Prader-Willi Syndrome

Clinical characteristics.

Prader-Willi syndrome (PWS) is characterized by severe hypotonia, poor appetite, and feeding difficulties in early infancy, followed in early childhood by excessive eating and gradual development of morbid obesity (unless food intake is strictly controlled). Motor milestones and language development are delayed. All individuals have some degree of cognitive impairment. Hypogonadism is present in both males and females and manifests as genital hypoplasia, incomplete pubertal development, and, in most, infertility. Short stature is common (if not treated with growth hormone). A distinctive behavioral phenotype (temper tantrums, stubbornness, manipulative behavior, and obsessive-compulsive characteristics) is common. Characteristic facial features, strabismus, and scoliosis are often present.

Diagnosis/testing.

PWS is a contiguous gene syndrome due to abnormal DNA methylation within the Prader-Willi critical region (PWCR) at 15q11.2-q13. The diagnosis and molecular cause can be identified in a proband by simultaneous DNA methylation analysis and oligo-SNP combination array (OSA). DNA methylation analysis identifies maternal-only imprinting within the PWCR. OSA can identify the molecular cause in those with a 15q11.2-q13 deletion, imprinting center deletion, and uniparental isodisomy and segmental isodisomy. In individuals with maternal-only imprinting identified on DNA methylation analysis and a normal OSA, DNA polymorphism analysis can be used to distinguish uniparental heterodisomy from an imprinting defect by epimutation.

Management.

Treatment of manifestations: In infancy, special nipples or nasogastric tube feeding to assure adequate nutrition. In childhood, strict supervision of daily food intake based on height, weight, and body mass index (BMI) to provide energy requirements while limiting excessive weight gain (maintain BMI z score <2); encourage physical activity. Developmental services and educational support; hormonal and surgical treatments can be considered for cryptorchidism; growth hormone therapy to normalize height, increase lean body mass and mobility, and decrease fat mass; endocrine management of sex hormone replacement at puberty; treatment for those with precocious puberty, type 2 diabetes, and hypothyroidism; urgent evaluation for those with acute gastrointestinal manifestations; topiramate or N-acetylcysteine as needed for skin picking; standard treatment for neurobehavioral and ophthalmologic manifestations, sleep issues, scoliosis, hip dysplasia, and seizures; modafinil may be helpful for daytime sleepiness; calcium and vitamin D supplementation to avoid osteoporosis; sex steroid therapy, growth hormone, or bisphosphonates for low bone density; products for dry mouth and frequent dental hygiene; social work support and care coordination. In adulthood, a residential facility for individuals with PWS that helps regulate behavior and weight management may prevent morbid obesity, and growth hormone may help to maintain muscle mass.

Surveillance: Monitor development, growth, skin, sleep issues, and family needs at each visit. Assess testicular position annually in males; assess glycosylated hemoglobin and/or glucose tolerance test in adolescents and those with obesity or rapid weight gain; and assess free T4 and TSH every six to 12 months. Assess for central adrenal insufficiency as needed; monitor height, weight, and BMI monthly in infancy, every six months until age ten years, and then annually. Assess for behavioral issues annually after age two years, and for psychosis annually in adolescent and adults. Assess for vision issues and sleep issues annually; sleep study prior to starting growth hormone therapy and four to eight weeks after starting growth hormone therapy. Clinical examination for scoliosis at each visit when child can sit independently; spine x-rays annually in those with clinical findings of scoliosis or obesity; DXA scan every two years beginning in adolescence. Assess for new seizures or monitor those with seizures at each visit. Dental evaluations every six months or more frequently in those with dental issues.

Genetic counseling.

Individuals with PWS typically represent simplex cases (i.e., a single affected family member) and have the disorder as the result of a de novo genetic alteration. The vast majority of families have a recurrence risk of less than 1%. However, certain etiologies involve a recurrence risk as high as 50%, and a scenario with a risk of almost 100%, though very unlikely, is theoretically possible. Reliable PWS recurrence risk assessment therefore requires identification of the genetic mechanism of PWS in the proband (i.e., a 15q deletion, UPD 15, or an imprinting defect) and parental testing to discern the presence of a predisposing genetic alternation (e.g., a parental chromosome rearrangement or paternal heterozygosity for an imprinting center deletion). Once the causative genetic mechanism has been identified in the proband, prenatal testing for PWS is possible.

Suggestive Findings

Prader-Willi syndrome (PWS) should be suspected in individuals with the following specific clinical findings and/or laboratory findings.

Establishing the Diagnosis

The diagnosis of PWS is established in a proband by identification of abnormal DNA methylation within the Prader-Willi critical region (PWCR) at 15q11.2-q13 in which the region demonstrates maternal-only imprinting due to one of the following:

• Deletion of the paternally inherited 15q11.2-q13 region
• Uniparental disomy of the maternal chromosome 15q11.2-q13 region (UPD 15)
• An imprinting defect of the paternal chromosome 15q11.2-q13 region either due to an imprinting center deletion or epimutation

Molecular genetic testing approaches include first-tier, second-tier, and other testing options.

Recommended first-tier testing. Testing should begin with both DNA methylation analysis and oligo-small nucleotide polymorphism (SNP) combination array (OSA) to establish the diagnosis and identify the molecular cause in most individuals (see Figure 1 and Table 1).

• DNA methylation analysis, typically by methylation-specific PCR (MSP), can establish the diagnosis of PWS by identification of maternal-only imprinting at 15q11.2-q13 but cannot identify the cause of the abnormal DNA methylation (i.e., test results cannot distinguish between a 15q deletion, UPD 15, or imprinting defect).
• OSA uses a combination of both oligonucleotide and SNP probes to detect deletions/duplications, distinguish type 1 and 2 deletions as well as atypical deletions (see Figure 2), and determine if there are any other significant chromosomal abnormalities (in the rare instances of unbalanced translocations). Most current OSAs will also detect small imprinting center deletions, as well as other genetic conditions that have clinical features that overlap with PWS (e.g., deletions of the SNORD116 gene cluster; see Differential Diagnosis). In addition, an OSA will identify individuals with UPD 15 due to isodisomy and segmental isodisomy.

