatal screening + NIPT if indicated + amniocentesis if positive, support families in the prenatal diagnostic process, and provide vaccinations and routine screenings. Consultations are available at several points of service in Quebec and via telemedicine. To book an appointment, visit cliniqueomicron.ca.

The content of this page is provided for information purposes only and does not replace the advice of a physician, pediatrician or geneticist. Translocation trisomy 21 (4 % of cases) requires parental carrier research to assess the risk of recurrence - parental karyotyping is essential in this case. Increased nuchal translucency on 1st-trimester ultrasound is a suggestive but not diagnostic sign of trisomy 21 - confirmation by karyotype is always necessary.

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