Prader-Willi syndrome (PWS) is a genetic condition caused by the absence of chromosomal material from chromosome 15. The genetic basis of PWS is complex. Characteristics of the syndrome include developmental delay, poor muscle tone, short stature, small hands and feet, incomplete sexual development, and unique facial features. Insatiable appetite is a classic feature of PWS. This uncontrollable appetite can lead to health problems and behavior disturbances.
Description
The first patients with features of PWS were described by Drs. Prader, Willi, and Lambert in 1956. Since that time, the complex genetic basis of PWS has begun to be understood. Initially, scientists found that individuals with PWS have a portion of genetic material deleted (erased) from chromosome 15. In order to have PWS, the genetic material must be deleted from the chromosome 15 received from one's father. If the deletion is on the chromosome 15 inherited from one's mother, a different syndrome develops. This was an important discovery. It demonstrated for the first time that the genes inherited from one's mother can be expressed differently than the genes inherited from one's father.
Over time, scientists realized that some individuals with PWS do not have a deletion of genetic material from chromosome 15. Further studies found that these patients inherit both copies of chromosome 15 from their mother. This is not typical. Normally, an individual should receive one chromosome 15 from one's father and one chromosome 15 from one's mother. When a person receives both chromosomes from the same parent it is called "uniparental disomy." When a person receives both chromosomes from one's mother it is called "maternal uniparental disomy."
Scientists are still discovering other causes of PWS. A small number of patients with PWS have a change (mutation) in the genetic material on the chromosome 15 inherited from their father. This mutation prevents certain genes on chromosome 15 from working properly. PWS develops when these genes do not work normally.
Newborns with PWS generally have poor muscle tone (hypotonia) and do not feed well. This can lead to poor weight gain and failure to thrive. Genitalia can be smaller than normal. Hands and feet are also typically smaller than normal. Some patients with PWS have unique facial characteristics. These unique facial features are typically subtle and only detectable by physicians.
As children with PWS age, development is typically slower than normal. Developmental milestones, such as crawling, walking, and talking occur later than usual. Developmental delay continues into adulthood for approximately 50% of individuals with PWS. At about one to two years of age, children with PWS develop an uncontrollable, insatiable appetite. Left to their own devices, individuals with PWS will eat until they have life-threatening obesity. The desire to eat can lead to significant behavior problems.
The symptoms and features of PWS require life-long support and care. If food intake is strictly monitored and various therapies provided, individuals with PWS have a normal life expectancy.
Genetic profile
In order to comprehend the various causes of PWS, the nature of chromosomes and genes must be well-understood. Human beings have 46 chromosomes in the cells of their body. Chromosomes contain genes. Genes regulate the function and development of the body. An individual's chromosomes are inherited from their parents. A child should receive 23 chromosomes from the mother and 23 chromosomes from the father.
The 46 chromosomes in the human body are divided into pairs. Each pair is assigned a number or a letter. Chromosomes are divided into pairs based on their physical characteristics. Chromosomes can only be seen when viewed under a microscope. Chromosomes within the
same pair appear identical because they contain the same genes.
Most chromosomes have a constriction near the center called the centromere. The centromere separates the chromosome into long and short arms. The short arm of a chromosome is called the "p arm." The long arm of a chromosome is called the "q arm."
Chromosomes in the same pair contain the same genes. However, some genes work differently depending on if they were inherited from the egg or the sperm. Sometimes, genes are silenced when inherited from the mother. Other times, genes are silenced when inherited from the father. When genes in a certain region on a chromosome are silenced, they are said to be "imprinted." Imprinting is a normal process. Imprinting does not typically cause disease. If normal imprinting is disrupted a genetic disease can develop.
Individuals should have two complete copies of chromosome 15. One chromosome 15 should be inherited from the mother, or be "maternal" in origin. The other chromosome 15 should be inherited from the father, or be "paternal" in origin.
