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Example clinical scenario

A family attends clinic concerned because their five-year-old daughter’s development is delayed and she is displaying some autistic traits. On examination, you note that the child’s head circumference is above the 99th centile. Family history reveals that the mother had follicular thyroid cancer, and you note that she also has macrocephaly and multiple facial papules.

When to consider genomic testing

  • In children, consider testing for PTEN hamartoma tumour syndrome when a patient presents with macrocephaly (usually over two standard deviations (2SD) above the mean) and one or more of the following:
    • developmental delay or autism; and/or
    • mucocutaneous features, such as:
      • lipomas;
      • trichilemmomas;
      • oral papillomas;
      • penile freckling (typically over the glans);
      • vascular features;
      • arteriovenous malformations;
      • haemangiomas;
      • gastrointestinal polyps; and
      • thyroid cancer or germ cell tumours (rare below 10 years of age).
  • In cases in which a pathogenic PTEN gene variant has been inherited, the family history may reveal benign or malignant tumours of the breast, thyroid, endometrium and kidney.
  • For a wider guide to approaching genomic testing in a child with macrocephaly, see Child with macrocephaly.

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.
  • If you have a strong clinical suspicion of PTEN hamartoma tumour syndrome, check whether your patient is eligible for targeted R213 PTEN hamartoma tumour syndrome (single gene sequencing and multiplex ligation-dependent probe amplification (MLPA)). If you are not listed as a requesting speciality, you may need to discuss testing with your local clinical genetics service.
  • If your differential is wider and the child has a developmental condition, there are a number of available panels, including the following.
    • R377 Intellectual disability – microarray only. This should be considered if you wish only to investigate chromosomal causes of developmental delay or intellectual disability, which would be undertaken by microarray;
    • R29 Intellectual disability. This will investigate chromosomal and single-gene causes of developmental delay and/or intellectual disability (the test includes microarray and a whole genome sequencing (WGS) panel of all genes known to cause intellectual disability); and
    • 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. The test includes microarray and a 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.
  • For tests that are undertaken using WGS, such as R27 and R29, you will need to:
  • For tests that do not include WGS, such as R213 and R377:
    • 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.
  • 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

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  • Last reviewed: 30/04/2024
  • Next review due: 30/04/2025
  • Authors: Dr Melody Redman
  • Reviewers: Dr Danielle Bogue, Dr Eleanor Hay, Dr Emile Hendriks