Presentation: Clinical suspicion of Edwards syndrome (trisomy 18)

A baby is admitted to the neonatal intensive care unit (NICU) after birth. Antenatal scans had shown intrauterine growth restriction and a ventricular septal defect. The parents had declined amniocentesis. The baby requires ventilatory support and has physical features suggestive of Edwards syndrome, including a small jaw, prominent occiput, overlapping fingers and smooth soles with prominent heels.

Edwards syndrome can present in a variety of ways.

• Prenatally. Most cases are identified at this stage. Many parents opt to have routine screening for Edwards syndrome (alongside Down syndrome and Patau syndrome), and signs are typically evident on prenatal ultrasounds. For more information, see Presentation: Patient with a higher-chance first-trimester combined screening result, Presentation: Fetus with raised nuchal translucency and Presentation: Patient with a higher-chance non-invasive prenatal test (NIPT) result.
• Postnatally. Neonates may present with intrauterine growth restriction and typical physical features (there are numerous medical conditions that are more common in the context of Edwards syndrome). Signs and symptoms are listed below.
  • 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 (rocker bottom feet); 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 tracheo-esophageal 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.

• Consult the National Genomic Test Directory. From here you can access the rare and inherited disease eligibility criteria, which provides information about individual tests and their associated eligibility criteria. You can also access a spreadsheet containing details of all available tests.
  • For information about how to arrange testing in Wales, Scotland or Northern Ireland, see our dedicated Knowledge Hub resource.
• To find out which genes are included on different gene panels, see the NHS Genomic Medicine Service (GMS) Signed Off Panels Resource.
• Decide which of the panels best suits the needs of your patient or family. It may be appropriate to select more than one.
  • R26 Likely common aneuploidy testing: This is the correct test if you are reasonably confident that the patient has Edwards syndrome. The common aneuploidy (QF-PCR) test looks for the presence of trisomy 13, trisomy 18, trisomy 21 and Turner syndrome. Note that this test request indication does not include gene sequencing. If a negative result is returned, further genomic testing may be indicated. This is the fastest way to diagnose the common trisomies and sex chromosome aneuploidies.
  • R28 Congenital malformation and dysmorphism syndromes – microarray only: This test may be considered where clinical features are highly suggestive of a chromosomal cause, though not completely typical for the common trisomies or sex chromosome aneuploidies. If relating to an in-patient, urgent analysis can be requested (typically return results within 2 weeks). A microarray is not a requirement prior to R27 being initiated in patients with a possible monogenic cause of a syndromic paediatric disorder.
  • R27 Paediatric disorders: This testing indication throws the net much more widely, investigating chromosomal and single-gene causes of congenital malformations and dysmorphism syndromes. You might consider R27 if you are less certain of the clinical diagnosis of Edwards syndrome or where R26 is negative. Ideally you would do this test as a trio with parental samples.
  • R14 Acutely unwell children with a likely monogenic disorder: This rapid agnostic test may be considered in the context of an acutely unwell infant with multiple congenital anomalies and a normal R26 result, where a diagnosis may change management. Both parents should be available for trio analysis, though occasional exceptions may be made. As with R27, this test will investigate chromosomal and single-gene causes of congenital malformations and dysmorphism syndromes.
  • R265 Chromosomal mosaicism (karyotype): A minority of individuals with Edwards syndrome have some cells with trisomy 18 and some cells with the usual two copies of chromosome 18. This is termed mosaicism. R265 can be requested when R26 is suggestive of mosaicism, or if the clinical features are highly suggestive of Edwards syndrome but R26 returns a negative result.
  • R297 Possible structural chromosomal rearrangement – karyotype or targeted chromosome analysis: This should be considered if findings from microarray, whole genome sequencing (WGS) or other laboratory techniques suggest a possible Robertsonian translocation, reciprocal translocation, ring chromosome or other microscopically visible structural rearrangement. This is also the test indication you would use for parents of a patient with partial Edwards syndrome, which may result from a parental balanced reciprocal translocation.
• For tests that do not include WGS, including R26, R28, R265 and R297:
  • you should use your local Genomic Laboratory Hub test order and consent (record of discussion (RoD)) forms; and
  • parental samples may be needed for interpretation of the child’s result. Parental samples can be taken alongside that of the child, and their DNA stored, or can be requested at a later date if needed.
• For tests that are undertaken using WGS, including R27, you will need to:
  • complete an NHS GMS test order form with details of the affected child (proband) and their parents, including details of the phenotype (using human phenotype ontology (HPO) terms) and the appropriate panel name(s) with associated R number (see How to complete a test order form for WGS for support in completing WGS-specific forms);
  • complete an NHS GMS RoD form for each person being tested – for example, if you are undertaking trio testing of an affected child and their parents, you will need three RoD forms (see How to complete a record of discussion form for support); and
  • submit parental samples alongside the child’s sample (this is trio testing) to aid interpretation, especially for the larger WGS panels (where this is not possible, for example because the child is in care or the parents are unavailable for testing, the child may be submitted as a singleton).
• R27 is an amalgamation of over 10 panels of genes known to be associated with a broad range of paediatric developmental disorders. It may now be ordered directly by paediatricians, though a discussion with clinical genetics services may be beneficial.
• R14 is a WGS test that looks agnostically across the entire genome. Requesting it currently requires authorisation from clinical genetics services. There is a special test order form and RoD form for this test, both of which are available from the Exeter Genetics Laboratory.
• The majority of tests are DNA-based, and an EDTA sample (typically a purple-topped tube) is required. Exceptions include karyotype testing and DNA repair defect testing (for chromosome breakage), which require lithium heparin (typically a green-topped tube).
• Information about patient eligibility and test indications was correct at the time of writing. When requesting a test, please refer to the National Genomic Test Directory to confirm the right test for your patient.

• Genomics England: NHS Genomic Medicine Service (GMS) Signed Off Panels Resource
• NHS England: National Genomic Test Directory
• StatPearls: Edwards Syndrome

For patients

• NHS England: Whole genome sequencing patient information leaflets
• Sands (support for anyone who has been affected by the death of a baby)
• Soft UK (support for families of children born with trisomy 13 or trisomy 18)
• Together for Short Lives (support for families of seriously ill children)
• Trisomy 18 Foundation