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;
• 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 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. This is known as full trisomy 18 and is the most common form, responsible for 94% of cases.

Mosaic Edwards syndrome is where 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. 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.

Testing for Edwards syndrome can be pre- or postnatal.

Prenatal screening and diagnosis

Screening is offered for Edwards syndrome – along with screening for trisomies 21 and 13 – to all pregnant women in the first trimester, as part of the NHS Fetal Anomaly Screening Programme.

A separate in the National Genomic Test Directory (R445) exists for individuals who have had a previous pregnancy or child diagnosed with full trisomy 18. 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, the nuchal translucency can only be measured when the fetal crown-rump length is between 45.0mm and 84.0mm (up to 14⁺¹ weeks gestation). For cases in which the nuchal translucency measurement is raised, please see Fetus with raised nuchal translucency.

If the patient’s chance of trisomy is found to be greater than or equal to 1 in 150, the patient is offered further testing.

• Where a structurally normal fetus is seen on ultrasound imaging, this testing may be in the form of advanced screening with non-invasive prenatal testing (NIPT). See Patient with a higher-chance non-invasive prenatal test result.
• Where anomalies are seen on the scan, it may be cytogenetic testing. This would require an invasive procedure – involving amniocentesis or chorionic villus sampling – to obtain fetal or placental DNA.

For more information, see Pregnancy in which the mother has a higher-chance first-trimester combined screening test result.

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 and 20⁺⁶ weeks to screen for 11 physical conditions, including Edwards syndrome. Where unexpected scan findings are identified, women are referred to fetal medicine for further discussions, detailed scanning and an offer of invasive testing where appropriate.

Postnatal diagnosis

Where a baby is born with clinical features suggestive of Edwards 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.

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.

Antenatal management

Where invasive testing has confirmed a diagnosis of Edwards syndrome during pregnancy, the parents should be counselled regarding the nature of the condition and expected antenatal and postnatal management. The severity and subsequent predicted prognosis need to be explained. The options for both continuing the pregnancy and termination should be discussed.

For ongoing pregnancies, care should be delivered by a multidisciplinary team and involve midwifery, obstetrics, fetal medicine and paediatrics. Planning for pregnancy, labour and postnatal care should involve parents at all stages. Parents should also be signposted to the relevant charity for additional support and information.

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 during both the antenatal and postnatal periods. 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
• Gov.uk: Screening for Down’s syndrome, Edwards’ syndrome and Patau’s syndrome
• 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 & Choices
• Gov.uk: Screening tests for you and your baby (STFYAYB)
• Gov.uk: Your choices after a higher chance screening result
• NHS Health A to Z: Edwards’ syndrome
• Sands
• SOFT UK
• Together for Short Lives