Clinical review: Down's syndrome

The aetiology of Down's syndrome, the screening process and management of comorbidities in childhood and adulthood.

Section 1: Epidemiology and aetiology

Down's syndrome is one of the most common genetic causes of developmental disability, with an incidence of 1.1 per 1,000 live births. In the UK, around 60,000 people have Down's syndrome.

Owing to improvement in managing associated medical problems, especially congenital cardiac abnormalities, more babies survive and adults are living longer. Mean life expectancy at birth has increased fivefold in the past 50 years and is now 60 years in the UK.

The RCGP curriculum statement Care of people with intellectual disabilities highlights the need to be person-centred, recognising additional health and support care required.

The GP has a role in keeping a register of people with learning disability and in ensuring an annual health check-up takes place from the age of 14 years. This will facilitate transfer from paediatric to adult services.1,2

Down's syndrome can be classified according to the chromosomal changes found:

Nondisjunction trisomy 21
Ninety-five per cent of cases are due to an additional copy of chromosome 21.

In the majority an error occurs in cell division so that one gamete has an additional chromosome 21. Research shows that in most cases the additional copy is maternally derived.

Mosaicism occurs in 1-2% of cases with trisomy 21. The abnormality occurs after fertilisation during cell division. The number of cell lines affected depends on when abnormal separation occurs.

This result is reported as a percentage of cell lines affected.

Translocation occurs in 4% of cases when part of chromosome 21 separates during meiosis and attaches to a different chromosome (commonly chromosome 14), as in the Robertsonian translocation.

There is a spectrum of difficulties in people with Down's syndrome. Genetic research has studied the location on chromosome 21 in relation to each of the different abnormalities found in Down's syndrome, such as cardiac abnormalities and typical facial features.

We do not have a full enough understanding to predict the extent of developmental difficulties or medical problems that people will face simply from the chromosomal configuration, with the exception of mosaicism where the clinical features and developmental difficulties may be less significant.

Section 2: Screening

In 2013, there were 1,886 antenatal and postnatal diagnoses of Down's syndrome in England and Wales (see table).3,4 The majority of diagnoses are made antenatally via screening.

Down syndrome cases diagnosed in 2013* according to maternal age at observed or expected date of delivery3

Maternal age (years)NumberPercentage (95% CI)
<20 21 1 (1-2)
20-24 81 4 (3-5)
25-29 81 9 (8-11)
30-34 327 17 (16-19)
35-39 603 32 (30-34
40-44 457 24 (22-26)
≥45 42 2 (2-3)
Missing 180 10 (8-11)
Total 1,886 100

*2013 data are provisional due to late reporting of cases.

Around 75% of mothers whose fetuses are diagnosed with Down's syndrome choose to terminate the pregnancy and there is also a high rate of fetal loss and stillbirth. Despite the high termination rate, the UK live birth rate is fairly constant.

Maternal age and risk
The number of terminations seems to be balanced by an increased conception rate as women are delaying having children and risk of a pregnancy affected by Down's syndrome increases with maternal age. Oocytes are stored in the ovaries in prophase of meiosis 1 until ovulation. It is thought that 75% of abnormalities occur during meiosis 1 and 25% in meiosis 2.

The longer the oocyte has been stored the more likely it is that an abnormality will occur during cell division. The mean maternal age at diagnosis is 36 years.

The UK National Screening Committee model of best practice advises on standardised tests that should be offered at particular stages of pregnancy.5 This guides the antenatal Down's syndrome screening programme. Screening is also discussed in NICE guidance in antenatal care.6

Nuchal translucency (NT) test has been included in the screening programme. This involves measuring the nuchal fold at the back of the neck of the developing fetus. This is carried out at around 12 weeks' gestation.

More recently a new non-invasive test analysing DNA fragments detected in maternal plasma has been developed. Already available privately, its use in the NHS screening programme is being considered.

Other tests
For women booking between 10 and 14+1 weeks the combined test is used. This includes measuring crown to rump length to estimate gestation and the NT test. These tests are combined with serum tests, including pregnancy-associated plasma protein A (PAPP-A) and hCG. In pregnancies with Down's syndrome, NT and free hCG are high and PAPP-A is low. The approximate detection rate is >90%.

For those booking between 14+2 and 20 weeks the quadruple test is used. This test includes beta hCG, unconjugated estriol (uE3), alphafetoprotein (AFP) and inhibin A. In pregnancies with Down's syndrome the AFP and uE3 are low and the beta hCG and inhibin A are increased. The target detection rate is >75%.

