Overview
Down Syndrome (Trisomy 21)
1. Topic Overview (Clinical Overview)
Summary
Down Syndrome is the most common chromosomal abnormality and the most frequent genetic cause of intellectual disability. It is caused by the presence of an extra copy of Chromosome 21 (Trisomy 21), most commonly due to nondisjunction during meiosis. The risk increases with maternal age. Clinical features include characteristic dysmorphic facies (Upslanting palpebral fissures, Epicanthic folds, Flat nasal bridge, Single palmar crease), hypotonia, and intellectual disability. There are significant associated conditions: Congenital heart disease (especially AVSD), Duodenal Atresia, Hirschsprung's disease, Hypothyroidism, Atlantoaxial instability, Hearing/Vision problems, Leukaemia (ALL/AML), and Early-onset Alzheimer's disease. Management involves multidisciplinary surveillance and early intervention.
Key Facts
- Genetics: Trisomy 21 (47,XX,+21 or 47,XY,+21).
- Incidence: ~1 in 700-1000 live births.
- Maternal Age Risk: Increases with age (1 in 100 at age 40).
- Mechanisms: Nondisjunction (95%), Robertsonian Translocation (~4%), Mosaicism (~1%).
- Heart: AVSD (~40%), VSD, ASD, TOF, PDA.
- GI: Duodenal Atresia ("Double Bubble"), Hirschsprung's.
- Haem: Transient Abnormal Myelopoiesis (TMM) in neonates, Leukaemia (ALL/AML).
- Screening: Combined Test (NT + β-hCG + PAPP-A) at 11-14 weeks. NIPT (cffDNA).
Clinical Pearls
"AVSD is the Classic Heart Defect": Atrioventricular Septal Defect is strongly associated with Down Syndrome.
"Double Bubble on AXR = Duodenal Atresia": ~30% of Duodenal Atresia cases are in Down Syndrome.
"Atlantoaxial Instability – Check Before Anaesthesia/Sports": Risk of cervical spinal cord compression.
"Hypothyroidism is Common – Screen Annually": Often develops in childhood.
Why This Matters Clinically
Early detection of cardiac defects and systematic surveillance significantly improves life expectancy and quality of life for individuals with Down Syndrome.
2. Epidemiology
Incidence
- Overall: ~1 in 700-1000 live births.
- Maternal Age Effect: Risk increases exponentially with maternal age.
- Age 25: ~1 in 1,250.
- Age 35: ~1 in 400.
- Age 40: ~1 in 100.
- Age 45: ~1 in 30.
Life Expectancy
- Improved: Now ~60 years with modern care (vs. 9 years in 1929).
- Limiting Factors: Congenital heart disease, Alzheimer's (Early-onset).
3. Genetics
Mechanisms of Trisomy 21
| Type | Frequency | Mechanism |
|---|---|---|
| Nondisjunction | ~95% | Failure of chromosome 21 to separate during meiosis (Usually maternal). All cells have 47 chromosomes. |
| Robertsonian Translocation | ~4% | Extra copy of Chromosome 21 attached to another chromosome (Usually 14). May be inherited (Parental karyotype needed). |
| Mosaicism | ~1% | Some cells have Trisomy 21, some are normal. Variable phenotype. Milder features possible. |
Recurrence Risk
| Mechanism | Recurrence Risk |
|---|---|
| Nondisjunction | ~1% above age-related risk. |
| Translocation (De novo) | Low (~1%). |
| Translocation (Parental Carrier) | Higher (5-15% if mother carrier, 2-3% if father). |
| Mosaicism | Variable. |
4. Clinical Features
Dysmorphic Features
| Feature | Description |
|---|---|
| Upslanting Palpebral Fissures | Eyes slant upwards. |
| Epicanthic Folds | Skin folds at inner canthus. |
| Flat Nasal Bridge | Flat midface. |
| Protruding Tongue | Macroglossia (relatively). |
| Small Ears | Low-set, Folded helix. |
| Single Palmar Crease (Simian Crease) | ~50%. |
| Short Fingers (Brachydactyly) | Clinodactyly (Incurved 5th finger). |
| Sandal Gap | Wide gap between 1st and 2nd toes. |
| Short Stature | |
| Hypotonia | Neonates floppy. Improves with age. |
| Brushfield Spots | White spots on iris. |
Developmental Features
| Feature | Notes |
|---|---|
| Intellectual Disability | Mild to Moderate. IQ typically 35-70. |
| Delayed Motor Milestones | Sitting, Walking delayed. |
| Speech Delay | Often more delayed than motor. |
| Learning Difficulty | Variable. Early intervention helps. |
5. Associated Conditions
Cardiac (40-50%)
| Defect | Frequency | Notes |
|---|---|---|
| AVSD (Complete) | ~40% of CHD | Most characteristic. |
| VSD | ~30% | |
| ASD (Secundum) | ~10% | |
| Tetralogy of Fallot (TOF) | ~5% | |
| PDA |
All newborns with Down Syndrome should have an Echocardiogram.
