Key Facts

Down syndrome is the most common genetic cause of intellectual disability. Improved medical care, particularly cardiac surgery and treatment of infections, has dramatically improved life expectancy and quality of life. A structured health surveillance programme is essential to identify and manage the multiple associated conditions.

Epidemiology

Incidence is approximately 1 in 800-1,000 live births in the UK. Approximately 750 babies with Down syndrome are born annually in the UK. The incidence is strongly associated with maternal age, though the majority of babies with Down syndrome are born to younger mothers (due to higher overall birth rate). Screening programmes detect approximately 90% of cases prenatally.

Aetiology

• Free trisomy 21 (95%): Three separate copies of chromosome 21 due to non-disjunction (failure of chromosomal separation) during meiosis I (maternal ~90%) or meiosis II. Risk increases with maternal age.
• Robertsonian translocation (4%): Extra chromosome 21 material translocated onto another acrocentric chromosome (usually 14). May be de novo or inherited from a balanced carrier parent — recurrence risk 10-15% if mother is carrier, ~3% if father.
• Mosaicism (1%): Mixture of trisomy 21 and normal cells due to post-zygotic non-disjunction. Phenotype often milder.

Pathophysiology

Triplication of chromosome 21 genes leads to overexpression of ~300 genes on chromosome 21, disrupting normal development. Key genes include:

• DYRK1A: Contributes to intellectual disability and altered brain development
• APP (amyloid precursor protein): Predisposes to early-onset Alzheimer's disease
• DSCR1: Involved in cardiac and cognitive development
• ETS2: Linked to skeletal abnormalities The extra genetic material disrupts embryonic development across multiple organ systems.

Characteristic Features

• Craniofacial: Flat facial profile, upslanting palpebral fissures, epicanthic folds, Brushfield spots (iris), small ears, flat nasal bridge, protruding tongue, brachycephaly
• Hands: Single palmar crease (simian crease ~50%), short broad hands, clinodactyly of 5th finger, wide gap between 1st and 2nd toes (sandal gap)
• Hypotonia: Generalised, present from birth — contributes to feeding difficulties and motor delay
• Growth: Short stature — use Down syndrome-specific growth charts

Systemic Associations

• Cardiac (50%): AVSD (most characteristic), VSD, ASD, PDA, TOF
• GI (10-12%): Duodenal atresia (double bubble sign), Hirschsprung disease, tracheo-oesophageal fistula, imperforate anus
• Endocrine: Hypothyroidism (15-20%), type 1 diabetes (increased risk)
• Haematological: Transient abnormal myelopoiesis (neonatal — ~10%), ALL (20× risk), AML (especially megakaryoblastic)
• Immunological: Increased infection susceptibility, autoimmune conditions
• Musculoskeletal: Atlantoaxial instability (10-20%), hip dysplasia, joint hypermobility
• Neurological: Intellectual disability (mild-moderate in most), early-onset Alzheimer's disease (~50% by age 60), increased seizure risk
• ENT/Eyes: Conductive hearing loss (75%), secretory otitis media, refractive errors (50%), cataracts, strabismus
• Sleep: Obstructive sleep apnoea (~50-75%)

Red Flags

• Neck pain, gait disturbance, or new neurological symptoms — atlantoaxial instability/subluxation
• Declining function or personality change in adulthood — early Alzheimer's disease
• Unexplained cytopenias or lymphadenopathy — leukaemia
• Stridor, drooling, or swallowing difficulty — subglottic stenosis

Bedside

• Clinical examination: Identify characteristic features; cardiac auscultation; check for hypotonia
• Growth: Plot on Down syndrome-specific growth charts
• Hearing: Newborn hearing screen; ongoing audiological assessment

Bloods

• Karyotype: Gold standard for confirmation — identifies free trisomy 21, translocation, or mosaicism
• FISH (fluorescence in situ hybridisation): Rapid result (24-48 hours) for chromosome 21
• TFTs: At birth (newborn bloodspot) and annually thereafter
• FBC: Screen for transient abnormal myelopoiesis (neonates); annual FBC screening
• Coeliac screen (tTG-IgA): At age 2, then every 2-3 years or if symptomatic

Imaging

• Echocardiography: ALL neonates with Down syndrome — regardless of auscultation findings (~50% have CHD)
• Cervical spine X-ray: Lateral flexion/extension views if symptomatic atlantoaxial instability, or before general anaesthesia (controversial — clinical assessment preferred by some guidelines)

Special Tests

• Polysomnography: If OSA suspected (recommended screening at age 4 by some guidelines)
• Visual assessment: By 6 months then regular ophthalmology review
• Parental karyotype: Essential if translocation Down syndrome — to identify balanced carrier parent and counsel on recurrence risk

Non-pharmacological

• Early intervention programme: Physiotherapy, occupational therapy, speech and language therapy from infancy
• Educational support: Most children attend mainstream school with support; some require specialist provision; EHCP
• Down Syndrome Medical Interest Group (DSMIG) surveillance programme: Structured health checks throughout life
• Family support: Down's Syndrome Association, genetic counselling, parent support groups
• Transition planning: Preparing for adult life — housing, employment, social care

Pharmacological

• Levothyroxine: If hypothyroidism develops — dose titrated to normalise TSH
• Cardiac medications/surgery: As indicated for specific CHD
• Antibiotics: Prompt treatment of recurrent infections; low threshold for otitis media treatment
• Leukaemia treatment: Standard chemotherapy protocols (ALL often very responsive in Down syndrome)

Surgical/Interventional

• Cardiac surgery: Early repair of AVSD and other significant CHD — improved survival dramatically
• GI surgery: Repair of duodenal atresia, Hirschsprung pull-through if present
• Grommets/adenoidectomy: For recurrent otitis media with effusion/OSA
• Atlantoaxial stabilisation: If symptomatic instability or myelopathy

Referral Criteria

• All neonates with suspected Down syndrome — genetics (for karyotype and counselling)
• Echocardiography for ALL neonates — paediatric cardiology
• Speech and language therapy, physiotherapy, audiology — early referral
• Community paediatrics for developmental surveillance

• Life expectancy: Median approximately 60 years in developed countries (up from ~25 years in 1980s)
• Intellectual disability: Mild-moderate in most (IQ typically 35-70); some individuals have mild learning difficulties
• Cardiac: With surgical correction, cardiac-related mortality has decreased dramatically
• Alzheimer's disease: ~50% develop clinical dementia by age 60 (virtually all have neuropathological changes by 40)
• Leukaemia: 20× increased risk of ALL; transient myeloproliferative disorder in 10% of neonates (most resolve spontaneously but 20-30% progress to AML)
• Independence: Many adults with Down syndrome live semi-independently with support; employment rates are improving
• Quality of life: Studies consistently report high self-reported quality of life and life satisfaction

DSMIG Surveillance Schedule

Recurrence Risk Counselling