Information on the following diseases can be found in the Related Disorders section of this report:

• congenital myotonic dystrophy
• Cohen syndrome
• Angelman syndrome
• Bardet-Biedl syndrome
• spinal muscular atrophy

Early symptoms of Prader-Willi syndrome include decreased fetal movement, low birth weight, muscular weakness (hypotonia), sleepiness, a weak cry and poor sucking ability. Other characteristics may include unusually small hands and feet (acromicria), narrow forehead (bifrontal diameter), crossing of the eyes (strabismus), almond-shaped eyes (palpebral fissures), and developmental delays relating to head control and the ability to crawl.

A need to eat an extraordinary amount of food (hyperphagia) usually develops between 1 to 3 years of age. If left uncontrolled, the obesity of Prader-Willi syndrome can lead to life-threatening heart and lung complications, diabetes, hypertension and to other serious disorders. The compulsion to eat is so overwhelming in people with this disorder that, if left unsupervised, they may endanger themselves by eating inedible objects. Obesity in Prader-Willi syndrome may be related to an abnormality in the hypothalamus and to a lower rate of metabolism.

All individuals with Prader-Willi syndrome have some cognitive impairment that ranges from borderline normal with learning disabilities to mild mental retardation. Behavior problems can be related to a change in routine or lack of a structured environment.

The genital abnormalities in Prader-Willi syndrome can include failure of the testes to descend into the scrotum (cryptorchidism) in males. In females, there is often an unusually small and underdeveloped (hypoplastic) labia that is often overlooked. Puberty is often delayed, incomplete and disordered and most affected individuals are infertile.

Prader-Willi syndrome occurs when the genes in a specific region of chromosome 15 do not function. This region of chromosome 15 is located at 15q11.2-q13 and has been designated the Prader-Willi syndrome/Angelman syndrome region (PWS/AS). The nonfunctioning PWS/AS region is always located on the number 15 chromosome inherited from the father. In most cases (70%), the PWS/AS region of the father’s chromosome 15 is missing. This deletion of chromosome results from a random error in development. In about 25% of cases, the affected person inherits two copies of the mother’s chromosome 15 and no copy of the father’s chromosome 15 (maternal uniparental disomy). This type of genetic change also occurs as a result of a random error in development. In less than 5% of cases, the PWS/AS region of the father’s chromosome 15 is present but the genes do not work properly. This form of Prader-Willi syndrome is due to a defect in genes called the imprinting control center and is sometimes due to a genetic change that can be passed from one generation to the next.

Chromosomes, which are present in the nucleus of human cells, carry the genetic information for each individual. Human body cells normally have 46 chromosomes. Pairs of human chromosomes are numbered from 1 through 22 and the sex chromosomes are designated X and Y. Males have one X and one Y chromosome and females have two X chromosomes. Each chromosome has a short arm designated "p" and a long arm designated "q". Chromosomes are further sub-divided into many bands that are numbered. For example, "chromosome 15q11.2" refers to band 11.2 on the long arm of chromosome 15. The numbered bands specify the location of the thousands of genes that are present on each chromosome.

The frequency of Prader-Willi syndrome is 1 in 10,000 to 1 in 15,000. This condition occurs in both sexes and all ethnic groups.

Symptoms of the following disorders can be similar to those of Prader-Willi syndrome. Comparisons may be useful for a differential diagnosis:

Congenital myotonic dystrophy is characterized by overall muscle weakness, facial muscle weakness and breathing difficulties. Death in the newborn period is common. Those who survive develop a progressive myopathy and frequently have mental retardation.

Cohen syndrome is a rare genetic disorder characterized by multiple facial, mouth and eye abnormalities, muscle weakness, obesity and mental retardation. Children who have Cohen syndrome usually have a low birth weight and delayed growth. Other symptoms of this disorder may include an usually small head (microcephaly), a high nasal bridge, an open mouth, prominent lips and large ears. The jaw may develop abnormally and there may be a mild down-slant to the eyes. (For more information on this disorder, choose "Cohen syndrome" as your search term in the Rare Disease Database.)

Angelman syndrome is a rare genetic disorder characterized by severe mental retardation, unusual facial expression and muscular abnormalities. It was first described in the medical literature as the "happy puppet syndrome". Other symptoms usually include a small head (microcephaly), a protruding jaw, an open mouth and protruding tongue. Affected individuals seem to smile and laugh excessively. Speech is often absent. Hypotonia is common in infancy. Most cases of Angelman syndrome are due to a deletion of the PWS/AS region on the maternally derived chromosome 15. In most affected individuals, the genetic defect causing Angelman syndrome occurs sporadically, however, some inherited cases have been reported. (For more information on this disorder, choose "Angelman syndrome" as your search term in the Rare Disease Database.)

Bardet-Biedl syndrome is a group of rare disorders inherited as autosomal recessive genetic traits. Major features of these disorders may include mental retardation, obesity, delayed sexual development or underdeveloped reproductive organs, progressive pigmentary degeneration of the retinas of the eyes, kidney abnormalities in structure or function, and/or abnormal or extra fingers and/or toes. (For more information on this disorder, choose "Bardet-Biedl syndrome" as your search term in the Rare Disease Database.)

Spinal muscular atrophy (SMA) is an inherited progressive neuromuscular disorder characterized by degeneration of groups of nerve cells within the lowest region of the brain and certain motor neurons in the spinal cord. Typical symptoms are a slowly progressive muscle weakness and muscle wasting (atrophy). Affected individuals have poor muscle tone, muscle weakness on both sides of the body without, or with minimal, involvement of the face muscles, twitching tongue and a lack of deep tendon reflexes. (For more information on this disorder, choose "Spinal Muscular Atrophy" as your search term in the Rare Disease Database.)

Diagnosis
The most accurate test for Prader-Willi syndrome is a DNA methylation test that can determine if the father’s PWS/AS region on chromosome 15 is present. This test is 99% accurate in confirming or ruling out a diagnosis of Prader-Willi syndrome but additional testing is necessary to determine if it is due to a deletion, uniparental disomy or an imprinting defect. A specialized chromosome analysis called FISH (fluorescent in-situ hybridization) is sometimes used as a first step in diagnosis because it is more readily available than the methylation test. If the FISH test reveals a deletion in the PWS/AS region, the diagnosis is confirmed. Additional testing is needed to determine if the Prader-Willi syndrome is due to uniparental disomy or an imprinting defect.

Prenatal diagnosis is available for Prader-Willi syndrome.

Treatment
Infants with Prader-Willi syndrome may have difficulty feeding and need special feeding techniques. Physical therapy can be beneficial in improving muscle strength.

Growth hormone replacement therapy (GHRT) can help with weight management in children with Prader-Willi syndrome. GHRT can accelerate scoliosis so monitoring for scoliosis should be done regularly. The U.S. Food and Drug Administration has approved a recombinant human growth hormone, somatropin [rDNA] (Genotropin), for the long-term treatment of short stature in children with Prader-Willi syndrome (June 2000). The drug is produced by:

Pharmacia & Upjohn Corporation.
7000 Portage Road
Kalamazoo, MI 49001

The development of a well supervised nutrition and exercise program are necessary to reduce the risk for obesity. Learning disabilities and speech should be evaluated. Behavior management programs should be instituted when necessary.

A highly structured residential program is usually necessary for adults with Prader-Willi syndrome. Life span can be normal if obesity can be controlled.

Information on current clinical trials is posted on the Internet at www.clinicaltrials.gov. All studies receiving U.S. government funding, and some supported by private industry, are posted on this government website.

For information about clinical trials being conducted at the National Institutes of Health (NIH) in Bethesda, MD, contact the NIH Patient Recruitment Office:

Tollfree: (800) 411-1222
TTY: (866) 411-1010
Email: prpl@cc.nih.gov

Currently (2004) there is one clinical study listed on the clinical trials web site for Prader-Willi syndrome. This study is investigating the drug topiramate (Topamax) to help in modifying self-injurious behavior, particularly skin picking, which is sometimes exhibited by individuals with this disorder.

Recruitment is currently (2004) underway for children with a diagnosis of Prader-Willi syndrome to participate in a magnetic resonance brain imaging (MRI) study at the University of California at Los Angeles Medical Center. Vital signs will be recorded while the individual undergoes an approximately three-hour long brain scan. There is a $300 compensation for taking part in this study. For information, contact any one of the following healthcare professionals:

Ronald Harper, PhD
Brain Research Institute
UCLA
Telephone: (310) 825-5303

Mary Woo, DNSc
School of Nursing
UCLA
Telephone: (310) 206-2032

Thomas Keens, MD
Division of Pediatric Pulmonology
Children’s Hospital, Los Angeles
Telephone: (323) 669-2101

Prader-Willi syndrome is the subject of ongoing medical research including studies in the area of obesity, chromosomal abnormalities, compulsive behavior, diets, daily hormone cycles and brain scans. This syndrome and its association with diabetes and nutrition are also under investigation. For further information on a variety of studies dealing with these issues, contact the Prader-Willi Syndrome Association by using their contact information listed in the Resources section of this report.

The drug, etiocholamedione (RF1051) received an orphan drug designation in 1996 for the treatment of Prader-Willi syndrome.

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Cassidy, S. Prader-Willi Syndrome. In: The NORD Guide to Rare Disorders, Philadelphia: Lippincott, Williams and Wilkins, 2003:237-238.

Online Mendelian Inheritance in Man, OMIM (TM). John Hopkins University, Baltimore, MD. MIM Number 176270; 10/21/99. Available at: http://www.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim/176270.

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Lee ST, et al. Mutations of the P gene in oculocutaneous albinism, ocular albinism, and Prader-Willi syndrome plus albinism. New Engl J Med. 1994;8:529-534.

Buiting K, et al. Molecular definition of the Prader-Willi syndrome chromosome region and orientation of the SNRPN gene. Hum Molec Genet. 1993;2:1991-1994.

Driscoll DJ, et al. A DNA methylation imprint, determined by the sex of the parent, distinguishes the Angelman and Prader-Willi syndromes. Genomics. 1992;13:917-924.

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