Prader-Willi Syndrome


Prader-Willi Syndrome (PWS) is a genetic disorder and the most common syndromic cause of obesity. Its clinical manifestations involve primary neuropsychiatric and endocrine defects with secondary involvement in many different systems including respiratory and cardiovascular.



PWS is an imprinting disorder involving a region on chromosome 15. Genomic imprinting is the process of expressing only one of a pair of genes via epigenetic modification. The expression pattern depends on the parent of origin (i.e. maternal vs paternal chromosome). Imprinting occurs during gametogensis and <1% genes are imprinted.

The genetic defect in PWS is lack of expression of the normally paternally expressed genes in chromosomal region 15q11.2-q13.

  • 4 regions within 15q11.2-q13: 2 non-imprinted regions, 1 region with paternal-only expression (PWS region), 1 region with maternal-only expression (Angelman syndrome region) 
  • PWS region is normally expressed from the paternal allele, while the maternal allele is hypermethylated, thus “silencing” the transcription of genes on the maternal chromosome
  • Loss of paternal expression of PWS region results in PWS
  • Loss of maternal expression of Angelman syndrome (AS) region results AS (see separate page on AS)

There are 3 molecular mechanisms that can lead to lack of expression of these genes on the paternal chromosome, hence causing PWS:

  1. 65-75% of cases: De novo microdeletion of this region on the paternal chromosome (generally 3-4 megabases)
  2. 20-30% of cases: Maternal uniparental disomy (UPD)
    • Two maternal chromosomes, none from father
    • Associated with advanced maternal age
  3. 1-3% of cases: Imprinting error
    • In males who pass their own maternally inherited chromosome 15 to their offspring, the imprinting center normally “reactivates” the genes on this region of their chromosome 15.
    • Most imprinting errors result from epigenetic changes (epimutations) with normal DNA sequence. Errors occur during spermatogenesis. 
    • Another cause of aberrant imprinting is microdeletions in PWS region 
  4. <0.1% of cases are result of balanced translocation


What is the recurrence rate (RR) for subsequent children of parents with  PWS child?

For cases from a microdeletion or UPD the RR is <1%; for cases where the child has an imprinting defect the recurrence rate may be up to 50% , and 25% if a causal translocation is also found in the parent.


Which genes are involved?

The best described is the small nuclear ribonucleoprotein N (SNRPN) gene which is involved in the control of gene splicing; expression is highest in the heart and brain

Other identified genes include the NDN gene which is not expressed in PWS. This gene has been shown to be most highly expressed in mouse hypothalamus, the area of the brain where a large portion of dysfunctionality in PWS arises.



Incidence estimated at 1 in 15,000 to 1 in 20,000 live births. Occurs equally in both sexes and all races.


Clinical Manifestations

The phenotypic manifestations of PWS are thought to be related to impaired hypothalamic function leading to many of its manifestations including hypogonadism, impaired metabolic and appetite regulation, and impaired growth, which untreated leads to morbid obesity. In addition there are also prominent behavioral defects and characteristic dysmorphisms and an increased risk for seizure disorder.

An eight-year-old child with Prader–Willi syndrome, exhibiting characteristic obesity

The clinical manifestations of PWS manifest at different stages of development and are outlined below.


  • Hypotonia with resulting decrease in movement, poor sucking, weak cry and decreased arousal.
  • Hypogonadism:
    • Males: small penis, cryptorchidism, lack of scrotal pigmentation and rugae
    • Females: Hypoplastic labia minora, hypoplastic clitoris

Toddler-6 years:

  • Hyperphagia and Obesity:
    • From ages 1-6 there  is a marked increase in appetite leading to excessive eating and food-seeking behaviors. There is subsequent weight gain and obesity.
    • In addition, growth hormone deficiency in PWS leads to a high ratio of fat to lean body mass and centrally distributed obesity.
  • Global Developmental Delay:
    • Average age of sitting is 12 months and walking 24 months
    • Although verbal abilities generally are preserved in adulthood, there is significant speech delay with the first word occurring on average at 18 months.
    • Visual-spatial skills tend to be enhanced with some individuals showing unusual skill with jigsaw puzzles.

