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Prader-Willi syndrome

Prader-Willi syndrome (abbreviated PWS) is a very rare genetic disorder, in which seven genes (or some subset thereof) on chromosome 15 are missing or unexpressed (chromosome 15q partial deletion) on the paternal chromosome. It was first described in 1956 by Andrea Prader, Heinrich Willi, Alexis Labhart, Andrew Ziegler, and Guido Fanconi of Switzerland. The incidence of PWS is between 1 in 12,000 and 1 in 15,000 live births. The distinction of chromosome by parental origin is due to imprinting and PWS has the sister syndrome Angelman syndrome that affects maternally imprinted genes in the region.


PWS is characterized by hyperphagia and food preoccupations, as well as small stature and learning difficulties.

Traditionally, PWS was diagnosed by clinical presentation. Currently, the syndrome is diagnosed through genetic testing; testing is recommended for newborns with pronounced hypotonia (floppiness). Early diagnosis of PWS allows for early intervention as well as the early prescription of growth hormone. Daily recombinant growth hormone (GH) injections are indicated for children with PWS. GH supports linear growth and increased muscle mass, and may lessen food preoccupation and weight gain.

The mainstay of diagnosis is genetic testing, specifically DNA-based methylation testing to detect the absence of the paternally contributed Prader-Willi syndrome/Angelman syndrome (PWS/AS) region on chromosome 15q11-q13. Such testing detects over 97% of patients. Methylation-specific testing is important to confirm the diagnosis of PWS in all individuals, but especially those who are too young to manifest sufficient features to make the diagnosis on clinical grounds or in those individuals who have atypical findings.

Differential diagnosis

Prader-Willi syndrome is often misdiagnosed as Down syndrome, simply because of the relative frequency of Down syndrome compared to PWS. Also, marked obesity can occur in Down syndrome due to behavioral problems. Adding to the confusion, parents of children who already carry a diagnosis of Prader-Willi syndrome may tell friends, family, and even physicians and nurses that their child has Down syndrome because more people have heard of that condition.

PWS phenotype

Clinical Features And Signs
Holm et al (1993) describe the following features and signs as pretest indicators of PWS, although not all will be present.

In Utero:

  • Reduced fetal movement
  • Frequent abnormal fetal position

At Birth:



  • Speech delay
  • Poor physical coordination
  • Hyperphagia (over-eating) from age 2 - 4 years. Note change from feeding difficulties in infancy
  • Excessive weight gain


  • Delayed puberty
  • Short stature
  • Obesity
  • Extremely flexible


  • Infertility (males and females)
  • Hypogonadism
  • Sparse pubic hair
  • Obesity
  • Hypotonia
  • Learning disabilities/borderline intellectual functioning (but some cases of average intelligence)
  • Proneness to diabetes mellitus
  • Extremely flexible

General physical appearance (adults)

  • Prominent nasal bridge
  • Small hands and feet
  • Soft skin, which is easily bruised
  • Excess fat, especially in the central portion of the body
  • High, narrow forehead
  • Almond shaped eyes with thin, down-turned lips
  • Light skin and hair relative to other family members
  • Lack of complete sexual development
  • Frequent skin picking
  • Stria
  • Delayed motor development


PWS is caused by the deletion of the paternal copies of the imprinted SNRPN gene and necdin gene on chromosome 15 located in the region 15q11-13 . This so-called PWS/AS region may be lost by one of several genetic mechanisms which, in the majority of instances occurs through chance mutation. Other less common mechanisms include; uniparental disomy, sporadic mutations, chromosome translocations, and gene deletions. Due to imprinting, the maternally inherited copies of these genes are virtually silent, only the paternal copies of the genes are expressed. PWS results from the loss of paternal copies of this region. Deletion of the same region on the maternal chromosome causes Angelman syndrome (AS). PWS and AS represent the first reported instances of imprinting disorders in humans.

