Down’s syndrome Dr Sarah MacLennan

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Down’s syndrome

Dr Sarah MacLennan

GPST3, Norfolk

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 screening 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

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.

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

occurs as a random event during cell division in early fetal development.

Finally, around 4% of children with Down’s syndrome have an unbalanced Robertsonian translocation involving chromosome 21 (Hunter, 2005). An unbalanced Robertsonian translocation 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 translocations occur during egg development. Often a portion chromosome 21 attaches to chromosome 14. Unbalanced Robertsonian translocation may be inherited from a parent who is a translocation carrier. Being a translocation carrier means the individual has a balanced translocation, but no clinical defects.

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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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 11þ2 and 14þ1 weeks gestation and involves measuring nuchal translucency on an ultrasound scan, plus measuring maternal serum beta-hCG plus pregnancy-associated plasma protein A. Increased nuchal translucency 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 14þ2 and 20þ0 weeks gestation. This triple or quadruple test involves measuring maternal biochemical markers: alpha-FP, unconjugated oestriol, beta-hCG, þ/– inhibin-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 amniocentesis. 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 amniocentesis involves removing 20 ml of amniotic ﬂuid by transabdominal 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 performed 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 discussion 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, particularly, if the parents are elderly, which they are more likely to be as discussed in the above risks section. Healthcare professionals, including GPs should ensure their own beliefs do not compromise the content of the consultation or the management options offered to a patient when considering termination 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.

Table 1. The risk of having a child with Down’s syndrome based on maternal age.

Maternal age (years)

Estimated risk of having a child with Down’s syndrome

30 1 in 1000

35 1 in 330

40 1 in 110

45 1 in 37

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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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.

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 estimated to be 56% for those aged 60 years and over and who

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).

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.

Table 2. Clinical features.

General Facial Eye

Single transverse palmar crease Up slanting palpebral fissures

Brushfield spots in iris

Hypotonia Prominent epicanthic folds Congenital cataract

Short broad hands Protruding tongue Glaucoma

Short incurved little fingers Flat nasal bridge Sandal gap between first and

second toes

Small ears

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 leukaemia after 3 years of age)

Patent ductus arteriosus Intrahepatic biliary hypoplasia

Mild pancytopenia

Ventricular septal defect Duodenal atresia/stenosis Neutropenia

Transient abnormal myelopoiesis Polycythaemia

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Cardiovascular

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, new valve problems may present in adult life. One echocar- diogram in adult life is recommended (Bull, 2011).

Mental health

Depressive illness is more common in people with Down’s syndrome, and mental health problems generally are more common in people with learning disability (Capone et al., 2006). Mental health assessment may be required if the patient presents with changes in behaviour or mood, or loss of skills.

Immunisations

All individuals with Down’s syndrome should be offered routine immunisation in line with local policy. In addition, individuals with Down’s syndrome should be considered for annual inﬂu- enza vaccination given their increased risk of infection, espe- cially if they have chronic cardiac or respiratory disease. The pneumococcal vaccine should be considered in anyone with Down’s syndrome over the age of 2 years who has either had no pneumococcal polysaccharide vaccine before, or only had the pneumococcal conjugate vaccine (Marder, 2014).

Eyes

Full ophthalmological assessment by an optometrist or opti- cian should be carried out every 2 years. Congenital cataracts

are seen in 4% of children with Down’s syndrome (Hunter, 2005). Other ophthalmological complications may arise due to the facial structure.

Dental

The typical facial features of individuals with Down’s syndrome give rise to an increased risk of potential dental problems. Six monthly dental reviews are recommended.

Treatments and therapies

There is no cure for Down’s syndrome; however, early inter- ventions can improve functional outcomes. Treatments are based on each individual’s physical and intellectual needs, as well as his or her personal strengths and limitations. Any child diagnosed with Down’s syndrome should be offered multi-disciplinary input through the NHS. This will include assessment and intervention by physiotherapy, occupational therapy and speech and language therapy teams. In addition, any child with Down’s syndrome should receive both psychological and educational support. GPs should ensure all children have access to these services and offer referral if they are not already receiving them.

Prognosis

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 on to further education and employment. Furthermore, increasing numbers are able to live independently and main- tain relationships of their own. There are a number of support groups and resources available online, to which GPs can signpost patients and carers. These are listed in Box 3.

The future

It is believed that a new screening test may be introduced in the U.K to detect genetic disorders including Down’s syndrome. This non-invasive prenatal testing (NIPT) is a blood test carried out at 10 weeks gestation. The test calculates the Box 2. Annual health check monitoring.

Weight Mobility

Height Foot care

Blood pressure Continence

Pulse rate Well man awareness:

Prostate and testicular health Communication needs Well woman awareness:

Cervical and breast cancer screening

Medication review Sexual health Lifestyle factors

(smoking, exercise and alcohol)

Cardiovascular examination

Baseline functioning Sleep

Neurological examination

Mental health Neck examination Vision and hearing Thyroid function tests Immunisations

Box 3. Down’s syndrome support groups.

Down’s Syndrome Association: www.downs-syndrome.org.uk Down’s Syndrome Research Foundation Ltd: www.dsrf-uk.

org

Down’s Syndrome Scotland: www.dsscotland.org.uk Positive about Down Syndrome: www.positiveaboutdown- syndrome.co.uk

The Lejeune Clinic for Children with Down’s Syndrome:

www.lejeuneclinic.com

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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

. 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 individuals with Down’s syndrome

ORCID iD

Dr Sarah MacLennan https://orcid.org/0000-0001-8674-6978

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