About Prader-Willi Syndrome
What is Prader-Willi Syndrome?
Prader-Willi syndrome (pronounced PRAH-der WILL-ee) is a complex, rare genetic disorder that results from an abnormality on the 15th chromosome. Identified in 1956, it occurs in about one in 15,000 live births, in both males and females equally, and in all races. This video provides a brief overview of the genetics.
Though Prader-Willi syndrome is a rare disease, it is one of the ten most common conditions seen in genetics clinics and is the most common genetic cause of obesity that has been identified.
PWS affects growth, metabolism, appetite, behavior, and overall development. Persons with PWS typically have weaker muscles, short stature if not treated with growth hormone, incomplete sexual development, and a chronic feeling of hunger that, coupled with a metabolism that utilizes drastically fewer calories than normal, can lead to excessive eating and life-threatening obesity. The drive to eat is never satisfied no matter how much food is consumed, necessitating constant and continuous supervision.
PWS is a lifelong, life-threatening condition. There is no known cause of PWS, nor is there a cure — yet.
Symptoms of Prader-Willi Syndrome
PWS is a spectrum disorder which means that the degree and severity of symptoms amongst persons diagnosed even with the same subtype of PWS will vary from person to person. If the clinical diagnostic criteria below raise suspicion of PWS, genetic testing using DNA methylation analysis is recommended.
Clinical Symptoms in Infants
• Reduced fetal movement. Other obstetric symptoms may include polyhydramnios, malpresentation, and/or growth restriction
• Significant global hypotonia, poor suck reflex, weak cry
• Failure to thrive: feeding difficulties that often require special feeding techniques
• Characteristic facial features: almond shape eyes, long and narrow head shape, narrowing at the
temples, small down turned mouth with thin upper lip (more likely in those with a deletion)
• Hypogonadism; small genitalia in males and females, male cryptorchidism
• Hypopigmentation. Fair coloring compared to family members (more likely in those with a
• Excessive daytime sleepiness, narcolepsy, cataplexy
• Eye abnormalities including strabismus (esotropia more common than exotropia)
Clinical Symptoms in Children and Adults
• Global developmental delays
• Cognitive impairment, learning disorders, impaired judgment
• Eye abnormalities including myopia, amblyopia, strabismus
• Weight gain without increase in calories (20–31 months)
• Hyperphagia: insatiable drive to eat or find food without normal satiety. Excessive weight gain and
central obesity if diet and access to food are not strictly controlled (3+ years)
• High pain threshold
• Hypothalamic hypogonadism
• Scoliosis, kyphosis, kyphoscoliosis
• Sleep disturbance and apneas, narcolepsy, cataplexy
• Small hands and/or feet, narrow hands, straight ulnar borders
• Speech and articulation problems
• Temperature regulation irregularities
• Temperament and behavioral issues
• Thick viscous saliva with crusting at mouth corners
Older Children and Adults:
All of the above symptoms in young children and:
• Hyperphagia. Physiological drive to eat or obtain food without normal satiety. Excessive weight gain and central obesity if diet and access to food are not strictly controlled.
• High pain threshold
• Obsessive and compulsive tendencies
• Incomplete sexual development
• Behavior problems such as excessive temper tantrums, oppositionalism, obsessive-compulsive
• Short stature as compared with the family
• Skin picking
How is Prader-Willi Syndrome diagnosed?
Prader-Willi syndrome affects both sexes and all races and ethnicities equally, with the incidence of PWS occurring in approximately one in every 15,000-20,000 births. If Prader-Willi syndrome is suspected, genetic testing can confirm the diagnosis. A sample of blood will be drawn and sent to a specialized laboratory, and interpreted by a specialized physician called a geneticist.
Early diagnosis is critical for improving the prognosis. As soon as the diagnosis is made, therapeutic interventions such as occupational therapy, physical therapy, and speech and language therapy should begin, as well as medical interventions such as nutritional counseling and recombinant human growth hormone medication which can improve muscle tone, reduce developmental delays, improve short stature, and help manage excessive weight gain.
The mainstay for diagnosing PWS is a DNA Methylation Test which is the only test that will diagnose PWS caused by all three genetic mechanisms or subtypes: paternal deletion, maternal uniparental disomy (UPD), and imprinting center deletion. This test, also referred to as the “Prader-Willi/Angelman DNA methylation Panel”, detects more than 99% of affected individuals. DNA methylation-specific testing is important to confirm the diagnosis of PWS in all individuals, but especially in those who have atypical findings or are too young to show sufficient features to make the diagnosis on clinical grounds.
An oligo-SNP microarray will pick up the deletion class and size, as well as microdeletions that include the imprinting center and SNORD116, as well as 70% of uniparental disomy (UPD).
A FISH test (fluorescence in situ hybridization) will confirm a deletion on chromosome 15 if present, but will not reveal the size of the deletion nor the other two types of PWS, UPD or an imprinting center deletion, therefore it should not be used as the first genetic test.
If the DNA methylation test is positive, but the microarray or FISH test is normal, then the geneticist will need to do a DNA polymorphism analysis.
See GeneReviews for details of the PWS testing algorithm.