Prader-Willi syndrome

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Definition

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 Dr. Prader, Dr. Willi, and Dr. 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 deleted 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 receives one chromosome 15 from their father and one chromosome 15 from their mother. When a person receives both chromosomes from the same parent it is called "uniparental disomy." When a person receives both chromosomes from his or her 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 detectable only 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 suffer from 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.

PWS affects approximately 1 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.

— Holly Ann Ishmael, MS

(medicine) A genetic disorder that is caused by defects on the paternally derived chromosome 15, causing mild mental retardation, neonatal hypotonia, hypogonadism, compulsive overeating, childhood onset obesity, and mild facial dysmorphism.

A metabolic condition characterized by congenital hypotonia, hyperphagia, obesity, and mental retardation. The syndrome is associated with a less-than-normal secretion of gonado-tropic hormones by the pituitary gland.

Definition

Prader-Willi syndrome (PWS) is a genetic condition caused by the absence of chromosomal material from chromosome 15. Characteristics of the syndrome include developmental delays, 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 morbid obesity and behavior disturbances.

Description

The first patients with features of PWS were described by Dr. Prader, Dr. Willi, and Dr. 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, for 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 genetic material deleted from chromosome 15. Further studies found that these patients inherit both copies of chromosome 15 from their mother, which is not typical. Normally, an individual receives one chromosome 15 from his or her father and one chromosome 15 from his or her mother. When a person receives both chromosomes from the same parent it is called "uniparental disomy." When a person receives both chromosomes from his or her 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, and a male with PWS may have undescended testicles. Hands and feet are also typically smaller than normal. Some patients with PWS have unique and subtle facial characteristics that are detectable only 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 percent of individuals with PWS. At about one to two years of age, children with PWS develop an uncontrollable, insatiable appetite. These children, if not controlled, will eat until they suffer from life-threatening obesity, including respiratory failure with hypoxia (low blood oxygen levels), cor pulmonale (right-sided heart failure), and death. The desire to eat can also lead to significant behavior problems.

The symptoms and features of PWS require lifelong support and care. If food intake is strictly monitored and various therapies provided, individuals with PWS have a normal life expectancy.

Prader-Willi syndrome is also referred to as cryptochidism-dwarfism-subnormal mentality syndrome, Willi-Prader syndrome, Labhart-Willi syndrome, Prader-Labhart-Will Fancone syndrome, and hypotoniahypomentia-hypogonadism-obesity syndrome.

Demographics

PWS affects approximately one in 12,000 to 15,000 live births. It is the most common genetic cause of life-threatening obesity. It affects both males and females and can be seen in all races and ethnic groups.

Causes and Symptoms

Human beings have 46 chromosomes in the cells of their body. Chromosomes contain genes that regulate the function and development of the body. An individual's chromosomes are inherited from his or her parents. Each parent normally gives a child 23 chromosomes. A child receives 23 chromosomes from the egg and 23 chromosomes from the sperm.

The 46 chromosomes in the human body are divided into pairs based on their physical characteristics. Each pair is assigned a number or a letter. 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 and 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 that does not typically cause disease. However, if normal imprinting is disrupted, a genetic disease can develop.

Individuals have two complete copies of chromosome 15. One chromosome 15 is inherited from the mother, or is maternal in origin. The other chromosome 15 is inherited from the father, or is paternal in origin.

Chromosome 15 contains many different genes. There are several genes found on the q arm of chromosome 15 that 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.

Deletion in the Paternally Contributed Chromosome 15

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 occurs 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 percent of the cases of PWS, the deletion is sporadic. This means that it happens randomly, there is not an apparent cause, and the condition is not inherited. 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 percent. In fewer than 1 percent of the cases of PWS there is a chromosomal rearrangement in the family that causes the deletion. This chromosomal rearrangement is called translocation. If a parent has a translocation the risk of having a child with PWS is higher than 1 percent.

Maternal Uniparental Disomy

PWS can also develop if a child receives both chromosome 15s from his or her mother. This is seen in approximately 25 percent of the cases of PWS. Maternal uniparental disomy for chromosome 15 leads to PWS because the genes on chromosome 15 that should have been inherited from the father are missing, and the genes on both the chromosome 15s inherited from the mother are imprinted.