Gastrointestinal
| Condition | Notes |
|---|---|
| Duodenal Atresia | "Double Bubble" on AXR. ~30% Duodenal Atresia cases have T21. |
| Hirschsprung's Disease | Constipation. Failure to pass meconium. |
| Tracheo-Oesophageal Fistula (TOF/OA) | |
| Coeliac Disease | Increased risk. |
Haematological
| Condition | Notes |
|---|---|
| Transient Abnormal Myelopoiesis (TMM) | ~10% of neonates. May resolve spontaneously. Risk of later AML. |
| Acute Lymphoblastic Leukaemia (ALL) | 20x increased risk. |
| Acute Myeloid Leukaemia (AML – M7) | 500x increased risk. Often preceded by TMM. |
| Polycythaemia | Neonatal. |
Endocrine
| Condition | Notes |
|---|---|
| Hypothyroidism | ~15-20%. Often acquired. Screen annually (TSH). |
| Type 1 Diabetes | Increased risk. |
Musculoskeletal
| Condition | Notes |
|---|---|
| Atlantoaxial Instability (AAI) | ~10-20%. Risk of C-spine cord compression. Screen before surgery/anaesthesia, Contact sports. |
| Hip Dysplasia | |
| Ligamentous Laxity | Joint hypermobility. |
Sensory
| Condition | Notes |
|---|---|
| Hearing Loss | ~50-75%. Conductive (Glue ear) and Sensorineural. Screen regularly. |
| Visual Impairment | Cataracts (Congenital), Refractive errors, Strabismus, Nystagmus. |
Neurological
| Condition | Notes |
|---|---|
| Epilepsy | ~10%. |
| Early-Onset Alzheimer's Disease | Almost universal pathology by age 40. Clinical dementia in ~50% by age 60. |
Other
| Condition | Notes |
|---|---|
| Obstructive Sleep Apnoea (OSA) | Common. Large tongue, Hypotonia, Adenotonsillar hypertrophy. |
| Recurrent Infections | Immune dysfunction. |
| Dermatological | Dry skin, Alopecia areata. |
6. Antenatal Screening & Diagnosis
Screening
| Test | Timing | Components | Detection Rate |
|---|---|---|---|
| Combined Test | 11-14 weeks | NT (Nuchal Translucency) + β-hCG + PAPP-A | ~85-90% |
| Quadruple Test | 15-20 weeks | AFP + β-hCG + Inhibin A + uE3 | ~80% |
| NIPT (Non-Invasive Prenatal Testing) | From 10 weeks | Cell-free fetal DNA (cffDNA) in maternal blood | >9% |
NIPT is a screening test. Positive NIPT requires confirmation by diagnostic test.
Diagnostic Testing (Confirmatory)
| Test | Notes |
|---|---|
| Amniocentesis | 15+ weeks. ~0.5-1% miscarriage risk. |
| Chorionic Villus Sampling (CVS) | 11-14 weeks. ~1-2% miscarriage risk. |
| Fetal Karyotyping | From amnio or CVS cells. Gold standard. |
7. Postnatal Management
Newborn Checks
| Investigation | Rationale |
|---|---|
| Echocardiogram | Detect CHD (AVSD, VSD, etc.). All newborns. |
| Karyotype (if not done antenatally) | Confirm diagnosis. Identify mechanism. |
| Thyroid Function (TSH) | Congenital Hypothyroidism. |
| Haematology (FBC, Blood Film) | TMM, Polycythaemia, Leukaemia. |
| Feeding Assessment | Hypotonia. Difficulty feeding. |
| Hearing Screen (AABR/OAE) | High risk of hearing loss. |
Ongoing Surveillance (DSMIG Guidelines – UK)
| Age / Frequency | Assessment |
|---|---|
| Neonatal | Echo, TSH, FBC, Karyotype, Hearing. |
| 6 Monthly (0-5 years) | Growth (DS-specific charts), Development. |
| Annually (All ages) | Thyroid (TSH), Hearing, Vision. |
| Before 5 years | Atlantoaxial assessment (if symptomatic or before surgery/GA). |
| School Entry | Vision, Hearing. |
| Adolescence | Cardiac review (MVP, AR develop). Transition planning. |
| Adults | Alzheimer's screening (Memory/Behaviour). Ongoing health checks. |
8. Management Principles
Multidisciplinary Team
| Specialist | Role |
|---|---|
| Paediatrician | Coordination. General health. |
| Cardiologist | Cardiac surveillance/surgery. |
| ENT / Audiology | Hearing. |
| Ophthalmology | Vision. Cataracts. |
| Endocrinology | Thyroid. Diabetes. |
| Speech & Language Therapy | Communication. |
| Physio/OT | Motor development. Hypotonia. |
| Genetics | Counselling. Recurrence risk. |
Early Intervention
- Speech therapy.
