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 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 copies of chromosome 21, rather than the usual two. 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.

Partial Down syndrome occurs when individuals with Down syndrome have partial trisomy 21. 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.

Mosaic Down syndrome occurs when some affected individuals have three copies of chromosome 21 in some of their cells and two copies in the other cells. 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.

Testing for Down syndrome can be pre- or postnatal.

Prenatal screening and diagnosis

Screening is offered for Down syndrome – along with screening for trisomies 18 and 13 – to all pregnant women in the first trimester, as part of the NHS Fetal Anomaly Screening Programme.

A separate pathway in the National Genomic Test Directory (R445) exists for anyone who has previously had any pregnancy or child diagnosed with full trisomy 21 (Down syndrome). See Pregnancy in which a previous pregnancy or child was diagnosed with trisomy 21, 18 or 13.

First-trimester screening

The combined first-trimester screening test is offered in the first trimester and uses maternal age, nuchal translucency measurement and blood tests (human chorionic gonadotropin (hCG) and pregnancy-associated plasma protein-A (PAPP-A)) to calculate the chance of trisomy. The combined test can be performed in both singleton and twin pregnancies.

While the blood test can be taken from 10 weeks of pregnancy, nuchal translucency can only be measured when the fetal crown-rump length is between 45mm and 84mm (up to 14⁺¹ weeks’ gestation). For cases in which the nuchal translucency measurement is raised, please see Fetus with raised nuchal translucency.

Second-trimester screening

If an individual presents too late for the combined test or if the nuchal translucency cannot be measured, a quadruple screening test is offered between 14⁺² and 20⁺⁰ weeks’ gestation. This involves a blood test and combines the results of four biochemical markers (inhibin A, hCG, alpha-fetoprotein (AFP) and unconjugated oestriol (uE3)), along with maternal age, to assess the chances of the pregnancy being affected. The quadruple test can be performed in both singleton and twin pregnancies.

The 20-week screening scan

As part of the NHS Fetal Anomaly Screening Programme, an ultrasound scan is offered to all pregnant women between 18⁺⁰ to 20⁺⁶ weeks. This scan screens for 11 conditions and, although Down syndrome is not one of them, it may pick up other anomalies that trigger invasive testing and, ultimately, an incidental diagnosis of Down syndrome.

Screening results

If the patient’s chance of trisomy is found to be greater than or equal to 1 in 150, on either the combined test or the quadruple test, the mother is offered either non-invasive prenatal testing (NIPT) or an invasive test, such as amniocentesis or chorionic villus sampling.

For more information about screening results, see Patient with a higher-chance first-trimester combined screening result. Where NIPT is chosen, see Patient with a higher-chance non-invasive prenatal test (NIPT) result.

Postnatal diagnosis

Where a baby is born with clinical features suggestive of Down syndrome (in the absence of a prenatal diagnosis), a blood sample may be taken for confirmatory diagnostic testing following discussion with and consent from the parents.

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.

Down syndrome usually arises spontaneously due to an error during 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

Where invasive testing has confirmed a diagnosis of Down syndrome during pregnancy, the parents should be counselled regarding the nature of the condition and expected antenatal and postnatal management.

The options for both continuing the pregnancy and termination should be discussed with the parents.

For ongoing pregnancies, care should be delivered by a multidisciplinary team and involve midwifery, obstetrics, fetal medicine and paediatrics. Parents should also be signposted to the relevant charity for additional support and information.

Postnatal management

Management of children with Down syndrome 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.

There is currently no gene therapy to manage patients with Down syndrome.

For clinicians

• Down Syndrome Education International
• Gov.uk: NHS Fetal Anomaly Screening Programme (FASP): Programme overview
• NHS England: National Genomic Test Directory
• Patient UK (professional articles): Down’s syndrome
• The Down Syndrome Medical Interest Group

References:

• Shapiro BL: ‘The Down syndrome critical region‘. Journal of Neural Transmission 1999: volume 57, pages 41–60. DOI: 10.1007/978-3-7091-6380-1_3

For patients

• Down’s Heart Group
• Down’s Syndrome Association
• Down Syndrome Ireland
• Down’s Syndrome Scotland
• Gov.uk: Screening tests for you and your baby (STFYAYB)
• Gov.uk: Your choices after a higher chance screening result
• International Mosaic Down Syndrome Association
• NHS Health A to Z: What is Down’s syndrome?