Prader-Willi Syndrome


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



PWS involves an imprinted region on chromosome 15, and was the first identified imprinting disorder.

  • Imprinting: process of expressing only one of a pair of genes via silencing (hypermethylation of DNA)


The genetic defect in PWS is lack of expression of the paternally inherited region of chromosome 15 (15q11-q13).

  • Normally this region on chromosome 15 is expressed from the paternal allele, while the maternal allele is hypermethylated, thus “silencing” the transcription of genes on the maternal chromosome.


Figure 1: Schematic depiction of the chromosomal basis of Prader-Willi SyndromeImage from

Different mechanisms can lead to lack of expression of the paternal chromosome 15q11-q13 genes, hence causing PWS:

  1. 75% cases: De novo microdeletion of this region on the paternal chromosome (generally 3-4 megabases)
  2. 20% cases: Maternal uniparental disomy (UPD)
    • Two maternal chromosomes, none from father
    • Associated with advanced maternal age
  3. 5% or fewer cases: Imprinting error
    • In males who pass their own maternally inherited chromosome 15 to their offspring, the imprinting center “reactivates” the genes on this region of their chromosome 15
    • A microdeletion in this area may  cause aberrant imprinting leading to PWS
    • Seen in virtually all cases of recurrent PWS within a family
  4. PWS as a result of balanced translocation has been described


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 n 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 it’s manifestations including hypogonadism, impaired metabolic and appetite regulation and impaired growth. In addition there are also prominent behavioral defects and characteristic dysmorphisms and an increased risk for seizure disorder.


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 à 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 à 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.


Dysmoprhic Features



Figure 2. Characteristic facial features in PWS (Wattendorf 2005).  Other physical features include hypopigmentation, small hands and feet, and thick viscous saliva.



People with Prader-Willi Syndrome, exhibiting characteristic facial appearance including narrow temples, an elongated face, thin upper lip, and a prominent nose.



There is now genetic testing that can be done in suspected cases of PWS. Age at the assessment features below are sufficient to prompt DNA testing.

Birth to 2 y

1. Hypotonia with poor suck.

2 y–6 y

1. Hypotonia with history of poor suck.
2. Global developmental delay.

6 y–12 y 1. History of hypotonia with poor suck (hypotonia
    often persists).
2. Global developmental delay.
3. Excessive eating (hyperphagia; preoccupation with 
    food) with central obesity if uncontrolled.
13 y through adulthood 1. Cognitive disabilities; usually mild mental
2. Excessive eating (hyperphagia; preoccupation with
    food) with central obesity if uncontrolled.
3. Hypothalamic hypogonadism and/or typical behavior 
    problems (including temper tantrums, perseverative
    and compulsive-like behaviors).



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.



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: