Down syndrome

At a glance

• Trisomy 21, the commonest viable autosomal aneuploidy: about 1 in 1,000 to 1,100 live births in Australia. Median life expectancy is now around 60.
• Most cases are non-disjunction linked to maternal age. A translocation changes recurrence risk and means the parents need karyotypes.
• Adults carry a predictable load: hypothyroidism, coeliac disease, obstructive sleep apnoea, obesity, hearing and vision loss, and Alzheimer disease from the 40s and 50s.
• Change in function or behaviour is usually a treatable medical problem (thyroid, sleep apnoea, hearing, pain, depression) until proven otherwise. Dementia is a diagnosis of exclusion against the person's own baseline.

Genetics

Mechanism	Share	Notes	Recurrence
Free trisomy 21	About 95%	Non-disjunction, about 90% maternal, mostly meiosis I. Risk rises with maternal age	About 1%, or the maternal age risk if higher
Robertsonian translocation	3 to 4%	Usually t(14;21). Up to a third of cases are inherited from a balanced carrier parent	Mother carrier 10 to 15%; father carrier under 5%; t(21;21) carrier 100%
Mosaicism	1 to 2%	Post-zygotic error; often a milder phenotype	Low
Partial trisomy	Rare	Duplication of the Down syndrome critical region on 21q22	Depends on mechanism

• Diagnosis: karyotype confirms the mechanism. Rapid QF-PCR or FISH gives an answer in 1 to 2 days but doesn't show a translocation, so a karyotype still follows.
• Genes on chromosome 21 explain several features: APP (amyloid and Alzheimer disease), CBS, SOD1, and the interferon receptor genes (immune dysregulation and autoimmunity).

Pitfall: the karyotype of the child decides whether parents are tested. A free trisomy needs no parental karyotype; a translocation always does.

Prenatal screening and diagnosis

Test	Timing	Performance	Notes
Combined first trimester screen (nuchal translucency, PAPP-A, free beta-hCG, maternal age)	11 to 13+6 weeks	Detects about 85 to 90% at a 5% screen-positive rate	Medicare-rebated ultrasound and bloods
Cell-free DNA screening (NIPT)	From 10 weeks	Detects over 99% with a false-positive rate around 0.1%	Not Medicare funded; about $400 to $800 out of pocket
Chorionic villus sampling	11 to 14 weeks	Diagnostic	Placental mosaicism can mislead
Amniocentesis	From 15 weeks	Diagnostic	Procedure-related loss under 0.5%

• NIPT is a screening test. A high-chance result needs CVS or amniocentesis before any decision, because the DNA is placental and positive predictive value falls in younger women.
• Pre-test counselling should be neutral and include what life with Down syndrome is like now. Down Syndrome Australia provides parent information.

Recognition

• Newborn: hypotonia, upslanting palpebral fissures, epicanthic folds, flat facial profile, small ears, single palmar crease, sandal gap, Brushfield spots.
• Development: intellectual disability, usually mild to moderate, with relative strength in social skills and visual learning.
• Life expectancy has roughly doubled since the 1980s, mainly from early cardiac surgery. Many adults now live independently or with support, and come to adult physicians for the first time during transition.

