Presentation: Clinical suspicion of Silver-Russell syndrome

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.

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.

• 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 those working within NHS Wales, please consult the All Wales Medical Genomics Service website for information on how to arrange testing.
• 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.
  • R147 Growth failure in early childhood: This is a multi-level test request and includes:
    • 11p15 imprinted growth regulatory region and uniparental disomy of chromosome 7 (UPD7) growth regulatory critical region methylation testing (via methylation-specific multiplex ligation-dependent probe amplification (MLPA);
    • whole exome sequencing (WES) of a panel of genes known to be associated with growth failure in early childhood.
      • See: Presentation: A child with proportionate short stature and normal learning; and
    • copy number variant analysis (via methylation-specific MLPA).
  • R267 is also available to test for Temple syndrome, which is an important differential diagnosis for SRS. Temple syndrome is associated with abnormal methylation at 14q32 and includes patients with maternal uniparental disomy of chromosome 14 (mUPD14). At present, this test can only be requested by endocrinologists or following discussion with clinical genetics. It should be arranged if the patient meets the criteria for testing for SRS where methylation analysis of chromosome 11 and 7 (R147) is normal.
  • R147 (microarray): This should be arranged if the patient meets the criteria for testing for SRS where methylation analysis of chromosome 11 and 7 and 14 is normal.
  • R27 Paediatric disorders: This should be considered if there is developmental delay or intellectual disability plus congenital malformation. The test includes microarray and 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, 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 (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).
• For tests that do not include WGS, including R147 and R267:
  • 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 (purple-topped tube) is required. Exceptions include karyotype testing and DNA repair defect testing (for chromosome breakage), which require lithium heparin (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.

For clinicians

• Genomics England: NHS Genomic Medicine Service (GMS) Signed Off Panels Resource
• National Organization for Rare Disorders: Silver-Russell syndrome
• NHS England: National Genomic Test Directory

References:

• Azzi S, Salem J, Thibaud N and others. ‘A prospective study validating a clinical scoring system and demonstrating phenotypical-genotypical correlations in Silver-Russell syndrome’. Journal of Medical Genetics 2015: volume 52, issue 7, pages 446–453. DOI: 10.1136/jmedgenet-2014-102979
• Rabago J, Marra K, Allmendinger N and others. ‘The clinical geneticist and the evaluation of failure to thrive versus failure to feed’. American Journal of Medical Genetics Part C: Seminars in Medical Genetics 2015: volume 169, issue 4, pages 337–348. DOI: 10.1002/ajmg.c.31465

• Wakeling E, Brioude F, Lokulo-Sodipe O and others. ‘Diagnosis and management of Silver–Russell syndrome: First international consensus statement’. Nature Reviews Endocrinology 2017: volume 13, pages 105–124. DOI: 10.1038/nrendo.2016.138

For patients

• Child Growth Foundation
• Child Growth Foundation and Silver Russell Syndrome Global Alliance: Highlights and summary of ‘Diagnosis and management of Silver-Russell syndrome: First international consensus statement’ (PDF, 12 pages)
• Silver Russell Syndrome Global Alliance
• The Magic Foundation: Russell Silver syndrome