PWS caused by maternal uniparental is sporadic. This means that it occurs randomly and there is not an 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 percent.

Error in Imprinting Process Than Renders Paternal Contribution Non-Functional

Approximately 2–5 percent 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. This mutation causes genes inherited from the father to be imprinted or silenced, which 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 percent.

Signs of PWS can be seen at birth. Infants with PWS have weak muscle tone (hypotonia). This hypotonia causes problems with sucking and eating so that infants with PWS may initially have problems gaining weight. Consequently, some infants with PWS may be diagnosed with failure to thrive due to slow growth and development. Hypotonia may also 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 (hypogonadism) 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 at one to two years, 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 because of a flaw in the hypothalamus part of their brain, which normally registers feelings of hunger and satiety. Over-eating (hyperpahgia), a lack of a desire to exercise, and decreased calorie utilization (typically 1,000–1,200 calories per day for adults, due to low muscle mass and inactivity) places individuals with PWS at high risk for severe obesity. Obesity-related problems include hypoventilation, hyertension, right-sided heart failure, cellulitis, and skin problems with fat folds. Some individuals with PWS may also have a reduced ability to vomit.

Behavior problems are a common feature of PWS. Although infants and young children are typically happy and loving and exhibit few behavior problems, most older children and adults do have difficulties with behavior regulation, such as difficulties with transistions and unanticipated changes. Onset of behavioral problems usually coincides with the onset of the compulsive eating. Difficulties peak in adolescence or early adulthood. Reported problems include obsessive/compulsive behaviors, depression, temper tantrums and violent outbursts, and tendencies to be argumentative, oppositional, rigid, manipulative, possessive, and stubborn. Individuals with PWS may also pick their own skin (skin picking). This unusual behavior may be due to a reduced pain threshold.

IQs range from 40 to 105, with an average of 70. Those with normal IQs typically have learning disabilities. Problem areas may include attention, short-term auditory memory, and abstract thinking. Common strengths include long-term memory, reading ability, and receptive language.

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 is increased.

When to Call the Doctor

Parents should call a doctor if they notice symptoms that are characteristic of PWS.

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 delays, uncontrollable appetite, small genitalia, etc.). There are several different genetic tests that can detect PWS. All of these tests can be performed usnig a blood sample.

Methylation testing detects 99 percent 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 is only recommended if the mother or father is known to have a chromosome rearrangement, or if they already have a child with PWS syndrome.

Treatment

There is currently not a cure for PWS. Treatment during infancy includes therapies to improve muscle tone. Some infants with PWS also require special nipples or tube feeding to improve weight gain.

Growth hormone therapy has been shown to improve the poor muscle tone and reduced height typically associated with PWS. Hypogonadism may be corrected at puberty with hormone replacement. Skin picking is best managed by ignoring the behavior, treating and bandaging sores, and providing substitute activities for the hands. Other behavioral problems can be managed through daily routines and structure, firm rules and limits, "time outs," positive rewards, and the use of psychotropic drugs.

Special education may be helpful in treating developmental delays and behavior problems. Individuals with PWS typically excel in highly structured environments. Physical and occupational therapies promote skill development and proper function. Exercise and sport activities should be encouraged, with adaptations made as necessary. Proficiency with jigsaw puzzles have been frequently reported, reflecting strong visual-perceptual skills. The need for speech therapy, due to speech difficulties caused by hypotonia, should be assessed. Sign language and picture communication boards can be used to reduce frustration and to aid communication. Products to increase saliva may help articulation problems. Social skills training can improve pragmatic language use. Verbal ability often becomes an area of strength for children with PWS.

Nutritional Concerns

Treatment and management of PWS 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 balanced restricted-calorie diet with vitamin and calcium supplementation and a regular exercise program (at least 30 minutes per day) are also suggested. The best meal and snack plan is one that the family or caregiver is able to aply routinely and consistently. Unfortunately, diet medications nor surgery have not been shown to significantly prevent obesity in PWS or eliminate the need for strict dieting and supervision around food.

