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 (excessive hunger and eating) with central obesity, hypogonadism (underdeveloped sex glands), and characteristic behaviour.
Cause: loss of paternal expression at 15q11.2-q13
Most genes are expressed from both parental copies, but some are imprinted: only the copy from one parent is active. In chromosome region 15q11.2-q13, the genes involved in PWS are normally active only on the copy inherited from the father. PWS is loss of that paternal expression.
Three mechanisms produce it:
- deletion of the paternally inherited region
- maternal uniparental disomy of chromosome 15 (UPD 15), in which both copies of chromosome 15 come from the mother
- imprinting defects, in which the region is present but its imprint is wrong
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.
Methylation confirms, then array sorts
Imprinting is marked on DNA by methylation, chemical tags that record which parent a copy came from, so testing starts there. 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 (the Prader-Willi critical region) at 15q11.2-q13 showing maternal-only imprinting.
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.
Sorting the mechanism is the second step: oligo-SNP array with polymorphism analysis, which reads DNA variants that differ between the parents, separates deletion, UPD subtypes, and epimutation. Assay names evolve, so the logic to keep is methylation first, array and polymorphism analysis second.
Management from infancy to childhood
The floppy newborn’s first problem is feeding. Infant feeding needs special support including nasogastric feeds.
Growth hormone (GH) insufficiency is considered universal in PWS, so provocative diagnostic testing (stimulation tests of GH release) 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.
As hyperphagia emerges, weight becomes the main concern. Childhood weight control rests on a supervised diet holding BMI z-score (BMI expressed as standard deviations from the average for age and sex) 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.