Prader-Willi syndrome

Prader-Willi syndrome is the most common of the genetic disorders that cause life-threatening obesity in children. The syndrome affects many aspects of the person's life, including eating, behavior and mood, physical growth, and intellectual development. The NICHD is one of many federal agencies and NIH Institutes working to understand Prader-Willi syndrome. The NICHD supports and conducts research on the factors that cause the syndrome and how best to diagnose and treat it.

Common name
Prader-Willi syndrome

Medical or scientific names
Prader-Willi
Prader-Labhart-Willi syndrome
PWS
Willi-Prader syndrome
Prader-Willi-Fanconi syndrome
Pw

What is Prader-Willi syndrome?

The term Prader-Willi syndrome refers to a genetic disorder that affects many parts of the body. Genetic testing can successfully diagnose nearly all infants with Prader-Willi syndrome (Cassidy et al 2011).

The syndrome usually results from deletions or partial deletions on chromosome 15 that affect the regulation of gene expression, or how genes turn on and off. Andrea Prader and Heinrich Willi first described the syndrome in the 1950s (Prader et al 1956).

One of the main symptoms of Prader-Willi syndrome is the inability to control eating. In fact, Prader-Willi syndrome is the leading genetic cause of life-threatening obesity. Other symptoms include low muscle tone and poor feeding as an infant, delays in intellectual development, and difficulty controlling emotions.

There is no cure for Prader-Willi syndrome, but people with the disorder can benefit from a variety of treatments to improve their symptoms. These treatments depend on the individual's needs, but they often include strict dietary supervision, physical therapy, behavioral therapy, and treatment with growth hormone, among others. As adults, people with Prader-Willi syndrome usually do best in special group homes for people with this disorder. Some can work in sheltered environments.

Scientists do not know what increases the risk for Prader-Willi syndrome. The genetic error that leads to Prader-Willi syndrome occurs randomly, usually very early in fetal development. The syndrome is usually not hereditary (McCandless and Committee on Genetics 2010).

What are the symptoms of Prader-Willi syndrome?
Scientists think that the symptoms of Prader-Willi syndrome may be caused by a problem in a portion of the brain called the hypothalamus (pronounced hahy-puh-THAL-uh-muhs). The hypothalamus lies in the base of the brain. When it works normally, it controls hunger or thirst, body temperature, pain, and when it is time to awaken and to sleep (McCandless and Committee on Genetics 2010). Problems with the hypothalamus can affect various body functions and pathways, leading to a variety of symptoms.

Individuals with Prader-Willi syndrome may have mild to severe symptoms, which often include:

Feeding and metabolic symptoms: An important early symptom of Prader-Willi syndrome is an infant's inability to suck, which affects the ability to feed. Nearly all infants with Prader-Willi syndrome need help with feeding. Infants may require feeding support for several months. Without assistance, they will not grow. Nursing systems with one-way valves and manual sucking assistive devices, similar to those used with cleft palate (such as bottles with special nipples for babies who do not have the sucking reflex), often are needed. Occasionally, feeding tubes are required, but generally for no more than the first 6 months after birth. The infants may need fewer calories because of the reduced metabolism associated with Prader-Willi syndrome and may not demand feeding on their own. Frequent weight checks will help in adjusting the infant's diet to maintain a suitable weight gain.

As the infants grow into toddlers and children, compulsive overeating replaces the need for feeding support. Because the metabolic rate of individuals with Prader-Willi syndrome is lower than normal, their caloric intake must be restricted to maintain a healthy weight, often to 60% of the caloric requirement of comparably sized children without the syndrome.

Feeding and metabolic symptoms persist into adulthood. Unless individuals with Prader-Willi syndrome live in environments that limit access to food (such as locked cabinets and a locked refrigerator), they will eat uncontrollably, even food that is rotten or sitting in the garbage. Uncontrollable eating can cause choking, a ruptured esophagus, and blockages in the digestive system. It can also lead to extreme weight gain and morbid obesity. Because of their inability to stop eating, people with Prader-Willi syndrome are at increased risk for diabetes, trouble breathing during sleep, and other health risks (McCandless and Committee on Genetics 2010). For these reasons, people with Prader-Willi syndrome need to be monitored by a healthcare professional their entire lives.

