Prader-Willi syndrome (PWS) is a genetic disorder caused by the lack of expression of paternally inherited genes in the 15q11.2-q13 region of chromosome 15. It was first described in 1956, and over 3,500 papers have been published to date 1). It is classified as Q87.11 in ICD-10-CM.
The incidence is approximately 1 in 20,000 to 25,000 live births 3), with no gender difference. About 350,000 to 400,000 people worldwide are affected. By genetic type, paternal deletion accounts for 65-75%, maternal uniparental disomy (UPD) for 20-30%, and imprinting center (IC) defects for 1-3% 4). Most cases occur sporadically, and the recurrence risk for siblings is less than 1% unless there is an IC deletion.
Obesity rates are high: 40% in children and 82-98% in adults. The annual mortality rate is about 3% in PWS, compared to about 1% in the general population 3).
It occurs in approximately 1 in 20,000 to 25,000 live births. There is no gender difference, and about 350,000 to 400,000 people worldwide are affected. Most cases are sporadic, and the recurrence risk for siblings is less than 1% unless there is an imprinting center deletion.
Ophthalmic Findings
Strabismus: Prevalence 40%. 91% diagnosed by age 5, 42% have undergone surgery.
Refractive errors: According to the global PWS registry, myopia 41%, hyperopia 25%, astigmatism 25%, amblyopia 16%.
Iris and choroidal hypopigmentation: Associated with deletion of the OCA2 gene in the critical region.
Others: Nystagmus, cataract, diabetic retinopathy, congenital fibrosis of the extraocular muscles, congenital uveal ectropion.
Systemic Findings
Neonatal period: Severe hypotonia, feeding difficulties, hypogenitalism, hypopigmentation.
Infancy: Motor developmental delay (walking at 27 months, speech at 39 months). Onset of hyperphagia and obesity.
Childhood to adolescence: Short stature due to GH deficiency, sleep apnea (50–100%), seizures (26%), diabetes, scoliosis, behavioral problems (similar to autism spectrum disorder), skin picking, cognitive impairment (100%).
Other: Reduced ability to vomit, increased pain threshold.
Strabismus is the most common, with a prevalence of 40%. 91% are diagnosed by age 5. Refractive errors are next, with myopia 41%, hyperopia 25%, and astigmatism 25% reported. Amblyopia is also seen in 16%.
PWS is caused by the lack of expression of paternally inherited genes in the 15q11.2-q13 region. Due to genomic imprinting, only the paternal copy of genes in this region is active. Loss of the maternal copy causes Angelman syndrome.
| Genetic Type | Frequency | Mechanism |
|---|---|---|
| Paternal deletion | 65–75% | Microdeletion of 15q11.2-q134) |
| Maternal UPD | 20–30% | Both chromosome 15s are from the mother4) |
| IC defect | 1–3% | Mutation in the imprinting center4) |
Most cases are sporadic, and there are no specific risk factors other than a family history of IC deletion.
Most cases occur sporadically, with a recurrence risk of less than 1%. However, if caused by an imprinting center defect or chromosomal translocation, it may be inherited, and genetic counseling is recommended for family planning.
Clinical features that aid diagnosis include severe hypotonia and feeding difficulties in the neonatal period, hyperphagia and obesity from early childhood, developmental delay, hypogonadism, and short stature.
| Test | Features | Detection Rate |
|---|---|---|
| Methylation analysis | Gold standard | 99% |
| FISH | Detects only deletion type | Approximately 75% |
| Chromosomal microarray | Identifies deletion extent | Deletion type only |
| MS-MLPA | Detection of MKRN3, MAGEL2, etc.4) | High sensitivity |
| DNA markers | Detection of UPD | — |
Methylation analysis is the gold standard and can detect 99% of cases. FISH testing is effective but limited to detecting PWS due to deletion (approximately 75%).
Early diagnosis has been shown to delay the onset of obesity and related complications1).
Multidisciplinary collaboration is essential for managing PWS.
Growth hormone (GH) therapy is approved in many countries for children with PWS2).
Screening for strabismus, amblyopia, and refractive errors is extremely important. Perform refractive correction (prescription of glasses) and strabismus surgery as needed.
Growth hormone therapy is approved in many countries for children with PWS, and early initiation is recommended. It improves body composition (increase in lean body mass, decrease in body fat) and motor function. Currently, expansion of indications to adult PWS patients is being promoted internationally.
The 15q11-q13 region contains approximately 100 genes and transcripts, with more than 12 undergoing imprinting and being expressed only from the paternal copy. Major paternally expressed genes include SNURF-SNRPN, NDN (necdin), MKRN3, MAGEL2, and snoRNAs (SNORDs).
SNORD116 is a major candidate gene for PWS, and its involvement has been confirmed in atypical deletion cases presenting with PWS-like phenotypes 1). UBE3A and ATP10A are maternally expressed genes and are candidate causes of Angelman syndrome.
Deletion of the OCA2 gene, located in the critical region, leads to hypopigmentation of the iris and choroid. OCA2 is also the causative gene for oculocutaneous albinism type II.
Postprandial activation of the satiety center is delayed or absent, resulting in impaired satiety response 3). Hyperactivation of the reward system and hypoactivation of cortical inhibitory regions underlie hyperphagic behavior 3). Resting energy expenditure is reduced by 20–46% 3).
A syndrome with a phenotype similar to PWS has been reported due to mutations in the MAGEL2 gene.
| Syndrome | Causative gene | Main ophthalmic findings |
|---|---|---|
| Schaaf-Yang syndrome (SYS) | MAGEL2 | Exotropia, myopia, microcornea, microphthalmia, keratoconus, ptosis, coloboma |
| Severe arthrogryposis syndrome | MAGEL2 | Optic nerve hypoplasia, exotropia, nystagmus, juvenile-onset glaucoma |
| Opitz C syndrome | MAGEL2 | Retinitis pigmentosa, strabismus, coloboma |
Koceva et al. (2025) reported long-term outcomes of semaglutide (0.5–2 mg weekly) in three PWS patients3). A 28-year-old female (UPD type) had stable weight at 117 kg, a 39-year-old female (mosaic UPD type, post-metabolic surgery) achieved a maximum weight loss of 14.4%, and a 25-year-old male (UPD type) showed 11% weight loss. Tolerability was good in all cases.
In a case report of three patients, the GLP-1 receptor agonist (semaglutide) led to weight stabilization or a weight reduction of 11–14.4%. Research targeting KATP channel activation and the gut microbiota is also ongoing, but these are all at the research stage and have not been established as standard treatments.