Ages 6-12:

  • By this age many of the behavioral manifestations of PWS may be or become apparent.
    • Temper tantrums; lying and stealing to obtain food; aggressiveness, skin and rectal picking; obsessive-compulsive disorder
    • 5-10% will have psychosis


  • Short Stature.  One of the distinctive features of PWS is impaired growth, related to growth hormone deficiency.
  • Hypogonadism: Incomplete, delayed or abnormal pubertal development.
    • Men are thought to be infertile; in women there are two case reports of a PWS patient reproducing
  • Intellectual Disability: Functioning ranges from severe ID to low-normal intelligence. Most people with PWS have mild intellectual disability with IQs in the 60s to low 70s.
  • Consequences of the obesity associated with PWS may present in adulthood with disease such as sleep apnea and other respiratory problems, diabetes mellitus II and heart disease.



Characteristic facial features:

  • Narrow temporal diameter
  • Narrow nasal bridge
  • Almond-shaped eyes
  • Thin upper vermillion border
  • Downtured corners of mouth
  • Hypopigmentation of hair, eyes, skin



There is now genetic testing that can be done in suspected cases of PWS. Before genetic testing was available, clinical diagnosis could be made based on the following criteria: 

Clinical diag.gifSource: Cassidy, et al. (2012)

Nowadays, diagnosis of PWS must be confirmed by genetic testing. Various methods are used for testing. Tests differ in sensitivity and specificity as well as in ability to distinguish between molecular classes (i.e. deletions, UPD, imprinting defects). 

Test type Uses and limitations

DNA methylation analysis

  • First line test
  • Identifies >99% of PWS
  • Does NOT distinguish molecular class 
FISH (fluorescent in situ hybridization)
  • Chromosomal analysis used to identify deletions (most common cause of PWS)
  • Does NOT identify UPD or imprinting defects 
CMA (comparative genomic hybridization)
  • Similar to FISH
  • Identifies size of deletion with more precision than FISH but more expensive  
  • Does NOT identify UPD or imprinting defects 
DNA polymorphism analysis
  • Used when DNA methylation test is positive but no deletion detected
  • Identifies and distinguishes between UPD and imprinting defect



Treatment for PWS involves a multi-faceted approach to both the primary and secondary manifestations of disease.  Growth Charts specific for those with Prader-Willi have been created and their use is encouraged.  Click on the link below to access them.



Early Life:

  • PWS patient benefit from early intervention assessing and supporting appropriate developmental goals. When hyperphagia begins to occur, patients should be put on a low calorie diet of 1000-1200 kcal/day, with attempts made to increase physical activity and limit BMI to <30. Vitamin supplements may be needed.



  • FDA has approved growth hormone (GH) treatment for PWS patients. GH allows for a pubertal growth spurt and also helps to promote a healthier lean body mass.
  • Sex hormone replacement is controversial but done in some cases to promote secondary sexual development.
  • Treat secondary manifestations (DM Type II, OSA) as they come to clinical attention. Behavior problems can be managed in conjunction with a psychiatrist and often include SSRIs for obsessive-compulsive and tantrum behaviors.

w and wo gh.png       

(a and b) Seven- and 13-year-old children, respectively, not receiving growth hormone treatment. (c and d) Seven- and 13-year-old children, respectively, who have had growth hormone treatment and good weight control. Informed consent was obtained for publication of these photographs. Source: Cassidy, et al. (2012)



Support for families is crucially important, particularly given the long term behavior manifestations of PWS.  Providing social & emotional support, and enabling families to connect and network with others in a similar situation can be tremendously empowering.  Below is an example of one such organization, 




1) Chen, C., Visootsak, J., Dills, S., & Graham, J. M. (2007). Prader-Willi syndrome: an update and review for the primary pediatrician. Clinical pediatrics, 46(7), 580–91. doi:10.1177/0009922807299314

2) McCandless, S. E. (2011). Clinical report—health supervision for children with Prader-Willi syndrome. Pediatrics, 127(1), 195–204. doi:10.1542/peds.2010-2820

3) Wattendorf, D., & Muenke, M. (2005). Prader-Willi syndrome. American Family Physician, 272(5), 827–830.

4) Driscoll DJ, Miller JL, Schwartz S, et al. Prader-Willi Syndrome. 1998 Oct 6 [Updated 2012 Oct 11]. In: Pagon RA, Adam MP, Bird TD, et al., editors. GeneReviews™ [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2013.Available from:

5) Cassidy, S. B., Schwartz, S., Miller, J. L., & Driscoll, D. J. (2012). Prader-Willi syndrome. Genetics in Medicine, 14(1), 10–26.