Presentation: Clinical suspicion of Williams syndrome

You review a newborn with supravalvular aortic stenosis. He was born small for gestational age and has marked epicanthic folds and full cheeks. He has hypercalcaemia.

A combination of the features listed below may raise a suspicion of Williams syndrome.

• Facial features (which become more pronounced with age):
  • a face that is round in infancy but elongates over time;
  • epicanthic folds;
  • broad nasal bridge;
  • full cheeks;
  • prominent ears;
  • large mouth and thick lips;
  • widely spaced, underdeveloped teeth; and
  • stellate pattern to the iris.
• Mild to moderate learning difficulties:
  • friendly, outgoing personality; and
  • short attention span and anxiety.
• Cardiovascular disease (any artery may be narrowed):
  • supravalvar aortic stenosis (occurs in 75% of affected individuals); and
  • peripheral pulmonic stenosis (common in infancy).
• Connective tissue anomalies (hernias, joint laxity, soft lax skin, bowel and/or bladder diverticulae and rectal prolapse).
• Pre- and postnatal growth deficiency and persistent short stature.
• Feeding difficulties, reflux and/or constipation.
• Endocrine anomalies:
  • idiopathic hypercalcemia;
  • hypercalciuria;
  • hypothyroidism; and
  • early puberty.

• 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.
• For information about the genes that 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. For a clinical suspicion of Williams syndrome, testing options include:
  • R28 Congenital malformation and dysmorphism syndromes – microarray only: This test is for any clinical features strongly suggestive of a chromosomal cause, including patients with features characteristic of Williams syndrome. Where possible, the chromosomal disorder suspected should be specified on the test request form; or
  • R137 Congenital heart disease – microarray: This should be considered if a patient presents with tetralogy of Fallot, interrupted aortic arch or truncus arteriosus, or other forms of congenital heart disease with cleft palate and/or disorder of calcium homeostasis.
• If microarray testing does not identify Williams syndrome, consider an alternative diagnosis. Options for further testing include:
  • R27 Paediatric disorders: This should be considered if there is developmental delay or intellectual disability in association with congenital malformation or overgrowth, and you would like to investigate chromosomal and single-gene causes; or
  • R29 Intellectual disability: This should be considered if a child has global developmental delay or significant intellectual disability in the absence of congenital malformations or overgrowth, and you feel a monogenic cause is likely; or
  • R140 Elastin-related phenotypes: For a non-syndromic patient with supravalvular aortic stenosis, consider this option in those with congenital heart disease of a type associated with elastin variants (for instance supravalvular aortic stenosis), with an autosomal dominant pattern of inheritance in at least three family members, or supravalvular aortic stenosis characteristic of elastin variants.
• For tests that are undertaken using whole genome sequencing (WGS), including R29 and R27, you will need to:
  • complete an NHS Genomic Medicine Service 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 whole genome sequencing for support in completing WGS-specific forms); and
  • complete an NHS Genomic Medicine Service record of discussion (RoD) form for each person being tested – for example, if you are undertaking trio testing of an affected individual 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 R28, R137 and R140:
  • 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.
• R27 is a large WGS ‘super panel’ (a panel comprised of several different constituent panels forming one large 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

• DYSCERNE Williams Syndrome Guideline Development Group: Management of Williams syndrome: A clinical guideline (PDF, 40 pages)
• GeneReviews: Williams syndrome
• Genomics England: NHS Genomic Medicine Service Signed Off Panels Resource
• National Organization for Rare Disorders: Williams syndrome
• NHS England: National Genomic Test Directory

For patients

• NHS England: Whole genome sequencing patient information leaflets
• Mencap: Williams syndrome
• Williams Syndrome Foundation