NORD gratefully acknowledges Suzanne Cassidy, MD, Clinical Professor of Pediatrics, Division of Medical Genetics, University of California, San Francisco, for assistance in the preparation of this report.
Prader-Willi syndrome (PWS) is a genetic multisystem disorder characterized during infancy by lethargy, diminished muscle tone (hypotonia), feeding difficulties, and poor weight gain. In childhood, features of this disorder include short stature, small genitals and an excessive appetite because affected individuals do not feel satisfied after completing a mean (satiety). Without intervention, this can lead to overeating and the gradual onset of obesity. The food compulsion requires constant supervision. Individuals with severe obesity may have an increased risk of cardiac insufficiency, sleep apnea, diabetes, and other serious conditions that can cause life-threatening complications. All individuals with PWS have some cognitive impairment that ranges from low normal intelligence with learning disabilities to mild to moderate intellectual disability. Behavioral problems are common and can include temper tantrums, obsessive/compulsive behavior, and skin picking. Motor milestones and language development are often delayed. PWS occurs due to abnormalities affecting certain genes in a specific region of chromosome 15. These abnormalities usually result from random (sporadic) errors in development, but are sometimes inherited.
Originally described in the medical literature in 1956, PWS is the first disorder confirmed to be due to imprinting errors (see Causes section). It is the most common genetic cause of life-threatening childhood obesity. The disorder was once known as hypogonadism, hypotonia, hypomentia, obesity (HHHO).
The symptoms and severity of PWS can vary from one person to another. Many features of the disorder are nonspecific and others may develop slowly over time or can be subtle. It is important to note that affected individuals may not have all of the symptoms discussed below. Affected individuals should talk to their physician and medical team about their specific case, associated symptoms and overall prognosis.
Initially, infants will exhibit diminished muscle tone (hypotonia), which can cause a baby to feel “floppy” when held. Infantile hypotonia, which is often severe, is a near universal feature of the disorder. Hypotonia can be present before birth (prenatally) potentially causing decreased fetal movements and abnormal positioning of the fetus (e.g. breech position). Prenatal hypotonia is associated with an increased risk of requiring an assisted delivery. After birth, hypotonia is associated with lethargy, a weak cry, poor responsiveness to stimuli, and poor reflexes including poor sucking ability, which result in feeding difficulties and failure to thrive. Infants are usually unable to breastfeed and may require tube feeding. Hypotonia slowly improves over time, but some adults with PWS remain slightly hypotonic.
Affected infants may also have distinctive facial features including almond-shaped eyes, a thin upper lip, a downturned mouth, a narrow bridge of the nose, narrow forehead, and a disproportionately long, narrow head (dolichocephaly). Distinctive facial features can be noticeable shortly after birth or may develop slowly over time.
As affected infants grow older, their feeding and appetite will improve and they will grow appropriately. Typically, between 2-4.5 years of age, their weight increases although there may not be a noticeable change in appetite or caloric intake. Between 4.5-8 years old, appetite and caloric intake usually increases, often thereafter developing a need to eat an extraordinary amount of food (hyperphagia) usually because they do not feel satisfied after completing a meal (satiety). In addition, there is a decreased calorie requirement in people with PWS. Consequently, if untreated, overeating, rapid weight gain, and morbid obesity occur if not controlled by others. Not all affected children will go through these stages.
If left uncontrolled and untreated, morbid obesity can develop, potentially leading to life-threatening heart and lung complications, diabetes, high blood pressure (hypertension), and to other serious complications. The compulsion to eat is so overwhelming that people with this disorder, if left unsupervised, may endanger themselves by eating harmful food such as spoiled food or garbage. Affected children may also exhibit unusual behaviors regarding food including hoarding and/or foraging for food, stealing food, and stealing money to buy food.
Some affected individuals have developed serious, life-threatening gastrointestinal complications due to episodes of binge eating. Such complications can include severe bloating (gastric dilatation) with the development of a hole or tear in the abdominal wall (perforation) and tissue loss (necrosis).
