# Prader–Willi syndrome
**Prader–Willi syndrome** (PWS), also called Prader-Labhart-Willi syndrome, is a genetic neurodevelopmental disorder caused by the loss of expression of paternally inherited genes in a region of chromosome 15 known as the Prader-Willi critical region (PWCR) at 15q11.2-q13. It is defined by a two-stage clinical course: severe hypotonia, poor appetite, and feeding difficulties in early infancy, followed in early childhood by excessive eating (hyperphagia) and gradual development of morbid obesity unless food intake is strictly controlled.[1](https://www.ncbi.nlm.nih.gov/books/NBK1330/) The syndrome was first described by Prader and colleagues in 1956.[2](https://pmc.ncbi.nlm.nih.gov/articles/PMC4630255/)
| Key fact | Detail |
|---|---|
| Prevalence | An estimated 1 in 10,000 to 30,000 people worldwide[3](https://medlineplus.gov/genetics/condition/prader-willi-syndrome/) |
| Genetic cause | Loss of expression of paternally active genes in the PWCR at 15q11.2-q13, a contiguous gene syndrome[1](https://www.ncbi.nlm.nih.gov/books/NBK1330/) |
| Main mechanisms | Paternal deletion (about 70% of cases) and maternal uniparental disomy (25%); imprinting center defects are rare[3](https://medlineplus.gov/genetics/condition/prader-willi-syndrome/) • [4](https://pmc.ncbi.nlm.nih.gov/articles/PMC5253259/) |
| Diagnosis | DNA methylation analysis showing maternal-only imprinting, combined with an oligo-SNP array (OSA) to identify the mechanism[1](https://www.ncbi.nlm.nih.gov/books/NBK1330/) |
| Key gene | Deficiency of the SNORD116 snoRNA cluster causes the key characteristics of the PWS phenotype[5](https://pmc.ncbi.nlm.nih.gov/articles/PMC2877670/) |
| Recurrence risk | Less than 1% for the vast majority of families; up to 50% for certain etiologies such as paternal imprinting center deletions[1](https://www.ncbi.nlm.nih.gov/books/NBK1330/) |
| First approved drug | Vykat XR (diazoxide choline extended-release), approved by the FDA on March 26, 2025 for hyperphagia in PWS[6](https://www.pwsausa.org/wp-content/uploads/2025/04/PWSA-2024-Annual-Report.pdf) |
## Clinical features
The clinical picture changes with age. Newborns show hypotonia with a poor suck. From one month to two years, hypotonia with poor appetite and suck persists alongside developmental delay; from ages two to six, delay continues; from six to twelve, excessive eating with central obesity appears if intake is not externally controlled; and from thirteen years to adulthood, the picture includes cognitive impairment, hyperphagia with central obesity, and hypothalamic hypogonadism or typical behavioral findings.[1](https://www.ncbi.nlm.nih.gov/books/NBK1330/)
All individuals have some degree of cognitive impairment, with an average IQ of 65 reported in one review, and motor milestones and language development are delayed.[1](https://www.ncbi.nlm.nih.gov/books/NBK1330/) • [2](https://pmc.ncbi.nlm.nih.gov/articles/PMC4630255/) [Hypogonadism](https://www.edgepedia.org/hypogonadism) is present in both males and females, manifesting as genital hypoplasia, incomplete pubertal development, and, in most, infertility.[1](https://www.ncbi.nlm.nih.gov/books/NBK1330/) [Short stature](https://www.edgepedia.org/short-stature) is common if not treated with growth hormone, and characteristic facial features, strabismus, and scoliosis are often present.[1](https://www.ncbi.nlm.nih.gov/books/NBK1330/)
**Behavior.** A distinctive behavioral phenotype is common, including temper tantrums, stubbornness, manipulative behavior, and obsessive-compulsive characteristics such as skin picking.[1](https://www.ncbi.nlm.nih.gov/books/NBK1330/) • [3](https://medlineplus.gov/genetics/condition/prader-willi-syndrome/) Sleep abnormalities can also occur, and people with obesity may develop type 2 diabetes.[3](https://medlineplus.gov/genetics/condition/prader-willi-syndrome/)
## Genetics
PWS results from the loss of function of genes in the PWCR that are normally active only on the paternal copy of chromosome 15, a parent-specific pattern of gene activity called genomic imprinting. Because the corresponding maternal genes are normally inactive, they cannot compensate for the missing paternal genes, which normally play a fundamental role in regulating hunger and fullness.[3](https://medlineplus.gov/genetics/condition/prader-willi-syndrome/) • [7](https://www.nichd.nih.gov/health/topics/prader-willi/conditioninfo/causes)