Physical symptoms: Many physical symptoms of Prader-Willi syndrome arise from poor regulation of various hormones, including growth hormone, thyroid hormone, and possibly adrenalin. Individuals with Prader-Willi syndrome grow slowly and experience delays in reaching physical activity milestones (eg, standing, walking) (Gunay-Aygun et al 2001).

Children with Prader-Willi syndrome tend to be substantially shorter than other children of similar age. They may have small hands and feet and a curvature of the back, called scoliosis (pronounced skoh-lee-OH-sis). In addition, they frequently have difficulty making their eyes work together to focus, a condition called strabismus (pronounced struh-BIZ-muhs) (Gunay-Aygun et al 2001; Holm et al 1993).

Infants with Prader-Willi syndrome are often born with underdeveloped sex organs, including a small penis and scrotum or a small clitoris and vaginal lips. Most individuals with Prader-Willi syndrome are infertile (McCandless and Committee on Genetics 2010; Gunay-Aygun et al 2001; Cassidy and Schwartz 2009a).

Intellectual symptoms: Individuals with Prader-Willi syndrome have varying levels of intellectual disabilities. Learning disabilities are common, as are delays in starting to talk and in the development of language (Gunay-Aygun et al 2001; Holm et al 1993).

Behavioral and Psychiatric Symptoms: Imbalances in hormone levels may contribute to behavioral and psychiatric problems. Behavioral problems may include temper tantrums, extreme stubbornness, obsessive-compulsive symptoms, picking the skin, and general trouble in controlling emotions. The individual will often repeat questions or statements. Sleep disturbances may include excessive daytime sleepiness and disruptions of sleep. Many individuals with Prader-Willi syndrome have a high pain threshold (McCandless and Committee on Genetics 2010).

Stages of Prader-Willi syndrome symptoms
The appearance of Prader-Willi syndrome symptoms occurs in two recognized stages:

Stage 1 (Infancy to age 2 years)
• "Floppiness" and poor muscle tone
• Weak cries and a weak sucking reflex
• Inability to breastfeed, which may require feeding support, such as tube feeding
• Developmental delays
• Small genital organs

Stage 2 (Ages 2 to 8)
• Unable to feel satisfied with normal intake of food
• Inability to control eating, which can lead to overeating if not monitored
• Food-seeking behaviors
• Low metabolism
• Weight gain and obesity
• Daytime sleepiness and sleep problems
• Intellectual disabilities
• Small hands and feet
• Short stature
• Curvature of the spine (scoliosis)
• High pain threshold
• Behavioral problems, including the display of obsessive-compulsive symptoms, picking the skin, and difficulty controlling emotions
• Small genitals, often resulting in infertility in later life

What causes Prader-Willi syndrome?
Prader-Willi syndrome is caused by genetic changes on an "unstable" region of chromosome 15 that affects the regulation of gene expression, or how genes turn on and off. This part of the chromosome is called unstable because it is prone to being shuffled around by the cell's genetic machinery before the chromosome is passed on from parent to child.

The genetic changes that cause Prader-Willi syndrome occur in a portion of the chromosome, referred to as the Prader-Willi critical region (PWCR), around the time of conception or during early fetal development (McCandless and Committee on Genetics 2010). This region was identified in 1990 using genetic DNA probes. Although Prader-Willi syndrome is genetic, it usually is not inherited and generally develops due to deletions or partial deletions on chromosome 15.

Specific changes to the chromosome can include the following:

Deletions. A section of a chromosome may be lost or deleted, along with the functions that this section supported. About 65% to 75% of Prader-Willi syndrome cases result from the loss of function of several genes in one region of the father's chromosome 15, due to deletion. The corresponding mother's genes on chromosome 15 are always inactive and thus cannot make up for the deletion on the father's chromosome 15. The missing paternal genes normally play a fundamental role in regulating hunger and fullness.

Maternal uniparental disomy (pronounced yoo-nuh-puh-REN-tl DAHY-soh-mee). A cell usually contains one set of chromosomes from the father and another set from the mother. In ordinary cases, a child has two chromosome 15s, one from each parent. In 20% to 30% of Prader-Willi syndrome cases, the child has two chromosome 15s from the mother and none from the father. Because genes located in the PWCR are normally inactive in the chromosome that comes from the mother, the child's lack of active genes in this region leads to Prader-Willi syndrome.