Children with PWS also have varying levels of cognitive impairment, ranging from borderline or low normal intelligence with learning disabilities to mild to moderate intellectual disability. The attainment of motor milestones (e.g. walking or sitting up) and language development are often delayed.
Affected children generally have sweet and loving personalities, but often develop distinct behavioral issues. Such issues can include temper tantrums, stubbornness, obsessive/compulsive behavior, manipulative behavior, and skin picking, which can cause chronic open wounds, scarring and infection. In some cases, the behavior profile may be suggestive of autism. Psychosis occurs in approximately 10-20% of late adolescents and young adults.
Hypogonadism is a common finding in PWS. Hypogonadism refers to inadequate function of the sex organs, the testes in males and the ovaries in females. The sex organs in affected individuals fail to produce sufficient sex hormones, which can result in underdeveloped sex organs, incomplete development at puberty, delayed onset of puberty, and infertility. Genital underdevelopment is evident at birth. Affected males may exhibit a small penis, underdeveloped scrotum, and small testes. Failure of one or both testes to descend (cryptorchidism) is a common finding as well. Affected females may exhibit an abnormally small clitoris or labia minor. Absence of a menstrual cycle (primary amenorrhea) is common and in some cases the initial menstrual period (menarche) was reported to occur as late as in the 30s.
Individuals with PWS have growth hormone (GH) insufficiency, a condition characterized by the inadequate secretion of growth hormone from the anterior pituitary gland, a small gland located at the base of the brain that is responsible for the production of several hormones. Children may be significantly below average height based upon sex and age (short stature). GH deficiency affects both children and adults and final adult height of affected individuals is shorter than unaffected family members. GH insufficiency also results in an increase in fat and relative decrease in muscle (altered body composition).
Affected individuals may also have abnormally small hands and feet, side-to-side curvature of the spine (scoliosis), and, in approximately 10% of individuals, a malformed hip (hip dysplasia). Scoliosis can occur at any age including infancy and varies in severity. Sleep problems are common, including excessive daytime sleepiness, reduced rapid eye movement (REM) latency, disruption of the normal sleep cycle, and central and/or obstructive sleep apnea.
Some individuals may have lack of color (pigment) known as hypopigmentation affecting the hair, eyes and skin. They may appear fair-skinned compared to other family members. Nearsightedness (myopia) and misaligned eyes (strabismus) may also occur.
Affected individuals may also experience recurrent respiratory infections. Approximately 25% of affected individuals have an underactive thyroid gland (hypothyroidism). In addition, the rates of certain conditions are increased in individuals with PWS including fractures due to decreased bone density (osteopenia), altered temperature sensation, a high vomiting threshold, and swelling (edema) and ulcerations of the legs, especially in obese adults. Some individuals may have reduced flow of saliva with abnormally thick, sticky saliva. Additional symptoms that can occur in affected individuals include a high pain threshold, a tendency to bruise easily without known cause, and seizures.
Some individuals with PWS may develop central adrenal insufficiency (CAI), a condition characterized by deficiency of adrenocorticotropic hormone (ACTH). This hormone is produced by the pituitary gland. One of the main functions of ACTH is to stimulate the adrenal glands to produce cortisol, which helps to regulate blood sugar and helps the body deal with stress. In some cases, CAI may only be detectable during periods of stress (e.g. during illness). The exact percentage of affected individuals with CAI and its overall implications to individuals with PWS are not yet fully understood.
PWS occurs when the genes in a specific region of chromosome 15 are not present or do not function. This region of chromosome 15 is located at 15q11.2-q13 and has been designated the Prader-Will syndrome/Angelman syndrome region (PWS/AS). In individuals with PWS, the nonfunctioning PWS/AS region is always located on the number 15 chromosome inherited from the father. 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-q13” refers to bands 11.2-13 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 changes affecting the genes associated with PWS may involve changes in the structure of a gene (genetic factors) or changes in the function or expression of a gene (epigenetics). Three specific abnormalities are primarily associated with PWS – chromosomal deletion, uniparental disomy, and genetic imprinting errors.
