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Down’s Syndrome

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Overview

Down’s syndrome describes a set of features seen due to an extra copy of chromosome 21 (trisomy 21) resulting in learning disability and characteristic dysmorphic features. It is also associated with a number of conditions.

The extent to which the individual is affected varies and cognitive impairment may be mild or severe.

Mechanisms of inheritance

The most common cause (around 88% of cases) of inheriting an extra copy of chromosome 21 is non-disjunction, which describes the failure of homologous chromosomes or sister chromatids to separate during meiosis and being passed on together to the offspring.

Translocation is another mechanism that causes around 4% of cases.

Epidemiology

  • Down’s syndrome is the most common autosomal trisomy
  • Down’s syndrome can affect up to 1 in 650 births

Risk Factors

  • Family history
  • Maternal age – the risk is around 30 per 1000 births for people aged 45 years and older 

Presentation

Overview

Features of Down’s syndrome include:

  • Hypotonia
  • Head and face:
    • Brachycephaly and flat occiput
    • Oblique and up-slanting palpebral fissures, epicanthic folds
    • Brushfield’s spots – small grey/brown speckles on the iris
    • Small, low-set ears
    • Flat face and nose
  • Hands and feet:
    • Single palmar crease
    • A pronounced gap between the hallux and second toes

Associated Disorders

  • Congenital heart defects – affect up to 50% of people:
    • Atrioventricular canal defects (endocardial cushion defect) – most common
    • Ventricular septal defect
    • Secundum atrial septal defect
    • Tetralogy of Fallot or isolated persistent patent ductus arteriosus – least common
  • Haematological disorders:
  • Neurologic disorders:
    • Learning difficulties
    • Alzheimer’s disease – present in more than 60% of people with Down’s syndrome over 60 years old
  • Ear, nose, and throat disorders:
  • Ophthalmic disorders:
  • Orthopaedic disorders:
    • Atlantoaxial instability
  • Other:
    • Hypothyroidism
    • Short stature
    • Fertility problems:
      • Males are almost always infertile due to problems with spermatogenesis
      • Females are often subfertile but have an increased risk of problems with pregnancy

Antenatal Screening

Overview

All pregnant people are offered screening for Down’s syndrome which stratifies them into a ‘lower chance’ or ‘higher chance’ group. This helps guide which people should go on to have more diagnostic tests, which are more invasive.

It is important to note that screening does not give a definitive diagnosis, it only gives the risk of Down’s syndrome being present.

Screening tests

The combined test is the 1st-line screening test and is performed between 11 and 13+6 weeks gestation. It involves the following tests:

  • Ultrasound scans measuring nuchal translucency (the thickness of the back of the neck of the foetus):
    • Thickened nuchal translucency suggests an increased risk of Down’s syndrome
  • Maternal blood tests:
    • Beta-human chorionic gonadotropin (beta-hCG): increased risk if elevated
    • Pregnancy-associated plasma protein-A (PAPPA): increased risk if elevated

The quadruple test is offered to people between 15-20 weeks. This involves the following tests:

  • Alpha-fetoprotein: increased risk if low
  • Serum oestradiol: increased risk if low
  • Beta-human chorionic gonadotropin (beta-hCG): increased risk if elevated
  • Inhibin A: increased risk if elevated

The results of both the combined screening tests place people in a ‘lower chance’ or ‘higher chance’ group:

  • Lower chance – 1 in 150 chance or more (such as 1 in 400)
  • Higher chance – 1 in 150 or less (such as 1 in 100)

Further tests after screening 

People who are in the ‘higher chance’ group are offered further tests such as:

  • Chorionic villus sampling (CVS) – offered at <13 weeks:
    • Involves using an ultrasound and needle to take a sample of placenta tissue
    • Carries a 2% risk of miscarriage
    • A definitive test
  • Amniocentesis – offered between weeks 15-20 when more amniotic fluid is available:
    • Involves using an ultrasound and needle to aspirate amniotic fluid
    • Carries a 1% risk of miscarriage
    • A definitive test
  • Non-invasive prenatal screening test (NIPT):
    • Pregnant people in a ‘higher chance’ group may have NIPT instead of amniocentesis or CVS
    • Less invasive and tests the maternal blood for foetal DNA fragments
    • Not a definitive test but has a very high sensitivity and specificity for Down’s syndrome

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