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Paediatrics

Presentation: Clinical suspicion of Prader-Willi syndrome

Prader-Willi syndrome is a genomic imprinting disorder that typically presents neonatally with central hypotonia, poor feeding and failure to thrive. In childhood, patients typically present with hyperphagia, obesity and intellectual disability.

Example clinical scenario

A full-term baby is admitted on day one to the neonatal unit because he is profoundly floppy (hypotonic) and feeding poorly. On examination he is difficult to wake, and you notice that he has delicate facial features with a thin upper lip and an extremely weak suck. Empirical treatment for sepsis is commenced, but investigations exclude an infective cause for his presentation.

When to consider genomic testing

Presence of the following clinical features, classified by age, should prompt consideration of genomic testing for Prader-Willi syndrome (PWS).

  • Birth to two years old:
    • hypotonia with a poor suck; and
    • feeding difficulties.
  • Two to six years old:
    • history of congenital central hypotonia with a poor suck;
    • global developmental delay; and
    • distinctive features (bitemporal narrowing, almond-shaped eyes, thin upper lip, down-turned corners of the mouth).
  • Six to 12 years old:
    • history of congenital central hypotonia with a poor suck;
    • global developmental delay;
    • hyperphagia; and
    • central obesity with short stature.
  • 13 years to adulthood:
    • intellectual disability;
    • hyperphagia;
    • central obesity with short stature;
    • behavioural difficulties (obsessive-compulsive disorder, temper tantrums, stubbornness); and
    • hypothalamic hypogonadism (genital hypoplasia, incomplete pubertal development and, usually, infertility).

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.
    • Imprinting disorders are not reliably picked up by sequencing tests and may require additional specialist tests. For that reason, if the clinical features are strongly suggestive of Prader-Willi syndrome or previous genomic testing (for example microarray) has suggested Prader-Willi syndrome, consider requesting:
      • R48 Prader-Willi syndrome: This panel includes the following tests:
        • R48.1 AS/PWS critical region methylation testing – this will assess the methylation level (it detects more than 99% of affected individuals, but cannot identify the causative genetic mechanism); and
        • R48.2 AS/PWS critical region multiplex ligation-dependent probe amplification (MLPA) or equivalent – this will identify copy number variants (most children with PWS have a deletion of the Prader-Willi critical region at chromosome location 15q11-13).
      • If testing via R48 is suggestive of maternal uniparental disomy (UPD), the genomics laboratory or clinical genetics team will request R263 Confirmation of uniparental disomy (UPD testing) for confirmation. The R48 report you receive will indicate whether this confirmation has been performed.
    • If Prader-Willi syndrome is plausible but not highly likely, broader testing via the following indications may be preferable:
        • R69 Hypotonic infant: To be considered if the clinical picture is suggestive of a likely central cause (this is a multi-faceted test; for more information, see Hypotonic infant);
        • R29 Intellectual disability: These tests are used to investigate chromosomal and single-gene causes of developmental delay and/or intellectual disability; they include microarray and a whole genome sequencing (WGS) panel of all genes known to cause intellectual disability (you may also wish to consult Child with developmental delay or intellectual disability); and
        • R377 Intellectual disability (microarray only): To be considered if a microarray to investigate chromosomal causes of developmental delay or intellectual disability is all that is required.
    • For tests that are undertaken using WGS, including R69.5 and R29, you will need to:
    • For tests that do not include WGS, including R48 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.
    • These 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.

Resources

For clinicians

References:

For patients

 

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  • Last reviewed: 21/03/2024
  • Next review due: 21/03/2025
  • Authors: Dr Danielle Bogue
  • Reviewers: Dr Elaine Clark, Dr Lianne Gompertz, Dr Eleanor Hay

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