Erfan Bashar
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Prader-Willi Syndrome

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Educational scope notice: This is a study note for medical students, not medical advice, diagnosis, or treatment guidance. Clinical management should follow local protocols and current guidelines.

Prader-Willi syndrome (PWS) pairs severe neonatal hypotonia with a feeding course that reverses direction in early childhood. Early infancy brings poor appetite with feeding difficulty, followed in early childhood by excessive eating that progresses to morbid obesity unless food intake is strictly controlled. Neonatal suspicion rests on hypotonia with poor suck, while later stages add developmental delay, hyperphagia with central obesity, hypogonadism, and characteristic behaviour.

Cause, and why it sets recurrence risk

PWS is loss of paternal expression at chromosome region 15q11.2-q13. Three mechanisms produce it: deletion of the paternally inherited region, maternal uniparental disomy of chromosome 15 (UPD 15), and imprinting defects. Deletions account for roughly 60-70% of cases, segmental UPD 15 for 17-23%, and epimutation imprinting defects for a small minority. These percentages are estimates that shift with testing era, so treat them as approximate.

Abnormal methylation confirms the diagnosis but cannot itself distinguish which mechanism caused it. That distinction matters because most families face a recurrence risk under 1%, while some mechanisms carry up to 50%. Identifying the mechanism plus testing the parents drives counselling.

Methylation confirms, then array sorts

Diagnostic testing begins with methylation analysis to confirm the absence of paternally imprinted genes in the PWS region of chromosome 15. Current practice confirms with abnormal methylation in the PWCR at 15q11.2-q13 showing maternal-only imprinting, then uses oligo-SNP array with polymorphism analysis to sort deletion, UPD subtypes, and epimutation. Assay names evolve, so the logic to keep is methylation first, array and polymorphism analysis second.

Feed the floppy infant, start GH, watch sleep and weight

Growth hormone (GH) insufficiency is considered universal in PWS, so provocative diagnostic testing is not required when growth velocity is reduced. GH therapy normalizes height, increases lean body mass and mobility, and decreases fat mass. A sleep study is needed before starting GH and again 4 to 8 weeks after starting.

Infant feeding needs special support including nasogastric feeds. Childhood weight control rests on a supervised diet holding BMI z-score under 2, with physical activity encouraged. Gastric bypass is not recommended because it does not correct the lack of satiety and will not prevent overeating. Supportive-care guidance here predates newer targeted hyperphagia therapies, so it should not be read as the current therapeutic ceiling.

Evidence anchors

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