Prader-Willi syndrome

Since most cases of Prader-Willi syndrome are caused by a random change to the affected individual’s genetic material, it is unlikely that other family members will be affected. However, there are rare cases in which Prader-Willi syndrome can be inherited from a change to a parent’s genetic material. Depending upon the type of genetic change in the affected individual, testing of siblings and/or parents may be recommended. For more information about this, speak with a Medical Geneticist or a [link url="www.nsgc.org” target=”_blank”>Genetic Counselor.

Because Prader-Willi syndrome is rare, you may not know anyone else with the disease in your town. But you are not alone. You can connect with other families through online support groups. You may wish to start by looking at The Prader-Willi Syndrome Association USA’s website with listing of support groups by state.

Prader-Willi syndrome (PWS) is a rare and complex genetic disease. PWS affects the whole body. When babies are born with Prader-Willi syndrome, they have low muscle tone (hypotonia), problems feeding, poor growth (failure to thrive), and developmental delays. Baby boys usually have undescended testicles.

Unlike babies with Prader-Willi syndrome, children with Prader-Willi syndrome are unable to feel full when they eat, so they have the urge to eat all the time (hyperphagia), which leads to severe and often life-threatening obesity as well as other related conditions, such as type 2 diabetes, high blood pressure, and heart disease. Individuals with Prader-Willi syndrome also tend to have decreased levels of hormones that control the development of secondary sexual characteristics, which leads delayed or absent puberty and typically also to infertility.

People with Prader-Willi syndrome can also be shorter than average (small stature) and typically have small hands and feet. Mild-to-moderate learning difficulties and intellectual disabilities are common, as are certain behaviors, such as obsessive-compulsive disorder, poor mood control, and stubbornness.

For individuals with Prader-Willi syndrome, weight management is the most difficult part of managing their disorder. Not only do individuals with Prader-Willi syndrome lack the ability to feel full, they also gain weight more easily and lose it more difficultly than those who do not have Prader-Willi syndrome. Early weight management is needed, with a low-calorie diet and frequent, regular exercise. Individuals with Prader-Willi syndrome are driven to seek food, and are often quite effective at finding food, or enlisting the help of others to obtain food. Behavioral therapy can be helpful in managing food-seeking behaviors, but occasionally, more serious measures are needed, such as keeping food inaccessible during non-meal times.

Growth hormone is now widely recognized as an important component in treating Prader-Willi syndrome, beginning in infancy. Not only does growth hormone treatment help increase lean muscle mass, decrease fat mass and help increase height and mobility, there is now evidence that it may also be helpful in improving cognitive skills and possibly decreasing the severity of some types of undesirable behavior.

Hormone support for individuals with delayed or absent puberty can help support the development of secondary sexual characteristics. Although most individuals with Prader-Willi syndrome are infertile, this is not always the case.

Behavioral issues are best managed with behavioral therapy, and tend to emphasize firm limit-setting. Sometimes medication may be prescribed in combination with behavioral therapy, depending on the specific issues present.

Studies have shown us that delayed motor development is present in 90%-100% of children with Prader-Willi Syndrome (PWS). The rule of thumb is that early milestones are reached in about double the "normal" age. For example, kids with PWS often sit at 12 months and walk at 24 months. The majority of children are able to walk and it is rare for a child to never walk. Of course, children may stop walking if their weight increases to the point that walking is very difficult.

The exact reason for delays in walking and sitting in children is not known, but there are two big theories right now. One is that the extreme floppiness (hypotonia) and muscle weakness causes the problems in sitting and walking. This weakness may be caused by the high amount of fat and low amount of muscle (even in underweight babies). The second theory is that children with PWS have fewer motor neurons at birth.

The good news is that there are several studies that show that use of growth hormone therapy in babies and children before age 3 combined with physical therapy helps kids in reaching their milestones faster by increasing muscle strength. There has also been an increase in speaking and cognitive skills shown that come as well. There is also evidence that growth hormone helps the motor neurons in the motor cortex work better.

To learn more about specific kids and therapy, reach out to one of the excellent PWS support groups like the Prader-Willi Syndrome association.

While many genetic diseases are caused by a change to a single gene, the genetic cause of Prader-Willi syndrome is a bit more complicated. PWS is not caused by a change in one specific gene, but rather by a genetic change that affects multiple genes on chromosome 15. This group of genes is located in a region on the "long arm" of chromosome 15, at 15q11-15q13. The region of genes affected by this genetic change is referred to as the Prader-Willi Critical Region (PWCR). Some of the genes in the PWCR have known functions, but the role of other genes in Prader-Willi syndrome remains unclear.

Prader-Willi syndrome is part of a group of genetic disorders referred to as "imprinting disorders". Imprinting works a lot like a power switch.Typically, our bodies use both the maternally-inherited and paternally-inherited copies of our genes to make whatever that particular gene’s product is, like an enzyme or a protein. With imprinted genes however, one copy of the gene is switched on, and the other copy is switched off, based on which parent the gene was inherited from. Normally, the paternally-inherited copies of the PWCR genes are "switched on", which means they are busy making proteins that are needed by the body, while the maternally-inherited copy of the PWCR is "switched off" (imprinted) and does not make any of these proteins.

There are three primary ways that the body ends up without a switched on copy of the PWCR:

Prader-Willi
Prader-Labhart-Willi syndrome
PWS

The symptoms of Prader-Willi syndrome change with age. In the beginning of their lives, babies and toddlers with Prader-Willi syndrome often:

While there is no cure for Prader-Willi syndrome, early diagnosis and treatment may help prevent or reduce the health issues that people with PWS may experience.

