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Example clinical scenario

A two-year-old girl is referred to the paediatric clinic by her GP because of short stature and poor weight gain. There are no developmental concerns, but her mother mentions that, when pregnant, she was monitored closely for poor fetal growth. Birth weight was three standard deviations (3SD) below the mean and her weight continues to be over 3SD below the mean at the age of two years.

When to consider genomic testing

You should consider investigating for Silver-Russell syndrome (SRS) if a child presents with suggestive clinical features, defined by the presence of three or more of the following:

  • small for gestational age: birth weight and/or birth length is 2SD below the mean (below the second centile) for gestational age;
  • postnatal growth failure: height at 24 months is 2SD below the mean (below the second centile), or 2SD below mid-parental target height;
  • relative macrocephaly at birth: head circumference at birth is 1.5SD above birth weight and/or length SD (the relative macrocephaly can make the face appear triangular in shape with a protruding forehead);
  • protruding forehead: forehead projecting beyond the facial plane on a side view as a toddler (one to three years);
  • body asymmetry: a leg length discrepancy of over 0.5 centimetres, or arm asymmetry or leg length discrepancy of under 0.5 centimetres with at least two other asymmetrical body parts (one non-face); and
  • feeding difficulties and/or low body mass index (BMI): BMI is 2SD below the mean (below the second centile) at 24 months, or there is current use of a feeding tube or cyproheptadine for appetite stimulation.

What do you need to do?

  • 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.
  • 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. A genetic cause is identified in around 70% of individuals presenting with clinical features suggestive of Silver-Russell syndrome.
    • R452 Silver Russell Syndrome and Temple Syndrome: Temple syndrome is an important differential diagnosis for SRS. This test should be used if you feel a diagnosis of SRS is likely. It includes 11p15 imprinted growth regulatory region and uniparental disomy of chromosome 7 (UPD7) and chromosome 14 (UPD14) growth-regulatory critical-region methylation testing (via methylation-specific multiplex ligation-dependent probe amplification (MLPA))
    • R453 Monogenic short stature: Should be used if the patient has significant short stature, but lacks the more specific features of SRS. Detailed testing criteria are available on the test directory.
    • R88 Severe microcephaly: Should be considered if the presentation includes severe microcephaly.
    • R104 Skeletal dysplasia: Should be considered if there is skeletal disproportion or a skeletal survey suggestive of primary bone pathology. This would typically be ordered with the involvement of a clinical geneticist or radiologist expert in skeletal dysplasias.
    • R27 Paediatric disorders: This should be considered if there is developmental delay or intellectual disability plus congenital malformation. The test is a whole genome sequencing (WGS) ‘super panel’ (a panel comprised of several different constituent panels forming one large panel), and requesting it currently requires authorisation from clinical genetics.
  • For tests that are undertaken using WGS, including R27 and R104, you will need to:
  • For tests that do not include WGS, including R452 and R453:
    • you can use your local Genomic Laboratory Hub test order and consent (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.
  • 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.

Resources

For clinicians

References:

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  • Last reviewed: 13/09/2024
  • Next review due: 13/09/2025
  • Authors: Professor Kate Tatton-Brown
  • Reviewers: Dr Amy Frost, Dr Eleanor Hay, Dr Emile Hendriks, Dr Joanna Kennedy