- Physiotherapy (Hypotonia, Motor delay).
- Educational support (Mainstream/Special Education).
Surgical Management
- Cardiac surgery for CHD (AVSD repair, etc.).
- GI surgery (Duodenal Atresia – Duodenoduodenostomy).
- Adenotonsillectomy for OSA.
9. Complications
| Complication | Notes |
|---|---|
| Congenital Heart Disease | Major cause of infant morbidity. |
| Atlantoaxial Instability -> Cord Compression | Limb weakness, Incontinence, Neck pain. |
| Leukaemia | Increased risk. Monitor. |
| Dementia (Alzheimer's) | ~50% by age 60. Early onset. |
| Respiratory Infections | Immune dysfunction. OSA. |
10. Prognosis & Outcomes
| Era | Life Expectancy |
|---|---|
| 1929 | ~9 years (Infections, CHD untreated). |
| 2020s | ~60 years (Cardiac surgery, Vaccinations, Modern care). |
Quality of life is generally good with appropriate support and inclusion.
11. Evidence & Guidelines
Key Guidelines
| Guideline | Organisation | Notes |
|---|---|---|
| DSMIG (Down's Syndrome Medical Interest Group) | UK | Surveillance guidelines. Gold standard. |
| AAP Health Supervision for Down Syndrome | American Academy of Pediatrics | US guidelines. |
| NICE Antenatal Care | NICE | Screening pathways. |
12. Exam Scenarios
Scenario 1:
- Stem: A newborn with Down Syndrome phenotype is found to have a heart murmur. What is the most likely cardiac defect?
- Answer: AVSD (Atrioventricular Septal Defect). This is the most characteristic heart defect in Down Syndrome.
Scenario 2:
- Stem: A baby with Down Syndrome has bilious vomiting on day 1. AXR shows "Double Bubble". What is the diagnosis?
- Answer: Duodenal Atresia.
Scenario 3:
- Stem: What is the mechanism for Trisomy 21 in 95% of cases?
- Answer: Nondisjunction (Usually during maternal meiosis I).
14. Triage: When to Refer
| Scenario | Urgency | Action |
|---|---|---|
| Suspected Down Syndrome (Newborn) | Urgent | Genetics, Cardiology (Echo). |
| Heart Murmur in Known DS | Urgent | Cardiology. |
| Bilious Vomiting in Newborn | Emergency | Surgical review (GI Obstruction). |
| New Weakness / Gait Change | Urgent | Neurosurgery (Atlantoaxial). |
| Suspected Leukaemia (Bruising, Pallor, Fatigue) | Urgent | Haematology. |
15. Patient/Layperson Explanation
What is Down Syndrome?
Down Syndrome is a genetic condition caused by having an extra copy of Chromosome 21. It affects how the body and brain develop.
What are the features?
- Distinctive facial features.
- Some degree of learning difficulty.
- Increased risk of heart problems, hearing and vision issues, and certain other health conditions.
How is it managed?
- Regular check-ups: Heart, Thyroid, Hearing, Vision.
- Early intervention: Speech therapy, Physiotherapy, Educational support.
- Treating associated conditions: Heart surgery if needed, Glasses, Hearing aids.
What is the outlook?
With modern care, many people with Down Syndrome live into their 60s and beyond. Most live happy, fulfilling lives with appropriate support.
Key Counselling Points
- Multidisciplinary Care: "Your child will have a team of specialists supporting them."
- Early Intervention Works: "Therapy and support early on can make a big difference."
- Connect with Support Groups: "Organisations like the Down's Syndrome Association can be very helpful."
16. Quality Markers: Audit Standards
| Standard | Target |
|---|---|
| Echocardiogram performed in all newborns with DS | 100% |
| Annual TSH screening | 100% |
| Hearing screen by 6 months and annually | 100% |
| Karyotype confirmed | 100% |
17. Historical Context
- John Langdon Down (1866): First described the syndrome ("Mongolism" – now deprecated).
- Jérôme Lejeune (1959): Identified the cause as Trisomy 21.
- Antenatal Screening: Developed 1980s-2000s (AFP, Triple/Quadruple Test, NT, NIPT).
18. References
- DSMIG Guidelines. dsmig.org.uk
- Bull MJ, et al. Health Supervision for Children and Adolescents With Down Syndrome. Pediatrics. 2022. PMID: 35190807
Last Reviewed: 2025-12-24 | MedVellum Editorial Team
Medical Disclaimer: MedVellum content is for educational purposes and clinical reference. If you have concerns about your child, please consult a healthcare professional.