PWS is associated with a specific process known as genetic imprinting. Normally, everyone has two copies of every gene – one received from the father and one received from the mother. In most cases, both genes are “turned on” or active. However, some genes are preferentially silenced or “turned off” based upon which parent that gene came from (genetic imprinting). Genetic imprinting is controlled by chemical switches through a process called methylation and other chemical changes. Proper genetic imprinting is necessary for normal development. Defective imprinting has been associated with several disorders including PWS.
Imprinted genes tend to be found clustered or grouped together. Several imprinted genes are found in a cluster on the long arm (q) of chromosome 15. The cluster contains a functional region known as an imprinting center that regulates the imprinted genes in this region.
In most cases (70%), the PWS/AS region of the father’s chromosome 15 is missing. This chromosomal deletion results from a random error in development and is not inherited (de novo deletion). Thus, most cases of PWS occur sporadically and the risk of recurrence in another pregnancy is less than 1%.
In about 25% of cases of PWS, the affected person inherits two copies of chromosome 15 from the mother 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 most cases, the risk of recurrence of uniparental disomy is estimated to be less than 1%.
In less than 5% of cases of PWS, the PWS/AS region of the father’s chromosome 15 is present, but the genes do not work properly. This form of PWS is due to a defect in genes called the imprinting center and is sometimes due to a genetic change (e.g. microdeletion) that can be passed from one generation to the next.
In a very small proportion of cases, PWS has occurred due to a balanced translocation of chromosome 15. Translocations occur when portions of certain chromosomes break off and are rearranged, resulting in shifting of genetic (e.g. genes of the imprinting center) material and an altered set of chromosomes. If a chromosomal translocation is balanced (meaning that it consists of rearranged chromosomes without anything missing or extra), then it is usually harmless to the carrier. However, such a chromosomal rearrangement may be associated with an increased risk of abnormal chromosomal development in the carrier’s offspring.
A number of imprinted genes have been mapped to the PWS/AS region of chromosome 15. However, the specific genes involved and their role in the development of the various symptoms of PWS are not yet known. Many symptoms associated with PWS are believed to be due to malfunction of the hypothalamus, a gland in the brain that regulates hormone secretions. Hormones produced by the hypothalamus control body temperature, hunger, moods, sex drive, sleep, and thirst. The hypothalamus also influences the release of hormones from other glands, especially the pituitary gland, which regulates certain hormones including growth hormone and sex hormones.
PWS affects males and females in equal numbers and occurs in all ethnic groups and geographic regions in the world. Most estimates place the incidence between 1 in 10,000-30,000 individuals in the general population.
A diagnosis of PWS is based upon a detailed patient history, a thorough clinical evaluation, and identification of characteristic symptoms. Consensus diagnostic criteria for PWS have been established and are effective for identifying potential cases of PWS. All infants and newborns with unexplained hypotonia and poor suck should be tested for PWS. To confirm a diagnosis of PWS, certain specialized tests are required including DNA methylation tests and fluorescent in situ hybridization (FISH).
Clinical Testing and Workup
Approximately 99% or more of cases of PWS can be diagnosed by DNA methylation study. This test allows for the examination of the PWS/AS critical region of chromosome 15. If the methylation pattern is consistent with maternal inheritance, then this indicates that the parental chromosome 15 is not present or not active. This finding is diagnostic of PWS, but methylation tests cannot distinguish among the different underlying causes of PWS.
If DNA methylation tests indicate PWS, then additional tests are necessary to determine the underlying cause of the disorder. This is important for determining whether there is an increased risk for the parents or other family members to have an affected child. A FISH test, which analyses chromosomes, can detect a deletion, the most common cause of PWS. If no deletion is present, then additional testing is performed to distinguish between uniparental disomy and or a defect of the imprint center.
Prenatal diagnosis is possible in families with a previous history of PWS. Prior identification of a disease causing abnormality can facilitate prenatal testing, but it is available by methylation analysis following amniocentesis regardless of cause.
The treatment of PWS is directed toward the specific symptoms that are apparent in each individual. Early intervention and strict maintenance to treatment can greatly improve the overall health and quality of life for affected individuals and their families. Treatment may require the coordinated efforts of a team of specialists. Pediatricians, orthopedists, endocrinologists, speech therapists, psychologists, dieticians, nutritionists, and other healthcare professionals may need to systematically and comprehensively plan an affect child's treatment. Genetic counseling may be of benefit for affected individuals and their families. Parents are strongly recommended to undergo appropriate parenting techniques for the behavioral and eating issues associated with PWS; such education correlates with better prognosis.
Specific therapeutic procedures and interventions may vary, depending upon numerous factors, such as disease severity; the presence or absence of certain symptoms; an individual's age and general health; and/or other elements. Decisions concerning the use of particular drug regimens and/or other treatments should be made by physicians and other members of the health care team in careful consultation with the patient based upon the specifics of his or her case; a thorough discussion of the potential benefits and risks, including possible side effects and long-term effects; patient preference; and other appropriate factors.
In infants, special nipples or gavage feeding may be used to ensure adequate nutrition. Gavage feeding is a procedure in which a small, thin tube is passed through the nose and mouth to the stomach to directly feed a newborn who has feeding difficulties.
In males, the treatment of hypogonadism with either testosterone or human chorionic gonadotropin may be beneficial during infancy, potentially increasing the size of genitalia or prompting testicular descent into the scrotum. Although cryptorchidism may occasionally resolve spontaneously or with hormone therapy, most males may require surgical treatment.
Individuals with PWS also benefit from growth hormone (GH) therapy, which can help to increase height, lean body mass and mobility, improve respiratory function, and decrease body fat. Some studies have shown that GH therapy also has positive effects on development and behavior. In June of 2000, the Food and Drug Administration (FDA) approved the use of human growth hormone for the treatment of children with genetically-confirmed PWS and evidence of growth failure. Studies have shown that the earlier GH therapy is started the more beneficial it is and that therapy can begin as early as two to three months of age. GH therapy has been shown to improve facial appearance and overall body build (body habitus). It is recommended that affected individuals undergo a sleep study to detect and treat obstructive sleep apnea before initiating GH therapy because some reports suggested a link between premature death and GH therapy in certain individuals with PWS (e.g., those with profound hypotonia or obesity and pre-existing respiratory or cardiac problems). However, other researchers have expressed doubt as to whether GH therapy had a direct role in these cases. Decisions regarding GH therapy in individuals with PWS are best made after consultation with a pediatric endocrinologist.
Children with PWS require early intervention to assess and treat issues with motor skills, intellectual disability, and speech and language development. Early intervention may include physical and occupational therapy, special education, and speech therapy. An individualized education plan should be created at the start of school. Behavioral therapy and, in some cases, psychoactive medications such as specific serotonin reuptake inhibitors may be beneficial to manage difficult behavior or psychosis.
Children should receive an ophthalmological exam to evaluate eye abnormalities potentially associated with PWS such as strabismus and to assess visual acuity. Children should also be assessed for hip dysplasia and scoliosis. Evaluation and treatment of sleep disturbance is recommended as well. Some researchers recommend that all individuals with PWS be screened for hypothyroidism (which occurs with increased incidence in PWS) and central adrenal insufficiency.
During childhood, a program consisting of a low calorie diet, regular exercise and a strict supervision of food intake and access should be formulated. Strict supervision of food intake should be based upon height, weight and body mass index (BMI). Such a program should begin before signs of obesity to help to prevent its development. Limiting the access to food may require locking cabinets and refrigerators. Some individuals may require vitamin supplementation, especially for calcium and vitamin D.
Sex hormones can be replaced at puberty as they can stimulate the development of secondary sexual characteristics and improve self-image and bone density. In males, the use of such therapy has been controversial because testosterone replacement by monthly injection may contribute to behavioral issues in males; use of a testosterone patch or gel will avert this problem. Sex hormone replacement therapy may increase the risk of stroke in females, as in the general population, and hygiene issues should also be considered. Sex education and consideration of contraception are important, particularly in females, as rarely pregnancy has occurred.
Decreased flow of saliva may be improved with special toothpastes, gels, mouthwash and gum.
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