InnovAiT, 13(1), 47–52

Down’s syndrome
Dr Sarah MacLennan
GPST3, Norfolk
Email: sjmaclennan1@gmail.com

D own’s syndrome is caused by trisomy of chromosome 21; it is one of the best known
chromosomal disorders in humans. It has effects on most body systems, giving rise to a
variety of characteristic clinical features including intellectual impairment, short stature,
flat face, flat nasal bridge, prominent epicanthic folds, up slanting palpebral fissures and
protruding tongue. Down’s syndrome is also associated with an increased risk of other
medical conditions. All patients with Down’s syndrome have a degree of intellectual impair-
ment ranging from mild to severe. This article considers the epidemiology, genetics, asso-
ciated risks, antenatal screening and potential ethico-legal issues relating to the disorder
before discussing clinical features, complications and monitoring requirements. Finally,
Down’s syndrome management, prognosis, and future diagnostic tests are outlined.

The RCGP curriculum and Down’s syndrome

Intellectual disability is associated with increased mortality and morbidity. The role of the GP in the neurodevelopmental
disorders, intellectual and social disability clinical topic guide is to:
. Recognise a range of associated psychological and physical conditions, some of which may profoundly affect a person’s
capacity for self-care, mobility or communication
. Identify, monitor and review all patients who have difficulties with communication, social relationships and managing
their own affairs; this may require additional skills in diagnosis, examination and consultation, and an understanding of
legislation and guidance on mental capacity
. Carry out annual health checks for people with intellectual disability
. Be aware of the effects of intellectual disability on the life history of the patient and family
. Signpost patients and their families or carers to appropriate resources, knowing when and where to seek specialist help
. Support people transitioning from paediatric to adult services
. Advocate for people with intellectual and social disabilities; promote fairness and equity in the community, including
equal access to health care
The role of the GP in caring for people with long-term conditions:
. Work with patients, their families and carers in a collaborative manner; encouraging individuals to develop the know-
ledge, skills and confidence to take an active role in self-care
. Work collaboratively with people living with long-term health conditions
. Work towards a person-centred system with a biopsychosocial, holisitic approach
. Involve the whole multi-disciplinary team to facilitate person-centred approaches to care
. Proactively encourage lifestyle changes that will reduce the risk of other health problems
Genomic medicine involves using genomic information about an individual as part of their clinical care. As a GP your role
is to:
. Take and consider family histories in order to identify families with, or at risk of, genetic conditions

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. Identify patients and families who would benefit from being referred to appropriate specialist services
. Manage the day-to-day care of patients with genetic conditions, even if the patient is under specialist care
. Coordinate care across services, including transitions from paediatric to adult services
. Communicate information about genetics and genomics, including discussing results from antenatal and new-born screen-
ing programmes
. Understand how genomic information is used within the context of routine clinical practice
Emerging issues:
. All mainstream services should offer patients with intellectual disabilities professional resources and facilities that are
appropriate and tailored to their needs. The GP may be the only significant medical practitioner in their lives.
. GPs need to address issues facing people with intellectual disability; this must also include awareness of the needs of
people with social and adaptive problems. Difficulties include poor social functioning, employment issues, mental health
problems and lack of support from mainstream services (e.g. learning disability teams)
. GPs should recognise that empowering people with intellectual disabilities may involve challenging the values of the local
community and society in general
. Information about genetic susceptibility to common complex conditions (conditions with a multi-factorial inheritance
pattern, such as ischaemic heart disease and cancer) is likely to offer additional information about risk, which will aid
stratification into risk categories or disease sub-types and inform clinical management
. Such clinical advances will have implications for service planning
. As access to genomic testing increases, patients and their relatives will turn to their GP for discussion and advice, and GPs
must be aware of the implications of this eventuality

Epidemiology occurs as a random event during cell division in early fetal

Down’s syndrome is the most common autosomal abnormality
worldwide, affecting around 1 in 1000 live births (World
Health Organization, 2018). In 2011, it was estimated that
there were 37 000 people with the condition in England and
Wales, with a population prevalence of 0.66 per 1000 (Wu and
Morris, 2013). Down’s syndrome accounts for one-third of
cases of severe learning disability. It is unclear when Down’s
syndrome was first identified, but it is believed to have always
existed as a potential genetic abnormality. The name comes
from Dr John Langdon Down who published a description of
the condition in 1866.
development.
Finally, around 4% of children with Down’s syndrome have
an unbalanced Robertsonian translocation involving chromo-
some 21 (Hunter, 2005). An unbalanced Robertsonian trans-
location occurs when the long arm of chromosome 21
becomes attached to another chromosome during cell division
(Rare Chromosome Disorder Support Group, 2005). This error
in cell division occurs before or at conception. Most transloca-
tions occur during egg development. Often a portion chromo-
some 21 attaches to chromosome 14. Unbalanced Robertsonian
translocation may be inherited from a parent who is a transloca-
tion carrier. Being a translocation carrier means the individual
has a balanced translocation, but no clinical defects.

