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Prader-Willi syndrome

MIM.176270 15q12 or 15q11-q13

Thursday 2 October 2003

1956 - Andrea Prader, Heinrich Willi, Alexis Labhart, Andrew Ziegler, Guido Fanconi.

Definition: Prader-Willi syndrome (PWS) is characterized by psychomotor and growth retardation, infantile hypotonia, characteristic facies, small hands and feet, dental abnormalities, and early onset of childhood hyperphagia with consequent obesity.

PWS is associated with abnormalities of chromosome 15. Approximately 75% of patients have a deletion of 15q11q13 on the paternal homologue, whereas 20-25% have inherited both chromosome 15s from the mother and none from the father, a condition known as maternal uniparental disomy (UPD).

Thus, it is a lack of paternal alleles in the 15q11q13 region that results in PWS.

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.

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.


- normal birth length
- length deceleration in first few months
- mean adult male height, 155 cm
- mean adult female height, 147 cm
- steady childhood growth
- fall-off in adolescent growth
- failure to thrive in infancy
- onset of obesity from 6 months to 6 years
- central obesity
- dolichocephaly
- narrow bitemporal diameter
- almond-shaped eyes
- strabismus
- upslanting palpebral fissures
- myopia
- hyperopia
- thin upper lip
- small-appearing mouth
- Down-turned corners of mouth
- thick, viscous saliva
- early dental caries
- hypoventilation
- hypoxia
- feeding problems in infancy requiring gavage feeds
- decreased vomiting
- hypogonadotropic hypogonadism
- small penis
- scrotal hypoplasia
- hypoplastic labia minora
- hypoplastic clitoris
- internal genitalia, male
- cryptorchidism
- amenorrhea
- oligomenorrhea
- osteoporosis
- osteopenia
- scoliosis
- kyphosis
- small hands (@<@25th percentile for height age)
- narrow hands with straight ulnar border
- clinodactyly
- syndactyly
- small feet (@<@10th percentile for height age)
- hypopigmentation
- fair skin
- sun sensitivity
- blonde to light brown hair
- frontal hair upsweep
- mild-to-moderate mental retardation ( 90%)
- learning disabilities
- severe neonatal hypotonia improving with age
- normal neuromuscular studies
- seizures
- poor gross motor coordination
- poor fine motor coordination
- unusual skill with jigsaw puzzle
- global developmental delay
- behavioral problems
- sleep disturbances
- high pain threshold
- poor neonatal suck and swallow reflexes
- speech articulation problems
- childhood polyphagia
- hypernasal speech
- weak or squeaky cry in infancy
- hyperinsulinemia
- growth hormone deficiency
- hypogonadotropic hypogonadism
- excessive skin picking of sores
- food related behavioral problems include excessive appetite and obsession with eating
- temperature instability
- high pain threshold
- decreased fetal activity
- breech position
- behavioral problems including stubborness and rage
- sleep disturbance or sleep apnea (obstructive, central, or mixed)

- digestive anomalies

- sudden cardiac death (15750809)
- premature coronary artery atherosclerosis (3688025, 2362894)
- cerebral venous thrombosis (18058630)

- salivary anomalies (9599302)

  • A sticky saliva is a consistent finding in patients with PWS.
  • The salivary ions and proteins are present in increased amounts, possibly reflecting a concentration effect relative to decreased water in the saliva.

Clinical signs

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.

Individuals with Prader-Willi syndrome (PWS) have excessive appetite with the ability to consume large quantities of food.

Absence of vomiting and a high pain threshold are considered manifestations of the disorder.


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 issues.


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.

Risk of recurrence

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.

Animal model

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.

15q11-q13 region

Prader-Willi and Angelman syndromes (PWS and AS) typically result from an approximately 4-Mb deletion of human chromosome 15q11-q13, with clustered breakpoints (BP) at either of two proximal sites (BP1 and BP2) and one distal site (BP3).


- Microdeletion of 15q11 in 70% of patients confirmed by fluorescent in situ hybridization
- Remainder of cases secondary to maternal disomy
- Rare cases secondary to chromosome translocation


- Goldstone AP. Prader-Willi syndrome: advances in genetics, pathophysiology and treatment. Trends Endocrinol Metab. 2004 Jan-Feb;15(1):12-20. PMID: 14693421

- Mann MR, Bartolomei MS. Towards a molecular understanding of Prader-Willi and Angelman syndromes. Hum Mol Genet. 1999;8(10):1867-73. PMID: 10469839