Recommend second-tier testing. In individuals with abnormal DNA methylation at 15q11.2-q13 demonstrating maternal-only imprinting and no 15q deletion or UPD 15 (no absence of heterozygosity by isodisomy or segmental isodisomy) identified on OSA, DNA polymorphism testing of the proband and parents is recommended to identify UPD 15 due to heterodisomy or abnormal DNA methylation due to an epigenetic imprinting defect.

Other testing options

• Methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) can establish the diagnosis of PWS by identification of maternal-only imprinting at 15q11.2-q13 and can (1) identify and approximate the size of the deletion of the paternally inherited 15q11.2-q13 region; (2) identify type 1 and 2 deletions (see Figure 2); (3) interrogate six differentially methylated regions versus only one region interrogated by MSP; (4) often identify and quantify mosaicism; and (5) identify imprinting center and SNORD116 deletions (see Figure 1 and Differential Diagnosis). MS-MLPA cannot distinguish UPD 15 from an imprinting defect by epimutation.
• DNA sequence analysis. In individuals with abnormal DNA methylation at 15q11.2-q13 demonstrating maternal-only imprinting, DNA sequence analysis can identify imprinting defects due to imprinting center deletions. Note: This test is not often used, since MS-MLPA and most OSAs have concentrated probes to detect imprinting center deletions.
• FISH analysis is limited by the specific probes used (e.g., SNRPN) and can identify a deletion of 15q11.2-q13. FISH does not (1) query the whole PWCR; (2) determine the size of the deletion; (3) provide information about the rest of the chromosomes; or (4) identify UPD 15 or imprinting defects. FISH analysis is not a recommended first-tier test but may be used to clarify recurrence risk (see Tables 9 and 10).

Note: The underlying genetic etiology of PWS is important to discern for genetic counseling (see Tables 9 and 10).

Clinical Description

Prader-Willi syndrome (PWS) is a complex, multisystem disorder characterized by neonatal hypotonia with poor suck and poor weight gain without nutritional support, developmental delay, mild cognitive impairment, hypogonadism leading to genital hypoplasia and pubertal insufficiency, short stature if untreated with growth hormone (GH), childhood-onset obesity if excessive eating is not limited, behavioral findings, and typically a characteristic facial appearance. Less consistent but common features include decreased fetal movements, small hands and/or feet, hypopigmentation compared to the affected individual's family members, skin picking, strabismus and visual acuity abnormalities, sleep disturbance (including daytime sleepiness and sometimes sleep apnea), thick, viscous saliva, and articulation differences. There is some variability in clinical findings depending on the molecular cause of PWS.

Perinatal findings. A retrospective study of prenatal ultrasounds of 47 individuals with PWS younger than age ten years found that affected individuals had decreased fetal movements (88%), were small for gestational age (65%), had asymmetrical intrauterine growth with increased head-to-abdomen circumference ratio (43%), and had polyhydramnios (34%) when compared to controls [Gross et al 2015]. Prenatal hypotonia usually results in decreased fetal movements, abnormal fetal position at delivery, and increased incidence of assisted delivery or cesarean section. Fetal size is generally within the normal range, but the birth weight and body mass index (BMI) are on average 15% lower than in typically developing sibs [Miller et al 2011].

Hypotonia. Infantile hypotonia is a nearly universal finding, causing decreased movement and lethargy with decreased spontaneous arousal, weak cry, and poor reflexes, including poor suck. Hypotonia is central in origin, and neuromuscular studies including muscle biopsy, when done for diagnostic purposes, are generally normal or show nonspecific signs of disuse.

Poor suck, dysphagia, lethargy, and poor appetite result in poor weight gain in early infancy without assisted feeding. Feeding difficulties are reported in 99% of infants; nasogastric tube feeding (a gastrostomy tube is rarely needed) or the use of special nipples is generally required for a variable period of time, usually weeks to months. By the time the child is drinking from a cup or eating solids, a period of approximately normal eating behavior occurs.

The hypotonia improves over time. However, children and adults remain mildly hypotonic, with decreased muscle bulk and tone.

Developmental delay. Early motor milestones are achieved at approximately double the normal age (e.g., sitting at 12 months, walking at 24 months). Language milestones are also typically delayed and speech is impaired [Dimitropoulos et al 2013]. Speech articulation is abnormal in many individuals with PWS. Speech apraxia has been reported in 7%-10% and is more common in those with 15q deletion. Although a small proportion of affected individuals have extremely impaired language development, verbal ability is a relative strength for most.

Intellectual disabilities are generally evident by the time the child reaches preschool age. Testing indicates that most individuals with PWS have mild intellectual disability (mean IQ: 60-70), with approximately 40% having borderline disability or low-normal intelligence and approximately 20% having moderate disability. Regardless of measured IQ, most children with PWS have multiple severe learning disabilities and poor academic performance for their intellectual abilities [Whittington & Holland 2017]. Based on the authors' experiences, a small percentage of individuals with PWS are able to attend and graduate from college. Increased skill with jigsaw puzzles is reported, particularly in individuals with a 15q deletion.

Endocrine manifestations

• Hypogonadism is present in both sexes and manifests as genital hypoplasia, incomplete pubertal development, and infertility in the vast majority. Genital hypoplasia is evident at birth and throughout life.
  • Males. The penis may be small, and most characteristic is a hypoplastic scrotum with poorly rugated scrotal skin and decreased pigmentation. Unilateral or bilateral cryptorchidism is present in 80%-90% of males.
  • Females. Genital hypoplasia is often overlooked; however, the labia majora, labia minora, and clitoris are often small from birth.
  Hypogonadism is usually associated with low serum concentration of gonadotropins and causes incomplete, delayed, and sometimes disordered pubertal development. Infertility is almost universal, although a few instances of reproduction in females have been reported [Cassidy et al 2012]. Although hypogonadism in PWS has long been believed to be entirely hypothalamic in origin, studies have suggested a combination of hypothalamic and primary gonadal deficiencies [Eldar-Geva et al 2009, Hirsch et al 2009, Eldar-Geva et al 2010, Gross-Tsur et al 2012], a conclusion largely based on the absence of hypogonadotropism and abnormally low inhibin B levels in some affected individuals of both sexes.
  Male infants with PWS and cryptorchidism can be treated with human chorionic gonadotropin (hCG), which results in anatomically lower testes as well as improvement in the size of the penis and scrotal sac, prior to urologic surgery. Undergoing orchiopexy at a younger age, as well as higher levels of inhibin B and testosterone after hCG treatment, have been associated with a greater number of germ cell-containing tubules on testicular histology [Bakker et al 2015].
  Premature pubarche has been reported in 15%-20% of males and 30% of females. Premature adrenarche was reported in 15%-20% of individuals with PWS. Premature pubarche and adrenarche have been associated with elevated dehydroepiandrosterone sulfate levels. Advanced bone age is also reported. Central precocious puberty, typically idiopathic, has been reported in 5% of individuals.
• Growth deficiency. Data from at least 15 studies involving more than 300 affected children document reduced GH secretion in individuals with PWS [Burman et al 2001]. Short stature is reported in 60%-70% of untreated individuals; if not apparent in childhood, short stature is almost always present during the second decade in the absence of GH treatment. The lack of a pubertal growth spurt results in an average untreated height of 155 cm for males and 148 cm for females. GH deficiency is also seen in adults with PWS [Grugni et al 2006, Höybye 2007]. Treatment with GH is beneficial in individuals with PWS regardless of GH sufficiency status [Alves & Franco 2020, Höybye et al 2021]. Growth charts for affected infants and children not treated with GH have been published [Butler et al 2011, Butler et al 2015], and growth charts for GH-treated children with PWS have been developed [Butler et al 2016].
  The hands and feet grow slowly and are generally below the fifth centile by age ten years (70%-90% of individuals) in the absence of GH treatment, with an average adult female foot size of 20.3 cm and average adult male foot size of 22.3 cm.
• Hypothalamic pituitary dysfunction. Impaired hypothalamic development and function results in multiple hormonal deficiencies, including GH deficiency, hypogonadism, hypothyroidism, corticotropin deficiency, and abnormal oxytocin neurons [Tauber & Hoybye 2021].
• Type II diabetes. Up to 25% of adults with PWS (particularly those with significant obesity) have type II diabetes [Tauber & Hoybye 2021], with a mean age of onset of 20 years. Earlier diagnosis, education of parents, GH therapy, and the availability of group homes specific for adults with PWS have led to a reduction in the development of morbid obesity and type II diabetes.
• Central hypothyroidism, with a normal thyroid-stimulating hormone and low free thyroxine, has been documented in up to 25% of individuals with PWS. The mean age of diagnosis is two years [Miller et al 2008, Diene et al 2010].
• Central adrenal insufficiency (CAI). A Dutch study initially suggested that CAI was common in individuals with PWS [de Lind van Wijngaarden et al 2008], but subsequent studies, including one large international study, found that CAI is rare (1.2%) in adults with PWS [Rosenberg et al 2020]. The international study concluded that there is no need for hydrocortisone supplementation in individuals with PWS in the absence of clinical manifestations and confirmation of adrenal insufficiency.

Appetite, obesity, and gastrointestinal manifestations. In contrast to the long-held view that there are only two distinct nutritional phases in PWS (i.e., poor weight gain followed by hyperphagia leading to obesity), a multicenter study found that the transition between nutritional phases is much more complex, with seven different nutritional phases through which individuals with PWS typically progress [Miller et al 2011] (see Table 3).

• Hyperphagia in PWS is believed to be caused by a hypothalamic abnormality resulting in lack of satiety. Food-seeking behaviors such as hoarding or foraging for food, eating of inedible objects, and stealing of food or money to buy food are common. At this time there are no consistently identified hormonal abnormalities to explain the hyperphagia, and the metabolic correlates of hyperphagia in PWS remain uncertain.
• Obesity results from these hyperphagic behaviors and from decreased total caloric requirement. The latter is due to decreased resting energy expenditure resulting from decreased activity and decreased lean body mass (primarily muscle) compared with unaffected individuals. Obesity in individuals with PWS is primarily central (abdomen, buttocks, and thighs) in both sexes. Interestingly, there is less visceral fat in obese individuals than would be expected for the degree of obesity. Obesity and its complications are the major causes of morbidity and mortality (see Life span at the end of this section).
  Early diagnosis allows the clinician to begin anticipatory guidance concerning the natural history of PWS, and in particular the nutritional phases (see Table 3), informing the family about the risks of obesity and the need to monitor weight gain and restrict calories beginning around age 18 to 36 months. Obesity may be prevented if the diet, exercise, and supervision program described in Treatment of Manifestations is instituted.
  If started at a young age, GH treatment, along with good dietary control, may prevent obesity and the high proportion of fat mass. It may also modify the typical PWS facial appearance, improve motor milestones, and improve some cognitive abilities [Butler et al 2019b, Ayet-Roger et al 2022].
• Acute gastrointestinal manifestations. In most affected individuals, gastric emptying is delayed (60%-80% of individuals), and vomiting is rare; decreased vomiting is reported in 80%-90%, increasing the risk of gastric necrosis with significant hyperphagia. Abdominal distention, bloating, pain, lethargy, loss of appetite, and vomiting may be signs of life-threatening gastric inflammation or necrosis. Individuals with these symptoms should be urgently evaluated by a medical professional and may require hospitalization. Radiographic imaging and possibly emergency surgery may be required. Use of antidiarrheal medications can lead to severe colonic distention, necrosis, and rupture.

Behavior. A characteristic behavior profile with anxiety, temper tantrums (outbursts), rigidity/resistance to change, obsessive-compulsive behaviors, and social cognition deficits becomes evident in early childhood in individuals with PWS [Ishii et al 2017, Schwartz et al 2021]. These behaviors increase with age and BMI in childhood and adolescence, although it was noted by Dykens [2013] that externalizing behavioral issues (e.g., aggression, impulsivity) tend to decline in older adults (age >40 years).

• Many of the behavioral characteristics are suggestive of autism. A recent meta-analysis including 786 individuals with PWS reported that 26.7% met criteria for autism spectrum disorder, including 18.5% of those with 15q deletion and 35.3% of those with UPD 15 [Bennett et al 2015].
• Attention-deficit/hyperactivity disorder is common and of early onset.
• Psychosis is evident by young adulthood in some affected individuals and is significantly more frequent in those with UPD 15. A meta-analysis of 95 individuals with PWS from five studies suggested an overall incidence of psychosis of about 25% in those with 15q deletion and 64% in those with UPD 15 [Yang et al 2013].

Behavioral and psychiatric issues interfere most with the quality of life in adolescence and adulthood, including affecting ability to live independently.

Pain insensitivity. Diminished typical pain perception is common and may mask the presence of infection, injury, or fractures. Individuals with PWS may not report pain until the condition is severe, and they may have difficulty localizing pain.

Dysmorphic features. Characteristic facial features (narrow bifrontal diameter, almond-shaped palpebral fissures, narrow nasal bridge, thin vermilion of the upper lip with down-turned corners of the mouth) may or may not be apparent at birth and may slowly evolve over time [Cassidy & Driscoll 2009, Cassidy et al 2012]. Treatment with GH may attenuate the dysmorphic features over time.

Hypopigmentation of hair, eyes, and skin is frequently found in individuals with 15q deletion due to the deletion of OCA2 located at 15q.

Dermatologic manifestations. Skin and mucosal picking, often leaving chronic open sores, is one of the more difficult issues. Picking at the nose, rectum, or vagina is common and often unknown to caregivers. Picking can result in pigmentary changes, scarring, and infections.

Peripheral edema is not uncommon in obese individuals with PWS and may lead to chronic changes of the legs.

Ophthalmologic manifestations. Strabismus in those with PWS is often diagnosed by age five years. Myopia and hyperopia are common [Bohonowych et al 2021].

Sleep abnormalities are well documented and include reduced rapid eye movement (REM) latency, altered sleep architecture, oxygen desaturation, and both central and obstructive apnea [Festen et al 2006, Priano et al 2006]. Primary hypothalamic dysfunction is thought to be the cause of the alterations in sleep microstructure and abnormalities in ventilation during sleep. Some individuals with PWS have excessive daytime sleepiness, which resembles narcolepsy, with rapid onset of REM sleep and decrease in non-REM sleep instability [Bruni et al 2010]. Narcolepsy, reported in 10%-35%, is often undiagnosed in individuals with PWS due to the prevalence of excessive daytime somnolence. Multiple sleep latency tests must be done to diagnose narcolepsy. Cataplexy has been known to occur in individuals with PWS, but the prevalence is not known.

Skeletal findings. Scoliosis, present in 40%-80% of affected individuals, varies in age of onset and severity, and may be present from infancy. It is presumed to be related to hypotonia, since there are no underlying structural anomalies. Kyphosis occurs commonly in adolescents and adults with PWS. Hip dysplasia occurs in approximately 20%-30% [Trizno et al 2018]. The incidence of osteopenia and osteoporosis is increased in individuals with PWS. Frequency of bone fractures, particularly of long bones, seems increased, although no well-designed study has been published.

Seizures, typically generalized seizures, may occur in early childhood. They tend to be infrequent and often resolve after a few years of anti-seizure medication [Takeshita et al 2013].

Dental issues. Saliva flow is decreased in people with PWS and can lead to increased dental caries and speech articulation difficulties. Dried material on the lips is common. Dental crowding and enamel hypoplasia are also more common.

Life span. The mortality rate in individuals with PWS is higher than in controls with intellectual disability. With improved management, the death rate has declined to 1.25% per annum [Whittington et al 2015]. Several large studies have indicated that respiratory failure and other febrile illnesses are the most frequent causes of death in children, and cardiac disease and failure, pulmonary thromboembolism, obesity-related complications, and gastric causes are most frequent in adults [Butler et al 2017, Pacoricona Alfaro et al 2019]. Of note, a family questionnaire-based survey of more than 2,000 individuals known to the Prader-Willi Syndrome Association (USA), of whom 114 were deceased, showed that those who were living had a significantly higher rate of GH treatment (threefold higher) than those who were deceased, even after adjusting for the greater age of those who were deceased [Proffitt et al 2019].

Acute gastric distention with gastric rupture and necrosis has been reported as a cause of death in several individuals with PWS, particularly following an eating binge among those who are thin but were previously obese. It may be unrecognized because of a high pain threshold.

Choking, especially on hot dogs, has been reported as cause of death in approximately 8% of deaths in individuals with PWS. Disordered pharyngeal and esophageal swallowing and lack of attempt to clear residue or coughing is common in PWS [Gross et al 2017], and combined with rapid eating may increase the risk of aspiration-related mortality.

Concern about the possible contribution of GH administration to unexpected death has been raised by reported deaths of individuals within a few months of starting GH therapy. The few reported deaths were mostly in obese individuals who had preexisting respiratory or cardiac disorders with evidence of upper airway obstruction and uncorrected tonsillar and adenoidal hypertrophy. In other studies, the rate of death in affected individuals on and off GH therapy did not differ; thus, the relationship of GH administration to unexpected death remains unclear. See Management for recommended evaluations prior to starting GH therapy.

Neuroimaging. Reported abnormalities on brain imaging include white matter lesions, ventriculomegaly, decreased volume of brain tissue in the parietal and occipital lobes, Sylvian fissure polymicrogyria, incomplete insular closure, gray matter volume changes, and reduced pituitary height. Their relationship to clinical manifestations remains unclear.

Genotype-Phenotype Correlations

No phenotypic feature is known to correlate exclusively with any one of the three main molecular mechanisms that result in PWS. However, some statistical differences in the frequency or severity of certain features between the two largest molecular classes (15q deletion and UPD 15) have been observed.

• Post-term delivery [Butler et al 2009] and advanced maternal age is more common with UPD 15 [Miller et al 2011].
• Individuals with UPD 15 are less likely to have the typical facial appearance, hypopigmentation [Mahmoud et al 2021], or skill with jigsaw puzzles [Dykens 2002]. They also have a somewhat higher verbal IQ [Rosenberg et al 2022] than those with 15q deletion.
• Individuals with UPD 15 are more likely to have psychosis [Yang et al 2013] and autism spectrum disorder [Bennett et al 2015]. Studies suggest that as many as 64% of those with UPD 15 develop atypical psychosis compared with 25% of those with 15q deletion [Yang et al 2013].

Penetrance

Penetrance is complete.

Nomenclature

The term "HHHO" (hypogonadism, hypotonia, hypomentia, obesity) is no longer used.

PWS is sometimes called Willi-Prader syndrome or Prader-Labhart-Willi syndrome.

Prevalence

The estimated prevalence of PWS is 1:10,000-30,000 in a number of populations.

A recent study screening 16,579 newborns for PWS in Australia found a birth incidence of 1:8,290 [Godler et al 2022].

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with PWS, the evaluations summarized in Table 6 (if not performed as part of the evaluation that led to the diagnosis) are recommended.

Treatment of Manifestations

Management by multidisciplinary specialists typically starting with neonatologists and followed by medical geneticists and genetic counselors, primary care physicians, endocrinologists, orthopedists, nutritionists, psychologists, psychiatrists, physical, occupational, and speech therapists, and educators is recommended.

Surveillance

Health supervision guidelines from the American Academy of Pediatrics (AAP) have been published [McCandless 2011] (full text). A multidisciplinary approach to care was recently published based on a survey of a group of experts on PWS and literature review [Duis et al 2019].

Agents/Circumstances to Avoid

Unsupervised access to food should be avoided, as hyperphagia may result in rapid ingestion and fatal choking, silent aspiration, and exposure to spoiled food.

Emetics are typically ineffective for induction of vomiting after ingestion of uncooked/spoiled food items, with potential toxicity from repeated administration. Instead, a nasogastric tube should be used for gastric decompression.

Antidiarrheal medications can cause severe colonic distention, necrosis, and rupture in individuals with PWS and should be avoided. Abdominal distention, bloating, pain, lethargy, loss of appetite, and/or vomiting may be signs of life-threatening gastric inflammation or necrosis. Individuals with these symptoms should be urgently evaluated by a medical professional and may require hospitalization. Radiographic imaging and possibly emergency surgery may be required.

Sedatives and other medications. People with PWS may have unusual reactions to standard dosages of medications. Use extreme caution in giving medications, especially those that may cause sedation; prolonged and exaggerated responses have been reported. The presence of obesity may also affect appropriate dosing.

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

Pregnancy is rare in women with PWS. Pregnancies in those with PWS require more frequent monitoring, given the high pain threshold observed in individuals with PWS, particularly in those who are obese.

Therapies Under Investigation

To date, the most promising data for treatment of hyperphagia has been reported in trials of diazoxide choline controlled release (DCCR). DCCR is a K-ATP channel agonist, which may exert beneficial effects in individuals with PWS by downregulating insulin secretion from pancreatic beta cells, downregulating neuropeptide Y secretion, and activating K-ATP channels in adipose tissue. DCCR improved hyperphagia questionnaire scores by more than nine points after one year of treatment. Data from an ongoing trial also shows improvements in body composition (improved lean body mass and lean-to-fat mass ratio by DXA scan) as well as improvements in many of the characteristic behavioral issues in PWS (e.g., repetitive questioning, anxiety, compulsive behaviors, skin picking) [Miller et al 2023]. This treatment is currently under review by the FDA.

Some reduction of hyperphagia was also demonstrated with carbetocin (a synthetic oxytocin analog). Carbetocin is an oxytocin receptor-specific compound designed to decrease activation of arginine vasopressin. The Phase II trial of this medication demonstrated promising results over a two-week trial, with reductions in hyperphagia questionnaire scores [Dykens et al 2018]. The recently completed Phase III trial of low-dose carbetocin (3.2 mg) showed improved hyperphagia questionnaire scores of 3.1 points, as well as improvements in obsessive-compulsive behaviors and anxiety [Roof et al 2023]. The FDA rejected the new drug application in November 2021 and indicated that further trials are necessary.

Several additional Phase II clinical trials are ongoing for treatment of hyperphagia in individuals with PWS, including investigations of oxytocin, canabadiolvarin, a melanin-concentrating hormone receptor 1 antagonist, a compound that activates bitter taste receptors in the gut, and cannabidiol.

There is an ongoing Phase II clinical trial of pitolisant for treatment of excessive daytime somnolence, as well as narcolepsy/cataplexy.

Transcutaneous vagal nerve stimulation showed significant positive effects on decreasing the frequency and intensity of temper outbursts in a small study in adults with PWS. Larger, placebo-controlled studies are being planned to determine the reproducibility and duration of effects [Manning et al 2019].

Search ClinicalTrials.gov in the US and EU Clinical Trials Register in Europe for access to information on clinical studies for a wide range of diseases and conditions. In addition, see a detailed review by Mahmoud et al [2023] of the clinical trials involving PWS.

Mode of Inheritance

Individuals with Prader-Willi syndrome (PWS) typically represent simplex cases (i.e., a single affected family member) and have the disorder as the result of a de novo genetic alteration. The vast majority of families have a recurrence risk of less than 1%. However, certain etiologies involve a recurrence risk as high as 50%, and a scenario with a risk of almost 100% (i.e., a mother with a 15/15 Robertsonian translocation), though very unlikely, is theoretically possible. Reliable PWS recurrence risk assessment therefore requires identification of the genetic mechanism of PWS in the proband (i.e., a 15q deletion, uniparental disomy [UPD] 15, or an imprinting defect) and the underlying genetic etiology, as well as parental testing to discern the presence of a predisposing genetic alternation (i.e., a parental chromosome rearrangement or paternal heterozygosity for an imprinting center deletion).

Risk to Family Members

Parents of a proband. The parents of the proband are unaffected.

Sibs of a proband

• The risk to sibs of a proband with PWS depends on the underlying genetic mechanism and genetic etiology of PWS in the proband and the genetic status of the parents (see Tables 9 and 10).
• Once a diagnosis of PWS is established in the proband through identification of abnormal DNA methylation at 15q11.2-q13 and an underlying genetic mechanism (15q deletion, maternal UPD 15, or an imprinting defect) has been identified on oligo-SNP combination array (OSA), the genetic etiology should be determined for recurrence risk assessment. Recommended testing to discern genetic etiology in the proband and the genetic status of the parents is summarized in Tables 9 and 10 (see also Figure 1).

Offspring of a proband

• With rare exceptions in females, individuals with PWS do not reproduce. No male with genetically confirmed PWS has ever been reported to have reproduced.
• The risk to offspring should be determined in the context of formal genetic counseling.

Other family members

• If a chromosome rearrangement (e.g., translocation or inversion) is identified in the proband and a parent, the sibs of the carrier parent should be offered genetic counseling and the option of genetic testing.
• If a proband's father is heterozygous for an imprinting center deletion, the father's sibs are also at risk of having the imprinting center deletion.

Related Genetic Counseling Issues

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to the parents of affected individuals.

Prenatal Testing

Families who have a child with PWS. Once the causative genetic mechanism has been identified in the proband, prenatal testing for PWS is possible [Butler 2017]. The approach to prenatal testing depends on the molecular mechanism identified in the proband; prenatal detection of all three molecular classes of PWS are possible. Note that DNA methylation analysis at the 5' SNRPN locus is the most reliable method to identify imprinting defects in prenatal tissue [Glenn et al 2000, Beygo et al 2019].

Pregnancies in which no family history of PWS exists. PWS may be a possibility in the following situations:

• If a 15q11.2 deletion is suspected on cytogenetic studies from testing of cells obtained by chorionic villus sampling (CVS) or amniocentesis, OSA is indicated. In this instance, parent-of-origin studies should be performed after confirmation of a deletion to determine if the deletion is maternally derived (fetus has Angelman syndrome) or paternally derived (fetus has PWS).
• If trisomy 15 or mosaic trisomy 15 is detected on testing of cells obtained by CVS, and if subsequent testing of cells obtained by amniocentesis reveals 46 chromosomes, the possibility of trisomy rescue leading to Angelman syndrome (paternal UPD) through loss of a maternal chromosome 15 or PWS (maternal UPD) through loss of a paternal chromosome 15 should be considered. In this instance, parent-of-origin (UPD) studies or DNA methylation analysis on amniocytes should be considered.
• If an inherited or de novo translocation involving chromosome 15 is present or if a supernumerary chromosome derived from chromosome 15 is detected, OSA (to rule out a deletion) and parent-of-origin or DNA methylation studies (to rule out the possibility of UPD) are indicated.

Noninvasive prenatal tests (NIPT) using fetal cell-free DNA is available for testing for deletions of 15q11.2 but has a high false positive rate (unlike testing for the major trisomy conditions [13, 18, and 21], which has high sensitivity and specificity). Also, NIPT will not distinguish an AS deletion from a PWS deletion and will not detect UPD and imprinting defects.

Preimplantation genetic testing (PGT) may be an option for some families in which an imprinting center deletion has been identified. PGT can also be used in cases of familial translocation to rule out UPD.

Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing. While most centers would consider use of prenatal testing to be a personal decision, discussion of these issues may be helpful.

Molecular Pathogenesis

The Prader-Willi syndrome (PWS) critical region (PWCR) is localized to a 5- to 6-Mb genomic region on the proximal long arm of chromosome 15 (15q11.2-q13) (see Figure 2). It lies within a smaller 2.5-Mb differentially imprinted region. PWS is a contiguous gene disorder; studies thus far indicate that the complete phenotype is due to the loss of expression of several genes [Cassidy et al 2012]. However, it has been shown that the loss of expression of the SNORD116 gene cluster plays a major role in the phenotype [Tan et al 2020]. PWS is also an imprinted condition, since the expression of relevant genes in the 15q11.2-q13 region is dependent on parental origin [Cassidy et al 2012].

The genomic and epigenetic changes causing PWS all lead to a loss of expression of the normally paternally expressed genes on chromosome 15q11.2-q13. Absence of the paternally inherited copy of these genes, or failure to express them, causes total absence of expression for those genes in the affected individual because the maternal contribution for these genes has been programmed by epigenetic factors to be silenced [Cassidy & Driscoll 2009, Cassidy et al 2012].

Deletion mechanism. An interstitial 15q11.2-q13 microdeletion on the paternal allele accounts for 60%-70% of individuals with PWS. The vast majority of deletions have one of two common proximal breakpoints (BP1 or BP2) and a common distal breakpoint (BP3) resulting in a 5- to 6-Mb deletion (see Figure 2). Multiple tandem repeats flank the common breakpoints (BP1, BP2, and BP3). These low copy 250- to 400-kb repeat sequences are subject to nonhomologous pairing during meiosis, leading to deletions (causing PWS or Angelman syndrome [AS] depending on parental origin), duplications (both maternal and paternal), triplications, and inverted duplication of chromosome 15. About 8% of individuals with PWS have unique or atypical-sized deletions caused by a variety of etiologies, including unbalanced translocations [Kim et al 2012, Butler et al 2019a]. Atypical deletions may result in clinical features that are milder or more severe than typical individuals with PWS.

Imprinting center deletion. Small deletions of the promoter region and the proximal upstream region of SNRPN (including the putative imprinting control element) have been identified in individuals with PWS who have maternal-specific DNA methylation patterns but do not have a 15q11.2-q13 deletion or maternal uniparental disomy (UPD).

Other individuals have biparental inheritance but maternal-only DNA methylation patterns in this region without detectable abnormalities in the imprinting center. These individuals are considered to have an imprinting defect by an epimutation.

Genes of interest in this region. The following genes have been mapped within the PWS/AS critical region (see Figure 2):

• ATP10A was originally thought to have preferential maternal expression, but subsequent publications in mice [DuBose et al 2010] and humans [Hogart et al 2008] have cast doubt on this gene being imprinted. Rather, it may have random monoallelic expression [Hogart et al 2008].
• GABRB3, GABRA5, and GABRG3 are all GABA receptor subunit genes involved in neurotransmission within the brain.
• HERC2 shuttles between the nucleus and cytoplasm and functions as an E3 ubiquitin ligase for the ubiquitination and degradation of target proteins, as an activator of other E3 ubiquitin ligases, and as an adaptor for assembly of DNA damage response proteins. The OCA2-HERC2 locus is responsible for the greatest proportion of eye color variation in humans [Suarez et al 2021]. This probably explains why individuals with PWS who have a deletion that encompasses this region are generally hypopigmented compared to their family members.
• IPW is a long noncoding RNA located between SNORD116-1 and SNORD115-1. It has been shown to be a regulator of the DLK1-DIO3 imprinted region on chromosome 14, and it may be involved in regulating other non-chromosome 15 imprinted regions in the genome [Stelzer et al 2014]. Its role in PWS in unclear, but interestingly this locus is included in all seven individuals with a SNORD116 deletion who have many of the major features of PWS [Tan et al 2020].
• MAGEL2 is transcribed only by the paternal allele and expressed predominantly in the brain. Individuals with loss-of-function variants in the paternal allele of MAGEL2 have Schaaf-Yang syndrome, a disorder with features that overlap with PWS.
• MKRN3 encodes a zinc finger protein expressed only from the paternal chromosome. Paternally inherited loss-of-function variants in MKRN3 are a cause of familial central precocious puberty in humans [Abreu et al 2013, Macedo et al 2014].
• NDN is only paternally expressed and encodes a DNA-binding protein that acts as an antiapoptotic or survival factor in the early development of the nervous system [Andrieu et al 2006]. It may play a role in gonadotropin-releasing hormone neurons [Chung et al 2020].
• NPAP1 is an intronless gene that is biallelically expressed in adult testes but monoallelically expressed in the fetal brain.
• OCA2 encodes a melanosomal protein, and pathogenic variants in this gene cause oculocutaneous albinism type 2; its deletion is associated with the hypopigmentation frequently seen in individuals with PWS.
• PWRN1, expressed in testes, demonstrates lower expression in the prostate, heart, kidneys, liver, lungs, skeletal muscles, trachea, spinal cord, and fetal brain; it is shown to have monoallelic expression in the fetal brain.
• SNORD115 (snoRNA HBII-52) is a cluster of C/D small nucleolar RNAs (snoRNAs) and consists of approximately 47 copies. It is almost exclusively expressed in neurons and only from the paternal contribution. It has been proposed that SNORD115 promotes the generation of the serotonin 2c receptor. However, there are some rare individuals with PWS whose deletion does not include this locus. Thus, it is not a major contributor to the PWS phenotype, but its absence may contribute to some of the behavioral features of PWS [Chung et al 2020].
• SNORD116 (snoRNA HBII-85). Evidence suggests that the snoRNA SNORD116 cluster, which consists of approximately 24 gene copies, is causative of many of the major features of PWS. There have been a few rare individuals with a SNORD116 deletion described in the literature who have many of the major features of PWS [Tan et al 2020]. The snoRNAs are probably involved in the modification of mRNA by alternative splicing, and each snoRNA gene may have multiple targets; however, no definitive targets have yet been found for SNORD116.
• SNURF-SNRPN (typically abbreviated as just SNRPN) is a complex bicistronic gene encoding two different proteins. Exons 4-10 were described first and encode the protein SmN, which is a spliceosomal protein involved in mRNA splicing. SNURF is encoded by exons 1-3 and produces a polypeptide of unknown function. It also serves as the host for the seven snoRNA genes located telomerically, which are regulated by the expression of SNURF-SNRPN [Chung et al 2020].
• UBE3A is an E3 ubiquitin ligase involved in protein degradation in the brain and is associated with AS.

Imprinted genes in the region. A number of the genes in the PWCR (MKRN3, MAGEL2, NDN, NPAP1, PWRN1, SNORD116, IPW, SNORD115, SNURF-SNRPN) are subject to genomic imprinting, thus accounting for the fact that the PWS phenotype results only when the paternally contributed PWCR is absent. DNA methylation, which is involved in the process of genomic imprinting, has been demonstrated for several of the genes identified within the PWCR [Cassidy et al 2012, Beygo et al 2019, Chung et al 2020]. Upstream of SNRPN, very small deletions of the putative imprinting control element for the PWCR have been identified in a few individuals with PWS who have maternal-specific DNA methylation patterns but have neither the usual large paternally derived deletion of the PWS/AS critical region nor maternal UPD [Cassidy et al 2012, Beygo et al 2019]. Other individuals demonstrate sporadic imprinting defects that are epimutations [Beygo et al 2019].