Three mechanisms produce this loss of expression:
1. **Paternal deletion.** About 70 percent of cases occur when a segment of the paternal chromosome 15 is deleted in each cell.[3](https://medlineplus.gov/genetics/condition/prader-willi-syndrome/) One review of diagnostic testing gives the deletion proportion as approximately 75 percent, with uniparental disomy at about 25 percent and imprinting center defects at about 1 percent.[4](https://pmc.ncbi.nlm.nih.gov/articles/PMC5253259/)
2. **Maternal uniparental disomy (UPD).** In about one-fourth of cases the child has two copies of chromosome 15 from the mother and none from the father; since the PWCR genes are normally inactive on the maternal chromosome, no active copy remains.[7](https://www.nichd.nih.gov/health/topics/prader-willi/conditioninfo/causes)
3. **Imprinting center defect.** In a small percentage of cases, the paternal chromosome 15 is imprinted in the same way as the maternal chromosome, often because of a small deletion in the imprinting center that controls the imprinting process.[7](https://www.nichd.nih.gov/health/topics/prader-willi/conditioninfo/causes)
The PWCR spans a 5- to 6-Mb genomic region and contains several paternally expressed genes, including MKRN3, MAGEL2, NDN, PWRN1, NPAP1, and SNURF-SNRPN.[1](https://www.ncbi.nlm.nih.gov/books/NBK1330/) • [8](https://www.ncbi.nlm.nih.gov/books/NBK1330/?report=reader) Studies suggest that loss of the SNORD116 cluster of small nucleolar RNA (snoRNA) genes, present in 24 copies in the region, may play a major role in causing the signs and symptoms of the syndrome, though it is unknown how its absence produces the intellectual disability, behavioral problems, and physical features.[3](https://medlineplus.gov/genetics/condition/prader-willi-syndrome/) • [5](https://pmc.ncbi.nlm.nih.gov/articles/PMC2877670/) In some people with PWS, loss of the OCA2 gene, located in the often-deleted segment, is associated with unusually fair skin and light-colored hair, but OCA2 loss does not cause the other features.[3](https://medlineplus.gov/genetics/condition/prader-willi-syndrome/)
Most cases are not inherited: the genetic changes occur as random events around the time of conception or in early embryonic development, and affected people typically have no family history.[3](https://medlineplus.gov/genetics/condition/prader-willi-syndrome/) • [7](https://www.nichd.nih.gov/health/topics/prader-willi/conditioninfo/causes) Once the mechanism in an affected individual is known, recurrence risk can be assessed: the vast majority of families have a risk below 1 percent, but certain etiologies, such as paternal heterozygosity for an imprinting center deletion, carry a risk as high as 50 percent.[1](https://www.ncbi.nlm.nih.gov/books/NBK1330/)
## Diagnosis
The diagnosis is established by identification of abnormal [DNA methylation](https://www.edgepedia.org/dna-methylation) within the PWCR showing maternal-only imprinting, due to one of the three mechanisms above.[1](https://www.ncbi.nlm.nih.gov/books/NBK1330/) Recommended first-tier testing combines DNA methylation analysis, typically by methylation-specific PCR, with an oligo-SNP combination array (OSA). Methylation analysis establishes the diagnosis but cannot distinguish between a deletion, UPD, or an imprinting defect; the OSA detects deletions, distinguishes deletion types, identifies isodisomy, and detects most small imprinting center deletions as well as overlapping conditions such as SNORD116 cluster deletions.[1](https://www.ncbi.nlm.nih.gov/books/NBK1330/) When methylation is abnormal but no deletion or isodisomy is found, second-tier DNA polymorphism testing of the proband and parents identifies heterodisomy or an epigenetic imprinting defect.[1](https://www.ncbi.nlm.nih.gov/books/NBK1330/) Methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) is an alternative that can also approximate deletion size and quantify mosaicism.[1](https://www.ncbi.nlm.nih.gov/books/NBK1330/)