Genetics
Down’s syndrome is primarily caused by autosomal duplica-
tion resulting in an additional chromosome 21 or additional
part of chromosome 21. The extra chromosome content can
arise through several different mechanisms. Most cases of
Down’s syndrome are not inherited, and instead occur by a
random error during cell division. Ninety-five percent of cases
are caused by a failure of the 21st chromosome to separate
during egg or sperm development, known as non-disjunction,
where a complete additional chromosome 21 is present
(Hunter, 2005). Of these non-disjunction cases, most are
caused during maternal egg development.
Around 1% of individuals with Down’s syndrome have
mosaicism, where some of the cells in the body are ‘normal’
(two copies of chromosome 21) and others have trisomy 21
(three copies of chromosome 21) (Hunter, 2005). Mosaicism
Risks
It is well known that the risk of Down’s syndrome dramatically
increases as maternal age increases over 30 years (Loane et al.,
2013). A mother aged 30 years has a risk of 1 in 1000 of having
a child with Down’s syndrome (Hook and Fabbia, 1978). The
risk of a mother having a child with Down’s syndrome can be
estimated by dividing the risk of 1 in 1000 by three, for every 5
years over the age of 30 years, as demonstrated in Table 1
(Hook and Fabbia, 1978).
For those who have had a previous pregnancy where the
foetus is diagnosed as having Down’s syndrome, the risk of
recurrence is 1 in 100 if the mother is aged under 35 years and
the genetic abnormality is caused by non-disjunction (Hunter,
2005). The risk of recurrence is 1 in 10 if the trisomy 21 is
caused by an unbalanced Robertsonian translocation of the

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Table 1. The risk of having a child with Down’s syn-
drome based on maternal age.
Maternal Estimated risk of having a child
age (years) with Down’s syndrome
30 1 in 1000
35 1 in 330
40 1 in 110
45 1 in 37
maternal chromosome, however, the risk of recurrence is 1 in
40 if the translocation is of the paternal chromosome (Hunter,
2005). Therefore, those at highest risk of having a second child
affected with trisomy 21 are those mothers who are
Robertsonian translocation carriers.
Antenatal screening
Screening for Down’s syndrome is an optional test that women
and their partners can choose to have as part of their antenatal
care in the UK. Current UK guidelines recommend screening
for Down’s syndrome in the first trimester using the ‘combined
test’ (Public Health England, 2013). The combined test can
only be performed between 11 þ 2 and 14 þ 1 weeks gestation
and involves measuring nuchal translucency on an ultrasound
scan, plus measuring maternal serum beta-hCG plus preg-
nancy-associated plasma protein A. Increased nuchal translu-
cency is associated with Down’s syndrome, congenital heart
defects and abdominal wall defects.
For women who book late in pregnancy or for whom the
nuchal translucency could not be measured, maternal serum
screening in the second trimester should be offered. This can
be performed between 14 þ 2 and 20 þ 0 weeks gestation. This
triple or quadruple test involves measuring maternal biochemical
markers: alpha-FP, unconjugated oestriol, beta-hCG, þ/– inhi-
bin-A. Down’s syndrome is associated with low alpha-FP, low
unconjugated oestriol, raised beta-hCG, and raised inhibin-A.
A woman is classed as being ‘high risk’ if her risk is calcu-
lated as 1 in 150. In such cases, she will be offered diagnostic
tests including chorionic villus sampling (CVS) and amniocen-
tesis. CVS is usually performed between 11 and 13 weeks
gestation. The procedure involves aspiration or biopsy of pla-
cental villi, which can be either transabdominal or transcervi-
cal. Amniocentesis is usually performed at 16 weeks gestation.
The risk of fetal loss is 0.5–1%. The procedure of amniocen-
tesis involves removing 20 ml of amniotic fluid by transabdom-
inal needle under ultrasound guidance. From this, the amniotic
fluid is sent for karyotyping, the results of this typically take 3
weeks. It is important to counsel patients of the risks and
management options associated with these tests. They
should be encouraged to give thought to how they are likely
to proceed after receiving the test results. Waiting for the
results may result in complications or a late termination of
pregnancy. Therefore, the diagnostic tests should only be per-
formed if they will change the management plan.
Ethico-legal considerations
Following the above screening tests, an important opportunity
for the woman to discuss the results with health professionals
knowledgeable about Down’s syndrome is offered. This dis-
cussion will include the offer of a termination of pregnancy or
continuing support through pregnancy. Currently in the UK,
legal abortion on the grounds of disability can take place up to
birth under the Abortion Act 1967 (UK Government, 2019). Up
to 90% of women who are found to have a pregnancy affected
by Down’s syndrome decide to terminate (Wise, 2016). Many
campaigners have challenged this law, and feel that often
women are encouraged to terminate such pregnancies, des-
pite the recent advances in health, life expectancy and well-
being for people born with Down’s syndrome (Wise, 2016).
On the other hand, it is worth considering the reasons for
terminating a pregnancy affected by Down’s syndrome.
These may include the difficulties of caring for someone
with a condition that may have additional care needs, particu-
larly, if the parents are elderly, which they are more likely to
be as discussed in the above risks section. Healthcare profes-
sionals, including GPs should ensure their own beliefs do not
compromise the content of the consultation or the manage-
ment options offered to a patient when considering termin-
ation or continuation of the pregnancy.
Clinical features
The extra chromosome 21 affects most body systems, and
results in a wide range of clinical features (Roubertoux and
Kerdelhue, 2006). It is important to note that not all individuals
with trisomy 21 will have all of the clinical features listed in
Table 2.
Complications
Patients with Down’s syndrome are at increased risk of
developing a number of co-morbidities (Bull, 2011). These
are listed in Box 1. Note that this list is not exhaustive.
Box 1. Complications.
. Hypothyroidism
. Subfertility
. Repeated respiratory infections
. Hearing impairment from glue ear
. Atlantoaxial instability
. Cervical spondylosis
. Alzheimer’s dementia
. Epilepsy
. Obstructive sleep apnoea
. Obesity
. Osteoporosis
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Table 2. Clinical features.