These tests, together with the woman's age, are used to estimate the risk of Down's syndrome. Recent guidance has changed the level classified 'high risk' to one in 150 for both first and second trimester compared with one in 150 for first trimester and one in 200 for second trimester in the previous recommendation.

At this level an amniocentesis or chorionic villus sampling is offered depending on stage of pregnancy. These investigations carry a 1% risk of miscarriage.

Testing can be affected by maternal weight, ethnic group, IVF pregnancies, insulin-dependent diabetes mellitus, smoking and vaginal bleeding. Adjustments in calculations are made in twin pregnancies.

Section 3: Management in childhood

Management is multidisciplinary and includes treatment of comorbidities and support for the family. Guidelines can be found on the Down syndrome medical interest group (DSMIG) website.7

The GP's role is pivotal in supporting both patient and family, in recognising problems and referring appropriately. Children with Down's syndrome can have complex medical problems and some need high levels of additional care.

There is increased susceptibility to respiratory infections. Contributing factors include poor immune function, hypotonia, mid-facial anatomy and gastro-oesophageal reflux. Thought should be given to early use of antibiotics. Sleep-related airway obstruction is common.

Around 40-60% of children with Down's syndrome have a congenital cardiac abnormality. Diagnosis is in the neonatal period as described in DSMIG guidelines. Without prompt treatment, irreversible pulmonary hypertension may result.

Abdominal symptoms are common and some are simple to manage, such as constipation or gastro-oesophageal reflux.

However, congenital abnormalities, such as GI atresias and Hirschsprung's disease, are more likely and could lead to life-threatening complications including bowel obstruction or enterocolitis. Coeliac disease is also more prevalent.

Orthopaedic complications are more common due to hypotonia and ligamentous laxity, in particular spinal cord damage due to cervical spine disorders.

Symptoms include torticollis, pain on walking, sensory abnormalities, changes in gait and urinary incontinence. Any concerns warrant discussion with a spinal surgeon.

Mild abnormalities of blood count occur frequently. The majority of these have no clinical significance. However 1-2% will develop childhood leukaemia.

Down's syndrome growth charts are available along with specific inserts for the personal child health record (red book).

Regular measurements of height, weight and head circumference should be made.

Time to regain birthweight may be longer than the usual 10 to 14 days. Feeding difficulties commonly occur. Later, obesity is a concern so early intervention is vital.

Developmental delay and learning difficulties require support throughout life. There is greater risk of epilepsy (infantile spasms), autistic spectrum disorder, behavioural difficulties and mood disorders than the general population.

Thyroid disorder
Thyroid disorders, mainly hypothyroidism, occur at all ages and regular screening is necessary as well as earlier tests if possible symptoms arise.

Hearing and vision
Hearing impairment and visual problems are common in children with Down's syndrome. Learning disability often means that the patient is less likely to recognise or communicate that they have a problem so regular screening is important.

In addition to routine vaccinations, influenza vaccination should be considered for older children and adults not yet covered by the universal programme, and pneumococcal polysaccharide vaccine in addition to the usual pneumococcal conjugate vaccine, particularly in those with cardiac and respiratory disorders.

Infants with significant left to right cardiac shunts are also eligible for respiratory syncytial virus vaccination.

Section 4: Adult care

Medical supervision by the GP is important in adult life with specialist input where necessary. Individuals may be less likely to complain of symptoms and there may be diagnostic overshadowing when symptoms are assumed to be 'part of Down's syndrome'.

Annual review should continue including weight, hearing and vision monitoring. Assessment should also include the following.

Thyroid screening
Around 12% of adults have thyroid disease. Thyroid function should be checked every two years. TFTs should be considered with any unexplained physical, psychological or functional deterioration.

Mental health
Studies have shown that most patients have the changes in the brain associated with Alzheimer's disease although not all develop the symptoms. Prevalence rates of Alzheimer's disease are similar to those in the general population but disease can occur 20 to 30 years earlier.

Depression is more common in adults who have Down's syndrome. With any new presentation of mental health problems, assessment should exclude common physical conditions, especially hypothyroidism.

Sexual health
Access to appropriate information and sexual health services is important. Fertility is reduced in males and females with Down's syndrome but pregnancies have been recorded.

Cardiac screening
Adults with congenital heart disease should still be under the supervision of a cardiologist.

Adults not under cardiology care should have an echocardiogram in early adult life because of the high incidence of mitral and aortic valve disease.

Assessment for possible cardiovascular disease should be considered at the annual review.