Prognosis

With help, people with PWS can expect to accomplish many of the things their "normal" peers do: complete school, achieve in their outside areas of interest, be successfully employed, and even move away from their family home. They do, however, need a significant amount of support from their families and from school, work, and residential service providers to both achieve these goals and to avoid obesity and the serious health consequences that accompany it. Even those with IQs in the normal range need lifelong diet supervision and protection from food availability.

Although in the past many people with PWS died in adolescence or young adulthood, prevention of obesity can enable those with the syndrome to live a normal lifespan. New medications, including psychotropic drugs and synthetic growth hormone, are already improving the quality of life for some people with PWS. Ongoing research offers the hope of new discoveries that will enable people affected by this unusual condition to live more independent lives.

Prevention

PWS currently cannot be prevented. Genetic counseling is recommended for parents who may be at risk for having a child with PWS.

Parental Concerns

While there is no medical prevention or cure, early diagnosis of Prader-Willi syndrome gives parents time to learn about and prepare for the challenges that lie ahead and to establish family routines that will support their child's diet and behavior needs. The constant need for food restriction and behavior management may be stressful for family members. It is also important for the parents to provide basic sex education to promote good health and to protect against abuse. Knowing the cause of their child's developmental delays can facilitate a family's access to important early intervention services and may help program staff identify areas of specific need or risk. Additionally, a diagnosis of PWS opens the doors to a network of information and support from professionals and other families who are dealing with the syndrome. Adolescents and adults with PWS can function well in group and supported living programs, if the necessary diet control and structured environment are provided. Employment in sheltered workshops and other highly structured and supervised settings is successful for many. However, residential and vocational providers must be fully informed regarding management of PWS.

Resources

Books

Couch, Cheryl. My Rag Doll. Couch Publishing, October 2000.

Icon Health Publications. Prader-Willi Syndrome: A Medical Dictionary, Bibliography, and Annotated Research Guide to Internet References. San Diego, CA: Icon Health Publications, 2004.

Jones, Kenneth Lyons. "Prader-Willi Syndrome." In Smith's Recognizable Patterns of Human Malformation. 5th edition Philadelphia: W.B. Saunders, 1997.

PM Medical Health News. 21st Century Complete Medical Guide to Prader-Willi Syndrome: Authoritative Government Documents, Clinical References, and Practical Information for Patients and Physicians. CDROM. Washington, DC: Progressive Management, 2004.

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." J. Am. Acad. Child. Adolesc. 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. www.geneticalliance.org.

International Prader-Willi Syndrome Organization. www.ipwsp.org.

National Organization for Rare Disorders, Inc. P.O. Box 8923, New Fairfield, CT 06812. (800) 999-6673. www.rarediseases.org.

Prader-Willi Foundation. 223 Main Street, Port Washington, NY 11050. (800)253-7993. www.prader-willi.org.

Prader-Willi Syndrome Association (USA). 5700 Midnight Pass Rd., Sarasota, FL 34242. (800) 926-4797. www.pwsausa.org.

Web Sites

Prader-Willi Syndrome. National Institutes of Health. www.nlm.nih.gov/medlineplus/praderwillisyndrome.html.

[Article by: Judith Sims, MS Holly Ann Ishmael, MS]

Prader-Willi syndrome
Classification and external resources
A 1680 painting by Juan Carreno de Miranda of a girl presumed to have Prader-Willi syndrome.
ICD-10	Q87.1
ICD-9	759.81
OMIM	176270
DiseasesDB	10481
eMedicine	ped/1880
MeSH	D011218

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. It was first described in 1956 by Andrea Prader, Heinrich Willi, Alexis Labhart, Andrew Ziegler, and Guido Fanconi of Switzerland.^[1] The incidence of PWS is between 1 in 10,000 and 1 in 15,000 live births. The distinction of chromosome by paternal origin is due to imprinting and PWS has the sister syndrome Angelman syndrome that affects maternally imprinted genes in the region.

