Edwards syndrome (trisomy 18)

Edwards syndrome, or trisomy 18, is a life-limiting, multisystem genetic condition that causes severe intellectual disability, a high chance of congenital anomalies and often recognisable physical features, including growth restriction, clenched hands and prominent heels.

Prenatal

Suggestive ultrasound findings may include:

• intrauterine growth restriction (IUGR);
• congenital heart anomalies;
• neural tube anomalies;
• strawberry-shaped skull;
• choroid plexus cysts (especially if large and bilateral);
• low-set ears;
• small chin;
• wide-set eyes;
• horseshoe kidney;
• omphalocele;
• clenched hands with overlap of second and third digits;
• rocker-bottom feet (prominent heel and rounded sole);
• single umbilical artery; and
• high rate of spontaneous intrauterine death.

Postnatal

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

• Low birth weight and/or slow weight gain.
• Craniofacial features:
  • triangular and asymmetric face;
  • small, widely spaced eyes with epicanthic folds;
  • upturned nose;
  • small jaw, cleft lip and/or palate;
  • small ears, or ears of an unusual shape;
  • low-set ears;
  • ears that are posteriorly rotated;
  • short neck with excess skin; and
  • prominent occiput.
• Limb anomalies:
  • joint contractures;
  • clenched hands with overriding fingers;
  • fused fingers;
  • single palmar crease;
  • bent fifth fingers;
  • underdeveloped thumb;
  • hypoplastic nails;
  • smooth curved sole of the foot with prominent heel; and
  • club feet.
• Cardiac anomalies (found in 90% of cases):
  • patent ductus arteriosus;
  • tetralogy of Fallot;
  • overriding of the aorta;
  • coarctation of the aorta;
  • hypoplastic left heart syndrome; and
  • polyvalvular heart disease.
• Respiratory symptoms:
  • apnoea;
  • pulmonary hypoplasia;
  • tracheobronchomalacia; and
  • laryngomalacia.
• Neurological symptoms:
  • hypotonia and feeding difficulties;
  • microcephaly;
  • severe developmental delay;
  • seizures;
  • cerebellar hypoplasia;
  • hypoplasia of the corpus callosum; and
  • spina bifida.
• Ophthalmological symptoms:
  • coloboma of iris;
  • cataracts; and
  • corneal clouding.
• Gastroenterological symptoms:
  • omphalocele;
  • umbilical hernia;
  • oesophageal atresia with tracheoesophageal fistula;
  • pyloric stenosis; and
  • Meckel diverticulum.
• Genital anomalies:
  • cryptorchidism;
  • hypospadias;
  • micropenis;
  • clitoral hypertrophy;
  • ovarian dysgenesis; and
  • bifid uterus.
• Renal symptoms:
  • horseshoe kidney;
  • absent kidney; and
  • hydronephrosis.
• Musculoskeletal symptoms:
  • short, prominent sternum;
  • small, widely spaced nipples; and
  • scoliosis.

Individuals with Edwards syndrome typically have a short life expectancy. There is a high rate of death in utero. Some infants fail to establish respiration after birth. Cardiopulmonary arrest and central apnoea are leading causes of death in the neonatal period. Survival time is increased for infants treated intensively and for those who are mosaic. Long-term survivors may be at risk of Wilms’ tumour.

Edwards syndrome usually arises when each cell has three copies of chromosome 18 (94% trisomy 18).

Some individuals with Edwards syndrome (around 1-in-20) have three copies of chromosome 18 in some of their cells and two in the other cells. This is known as mosaic Edwards syndrome. Individuals with mosaic Edwards 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 18) and the tissues involved. This can be difficult to accurately determine, so the prognosis (though often milder) is more unpredictable.

A small number of individuals with Edwards syndrome (around 1-in-100) have partial trisomy 18. This means that there are three copies of part of chromosome 18, and two copies of the rest of the chromosome. Individuals with partial Edwards syndrome tend to have milder features. Features can vary depending on the genes involved.

For information about prenatal genomic testing for cases in which Edwards 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.

Edwards syndrome usually arises spontaneously owing 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 18. It is very rare, but it should be considered in the context of two affected pregnancies. Referral to clinical genetics should be considered.

A minority of families may have a reciprocal translocation – a structural rearrangement of the chromosomes in which one copy of chromosome 18 is attached to another chromosome. When this appearance is seen on a karyotype from a patient with Edwards syndrome, parental karyotypes are essential to determine the recurrence risk. If the risk is highlighted in your patient’s family, consider a referral to clinical genetics.

Prenatal management

Testing for Edwards syndrome can be pre- or postnatal. It is offered, together with screening for trisomies 21 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

Management of children with Edwards syndrome is complex; it requires sensitive counselling, discussions with the family and shared decision making.

Patient support charity SOFT UK provides some guidance about managing such conversations with families. For some patients, a palliative approach may be pursued; for others, more intensive interventions may be undertaken. Care should be delivered via a multidisciplinary team.

For clinicians

• Genetic and Rare Diseases Information Center: Trisomy 18
• NHS England: National Genomic Test Directory
• SOFT UK
• StatPearls: Edwards syndrome

References:

• Carey JC and Kosho T. ‘Perspectives on the care and advances in the management of children with trisomy 13 and 18‘. The American Journal of Medical Genetics Part C: Seminars in Medical Genetics 2016: volume 172 issue 3, pages 249–250. DOI: 10.1002/ajmg.c.31527

For patients

• Antenatal Results and Choices
• Gov.uk: Screening tests for you and your baby (STFYAYB)
• NHS: Edwards’ syndrome
• Sands
• SOFT UK
• Together for Short Lives