Down syndrome (trisomy 21)

Down syndrome, or trisomy 21, is a multisystem genetic condition causing intellectual disability, a higher chance of congenital anomalies and other health problems. There are often recognisable physical features.

Prenatal

Suggestive ultrasound findings may include:

• raised nuchal translucency;
• nuchal cystic hygroma;
• hypoplastic or absent nasal bone;
• echogenic bowel;
• ventriculomegaly;
• dilation of the renal pelvis; and
• short femur length.

Postnatal

Some of the signs and symptoms of Down syndrome are listed below.

• Craniofacial features:
  • flattened facial profile;
  • flattened nose;
  • upslanting eyes;
  • epicanthic folds;
  • white spots on the iris (Brushfield spots); and
  • short neck.
• Cardiac anomalies (found in up to 50% of cases):
  • atrioventricular septal anomalies;
  • ventricular septal anomalies;
  • atrial septal anomalies;
  • Tetralogy of Fallot; and
  • patent ductus arteriosus.
• Visual symptoms:
  • cataracts;
  • strabismus;
  • myopia;
  • nystagmus;
  • retinal anomalies; and
  • iris anomalies.
• Hearing problems (conductive and/or sensorineural).
• Musculoskeletal symptoms:
  • wide, short hands and fingers;
  • single palmar creases; and
  • wide gaps between the big and second toes.
• Gastrointestinal symptoms:
  • Hirschsprung’s disease;
  • duodenal and small bowel atresia/stenosis;
  • annular pancreas;
  • imperforate anus; and
  • coeliac disease.
• Neurological symptoms:
  • mild to moderate learning difficulties;
  • hypotonia;
  • seizures; and
  • early-onset Alzheimer’s disease.
• Endocrine symptoms:
  • hypothyroidism (congenital or acquired);
  • short stature;
  • delayed puberty;
  • decreased virilisation in males; and
  • cryptorchidism.
• Frequent infections.
• Haematological symptoms:
  • newborns often experience transient neutrophilia, thrombocytopenia and polycythaemia;
  • transient myeloproliferative disorder can occur in babies under three months of age; and
  • increased chance of leukaemia (10 times the baseline population risk).

Down syndrome usually arises when each cell has three, rather than the usual two, copies of chromosome 21. A number of Down syndrome critical regions have been defined – that is, segments of chromosome 21 that contain genes thought to be responsible for many features of Down syndrome.

Some individuals with Down syndrome have partial trisomy 21 (known as partial Down syndrome). This means that there are three copies of part of chromosome 21, and two copies of the rest of the chromosome. Individuals with partial Down syndrome tend to have milder features. Features can vary depending on the genes involved.

Some individuals with Down syndrome have three copies of chromosome 21 in some of their cells and two in the other cells. This is known as mosaic Down syndrome. Individuals with mosaic Down syndrome tend to have milder features. Features can vary depending on the level of mosaicism (the number of cells containing an extra copy of chromosome 21) and the tissues involved. This can be difficult to accurately determine, so the prognosis (though often milder) is more unpredictable.

For information about prenatal genomic testing for cases in which Down syndrome is suspected, see:

• Presentation: Fetus with raised nuchal translucency;
• Presentation: Patient with a higher-chance first-trimester combined screening result; and
• Presentation: Patient with a higher-chance non-invasive prenatal test result.

Down syndrome usually arises spontaneously due to an error in cell division. This is most commonly in the egg, but it occasionally occurs in the sperm. The chance increases with maternal age. Recurrence risk is usually low, though some couples may have an increased recurrence risk due to parental germline mosaicism. This means that a patch of cells that includes the eggs or sperm has an extra copy of chromosome 21. It is very rare, but it should be considered in the context of two affected pregnancies. Referral to clinical genetics should be considered.

Some families may have a Robertsonian translocation – a structural rearrangement of the chromosomes in which one copy of chromosome 21 is attached to another chromosome. When this appearance is seen on a karyotype from a patient with Down syndrome, parental karyotypes are essential to determine the recurrence risk. This can vary from less than 1% to almost 100%, depending on the parent of origin and the type of Robertsonian translocation. If the risk is highlighted in your patient’s family, consider a referral to clinical genetics.

Women with Down syndrome have a 50% chance of having a child with Down syndrome in each pregnancy. Fertility in men with Down syndrome is exceptionally rare.

The table below summarises the various mechanisms that result in Down syndrome.

Table 1: Chromosomal causes of Down syndrome

Prenatal management

Diagnosed in 2.7 out of 1,000 pregnancies, Down syndrome is the most common chromosome condition in the UK. The live birth rate is 1.1 out of 1,000 owing to the rate of termination of pregnancy and pregnancy loss.

Testing for Down syndrome can be pre- or postnatal. It is offered, together with screening for trisomies 18 and 13, to all pregnant women in the first trimester. The screening, known as the combined test, uses maternal age, nuchal translucency measurement and blood tests (hCG and PAPP-A) and is performed at 10 to 14 weeks of pregnancy. Measuring nuchal translucency calculates the chance of trisomy, and can only be conducted from 11 to 14 weeks’ gestation. If the patient’s chance is found to be higher than 1 in 150, the mother is offered either non-invasive prenatal testing (NIPT) or an invasive test.

If a patient presents too late for the combined test, a quadruple test is offered between 14 and 20 weeks’ gestation. This involves combining the results of four blood tests (inhibin A, hCG, AFP and uE3) along with maternal age, to assess the chances of the pregnancy being affected.

Where the chance is found to be higher than 1 in 150, patients will be offered further testing. Where a structurally normal fetus is seen on ultrasound imaging, this testing may be in the form of advanced screening with NIPT; where anomalies are seen on the scan, it may be cytogenetic testing. Formal testing requires an invasive procedure to obtain fetal or placental DNA. See our Knowledge Hub resources on amniocentesis and chorionic villus sampling for further information about invasive testing.

Postnatal management

Currently there is no gene therapy to manage patients with Down syndrome. Management of children with the condition is complex and should be delivered via a multidisciplinary team.

Local guidelines, including yearly health checks, are available in many areas of the UK. The Down Syndrome Medical Interest Group provides useful resources for healthcare professionals, including a minimum safe standard of basic medical surveillance.

For clinicians

• Down Syndrome Education International
• The Down Syndrome Medical Interest Group
• NHS England: National Genomic Test Directory
• Patient UK: Down’s syndrome

For patients

• The Down’s Heart Group
• Down Syndrome Ireland
• Down’s Syndrome Association
• Down’s Syndrome Scotland
• International Mosaic Down Syndrome Association
• NHS: What is Down’s syndrome?