Health problems by system

System	Problem	Key facts
Cardiac	Congenital heart disease in about 50%	AVSD most characteristic, then VSD, ASD, PDA, tetralogy. Unrepaired shunts lead to Eisenmenger syndrome. Adults develop mitral valve prolapse and aortic regurgitation
Endocrine	Hypothyroidism	Congenital and acquired (autoimmune). Lifetime prevalence over 50%
	Diabetes	Type 1 diabetes 4 to 8 times more common; obesity raises type 2 risk
	Bone	Low bone mineral density and earlier osteoporosis
Gastrointestinal	Coeliac disease	5 to 10%. Screen with tTG-IgA and total IgA if symptoms, poor growth, anaemia or behaviour change
	Neonatal	Duodenal atresia ("double bubble"), Hirschsprung disease, imperforate anus
Respiratory	Obstructive sleep apnoea	Over 50% of children and most adults: midface hypoplasia, macroglossia, hypotonia, obesity
Haematology	Transient abnormal myelopoiesis	About 10% of newborns; GATA1 mutation; most resolve, 20 to 30% later develop AML M7
	Leukaemia	ALL about 20 times more common, with more treatment toxicity (methotrexate). AML M7 up to several hundred times more common before age 5
	Blood count	Macrocytosis is common and doesn't mean B12 deficiency on its own
Neurology	Atlantoaxial instability	Radiological in 10 to 20%, symptomatic in 1 to 2%
	Epilepsy	Infantile spasms in childhood; late-onset myoclonic epilepsy with dementia
Sensory	Hearing	Conductive (glue ear) and later sensorineural loss in most adults
	Eyes	Refractive error, cataract (congenital and early acquired), keratoconus
Immune	Autoimmunity and infection	Alopecia areata, vitiligo, hidradenitis; more severe respiratory infection (COVID-19 deaths were several times higher)
Reproductive	Fertility	Most men infertile; women fertile, with 50% risk of trisomy 21 in offspring. Earlier menopause

• Solid tumours (breast, most others) are less common, but testicular germ cell tumours are more common.
• Mental health: depression, anxiety and obsessive-compulsive behaviours. Down syndrome regression disorder is an acute loss of language, self-care and sleep in adolescents and young adults; screen for medical causes and refer, as some respond to treatment.

Adult health surveillance

The Global Down Syndrome Foundation adult guideline (JAMA 2020) and the AAP 2022 paediatric guideline are the evidence base most Australian clinicians use. Down Syndrome Australia's medical interest group (DSMIG-AUS) plans local guidance but has not yet published guidelines.

Item	Schedule
Thyroid	TSH every 1 to 2 years from 21, and with any functional change
Dementia	Annual assessment from 40, with a documented functional baseline (informant-based tools such as the DSQIID, or the NTG-EDSD)
Weight and diabetes	BMI yearly; HbA1c or fasting glucose every 3 years from 30 for all adults, every 2 to 3 years from 21 if obese
Bone	No routine DXA without risk factors; consider in those with fracture or risk factors
Atlantoaxial	No routine cervical spine X-rays; ask about myelopathy symptoms and examine yearly
Hearing and vision	Audiology and eye review regularly through adult life
Cardiac	Echo for adults with no prior study or new symptoms (acquired valve disease)
Sleep	Ask about snoring, daytime sleepiness and behaviour change; low threshold for polysomnography
Cancer screening	Usual population programs, adapted (cervical screening by self-collect where possible)

Alzheimer disease

• Amyloid plaques are near universal by 40. Clinical dementia affects about half by the mid-50s and most people who live to 65 and over. Average age at diagnosis is the early to mid-50s. Overlap with Dementia syndromes.
• Early signs are often behavioural and executive (apathy, withdrawal, personality change) before memory loss, and new seizures are common.
• Exclude first: hypothyroidism, depression, sleep apnoea, hearing or vision loss, B12 deficiency, coeliac disease, medication effects, pain and life events such as a carer's death.
• Cholinesterase inhibitors are used, with modest evidence. People with Down syndrome were excluded from the anti-amyloid antibody trials and have high rates of cerebral amyloid angiopathy, which raises the risk of ARIA.

Management principles

• Supported decision-making. Assess capacity for each decision. Many adults can consent with information in easy-read formats and time.
• Diagnostic overshadowing is the main error: attributing new symptoms to Down syndrome.
• NDIS funds disability supports. An annual health assessment is available through Medicare (items 701 to 707) for people with intellectual disability.
• Anaesthesia: ask about neck symptoms, airway problems, sleep apnoea and cardiac lesions.

Pitfalls

• Missing a translocation: a rapid FISH or QF-PCR result is not enough to counsel about recurrence.
• Dementia diagnosed too early: hypothyroidism, sleep apnoea, depression and sensory loss each mimic it and are treatable.
• Ordering routine cervical spine X-rays in asymptomatic adults. They don't predict injury.
• Treating NIPT as diagnostic.
• Missing coeliac disease in a person with weight loss, anaemia or behaviour change.
• Assuming low cancer risk applies to all cancers: leukaemia in children and testicular cancer in men are more common.