Down syndrome

Down syndrome (DS) is a genetic condition caused by trisomy 21.

Trisomy 21 is a genetic condition that refers to an additional copy of the 21^st chromosome. This condition is commonly known as Down syndrome and it is the most common chromosomal abnormality amongst liveborn children.

The additional genetic material leads to characteristic physical features of the head, neck, and extremities. Some of these features are universal, whereas others are more variable among people with Down syndrome.

Though intellectual disability is almost universal, the degree is highly variable. Educational, speech, and language support should be offered and tailored to each individual’s (and family’s) needs. Screening for relevant conditions should be offered and managed as appropriate.

It is estimated that there are 41,700 people with DS in England and Wales.

Figures vary by population and will tend to be higher in countries where the average maternal age is higher. In England, in 2018, there was a prevalence of 1 in 400 births for DS.

Figures from NCARDRS and DSMIG.

The most common cause of DS is nondisjunction of chromosome 21 during meiosis on the maternal side resulting in trisomy 21.

Trisomy 21 (94-95%): DS is most commonly caused by an extra chromosome 21 (trisomy 21) in all cells, meaning those affected have a total of 47 chromosomes in each cell. It occurs due to nondisjunction (failure of the two 21 chromosomes to separate) during meiosis. In 90-95% of cases, the additional chromosome 21 is inherited from the mother and the incidence increases with increasing maternal age.

Robertsonian translocation (3-4%): DS may be caused by translocation of the long arm of chromosome 21 to another chromosome, most commonly 14.

Trisomy 21 mosaicism (1-2%): this occurs following fertilisation. An error during cell division leads to a population of cells with trisomy 21 (47 chromosomes) and a population with 46 chromosomes.

Maternal age is the most significant risk factor for DS.

It is known that the risk of nondisjunction increases with advancing maternal age. This leads to a sharp increase in the incidence with increasing maternal age.

• 20: 1 in 1450
• 25: 1 in 1350
• 30: 1 in 940
• 35: 1 in 350
• 40: 1 in 85
• 45: 1 in 35
• 50: 1 in 25

Figures (rounded) from Morris et al (2002). Of note this is based on data gathered from England and Wales in the 90’s.

DS is a condition that has characteristic facial features and can affect multiple organ systems.

Dysmorphic features

There are a number of dysmorphic features seen in those people with DS. Brachycephaly (flattening of the back of the skull), epicanthal folds (fold of skin from upper eyelid that covers the inner corner of the eye, frequently appears in those without DS, particularly in Asian populations) and upward-slanting palpebral fissures (area between the open eyelids) are almost always seen.

In newborns, a number of features may be present. Facial signs include flat features, slanting palpebral fissures and dysplastic ears. General hypotonia and a poor moro reflex are commonly described. Clinodactyly and a transverse palmar crease are often seen.

• Head and neck:
  • Brachycephaly
  • Epicanthal folds
  • Upward-slanting palpebral fissures
  • Flat facial profile
  • Flat nasal bridge
  • Small open mouth
  • Protruding tongue
  • Small, low set, dysplastic ears
  • Short neck with excess skin
• Limbs:
  • Short, broad hands
  • Transverse palmar crease
  • Clinodactyly (incurved) and hypoplasia of middle phalanx of fifth finger
  • Joint hyperflexibility
  • Gap between first and second toes (‘sandal gap’)

Intellectual disability

Most people with DS will have a degree of intellectual disability though there is a great deal of variability in its severity. In most people, it is mild (IQ 50-75) or moderate (IQ 35-50).

A delay in reaching the various developmental milestones is commonly seen.

Dementia

Early-onset Alzheimer’s-like dementia is common in those with DS. By the age of 40 neuropathological changes are seen in virtually all patients. Figures of prevalence vary widely but the average age of onset is thought to be in the 50’s.

Cardiac disease

Around 40-50% of people with DS have a congenital heart disease (CHD). A study by Freeman et al found 44% of DS infants had a CHD. Of those affected the following abnormalities were seen:

• Atrioventricular septal defect (45%)
• Ventricular septal defect (35%)
• Isolated secundum atrial septal defect (8%)
• Isolated persistent patent ductus arteriosus (7%)
• Isolated tetralogy of Fallot (4%)
• Other (1%)

Fertility and reproductive organs

Due to impaired spermatogenesis males with DS are rarely fertile. Women however are fertile though may have trouble with subfertility and premature menopause can limit the time they are fertile.

Hypospadias (abnormal opening or urethra) and cryptorchidism (undescended testicle) appear to occur with greater frequency in males with DS.

Haematological

There are a number of haematological conditions that occur in people with DS:

• Polycythaemia: is common in newborns with DS, thought secondary to hypoxaemia.
• Transient abnormal myelopoiesis: a typically transient and self-limiting condition (though severe disease can occur) seen in newborns with DS.
• ALL: the risk is 10-20 times higher in children with DS than in the wider population.
• AML: increased risk
• Other (immunodeficiency, macrocytosis)

Other systems

Ears and eyes: hearing loss and recurrent otitis media are common. Refractive disorders, nystagmus (repetitive, uncontrolled movements), and strabismus (abnormal eye alignment) are common. Cataracts and glaucoma occur with greater frequency.