An imprinting center defect. Genes in the PWCR on the chromosome that came from the mother are normally inactivated, due to a process known as "imprinting" that affects whether the cell is able to "read" a gene or not. In less than 5% of Prader-Willi syndrome cases, the chromosome 15 inherited from the father is imprinted in the same way as the mother's. This can be caused by a small deletion in a region of the father's chromosome that controls the imprinting process, called the imprinting center. In these cases, both of the child's copies of chromosome 15 have inactive PWCRs, leading to Prader-Willi syndrome.

How do health care providers diagnose Prader-Willi syndrome?
In many cases of Prader-Willi syndrome, diagnosis is prompted by physical symptoms in the newborn.

If a newborn is unable to suck or feed for a few days and has a "floppy" body and weak muscle tone, a healthcare provider may conduct genetic testing for Prader-Willi syndrome (Gunay-Aygun et al 2001; Holm et al 1993; Cassidy and Schwartz 2009b). Formal diagnostic criteria for recognizing Prader-Willi syndrome depend on the age of the individual-specifically, whether the third birthday has been reached. Before age 3, the most important symptom is extremely poor muscle tone, called hypotonia (pronounced HAHY-poh-toh-nee-uh), which makes infants feel floppy. In affected children 3 years of age and older, other symptoms become apparent, such as obesity, intellectual delays, learning disabilities, or behavior problems, especially connected with food and eating (Cassidy and Schwartz 2009b).

• Children younger than 3 years must have at least four major criteria and at least one minor criterion for a Prader-Willi syndrome diagnosis.
• Those older than 3 years must have at least five major criteria and at least three minor criteria for a diagnosis of Prader-Willi syndrome.

Major clinical criteria of Prader-Willi syndrome
• Extremely weak muscles in the body's torso
• Difficulty sucking, which improves after the first few months
• Feeding difficulties and/or failure to grow, requiring feeding assistance, such as feeding tubes or special nipples to aid in sucking
• Beginning of rapid weight gain, between ages 1 and 6, resulting in severe obesity
• Excessive, uncontrollable overeating
• Specific facial features, including narrow forehead and downturned mouth
• Reduced development of the genital organs, including small genitalia (vaginal lips and clitoris in females and small scrotum and penis in males); incomplete and delayed puberty; infertility
• Developmental delays, mild-to-moderate intellectual disability, multiple learning disabilities

Minor clinical criteria of Prader-Willi syndrome

• Decreased movement and noticeable fatigue during infancy
• Behavioral problems-specifically, temper tantrums, obsessive-compulsive behavior, stubbornness, rigidity, stealing, and lying (especially related to food)
• Sleep problems, including daytime sleepiness and sleep disruption
• Short stature, compared with other members of the family, noticeable by age 15
• Light color of skin, eyes, and hair
• Small hands and feet in comparison to standards for height and age
• Narrow hands
• Nearsightedness and/or difficulty focusing both eyes at the same time
• Thick saliva
• Poor pronunciation
• Picking of the skin

Additional findings
• High pain threshold
• Inability to vomit
• Curvature of the spine (scoliosis)
• Earlier-than-usual activity in the adrenal glands, which can lead to early puberty
• Especially brittle bones (called osteoporosis, pronounced os-tee-oh-puh-ROH-sis)

Genetic testing must confirm the Prader-Willi syndrome diagnosis. More than 99% of individuals with Prader-Willi syndrome have an abnormality within a specific area of chromosome 15. Early diagnosis is best because it enables affected individuals to begin early intervention/special needs programs and treatment specifically for Prader-Willi symptoms.

Genetic testing can confirm the chance that a sibling might be born with Prader-Willi syndrome. Prenatal diagnosis also is available for at-risk pregnancies--that is, pregnancies among women with a family history of Prader-Willi syndrome abnormalities.