Section 5: Case study

A two-year-old girl with Down's syndrome is brought for review because of recurrent illness over the previous two months.

Her medical history includes pulmonary hypertension and recurrent respiratory tract infection requiring winter antibiotic prophylaxis. Her mother reports that she has had two episodes of diarrhoea and vomiting without complete return to her normal self.

The child has now developed pyrexia, food refusal and drooling. Her younger brother has had a similar clinical picture.

Examination reveals tonsillitis and advice is given regarding analgesia and fluids.

At review two weeks later, the mother reports that the child is irritable with reduced appetite and is passing frequent offensive stools. Clinical examination is unremarkable. However, her weight has fallen across one centile.

Stool samples are sent for microscopy, culture and reducing substances. Blood is taken for FBC, ferritin and coeliac screen. Stool tests, FBC and ferritin show normal results. One week later, the coeliac screen is reported as positive (tissue transglutaminase antibodies >100u/ml).

The mother is telephoned to discuss the results and she reports the child has developed a swollen stomach over the past few days. Urgent examination shows further weight loss and gross abdominal distension.

Hospital admission is arranged and the provisional diagnosis is coeliac disease. This is confirmed by duodenal biopsy showing crypt hyperplastic villous atrophic enteropathy. A gluten-free diet is started and at review six weeks later all symptoms have resolved and growth has returned to normal.

Down's syndrome and coeliac disease
The prevalence of coeliac disease in Down's syndrome is 4-17% depending on age and country of origin. Clinical diagnosis is difficult because of overlap with features commonly seen in Down's syndrome.

A coeliac screen should be considered in the following:

  • Diarrhoea or constipation of recent onset
  • Abdominal distension
  • Faltering growth
  • Arthritis
  • General malaise
  • Medical history including insulin-dependent diabetes mellitus, thyroid disease, anaemia
  • Rash suggestive of dermatitis herpetiformis

Section 6: Evidence base

There have been few clinical trials involving the management of Down's syndrome and medical practice is mainly based on consensus opinion.


  • Charleton P, Dennis J, Marder E. Medical management of children with Down's syndrome. Paediatr Child Health 2010; 20: 331-7.
  • The Down Syndrome Medical Interest Group (DSMIG) is a group of doctors in the UK and Ireland with a specialist interest in Down's syndrome. It aims to promote good medical management. The DSMIG website includes:

Key texts

  • Van Dyke D, Mattheis P, Schoon Eberly M et al. Medical and surgical care for children with Down's syndrome: A guide for parents. Bethesda, Woodbine House, 1995.
  • Pueschel S. Adults with Down syndrome. Baltimore, Brookes, 2006.
  • Polnay L. Community paediatrics. London, Churchill Livingstone, 2002. Chapter 36.
  • Newton R, Puri S and Marder E. Down Syndrome Current Perspectives. Mac Keith Press, 2015


    The Down's Syndrome Association (DSA) website provides health and educational publications for families and healthcare professionals. The DSA also produces Down's syndrome - a new parent's guide, a useful leaflet for families at the time of diagnosis, and a range of information booklets on health conditions written for parents and carers.
    Down's Heart Group provides advice and support for families and children with associated heart problems.
    The UK early support programme provides generic information about helping children with additional needs, support and services and sources of information and advice. It produces a Down's syndrome specific booklet, Information for parents - Down's syndrome.
    Down's Syndrome Education International supports successful education through research and provides information resources and training.

Dr Esther Corker, consultant paediatrician, Sherwood Forest Hospital Foundation Trust, Nottingham; Dr Claire McCall, associate specialist, Nottingham University Hospitals NHS Trust; Dr Liz Marder, consultant paediatrician, Nottingham University Hospitals NHS Trust

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  1. Houghton M. Adult Down's fundraising specific annual health checklist. A step-by-step guide for GP practices: Annual health checks for people with a learning disability.
  2. Down's syndrome association adult health book. (accessed 21 January 2016).
  3. Morris JK. The National Down Syndrome Cytogenetic Register for England and Wales 2013 Annual report. December 2014.
  4. Wolfson Institute of Preventative Medicine. National Down Syndrome Cytogenetic Register.
  5. NHS Fetal Anomaly Screening Programme. Screening for Down's Syndrome: UK NSC Policy recommendations 2011-2014 Models of Best Practice.
  6. NICE. Antenatal care: routine care for the healthy pregnant woman. CG62. London, NICE, 2008. Available at: (accessed 21 January 2016).
  7. Down syndrome medical interest group.

This is an updated version of an article that was first published in November 2011

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