## Management
**Growth hormone.** Recombinant human growth hormone (rhGH) treatment is recommended in PWS. A systematic review and meta-analysis of 16 randomized and 20 non-randomized controlled trials found that treated patients improved in height by 1.67 standard deviation scores (95% interval 1.54 to 1.81), in BMI z-scores by −0.67 SDS, and in fat mass proportion by −6.5% SDS compared with controls, leading the authors to conclude that rhGH modifies the disease's natural history.[9](https://pmc.ncbi.nlm.nih.gov/articles/PMC7213882/) Because of potential upper airway changes associated with GH therapy, a level 2 cardio-respiratory sleep study is mandatory before starting treatment.[10](https://pmc.ncbi.nlm.nih.gov/articles/PMC11301552/)
**Food access and safety.** [Management](https://www.edgepedia.org/management) centers on preventing unsupervised access to food; GeneReviews also lists emetics, antidiarrheal medications, and sedatives among agents and circumstances to avoid.[1](https://www.ncbi.nlm.nih.gov/books/NBK1330/) Care is multidisciplinary, ideally through a network of specialist centers, with blood monitoring of hormones, nutrition, and metabolic markers.[10](https://pmc.ncbi.nlm.nih.gov/articles/PMC11301552/)
**Drug development for hyperphagia.** In March 2025 the FDA approved Vykat XR (diazoxide choline extended-release tablets), the first drug approved to treat hyperphagia in adult and pediatric patients with PWS and the first PWS drug approval since growth hormone in 2000.[6](https://www.pwsausa.org/wp-content/uploads/2025/04/PWSA-2024-Annual-Report.pdf) • [11](https://www.fda.gov/media/191511/download?attachment=) In Europe, Soleno Therapeutics withdrew its marketing authorization application for the same drug (Viokat) in April 2026 after the [European Medicines Agency](https://www.edgepedia.org/european-medicines-agency)'s provisional opinion that the data were not sufficient to determine that benefits outweighed risks; US availability was not affected.[12](https://ipwso.org/updates-on-pharmaceutical-treatments-currently-in-development-for-pws/) Separately, the FDA placed a full clinical hold in May 2026 on Aardvark Therapeutics' ARD-101 program for PWS hyperphagia after electrocardiogram abnormalities were observed in healthy volunteers given higher-than-planned doses.[12](https://ipwso.org/updates-on-pharmaceutical-treatments-currently-in-development-for-pws/)
## References
1. [Driscoll DJ, Miller JL, Cassidy SB. Prader-Willi Syndrome. GeneReviews, updated February 19, 2026.](https://www.ncbi.nlm.nih.gov/books/NBK1330/)
2. [Angulo MA, Butler MG, Cataletto ME. Prader-Willi syndrome: a review of clinical, genetic, and endocrine findings. J Endocrinol Invest, 2015.](https://pmc.ncbi.nlm.nih.gov/articles/PMC4630255/)
3. [Prader-Willi syndrome, MedlinePlus Genetics, National Library of Medicine.](https://medlineplus.gov/genetics/condition/prader-willi-syndrome/)
4. [Butler MG et al. The dilemma of diagnostic testing for Prader-Willi syndrome. Am J Med Genet A, 2017.](https://pmc.ncbi.nlm.nih.gov/articles/PMC5253259/)
5. [Ramsden SC et al. Practice guidelines for the molecular analysis of Prader-Willi and Angelman syndromes. BMC Med Genet, 2010.](https://pmc.ncbi.nlm.nih.gov/articles/PMC2877670/)
6. [Prader-Willi Syndrome Association (USA) 2024 Annual Report.](https://www.pwsausa.org/wp-content/uploads/2025/04/PWSA-2024-Annual-Report.pdf)
7. [What causes Prader-Willi syndrome (PWS)? NICHD, NIH.](https://www.nichd.nih.gov/health/topics/prader-willi/conditioninfo/causes)
8. [Prader-Willi Syndrome, GeneReviews (reader view).](https://www.ncbi.nlm.nih.gov/books/NBK1330/?report=reader)
9. [Schnure M et al. Growth hormone treatment in Prader-Willi syndrome patients: systematic review and meta-analysis. Arch Dis Child, 2020.](https://pmc.ncbi.nlm.nih.gov/articles/PMC7213882/)
10. [Prader–Willi syndrome: guidance for children and transition into adulthood. Arch Dis Child, 2024.](https://pmc.ncbi.nlm.nih.gov/articles/PMC11301552/)
11. [FDA Office of Translational Sciences, 2025 Annual Report.](https://www.fda.gov/media/191511/download?attachment=)
12. [Updates on pharmaceutical treatments currently in development for PWS, IPWSO, May 29, 2026.](https://ipwso.org/updates-on-pharmaceutical-treatments-currently-in-development-for-pws/)
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*Topic: Encyclopedia › Life and health › Biological foundations › Genetics and genomic reference › Named hereditary disorders and syndromes*
*Initially written Sep 17, 2026 · Reviewed: Oct 21, 2026 · Edited: Oct 15, 2026; Oct 21, 2026 · Last review: Oct 21, 2026*
*Copyright 2026 EdgeChat AI, a subsidiary of Biostate AI.*
License: Edgepedia Community License 1.0, https://www.edgepedia.org/edgepedia/license