Contents 1 Diagnosis 2 Differential diagnosis 3 PWS phenotype 4 Genetics 5 Neuro-cognitive 6 Behavioral 7 Endocrine 8 Treatment 9 In the media 10 See also 11 References 12 External links

Diagnosis

Prader-Willi syndrome phenotype at 15 years of age . Note absence of typical PWS facial features and presence of mild truncal obesity.

PWS affects approximately 1 in 10,000 to 1 in 15,000 new borns.^[2] It is characterized by hypotonia, short stature, polyphagia, obesity, small hands and feet, hypogonadism, and mild mental retardation.^[2]

Traditionally, PWS was diagnosed by clinical presentation. Currently, the syndrome is diagnosed through genetic testing; testing is recommended for newborns with pronounced hypotonia. 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.

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 problems. Adding to the confusion, parents of children who already carry a diagnosis of Prader-Willi syndrome may tell friends, family, and even physicians and nurses that their child has Down syndrome because more people have heard of that condition.

PWS phenotype

Clinical Features And Signs
Holm et al. (1993) describe the following features and signs as pretest indicators of PWS, although not all will be present.

In Utero:

• Reduced fetal movement
• Frequent abnormal fetal position

At Birth:

• Often breech or caesarean births
• Lethargy
• Hypotonia
• Feeding difficulties (due to poor muscle tone affecting sucking reflex)
• Difficulties establishing respiration
• Hypogonadism

Infancy:

• Failure to thrive (continued feeding difficulties)
• Delayed milestones/intellectual delay
• Excessive sleeping
• Strabismus
• Scoliosis (often not detected at birth)

Childhood:

• Speech delay
• Poor physical coordination
• Hyperphagia (over-eating) from age 2 - 4 years. Note change from feeding difficulties in infancy
• Excessive weight gain

Adolescence:

• Delayed puberty
• Short stature
• Obesity
• Extremely flexible

Adulthood:

• Infertility (males and females)
• Hypogonadism
• Sparse pubic hair
• Obesity
• Hypotonia
• Learning disabilities/borderline intellectual functioning (but some cases of average intelligence)
• Prone to diabetes mellitus
• Extremely flexible

General physical appearance (adults)

• Prominent nasal bridge
• Small hands and feet
• Soft skin, which is easily bruised
• Excess fat, especially in the central portion of the body
• High, narrow forehead
• Almond shaped eyes with thin, down-turned lips
• Light skin and hair relative to other family members
• Lack of complete sexual development
• Frequent skin picking
• Stria
• Delayed motor development

Genetics

PWS is caused by the deletion of the paternal copies of the imprinted SNRPN and necdin genes along with clusters of snoRNAs: SNORD64, SNORD107, SNORD108 and two copies of SNORD109, 29 copies of SNORD116 (HBII-85) and 48 copies of SNORD115 (HBII-52). These are on chromosome 15 located in the region 15q11-13.^[3][4][5] 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.

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.

Studies of human and mouse model systems have shown that deletion of the 29 copies of the C/D box snoRNA SNORD116 (HBII-85) has been shown to be the primary cause of Prader-Willi syndrome.^{[6][7][8][9] [10]}

Neuro-cognitive

Individuals with PWS are at risk of learning and attention difficulties. Curfs and Frym (1992) conducted research into the varying degrees of learning disability found in Prader Willi Syndrome (PWS).^[11] Their results were as follows:

• 5%...IQ above 85 (Average to low average intelligence)

• 27%..IQ 70 - 85 (Borderline intellectual functioning)

• 34%..IQ 50 - 70 (Mild intellectual disability)

• 27%..IQ 35 - 50 (Moderate intellectual disability)

• 5%...IQ 20 - 35 (Severe intellectual disability)

• <1%..IQ <20 (Profound intellectual disability)

Cassidy found that 40% of individuals with PWS have borderline/low average intelligence,^[12] a figure higher than that found in Curfs and Frym's study (32%).^[11] However, both studies suggest that most individuals (50 - 65%) fall within the mild/borderline/low average intelligence range.

