Presentation: Child with suspected Beckwith-Wiedemann syndrome

A one-year-old girl is referred from primary care to paediatrics with a large left-sided abdominal mass that is ballotable. On examination, you note a large tongue, a left leg that is longer and wider than the right and a birthmark above her right eyelid. From the patient history, you note that she was born at 32 weeks’ gestation with a birthweight of 3.2kg. She had problems maintaining normal blood sugar levels after birth, necessitating top-up feeds.

According to 2018 consensus criteria by Brioude and others, which include a scoring system, a clinical diagnosis of Beckwith-Wiedemann syndrome (BWS) should be made (even in the absence of a confirmatory genetic test) when an individual scores at least four points (the cardinal features listed below attract a score of two and the suggesting features attract a score of one).

Genomic testing can help confirm the diagnosis, clarify recurrence risks and the availability of reproductive options, and give further information about malignancy risks and screening. A negative genomic test does not rule out the diagnosis.

Cardinal features of BWS (two points per feature)

The cardinal features of BWS are:

• macroglossia;
• exomphalos;
• lateralised overgrowth (hemihypertropy);
• multi-focal and/or bilateral Wilms tumour or nephroblastomatosis;
• hyperinsulinism (lasts beyond the first postnatal week); and
• pathology: adrenal cortex cytomegaly, placental mesenchymal dysplasia, pancreatic adenomatosis.

Suggestive features of BWS (one point per feature)

Suggestive features of BWS are:

• birthweight more than two standard deviations (2SD) above the mean (equivalent to the 98th percentile on the UK-World Health Organization growth charts);
• facial naevus flammeus;
• polyhydramnios and/or placentomegaly;
• anterior ear lobe creases and/or posterior helical pits;
• transient hypoglycaemia (resolves during the first postnatal week);
• BWS-associated tumour (not bilateral or multi-focal Wilms tumour), unilateral Wilms tumour, hepatoblastoma, neuroblastoma, rhabdomyosarcoma, adrenocortical carcinoma and/or phaeochromocytoma;
• nephromegaly and/or hepatomegaly; and
• umbilical hernia and/or diastasis recti.

• Consult the National Genomic Test Directory. From here you can access the rare and inherited disease eligibility criteria for information about individual tests and their associated eligibility criteria. You can also access a spreadsheet of all available tests.
  • For information about how to arrange testing in Wales, Scotland or Northern Ireland, see Genomic testing in the devolved nations.
• 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. Where BWS is clearly suspected and the patient meets the criteria discussed above, the following should be prioritised:
  • R49 Beckwith-Wiedemann syndrome: Methylation testing and multiplex ligation-dependent probe amplification (MLPA) initially; then, if these tests return negative results and clinical suspicion of BWS is strong, single gene sequencing for CDKN1C may also be completed.
• If the patient does not meet the clinical criteria for BWS but has hemihypertrophy, macroglossia or regional overgrowth, consider the following:
  • R50 Isolated hemihypertrophy or macroglossia: Methylation testing and MLPA; and/or
  • R110 Segmental overgrowth disorders – Deep sequencing: small panel.
• If the patient does not meet the clinical criteria for BWS but has a suspected generalised overgrowth-intellectual disability syndrome, with a height and/or head circumference at least two standard deviations (2SD) above the mean in association with a learning disability, consider the following:
  • R27 Paediatric disorders: This is a whole genome sequencing (WGS) ‘super panel’ (a panel comprised of several different constituent panels forming one large panel).
• For tests that do not include WGS, including R49, R50 and R110:
  • you can use your local Genomic Laboratory Hub (GLH) 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 individual (proband) and their parents where available, 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 a large WGS ‘super panel’. Paediatricians can order the panel directly. Discussion with clinical genetics may be helpful in some cases.
• Most tests are DNA based, and an EDTA sample (typically a purple-topped tube) is required. There are a few tests for which a different type of tube is used; see Samples for genomic testing in rare disease.
• If you are discussing genomics concepts with your patients, you may find it helpful to use the visual communication aids for genomics conversations.
• 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: Beckwith-Wiedemann syndrome
• NHS England: National Genomic Test Directory
• OMIM: 130650 Beckwith-Wiedemann syndrome

References:

• Beckwith JB, Shuman C and Weksberg R. ‘Beckwith-Wiedemann syndrome’. European Journal of Human Genetics 2009: volume 18, pages 8–14. DOI: 10.1038/ejhg.2009.106
• Brioude F, Kalish JM, Mussa A and others. ‘Clinical and molecular diagnosis, screening and management of Beckwith-Wiedemann syndrome: an international consensus statement’. Nature Reviews Endocrinology 2018: volume 14, pages 229–249. DOI: 10.1038/nrendo.2017.166

For patients

• Great Ormond Street Hospital for Children NHS Foundation Trust: Beckwith-Wiedemann syndrome
• NHS England: Whole genome sequencing patient information leaflets