General Facial Eye
Single transverse palmar crease Up slanting palpebral Brushfield spots in iris
fissures

Hypotonia Prominent epicanthic folds Congenital cataract

Short broad hands Protruding tongue Glaucoma
Short incurved little fingers Flat nasal bridge

Sandal gap between first and Small ears

second toes
Dislocation of knee Round/ flat face

Short stature Flat occiput

Poor feeding Short neck
Developmental delay

Learning disability
Cardiac Abdominal Haematological
Atrial septal defects Hirschsprung’s disease Congenital leukaemia (most commonly AML
acute megakaryoblastic leukaemia before 3
years of age, and ALL acute lymphoid leu-
kaemia after 3 years of age)
Patent ductus arteriosus Intrahepatic biliary Mild pancytopenia
hypoplasia
Ventricular septal defect Duodenal atresia/stenosis Neutropenia
Transient abnormal myelopoiesis

Polycythaemia

Subfertility
Both men and women with Down’s syndrome are likely to be
sub-fertile. In particular, most affected males are infertile (Bull,
2011). Females that do go on to become pregnant have an
increased risk of miscarriage, prematurity, and having a child
affected with Down’s syndrome (Parizot et al., 2019). The risk
of recurrence is 50% (Bull, 2011). Contraception and sexual
health should be discussed with females of child-bearing age.
Given the intellectual impairment known to affect those
with Down’s syndrome, it is important to consider that these
individuals may be vulnerable adults and any concerns sur-
rounding sexual activity should be referred to the local safe-
guarding team.
have Down’s syndrome (Zigman and Lott, 2007). Many people
first present with behavioural changes rather than cognitive
decline, but memory and orientation can also be affected
early on. Up to 90% of people with Down’s syndrome and
dementia develop epilepsy (Head et al., 2012).
Monitoring
All individuals with a diagnosis of Down’s syndrome should
be offered an annual health check in primary care. Box 2 lists
the areas that this assessment should cover (Bull, 2011;
Down’s Syndrome Association, 2015).

Dementia
Alzheimer’s dementia is more common in people with Down’s
syndrome and occurs much earlier in age, as early as 30 years,
with the mean age of onset being 50 years (Zigman and Lott,
2007). The prevalence of Alzheimer’s disease has been esti-
mated to be 56% for those aged 60 years and over and who
Obesity
Up to 95% of those with Down’s syndrome are overweight or
obese, particularly females (Head et al., 2012). Therefore, it
important to monitor weight and body mass index, and edu-
cate individuals and carers on healthy living and disease
prevention.

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Box 2. Annual health check monitoring. are seen in 4% of children with Down’s syndrome (Hunter,
2005). Other ophthalmological complications may arise due to
Weight Mobility the facial structure.