The risk to the sibling of an affected child of having PWS depends upon the genetic mechanism which caused the disorder. The risk to siblings is <1% if the affected child has a gene deletion or uniparental disomy, up to 50% if the affected child has a mutation of the imprinting control region, and up to 25% if a parental chromosomal translocation is present. Prenatal testing is possible for any of the known genetic mechanisms.

Mouse models of PWS show similar symptoms to humans (hyperphagia and growth deficiency), providing further evidence that PWS is directly linked to the deletion of the small nucleolar RNA SNORD116.


Individuals with PWS are at risk of learning and attention difficulties. Curfs and Frym (1992) conducted research into the varying degrees of learning disability found in Prader Willi Syndrome (PWS). Their results were as follows:

  • 5%...IQ above 85 (Average to low average intelligence)
  • 27%..IQ 70 - 85 (Borderline intellectual functioning)
  • 34%..IQ 50 - 70 (Mild intellectual disability)
  • 27%..IQ 35 - 50 (Moderate intellectual disability)
  • 5%...IQ 20 - 35 (Severe intellectual disability)
  • <1%..IQ <20 (Profound intellectual disability)

Cassidy found that 40% of individuals with PWS have borderline/low average intelligence, a figure higher than that found in Curfs and Frym's study (32%). However, both studies suggest that most individuals (50 - 65%) fall within the mild/borderline/low average intelligence range.

Children with PWS show an unusual cognitive profile. They are often strong in visual organisation and perception, including reading and vocabulary, but their spoken language (sometimes affected by hypernasality) is generally poorer than their comprehension. A marked skill in completing jigsaw puzzles has been noted.

Auditory information processing and sequential processing are relatively poor, as are arithmetic and writing skills, visual and auditory short term memory and auditory attention span. These sometimes improve with age, but deficits in these areas remain throughout adulthood.


Prader-Willi syndrome is also frequently associated with an extreme and insatiable appetite, often resulting in morbid obesity. There is currently no consensus as to the cause for this particular symptom, although genetic abnormalities in chromosome 15 disrupt the normal functioning of the hypothalamus. Given that the hypothalamus regulates many basic processes, including appetite, there may well be a link. However, no organic defect of the hypothalamus has been discovered on post mortem investigation.


There are several aspects of PWS that support the concept of growth hormone deficiency in individuals with PWS. Specifically, individuals with PWS have short stature, are obese with abnormal body composition, have reduced fat free mass (FFM), have reduced LBM and total energy expenditure, and have decreased bone density.

PWS is characterized by hypogonadism. This is manifested as undescended testes in males and benign premature adrenarche in females. Testes may descend with time or can be managed with surgery or testosterone replacement. Adrenarche may be treated with hormone replacement therapy.


Prader-Willi syndrome has no cure. However, several treatments are in place to lessen the condition's symptoms. During infancy, subjects should undergo therapies to improve muscle tone. Speech and occupational therapy are also indicated. During the school years, children benefit from a highly structured learning environment as well as extra help. Throughout their lives, the subject's food should literally be kept under lock and key, since the largest problem associated with the syndrome is severe obesity.

Because of severe obesity, obstructive sleep apnea is a common sequela, and a CPAP (continuous positive airway pressure) machine is often needed.

Prader-Willi Syndrome in the media

Prader-Willi Syndrome appeared in the UK media in July 2007 when Channel 4 aired a program surrounding the everyday lives of two Prader-Willi patients, Joe and Tamara. This program was criticised for not realistically depicting everyday life for Prader-Willi patients and for making fun of them. Families and sufferers of Prader-Willi were further angered when this program appeared on Youtube under the heading, "Can't Stop Eating, Funny Bits". The prime time TV Show CSI also did an episode about someone suffering from Prader-Willi Syndrome, 'Dog Eat Dog', that aired on November 24, 2005. British glamour model Jordan's son Harvey is also said to suffer from Prader-Willi Syndrome.

See also


External links

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