Introduction Prader-Willi syndrome (PWS) is a multisystem genetic disorder arising from lack of expression of paternally inherited imprinted genes on chromosome 15q11-q13.¹ The characteristic phenotype includes severe neonatal hypotonia, hyperphagia and childhood obesity, short stature, hypogonadism, learning disabilities and behavioural difficulties.

The evolving phenotype from birth to adulthood means that age-dependent diagnostic criteria are helpful to guide genetic testing.² Early diagnosis is pertinent due to emerging therapeutic benefits from prompt initiation of growth hormone including increased height, muscle mass, bone density and stamina, with decreased body fat.³

Objectives We performed an audit of PWS methylation requests and PWS diagnostic microarray by the North Thames Genomics Laboratory Hub from 2019-22, to better understand current PWS testing practice.

Results 59 tests were performed, identifying 28 patients with PWS (47% diagnostic yield). 50 patients for whom testing was requested met diagnostic testing criteria.² Much of the test cohort comprised neonates with hypotonia, demonstrating this is a key early feature of PWS.² Furthermore, 93% (25) of the diagnosed PWS patients presented with hypotonia.

However, under 50% of patients negative for PWS were referred to Clinical Genetics for further review. As per the National Genomic Test Directory, hypotonic neonates are eligible to have the R69 Hypotonic infant genetic test set⁴ yet this was undertaken in just 13% of hypotonic infants.

The main features in those tested for PWS above two years was obesity, hyperphagia and intellectual disability. From available data, we identified 8 patients with PWS on growth hormone, however only 1 patient started under 3 months old.

Conclusion PWS should always be considered in neonates with hypotonia, as part of the R69 hypotonic infant screen. Methylation testing should also be considered for children/adolescents with obesity and learning difficulties. Early diagnosis of PWS enables early intervention with growth hormone, with important therapeutic benefits.

References

1. Elena G, Bruna C, Benedetta M, Stefania DC, Giuseppe C. Prader-willi syndrome: clinical aspects. J Obes. 2012;2012:473941. doi: 10.1155/2012/473941. Epub 2012 Oct 23. PMID: 23133744; PMCID: PMC3486015.

2. Butler MG, Miller JL, Forster JL. Prader-Willi syndrome – Clinical genetics, diagnosis and treatment approaches: an update. Curr Pediatr Rev. 2019;15(4):207-244. doi: 10.2174/1573396315666190716120925. PMID: 31333129; PMCID: PMC7040524.

3. Passone CGB, Franco RR, Ito SS, Trindade E, Polak M, Damiani D, Bernardo WM. Growth hormone treatment in Prader-Willi syndrome patients: systematic review and meta-analysis. BMJ Paediatr Open. 2020 Apr 29;4(1):e000630. doi: 10.1136/bmjpo-2019-000630. PMID: 32411831; PMCID: PMC7213882.

4. National genomic test directory, Rare and inherited disease eligibility criteria. 1 June 2023 Version 5.2, www.england.nhs.uk/publication/national-genomic-test-directories/