Genetic counseling and testing of at-risk relatives
Genetic counseling and testing provide individuals and families with information about the nature, inheritance, and implications of genetic disorders so that they can make informed medical and personal decisions about having children. Genetic counseling helps people understand their risks. The risk of occurrence in siblings of patients with Prader-Willi syndrome depends on what caused the disorder to occur (Holm et al 1993).

To locate a genetics or prenatal diagnosis clinic, see the GeneTests Clinic Directory.

Is there a cure for Prader-Willi syndrome?
Prader-Willi syndrome has no cure. However, early diagnosis and treatment may help prevent or reduce the number of challenges that individuals with Prader-Willi syndrome may experience, and which may be more of a problem if diagnosis or treatment is delayed.

What are the treatments for Prader-Willi syndrome?
Parents can enroll infants with Prader-Willi syndrome in early intervention programs. However, even if a Prader-Willi syndrome diagnosis is delayed, treatments are valuable at any age.

The types of treatment depend on the individual’s symptoms. The healthcare provider may recommend the following:

Use of special nipples or tubes for feeding difficulties. Difficulty in sucking is one of the most common symptoms of newborns with Prader-Willi syndrome. Special nipples or tubes are used for several months to feed newborns and infants who are unable to suck properly, to make sure that the infant is fed adequately and grows. To ensure that the child is growing properly, the health care provider will monitor height, weight, and body mass index (BMI) monthly during infancy.

Strict supervision of daily food intake.Once overeating starts between ages 2 and 4 years, supervision will help to minimize food hoarding and stealing and prevent rapid weight gain and severe obesity. Parents should lock refrigerators and all cabinets containing food. No medications have proven beneficial in reducing food-seeking behavior.

A well-balanced, low-calorie diet and regular exercise are essential and must be maintained for the rest of the individual's life. People with Prader-Willi syndrome rarely need more than 1,000 to 1,200 calories per day. Height, weight, and BMI should be monitored every 6 months during the first 10 years of life after infancy and once a year after age 10 for the rest of the person's life to make sure he or she is maintaining a healthy weight. Ongoing consultation with a dietitian to guarantee adequate vitamin and mineral intake, including calcium and vitamin D, might be needed.

Growth Hormone (GH) therapy. GH therapy has been demonstrated to increase height, lean body mass, and mobility; decrease fat mass; and improve movement and flexibility in individuals with Prader-Willi syndrome from infancy through adulthood (Cassidy and Schwartz 2009b; Burman et al 2001; Carrel et al 2002). When given early in life, it also may prevent or reduce behavioral difficulties. Additionally, GH therapy can help improve speech, improve abstract reasoning, and often allow information to be processed more quickly. It also has been shown to improve sleep quality and resting energy expenditure (Burman et al 2001; Carrel et al 2002; Buiting et al 1998). GH therapy usually is started during infancy or at diagnosis with Prader-Willi syndrome. This therapy often continues during adulthood at 20% to 25% of the recommended dose for children.

Treatment of eye problems by a pediatric ophthalmologist. Many infants have trouble getting their eyes to focus together. These infants should be referred to a pediatric ophthalmologist who has expertise in working with infants with disabilities.

Treatment of curvature of the spine by an orthopedist. An orthopedist should evaluate and treat, if necessary, curvature of the spine (scoliosis). Treatment will be the same as that for people with scoliosis who do not have Prader-Willi syndrome.

Sleep studies and treatment. Sleep disorders are common with Prader-Willi syndrome. Treating a sleep disorder can help improve the quality of sleep. The same treatments that healthcare providers use with the general population can apply to individuals with Prader-Willi syndrome.

Physical therapy. Muscle weakness is a serious problem among individuals with Prader-Willi syndrome. For children younger than age 3, physical therapy may increase muscular strength and help such children achieve developmental milestones. For older children, daily exercise will help build lean body mass.

Behavioral therapy. People with Prader-Willi syndrome have difficulty controlling their emotions. Using behavioral therapy can help. Stubbornness, anger, and obsessive-compulsive behavior, including obsession with food, should be handled with behavioral management programs using firm limit-setting strategies. Structure and routines also are advised (Cassidy and Schwartz 2009b; Holm et al 1993).

Medications. Medications, especially serotonin reuptake inhibitors (SRIs), may reduce obsessive-compulsive symptoms. SRIs also may help manage psychosis.