Children with PWS show an unusual cognitive profile. They are often strong in visual organisation and perception, including reading and vocabulary, but their spoken language (sometimes affected by hypernasality) is generally poorer than their comprehension. A marked skill in completing jigsaw puzzles has been noted.^[13][14]

Auditory information processing and sequential processing are relatively poor, as are arithmetic and writing skills, visual and auditory short term memory and auditory attention span. These sometimes improve with age, but deficits in these areas remain throughout adulthood.^[13]

Behavioral

Prader-Willi syndrome is also frequently associated with an extreme and insatiable appetite, often resulting in morbid obesity. There is currently no consensus as to the cause for this particular symptom, although genetic abnormalities in chromosome 15 disrupt the normal functioning of the hypothalamus.^[12] Given that the hypothalamus regulates many basic processes, including appetite, there may well be a link. However, no organic defect of the hypothalamus has been discovered on post mortem investigation.^[12]

Endocrine

There are several aspects of PWS that support the concept of growth hormone deficiency in individuals with PWS. Specifically, individuals with PWS have short stature, are obese with abnormal body composition, have reduced fat free mass (FFM), have reduced LBM and total energy expenditure, and have decreased bone density.

PWS is characterized by hypogonadism. This is manifested as undescended testes in males and benign premature adrenarche in females. Testes may descend with time or can be managed with surgery or testosterone replacement. Adrenarche may be treated with hormone replacement therapy.

Treatment

Prader-Willi syndrome has no cure, however, several treatments are in place to lessen the condition's symptoms. During infancy, subjects should undergo therapies to improve muscle tone. Speech and occupational therapy are also indicated. During the school years, children benefit from a highly structured learning environment as well as extra help. Throughout their lives, the subject's food should literally be kept under lock and key, since the largest problem associated with the syndrome is severe obesity.

Prescription of daily recombinant growth hormone injections are indicated for children with PWS. GH supports linear growth and increased muscle mass, and may lessen food preoccupation and weight gain.^[15][16][17]

Because of severe obesity, obstructive sleep apnea is a common sequela, and a positive airway pressure machine is often needed.

In the media

Prader-Willi syndrome appeared in the UK media in July 2007 when Channel 4 aired a program surrounding the everyday lives of two Prader-Willi patients, Joe and Tamara.^[18]

The television series CSI: Crime Scene Investigation did an episode about someone suffering from Prader-Willi Syndrome, 'Dog Eat Dog', that aired on November 24, 2005.^[19]

See also

• Genomic imprinting.
• Angelman syndrome
• Epigenetics

References

1. ^ synd/1836 at Who Named It?
2. ^ ^{a b} Killeen, Anthony A. (2004). "Genetic Inheritance". Principles of Molecular Pathology. Humana Press. pp. 41. http://books.google.com/books?id=oHcDreGaMm0C&pg=PA41. 
3. ^ Omim - Prader-Willi Syndrome; Pws
4. ^ de los Santos T, Schweizer J, Rees CA, Francke U (November 2000). "Small evolutionarily conserved RNA, resembling C/D box small nucleolar RNA, is transcribed from PWCR1, a novel imprinted gene in the Prader-Willi deletion region, which Is highly expressed in brain". Am. J. Hum. Genet. 67 (5): 1067–82. doi:10.1086/303106. PMID 11007541. 
5. ^ Cavaillé J, Buiting K, Kiefmann M, et al. (December 2000). "Identification of brain-specific and imprinted small nucleolar RNA genes exhibiting an unusual genomic organization". Proc. Natl. Acad. Sci. U.S.A. 97 (26): 14311–6. doi:10.1073/pnas.250426397. PMID 11106375. 
6. ^ Skryabin BV, Gubar LV, Seeger B, et al. (2007). "Deletion of the MBII-85 snoRNA gene cluster in mice results in postnatal growth retardation". PLoS Genet. 3 (12): e235. doi:10.1371/journal.pgen.0030235. PMID 18166085. http://www.plosgenetics.org/article/info:doi/10.1371/journal.pgen.0030235. 
7. ^ Sahoo T, del Gaudio D, German JR, Shinawi M, Peters SU, Person RE, Garnica A, Cheung SW, Beaudet AL (2008). "Prader-Willi phenotype caused by paternal deficiency for the HBII-85 C/D box small nucleolar RNA cluster.". Nat Genet 40 (6): 719–21. doi:10.1038/ng.158. PMID 18500341. 
8. ^ Ding F, Li HH, Zhang S, Solomon NM, Camper SA, Cohen P, Francke U (2008). "SnoRNA Snord116 (Pwcr1/MBII-85) deletion causes growth deficiency and hyperphagia in mice.". PLoS ONE 3 (3): e1709. doi:10.1371/journal.pone.0001709. PMID 18320030. 
9. ^ Ding F, Prints Y, Dhar MS, Johnson DK, Garnacho-Montero C, Nicholls RD, Francke U (2005). "Lack of Pwcr1/MBII-85 snoRNA is critical for neonatal lethality in Prader-Willi syndrome mouse models.". Mamm Genome 16 (6): 424–31. doi:10.1007/s00335-005-2460-2. PMID 16075369. 
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External links