Several genes found on the q arm of chromosome 15 are imprinted. A gene called "SNPRN" is an example of one of these genes. It is normally imprinted, or silenced, if inherited from the mother. The imprinting of this group of maternal genes does not typically cause disease. The genes in this region should not be imprinted if paternal in origin. Normal development depends on these paternal genes being present and active. If these genes are deleted, not inherited, or incorrectly imprinted, PWS develops.
Seventy percent of the cases of PWS are caused when a piece of material is deleted, or erased, from the paternal chromosome 15. This deletion happens in a specific region on the q arm of chromosome 15. The piece of chromosomal material that is deleted contains genes that must be present for normal development. These paternal genes must be working normally, because the same genes on the chromosome 15 inherited from the mother are imprinted. When these paternal genes are missing, the brain and other parts of the body do not develop as expected. This is what causes the symptoms associated with PWS.
In 99% of the cases of PWS the deletion is sporadic. This means that it happens randomly and there is not an apparent cause. It does not run in the family. If a child has PWS due to a sporadic deletion in the paternal chromosome 15, the chance the parents could have another child with PWS is less than 1%. In less than 1% of the cases of PWS there is a chromosomal rearrangement in the family which causes the deletion. This chromosomal rearrangement is called a "translocation." If a parent has a translocation the risk of having a child with PWS is higher than 1%.
PWS can also develop if a child receives both chromosome 15s from his or her mother. This is seen in approximately 25% of the cases of PWS. Maternal uniparental disomy for chromosome 15 leads to PWS because the genes on the chromosome 15 that should have been inherited from the father are missing. These paternal genes must be present, since the same genes on both the chromosome 15s inherited from the mother are imprinted.
PWS caused by maternal uniparental disomy is sporadic. This means that it happens randomly and there is no apparent cause. If a child has PWS due to maternal uniparental disomy the chance the parents could have another child with PWS is less than 1%.
Approximately 3–4% of patients with PWS have a change (mutation) in a gene located on the q arm of chromosome 15. This mutation leads to incorrect imprinting and causes genes inherited from the father to be imprinted or silenced. These genes should not normally be imprinted. If a child has PWS due to a mutation that changes imprinting, the chance the parents could have another child with PWS is approximately 5%.
It should be noted that if an individual has a deletion of the same material from the q arm of the maternal chromosome 15 a different syndrome develops. This syndrome is called Angelman syndrome. Angelman syndrome can also happen if an individual receives both chromosome 15s from the father.
Demographics
PWS affects approximately one in 10,000 to 25,000 live births. It is the most common genetic cause of life-threatening obesity. It affects both males and females. PWS can be seen in all races and ethnic groups.
Signs and symptoms
Infants with PWS have weak muscle tone (hypotonia). This hypotonia causes problems with sucking and eating. Infants with PWS may have problems gaining weight. Some infants with PWS are diagnosed with "failure to thrive" due to slow growth and development. During infancy, babies with PWS may also sleep more than normal and have problems controlling their temperature.
Some of the unique physical features associated with PWS can be seen during infancy. Genitalia that is smaller
than normal is common. This may be more evident in males with PWS. Hands and feet may also be smaller than average. The unique facial features seen in some patients with PWS may be difficult to detect in infancy. These facial features are very mild and do not cause physical problems.
As early as six months, but more commonly between one and two years of age, a compulsive desire to eat develops. This uncontrollable appetite is a classic feature of PWS. Individuals with PWS lack the ability to feel full or satiated. This uncontrollable desire to eat is thought to be related to a difference in the brain, which controls hunger. Over-eating (hyperpahgia), a lack of a desire to exercise, and a slow metabolism places individuals with PWS at high risk for severe obesity. Some individuals with PWS may also have a reduced ability to vomit.
Behavior problems are a common feature of PWS. Some behavior problems develop from the desire to eat. Other reported problems include obsessive/compulsive behaviors, depression, and temper tantrums. Individuals with PWS may also pick their own skin (skin picking). This unusual behavior may be due to a reduced pain threshold.
Developmental delay, learning disabilities, and mental retardation are associated with PWS. Approximately 50% of individuals with PWS have developmental delay. The remaining 50% are described as having mild mental retardation. The mental retardation can occasionally be more severe. Infants and children with PWS are often delayed in development.