Author Notes

Daniel J Driscoll, MD, PhD, FAAP, FFACMGG

Professor of Pediatrics and Genetics

The John T & Winifred M Hayward Professor of Genetics Research

Division of Genetics and Metabolism

Department of Pediatrics

University of Florida College of Medicine

Gainesville, Florida, USA

Email: ude.lfu.sdep@jdcsird

Dr Driscoll is board certified in Pediatrics, Clinical Genetics, and Clinical Cytogenetics. He has been conducting clinical and laboratory research on Prader-Willi syndrome (PWS) since the late 1980s. He has been a major contributor to the understanding of the genetics of PWS and genomic imprinting in the PWS critical region, as well as to the elucidation of the natural history of PWS. His group first developed the technique (DNA methylation analysis) that is used around the world to diagnose PWS and also elucidated the nutritional phases of PWS that has gained wide acceptance by PWS experts.

Dr Driscoll is widely published on PWS and a major spokesperson on PWS in the US and internationally. He has had an active PWS clinic for the last 32 years and was the principal investigator for the PWS component of the NIH-funded 12-year national Rare Disease Center grant on the natural history of PWS. He served on the Prader-Willi Syndrome Association | USA (PWSA | USA) Board of Directors for 21 years and as Chair of the Clinical Advisory Board for PWSA | USA for 23 years. He is currently the Chair of the Clinical and Scientific Advisory Board for the International Prader-Willi Syndrome Organization (IPWSO).

Jennifer L Miller, MD, MS, FAAP

Professor of Pediatrics

Division of Endocrinology

University of Florida

Gainesville, Florida, USA

Email: ude.lfu.sdep@ljellim

Dr Miller is a Pediatric Endocrinologist who specializes in the care and treatment of individuals with PWS and other causes of childhood obesity. She has conducted many clinical trials for individuals with PWS, as well as clinical trials for other genetic obesity conditions and hypothalamic obesity. She is a member of the Scientific Advisory Board for the Foundation for Prader-Willi Syndrome Research (FPWR) and the Clinical Advisory Board for PWSA | USA.

Suzanne B Cassidy, MD, FFACMGG

Clinical Professor of Pediatrics

Division of Medical Genetics

University of California, San Francisco

San Francisco, California, USA

Email: ten.tsacmoc@ydissacennazus

Dr Cassidy is a Clinical Geneticist who has specialized in PWS clinically and in her clinical research throughout her career in academic medicine. She has conducted multidisciplinary clinics for people with PWS for 40 years. A founding member of IPWSO, she is currently on the IPWSO Clinical and Scientific Advisory Board and the PWSA | USA Clinical and Scientific Advisory Board. She has been a frequent speaker about PWS at educational and medical conferences around the world. She is an editor of Management of Genetic Syndromes, a resource book now in its fourth edition.

Acknowledgments

All the authors of this GeneReview acknowledge the incredible value of participation in clinical and scientific advisory boards of the IPWSO and the PWSA | USA, as well as from the scientific and medical conferences these organizations hold. We are grateful for the research support to the authors provided by a number of organizations throughout the years, including the NIH, US Department of Defense, March of Dimes, PWSA | USA, FPWR, and the Hayward and Schiller Foundations.

Much knowledge of clinical findings and insight into management has been gleaned from families of people with PWS over many years of contact. We are all grateful to the colleagues who worked with us in our respective PWS clinics and in our clinical and laboratory research on PWS throughout the years, as well as the knowledge gained from other experts on PWS whom we have consulted on a wide range of issues over the years. The authors would also like to acknowledge Carlos Sulsona for his expert assistance with the figures.

Author History

Suzanne B Cassidy, MD, FFACMGG (1998-present)

Daniel J Driscoll, MD, PhD, FFACMGG, FAAP (2012-present)

Jennifer L Miller, MD, MS, FAAP (2012-present)

Stuart Schwartz, PhD, FACMG; Laboratory Corporation of America (1998-2023)

Revision History

• 2 November 2023 (dd) Revision: Angelman syndrome added to Figure 1
• 9 March 2023 (sw) Comprehensive update posted live
• 4 February 2016 (ha) Comprehensive update posted live
• 11 October 2012 (me) Comprehensive update posted live
• 24 March 2008 (me) Comprehensive update posted live
• 16 June 2005 (me) Comprehensive update posted live
• 1 May 2003 (me) Comprehensive update posted live
• 13 November 2000 (me) Comprehensive update posted live
• 6 October 1998 (pb) Review posted live
• Spring 1997 (sc) Original submission

Published Guidelines / Consensus Statements

• Beygo J, Buiting K, Ramsden SC, Ellis R, Clayton-Smith J, Kanber D. Update of the EMQN/ACGS best practice guidelines for molecular analysis of Prader-Willi and Angelman syndromes. Eur J Hum Genet. 2019;27:1326-40. [PubMed]
• Deal CL, Tony M, Höybye C, Allen DB, Tauber M, Christiansen JS; 2011 Growth hormone in Prader-Willi Syndrome Clinical Care Guidelines Workshop Participants. Growth Hormone Research Society workshop summary: consensus guidelines for recombinant human growth hormone therapy in Prader-Willi syndrome. Available online. 2013. Accessed 10-30-23.
• Duis J, van Wattum PJ, Scheimann A, Salehi P, Brokamp E, Fairbrother L, Childers A, Shelton AR, Bingham NC, Shoemaker AH, Miller JL. A multidisciplinary approach to the clinical management of Prader-Willi syndrome. Mol Genet Genomic Med. 2019;7:e514. [PubMed]
• International Prader-Willi Syndrome Organization Clinical and Scientific Advisory Board. Guides for doctors: consensus documents for infants, children, adolescents, and adults with PWS. Available online. Accessed 10-30-23.
• McCandless SE, Committee on Genetics. Clinical report -- health supervision for children with Prader-Willi Syndrome. Available online. 2011. Accessed 10-30-23.

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