Wikimedia Commons has media related to: Prader-Willi syndrome

• Prader-Willi syndrome at the Open Directory Project
• Foundation for Prader-Willi Research
• Prader-Willi Syndrome Association (USA)
• Prader-Willi Syndrome (UK)
• Prader-Willi Syndrome Association (UK)
• Prader-Willi Syndrome Association (South Africa)
• SPINE Foundation (Argentina)

v • d • e Pathology: chromosome abnormalities (Q90-Q99 · 758) Autosomal Trisomies Down syndrome (21) · Edwards syndrome (18) · Patau syndrome (13) Trisomy 9 · Warkany syndrome 2 (8) · Trisomy 22/Cat eye syndrome (22) · Trisomy 16 Monosomies/deletions Wolf-Hirschhorn syndrome (4) · Cri du chat/Chromosome 5q deletion syndrome (5) · Williams syndrome (7) · Jacobsen syndrome (11) · Miller-Dieker syndrome/Smith-Magenis syndrome (17) · 22q11.2 deletion syndrome (22) genomic imprinting (Angelman syndrome/Prader-Willi syndrome (15)) X/Y linked Monosomy Turner syndrome (XO) Trisomy/tetrasomy other karyotypes Klinefelter's syndrome (47,XXY) · 48,XXYY · 49,XXXXY Triple X syndrome (47,XXX) · 48,XXXX · 49,XXXXX 47,XYY Translocations Leukemia/lymphoma Lymphoid Burkitt's lymphoma t(8 MYC;14 IGH) · Follicular lymphoma t(14 IGH;18 BCL2) · Mantle cell lymphoma/Multiple myeloma t(11 CCND1:14 IGH) · Anaplastic large cell lymphoma t(2 ALK;5 NPM1) · Acute lymphoblastic leukemia Myeloid Philadelphia chromosome t(9 ABL; 22 BCR) · Acute myeloblastic leukemia with maturation t(8 RUNX1T1;21 RUNX1) · Acute promyelocytic leukemia t(15 PML,17 RARA) · Acute megakaryoblastic leukemia t(1 RBM15;22 MKL1) Other Ewing's sarcoma t(11 FLI1; 22 EWS) · Synovial sarcoma t(x SYT;18 SSX) · Dermatofibrosarcoma protuberans t(17 COL1A1;22 PDGFB) · Myxoid liposarcoma t(12 DDIT3; 16 FUS) · Desmoplastic small round cell tumor t(11 WT1; 22 EWS) · Alveolar rhabdomyosarcoma t(2 PAX3; 13 FOXO1) t (1 PAX7; 13 FOXO1) Gonadal dysgenesis Mixed gonadal dysgenesis · XX gonadal dysgenesis Other Fragile X syndrome · Uniparental disomy

v • d • e Non-Mendelian inheritance: genomic imprinting Chromosome 15 Angelman syndrome · Prader-Willi syndrome Chromosome 11 Beckwith-Wiedemann syndrome · Silver-Russell dwarfism

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