Puberty may occur early or late, but it is usually incomplete. In addition to the effects on sexual development and fertility, individuals do not undergo the normal adolescent growth spurt and may be short as adults. Muscles often remain underdeveloped and body fat increased.
Diagnosis
During infancy the diagnosis of PWS may be suspected if poor muscle tone, feeding problems, small genitalia, or the unique facial features are present. If an infant has these features, testing for PWS should be performed. This testing should also be offered to children and adults who display features commonly seen in PWS (developmental delay, uncontrollable appetite, small genitalia, etc.). There are several different genetic tests that can detect PWS. All of these tests can be performed from a blood sample.
Methylation testing detects 99% of the cases of PWS. Methylation testing can detect the absence of the paternal genes that should be normally active on chromosome 15. Although methylation testing can accurately diagnose PWS, it can not determine if the PWS is caused by a deletion, maternal uniparental disomy, or a mutation that disrupts imprinting. This information is important for genetic counseling. Therefore, additional testing should be performed.
Chromosome analysis can determine if the PWS is the result of a deletion in the q arm of chromosome 15. Chromosome analysis, also called karyotyping, involves staining the chromosomes and examining them under a microscope. In some cases the deletion of material from chromosome 15 can be easily seen. In other cases, further testing must be performed. FISH (fluorescence in-situ hybridization) is a special technique that detects small deletions that cause PWS.
More specialized DNA testing is required to detect maternal uniparental disomy or a mutation that disrupts imprinting. This DNA testing identifies unique DNA patterns in the mother and father. The unique DNA patterns are then compared with the DNA from the child with PWS.
PWS can be detected before birth if the mother undergoes amniocentesis testing or chorionic villus sampling (CVS). This testing would only be recommended if the mother or father is known to have a chromosome rearrangement or if they already have a child with PWS syndrome.
Treatment and management
There is currently no cure for PWS. Treatment during infancy includes therapies to improve muscle tone. Some infants with PWS also require special nipples and feeding techniques to improve weight gain.
Treatment and management during childhood, adolescence, and adulthood is typically focused on weight control. Strict control of food intake is vital to prevent severe obesity. In many cases, food must be made inaccessible. This may involve unconventional measures such as locking the refrigerator or kitchen cabinets. A lifelong restricted-calorie diet and regular exercise program are also suggested. Unfortunately, diet medications have not been shown to significantly prevent obesity in PWS. However, growth hormone therapy has been shown to improve the poor muscle tone and reduced height typically associated with PWS.
Special education may be helpful in treating developmental delays and behavior problems. Individuals with PWS typically excel in highly structured environments.
Prognosis
Life expectancy is normal and the prognosis good if weight gain is well controlled.
BOOKS
Couch, Cheryl. My Rag Doll. Couch Publishing, 2000.
Jones, Kenneth Lyons. "Prader-Willi Syndrome." In Smith's Recognizable Patterns of Human Malformation. 5th ed. Philadelphia: W.B. Saunders, 1997.
PERIODICALS
Butler, Merlin G., and Travis Thompson. "Prader-Willi Syndrome: Clinical and Genetic Findings." The Endocrinologist 10 (2000): 3S–16S.
State, Matthew W., and Elisabeth Dykens. "Genetics of Childhood Disorders: XV. Prader-Willi Syndrome: Genes, Brain and Behavior." Journal of the American Academy of Child and Adolescent Psychiatry 39, no. 6 (June 2000): 797–800.
ORGANIZATIONS
Alliance of Genetic Support Groups. 4301 Connecticut Ave. NW, Suite 404, Washington, DC 20008. (202) 966-5557. Fax: (202) 966-8553. <http://www.geneticalliance.org>.
National Organization for Rare Disorders (NORD). PO Box 8923, New Fairfield, CT 06812-8923. (203) 746-6518 or (800) 999-6673. Fax: (203) 746-6481. <http://www.rarediseases.org>.