Prader-Willi syndrome is not routinely tested for on state newborn screening. If there is a reason to suspect Prader-Willi syndrome in the newborn period, genetic testing can be done.

Because Prader-Willi syndrome is a complex genetic disease, there are a number of different tests that your doctor may order to confirm a diagnosis. These tests are typically performed on a sample of blood or, in some cases, skin cells (from a check swab, for example). The purpose of the tests is not only to confirm the diagnosis, but also to identify the underlying genetic cause (paternal deletion, maternal uniparental disomy, or another imprinting defect).

Methylation analysis is the most common type of test used to confirm a diagnosis of Prader-Willi syndrome, however, it is not available everywhere which is why different methods may be used to test you or your child. Other tests include: chromosomal microarray analysis, Fluorescent In Situ Hybridization (FISH); deletion/duplication analysis; uniparental disomy studies; and sequencing analysis. The type of test and the laboratory used to perform the test vary depending on a number of factors, including your insurance and your location.

Clinical research on Prader-Willi syndrome continues across the globe. Research focuses on behavioral, mental, and physical health issues affecting people with Prader-Willi syndrome as well as research on understanding the genetics of Prader-Willi syndrome.

Pediatricians from the American Academy of Pediatrics have published a set of guidelines to help doctors treat and support people with Prader-Willi syndrome. Treatments will vary for each person depending on the type and severity of symptoms the person has. The recommendations made by the American Academy of Pediatrics can be found here.

Nutrition Concerns: Use of special nipples or feeding tubes for newborns and infants who are having difficulty gaining weight. For toddlers and older children, strict supervision of food intake is required to reduce the risk of over-eating and obesity. Ongoing support from a nutritionist can help families ensure their children are maintaining a healthy weight and getting necessary vitamins and minerals. Behavior management specialists can help a child learn to make appropriate food choices as they get older and become more independent.

Endocrine Issues: Growth hormone (GH) therapy may help children with Prader-Willi syndrome increase their height and lean muscle mass, which can help burn more calories. Some studies also suggest that, when given early in life, GH may also prevent or reduce behavioral difficulties and improve cognitive development.

In addition, older children with PWS often experience delayed or reduced puberty. The use of hormone replacement therapy (HRT) may enhance development of secondary sex characteristics (pubic hair; breasts; deep voice; etc). HRT and/or surgery can also be used to increase genital size.

General Health Concerns: It is recommended that people with Prader-Willi get routine care from health specialists such as ophthalmologists (eye doctors); orthopedists (bone doctors); cardiologists (heart doctors); and physical and occupational therapists. Psychologists can help treat behavioral symptoms such as obsessive-compulsive behavior and anger management. Sleep specialists can help treat sleep disorders.

Early Intervention Programs: Children with Prader-Willi syndrome can have varying degrees of cognitive impairment and learning disabilities. Early intervention programs, including speech therapy, should begin as early as possible and continue throughout childhood.

In addition to regular visits with your primary care provider, children and adults with Prader-Willi syndrome are often followed by a variety of specialists:

Most of the time, the genetic changes that cause Prader-Willi syndrome happen randomly, during the formation of an egg or sperm, or very early during pregnancy. These changes are sporadic, meaning that they happen by chance. In this situation, the parents’ chance of having another child with Prader-Willi syndrome is felt to be the same as that for the general population.

Very rarely, a mutation in the imprinting center can be passed from an unaffected parent to a child. In this situation, the chance of having another child with Prader-Willi syndroem is significantly increased.

Rarely (in fewer than 5% of people with PWS), a genetic change, such as a small deletion in the PWCR on the paternal chromosome 15, can be inherited. In these cases, this genetic change can be passed from one generation to the next and there may be more than one affected person in the family.

If a diagnosis of Prader-Willi syndrome is suspected based on physical symptoms in a newborn or young child (such as poor feeding, poor weight gain, very low muscle tone, developmental delays) or older children (such as history of low muscle tone, excessive eating, obesity, mild to moderate cognitive delays, obsessive-compulsive behaviors including skin picking), your doctor may recommend confirming the diagnosis through genetic testing.

DNA methylation analysis – is usually the first test to be ordered when a diagnosis of Prader-Willi syndrome is suspected. "Methylation" is one of the ways that the body switches off (imprints) genes. By looking to see what the methylation pattern is, the laboratory can tell whether or not any of the paternally-inherited PWCR genes are switched on, and therefore making proteins the body needs. However, DNA methyltion analysis does not detect the type of genetic problem present, so additional testing is needed to identify the specific genetic change. Deletions are the most common cause (~75%), and may be identified using fluorescence in situ hybridization (FISH), a PCR-based analysis or chromosomal microarray analysis. If no paternal deletion is identified, the next step is usually to test for maternal uniparental disomy (UPD). If maternal UPD is not present, the cause is likely an imprinting defect. Recent advances in the field of genetic testing have also led to an increased in the use of genome sequencing for diagnostic purposes. Sequencing is particularly useful in diagnosing those rare cases of Prader-Willi syndrome caused by imprinting defects.

Information about ongoing clinical trials can be found online at ClinicalTrials.gov or by contacting the Rare Diseases Clinical Research Network here.

There are a number of hospitals that offer specialty clinics for Prader-Willi syndrome. Your genetic specialist may also be able to help you identify other institutions.

Prader-Willi syndrome affects approximately 1 in 10,000 to 1 in 30,000 people worldwide.

There are a number of organizations across the globe who provide support for people with Prader-WIlli syndrome and their families. The following is a list of support groups available as of June 2016:

US: