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Paediatrics

Presentation: Child with macrocephaly

Macrocephaly is defined as a head circumference over three standard deviations (3SD) above the mean for the patient’s age. In some affected children, there may be an underlying genetic cause.

Example clinical scenario

A 2.5-year-old boy is referred from primary care to paediatric outpatients because of parental concern regarding his large head size. His general health is good, though he is noted to have mildly delayed speech and motor milestones.

When to consider genomic testing

Isolated macrocephaly with no developmental or health concerns may be familial, and parental head circumferences should be taken. Genomic testing may be advisable in the presence of any of the following features:

  • distinctive and/or coarse facial features;
  • neurodevelopmental conditions;
  • epilepsy or seizures;
  • MRI brain findings suggestive of megalencephaly, hydrocephalus or a wider neurogenetic condition;
  • neurocutaneous and other skin lesions (café-au-lait or hypopigmented macules, capillary haemangiomata or papillomata around the nose and mouth);
  • congenital malformations;
  • intellectual disability;
  • skeletal dysplasia, asymmetry or syndactyly;
  • signs of inborn errors of metabolism; and
  • signs of an overgrowth syndrome.

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 (note that it may be appropriate to select more than one).
  • If signs of developmental delay or intellectual disability (overgrowth-intellectual disability syndrome) are present, the following should be considered.
    • R53 Fragile X: This is undertaken by short tandem repeat testing. As fragile X syndrome is a nucleotide repeat expansion disorder, it would not be picked up on other forms of testing.
    • R29 Intellectual disability: This will investigate chromosomal and single-gene causes of developmental delay and/or intellectual disability. The test is a whole genome sequencing (WGS) panel of all genes known to cause intellectual disability.
    • 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 is 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.
      • If requesting R29 or R27, you may specify on the test order form that you wish to focus on overgrowth conditions.
  • If signs of skin and/or skeletal changes are present, the following should be considered (note that you may not be able to request these tests directly without discussion with clinical genetics services):
  • In the case of atypical brain imaging and/or metabolic testing results, the following should be considered (note that you may not be able to request these tests directly without discussion with clinical genetics services):
    • R87 Cerebral malformation;
    • R86 Hydrocephalus;
    • R109 Childhood-onset leukodystrophy; and/or
    • R98 Likely inborn error of metabolism (a semi-urgent whole exome sequencing testing pathway is available using R98.3).
  • If a seizure condition is present, the following should be considered (note that you may not be able to request these tests directly without discussion with clinical genetics services):
    • R59 Early onset or syndromic epilepsy.
  • For tests that are undertaken using WGS, including R29, R27, R104, R87, R86, R109, R98 and R59, you will need to:
  • For tests that do not include WGS, including R213, R214 and R110 (or R98.3 if performed using the semi-urgent pathway):
    • you should 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.

Resources

For clinicians

References:

For patients

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  • Last reviewed: 28/04/2024
  • Next review due: 28/04/2025
  • Authors: Dr Maria Gogou
  • Reviewers: Dr Elaine Clark, Dr Rhys Dore, Dr Eleanor Hay

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