Gastrointestinal: gastrointestinal tract anomalies affect around 5-10% of people with DS. Abnormalities include duodenal atresia, annular pancreas and imperforate anus.

Pulmonary: obstructive sleep apnea is more common in people with DS, both those who are overweight and those who are a normal weight.

Growth: short stature is common, those with DS are also more likely to be overweight or obese.

Endocrine: there is an increased incidence of thyroid dysfunction and type 1 diabetes mellitus.

Prenatal screening with the combined or quadruple test should be offered to pregnant people after appropriate councelling.

Pregnant people must be given appropriate information and time to make an informed decision with regard to prenatal screening.

Screening is used to assess the risk of DS. The combined test is generally used earlier in pregnancy whilst the quadruple test is used in those slightly later in pregnancy.

If the risk of DS is determined to be high by one of these tests then prenatal diagnosis with chorionic villus sampling or amniocentesis is offered.

Combined test

The combined test can be used to assess for the risk of DS, Patau’s syndrome (trisomy 13) and Edward’s syndrome (trisomy 18). This combines biochemical markers and ultrasound (12-week scan) measurements. In addition maternal age is used to estimate the risk.

Blood tests for the biochemical markers can be taken at the time of scan or earlier from 10-weeks gestation.

• Biochemical markers:
  • Free beta human chorionic gonadotropin (bhCG)
  • Pregnancy-associated plasma protein-A (PAPP-A)
• Ultrasound measurements:
  • Nuchal translucency (NT)
  • Crown-rump length (CRL)

NOTE: NT refers to the fluid under the skin at the back of the foetuses neck. Its thickness is related to the risk of trisomies as well as cardiac conditions.

Quadruple test

The quadruple test is only used to screen for DS. It is used when NT cannot be measured, the CRL > 84.0mm and head circumference (HC) is between 101.0mm and 172.0mm.

The risk of DS is obtained from the maternal age and four biochemical markers measured from 14+2 to 20+0 weeks:

• Alpha-fetoprotein (AFP)
• Human chorionic gonadotropin (hCG) or free bhCG
• Inhibin-A
• Unconjugated oestriol (uE3)

Non-invasive prenatal testing

NIPT is currently undergoing an ‘evaluative rollout’. Where it is being offered, it is used in those with a combined or quadruple test with a higher chance result (between 1 in 2 and 1 in 150). It can be used up to 21+6 weeks.

NIPT uses cell free DNA (cfDNA). In a pregnant person, cfDNA is made up of both maternal DNA and placental DNA. This cfDNA from the placenta is called cell free foetal DNA (cffDNA). The ratio of cfDNA from the pregnant person versus placenta differs in those with foetuses with T21, T13 or T18.

Those with a higher chance result should be offered prenatal diagnosis. Of those with a higher chance report for DS, 90% will be pregnant with a foetus with DS.

Prenatal diagnosis

Prenatal diagnosis is offered to those who have undergone the combined test or quadruple test with a higher chance result (between 1 in 2 and 1 in 150).

• Chorionic villus sampling (CVS): normally conducted at 11-14 weeks, it is a US-guided procedure that obtains a placental tissue sample for chromosomal/genetic analysis.
• Amniocentesis: normally conducted at 15-20 weeks, it is a US-guided procedure that obtains a sample of amniotic fluid for chromosomal/genetic analysis.

Approximately 1 in 200 pregnant patients who have amniocentesis or CVS will suffer from a miscarriage.

Individualised support and appropriate interventions should be offered to people with DS.

DS may be associated with a range of conditions affecting different systems within the body. The support and medical intervention required is dependent on the associated conditions that are present. New parents should be offered time to ask any questions they may have, relevant information and support.

Newborns should have the following screens completed:

• Karyotyping (imaging the chromosomes)
• FBC (check for evidence of transient abnormal myelopoiesis and other haematological abnormalities)
• CHD screening (echocardiogram)
• Neonatal hearing screen
• Eyes (routine check for cataracts)

All infants and children with DS should receive regular reviews with screening for common complications. Screening for hearing and ophthalmic disorders should continue. All children should have screening for sleep-related breathing disorders (e.g. OSA). Routine childhood vaccinations should be offered as should the annual flu vaccine.

Educational needs should be supported, and most children with DS will go to ‘mainstream’ schools. Speech and language therapists can help children with both eating and drinking and communication. Parents should be offered a referral to genetic counselling to discuss the chances of future children having DS.

Support must continue into adulthood. Individual needs should be supported as appropriate.

The median life expectancy of people with DS in the UK is 58 years.

Life expectancy has improved dramatically during the 20th century. Common causes of premature death include infections (e.g. pneumonia) cardiac disease (and CHD) and dementia.