Presentation: Clinical suspicion of Down syndrome (trisomy 21)

During a routine baby check, a neonate is found to have hypotonia and physical features (epicanthic folds, up-slanting palpebral fissures, a large tongue, single palmar creases and sandal gap toes) suggestive of Down syndrome. There is no family history of note.

Down syndrome can present in a variety of different ways.

• Prenatally. Many parents opt to have prenatal screening for Down syndrome, and some signs may be evident on ultrasounds. For more information, see Patient with a higher-chance first-trimester combined screening result, Fetus with raised nuchal translucency and Patient with a higher-chance non-invasive prenatal test (NIPT) result.
• Postnatally. Neonates may present with hypotonia and typical physical features (some health conditions are more common in the context of Down syndrome). Signs and symptoms include:
  • up-slanting eyes, epicanthic folds and/or white spots on the iris (Brushfield spots);
  • visual problems (cataracts, strabismus, myopia and nystagmus);
  • hearing problems (conductive and/or sensorineural);
  • flattened facial profile, flattened nose and short neck;
  • wide, short hands and fingers, single palmar creases and a wide gap between the big and second toes;
  • cardiac septal defects;
  • Hirschsprung disease;
  • hypothyroidism;
  • frequent infections; and
  • leukaemia.

Some children present in early childhood with developmental delay, hypotonia and some of the physical features and medical conditions outlined above.

• 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. This will be determined by when and how your patient is presenting.
• • R26 Likely common aneuploidy. This is the appropriate test if you are reasonably confident that the patient has Down 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.
• • R137 Congenital heart disease (microarray). You may request R137 if you are investigating a chromosomal cause for congenital heart disease, including Down syndrome. Note that this test request indication does not include gene sequencing. If a negative result is returned, further genomic testing may be indicated.
• • • See Infant or child with congenital heart disease for more information.
• • 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 Down syndrome or where R26 is negative. Ideally you would do this test as a trio with parental samples.
• • R265 Chromosomal mosaicism (karyotype). A minority of individuals with Down syndrome have some cells with trisomy 21 and some cells with the usual two copies of chromosome 21. This is termed mosaicism. R265 can be requested when R26 is suggestive of mosaicism, or if the clinical features are highly suggestive of Down syndrome but R26 has returned a negative result.
• • R297 Possible structural chromosomal rearrangement (karyotype). This is indicated 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 when a karyotype from a patient with Down syndrome indicates a Robertsonian translocation, as parental karyotypes are essential to determine the recurrence risk (below 1% to almost 100% depending on the parent of origin and the type of Robertsonian translocation).
• For tests that do not include WGS, including R26, R137 and R265:
• • you should use your local Genomic Laboratory Hub test order and consent (record of discussion) 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 record of discussion 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 a child is in care or the parents are unavailable for testing, the child may be submitted as a singleton).
• The majority of tests are DNA based, and an EDTA sample (purple-topped tube) is required. Exceptions include karyotype testing and DNA repair defect testing (for chromosome breakage), which require lithium heparin (green-topped tube).
• R27 is a large WGS ‘super panel’ (a panel comprised of several different constituent panels forming one large panel), and requesting it currently requires authorisation from clinical genetics services.
• 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.

For clinicians

• Down Syndrome Education
• Genomics England: NHS Genomic Medicine Service (GMS) Signed Off Panels Resource
• NHS England: National Genomic Test Directory
• Patient Info (professional article): Down’s syndrome (trisomy 21)
• The Down Syndrome Medical Interest Group UK and Ireland: Growth charts
• The Down Syndrome Medical Interest Group UK and Ireland: Guidance for essential medical surveillance

For patients

• Down’s Heart Group
• Down’s Syndrome Association
• Down Syndrome Education
• Down Syndrome Ireland
• Down’s Syndrome Scotland
• International Mosaic Down Syndrome Association
• NHS England: Whole genome sequencing patient information leaflets
• Telling Stories (Understanding Real Life Genetics): Down syndrome