Height Foot care

Blood pressure Continence Dental
Pulse rate Well man awareness:
Prostate and testicular health The typical facial features of individuals with Down’s syn-
drome give rise to an increased risk of potential dental prob-
Communication needs Well woman awareness: lems. Six monthly dental reviews are recommended.
Cervical and breast cancer
screening
Medication review Sexual health
Treatments and therapies
Lifestyle factors Cardiovascular examination
(smoking, exercise and There is no cure for Down’s syndrome; however, early inter-
alcohol) ventions can improve functional outcomes. Treatments are
based on each individual’s physical and intellectual needs,
Baseline functioning Neurological examination
as well as his or her personal strengths and limitations. Any
Sleep
child diagnosed with Down’s syndrome should be offered
Mental health Neck examination multi-disciplinary input through the NHS. This will include
Vision and hearing Thyroid function tests assessment and intervention by physiotherapy, occupational
therapy and speech and language therapy teams. In addition,
Immunisations
any child with Down’s syndrome should receive both psycho-
logical and educational support. GPs should ensure all chil-
dren have access to these services and offer referral if they are
Cardiovascular not already receiving them.
Between 40 and 60% of people with Down’s syndrome have
congenital heart problems (Bull, 2011). The most common of
these is atrioventrical septal defects (Bull, 2011). Furthermore, Prognosis
new valve problems may present in adult life. One echocar-
diogram in adult life is recommended (Bull, 2011). The median life expectancy for an individual with Down’s
syndrome is 58 years (Wu and Morris, 2013). This increasing
life expectancy is attributed to improved infant survival (Wu
and Morris, 2013). Many individuals with Down’s syndrome go
Mental health on to further education and employment. Furthermore,
Depressive illness is more common in people with Down’s increasing numbers are able to live independently and main-
syndrome, and mental health problems generally are more tain relationships of their own. There are a number of support
common in people with learning disability (Capone et al., groups and resources available online, to which GPs can sign-
2006). Mental health assessment may be required if the patient post patients and carers. These are listed in Box 3.
presents with changes in behaviour or mood, or loss of skills.
Box 3. Down’s syndrome support groups.
Down’s Syndrome Association: www.downs-syndrome.org.uk
Immunisations
Down’s Syndrome Research Foundation Ltd: www.dsrf-uk.
All individuals with Down’s syndrome should be offered routine org
immunisation in line with local policy. In addition, individuals
Down’s Syndrome Scotland: www.dsscotland.org.uk
with Down’s syndrome should be considered for annual influ-
enza vaccination given their increased risk of infection, espe- Positive about Down Syndrome: www.positiveaboutdown-
cially if they have chronic cardiac or respiratory disease. The syndrome.co.uk
pneumococcal vaccine should be considered in anyone with The Lejeune Clinic for Children with Down’s Syndrome:
Down’s syndrome over the age of 2 years who has either had www.lejeuneclinic.com
no pneumococcal polysaccharide vaccine before, or only had
the pneumococcal conjugate vaccine (Marder, 2014).
The future
It is believed that a new screening test may be introduced in
Eyes the U.K to detect genetic disorders including Down’s syn-
Full ophthalmological assessment by an optometrist or opti- drome. This non-invasive prenatal testing (NIPT) is a blood
cian should be carried out every 2 years. Congenital cataracts test carried out at 10 weeks gestation. The test calculates the

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cell-free fetal DNA, particularly chromosome 21, which is then
used to estimate the likelihood of the foetus having Down’s
syndrome. The RAPID (Reliable Accurate Prenatal Non-
Invasive Diagnosis) evaluation study has shown that the test
is about 99% accurate in detecting Down’s syndrome, which
compares with an accuracy of 84–90% for the currently offered
combined test (Wise, 2016). The proposed benefit of such a
test is that it will reduce the number of women who need to
have a confirmatory amniocentesis or CVS and subsequently
will reduce the number of miscarriages. It has been suggested
that the introduction of NIPT may reduce the number of late
terminations (Wise, 2016).
KEY POINTS
. Down’s syndrome is a common chromosomal disorder
characterised by intellectual impairment, dysmorphic
facial features and other distinctive phenotypic traits
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ajmg.c.30097.
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InnovAiT
. Most cases of Down’s syndrome are not inherited, and
are caused by a failure of chromosome 21 to separate
during egg development
. The risk of Down’s syndrome dramatically increases as
maternal age increases over 30 years
. Antenatal screening to detect Down’s syndrome is
offered to all pregnant women in the UK
. There are several complications and co-morbidities
associated with Down’s syndrome, and an annual
health check in primary care is recommended
. Quality of life and life expectancy is increasing for indi-
viduals with Down’s syndrome
ORCID iD
Dr Sarah MacLennan https://orcid.org/0000-0001-8674-6978
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