Early interventions/Special needs programs. Individuals with Prader-Willi syndrome have varying degrees of intellectual difficulty and learning disabilities. Early intervention programs, including speech therapy for delays in acquiring language and for difficulties with pronunciation, should begin as early as possible and continue throughout childhood (Gunay-Aygun et al 2001).

Special education is almost always necessary for school-age children. Groups that offer training in social skills may also prove beneficial. An individual aide is often useful in helping Prader-Willi syndrome children focus on schoolwork.

Sex hormone treatments and/or corrective surgery. These treatments are used to treat small genitals (penis, scrotum, clitoris).

Replacement of sex hormones. Replacement of sex hormones during puberty may result in development of adequate secondary sex characteristics (eg, breasts, pubic hair, a deeper voice).

Placement in group homes during adulthood. Group homes offer necessary structure and supervision for adults with Prader-Willi syndrome, helping them avoid compulsive eating, severe obesity, and other health problems (Burman et al 2001).

References cited:

Buiting K, Dittrich B, Gross S, et al. Sporadic imprinting defects in Prader-Willi syndrome and Angelman syndrome: Implications for imprint-switch models, genetic counseling, and prenatal diagnosis. American Journal of Human Genetics 1998;63:170-80.

Burman P, Ritzén EM, Lindgren AC. Endocrine dysfunction in Prader-Willi syndrome: A review with special reference to GH. Endocrine Reviews 2001;22:787-99. Retrieved June 13, 2012, from https://pubmed.ncbi.nlm.nih.gov/11739333/

Carrel AL, Myers SE, Whitman BY, Allen DB. Benefits of long-term GH therapy in Prader-Willi syndrome: A 4-year study. Journal of Clinical Endocrinology & Metabolism 2002;87:1581-5.

Cassidy SB, Schwartz S, Miller JL, Driscoll DJ. Prader-Willi syndrome. Genetics in Medicine 2011;14:10-26.

Cassidy SB, Schwartz S. Prader-Willi syndrome. NCBI Bookshelf, a Service of the National Library of Medicine, National Institutes of Health, 2009a. Bookshelf ID: NBK1330.

Cassidy SB, Schwartz S. Prader-Willi syndrome. In Pagon RA, Bird TD, Dolan CR, Stephens K, Adam MP, editors. Gene reviews 2009b. Seattle, WA: University of Washington. Retrieved June 13, 2012, from https://www.ncbi.nlm.nih.gov/books/NBK1330.

Gunay-Aygun M, Schwartz S, Heger S, O'Riordan MA, Cassidy SB. The changing purpose of Prader-Willi syndrome clinical diagnostic criteria and proposed revised criteria. Pediatrics 2001;108:e92. Retrieved on May 30, 2012, from https://publications.aap.org/pediatrics/article-abstract/108/5/e92/63709/The-Changing-Purpose-of-Prader-Willi-Syndrome.

Holm VA, Cassidy SB, Butler MG, et al. Prader-Willi syndrome: consensus diagnostic criteria. Pediatrics 1993;91:398-402.

McCandless SE, Committee on Genetics. Clinical report-health supervision for children with Prader-Willi syndrome. Pediatrics 2010;127:195-204.

Prader A, Labhart A, Willi H. [A syndrome characterized by obesity, short stature, cryptorchidism, and oligophrenia following a myotonia-like condition in infancy]. Schweizerische Medizinische Wochenschrift 1956;86:1260.

Additional resources
Foundation for Prader-Willi Research
5455 Wilshire Blvd, Suite 2020.
Los Angeles, CA 90036
888-322-5487
https://www.fpwr.org/

Prader-Willi Syndrome Association (USA)
8588 Potter Park Drive, Suite 500
Sarasota, Florida 34238
800-926-4797
https://www.pwsausa.org

This information was developed by the National Institutes of Health, National Institute of Child Health & Human Development.

National Institutes of Health, National Institute of Child Health & Human Development. Prader-Willi Syndrome (PWS): Condition Information. Available at: https://www.nichd.nih.gov/health/topics/prader-willi/conditioninfo/Pages/default.aspx. Last accessed February 13, 2014.

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