INTRODUCTION — Prader-Willi syndrome (PWS) is the most common syndromic form of obesity. The syndrome is caused by absence of expression of the paternally active genes on the long arm of chromosome 15. The vast majority of cases occur sporadically.

The clinical features, diagnosis, and approaches to treatment of PWS will be reviewed here. The epidemiology and genetics of this disorder are discussed separately. (See "Epidemiology and genetics of Prader-Willi syndrome".)

CLINICAL MANIFESTATIONS

Prenatal — Affected pregnancies often exhibit reduced fetal activity (later perception of movement, historically known as delayed quickening, as well as an overall reduction in the vigor of the movement), small size for gestational age, polyhydramnios, breech positioning, and asymmetrical intrauterine growth (increased head:abdomen circumference ratio) [1]. Third-trimester ultrasounds may show unusual positioning of the fetal hands and feet, with flexed wrists and dorsi-extended feet with flexed toes [2]. These abnormalities of limb positioning are supported only by case reports but are probably more specific than other ultrasound findings for PWS. Cytogenetic examination is revealing only if specific molecular diagnosis for PWS is requested. (See 'Genetic testing' below.)

Infancy — Neonatal hypotonia is one of the hallmark features of this disorder and is a valuable clue to initiate diagnostic testing. The profound hypotonia can lead to asphyxia. Affected infants often have feeding difficulties, including a poor suck, which may lead to failure to thrive. Other common features include a weak cry and genital hypoplasia (eg, cryptorchidism, scrotal hypoplasia, or clitoral hypoplasia). Hypopigmentation of the skin, eyes (iris), and hair relative to the familial background is present in 30 to 50 percent of patients [3,4].

Early childhood — Toddlers with PWS demonstrate late acquisition of major motor milestones (eg, average age for walking 27 months and for talking 39 months) [5].

Children between one and six years of age commonly manifest symptoms of hyperphagia with progressive development of obesity if access to food is unrestricted. Body composition is abnormal, with reduced lean body mass and increased fat mass as compared with normal and obese controls [6,7]. Perhaps as a result of the reduced lean body mass, resting energy expenditure is also reduced [8]. Short stature is usually present during childhood and most patients fail to have a pubertal growth spurt. Most patients with PWS have growth hormone (GH) deficiency. (See 'Growth hormone deficiency' below.)

Late childhood and adolescence — Pubic and axillary hair may arise prematurely in children with PWS due to adrenarche, but other secondary sexual characteristics generally are delayed or incomplete. Testicular descent has occurred as late as adolescence. Menarche is often delayed, perhaps in part because of concurrent obesity: Menarche may occur as late as age 30 years in response to significant weight loss [9]. Other complications of obesity (eg, sleep apnea, cor pulmonale, diabetes mellitus, and atherosclerosis), hypogonadism (osteoporosis), and behavioral issues are common problems in adolescents and adults with PWS. Up to 25 percent of patients with PWS have epilepsy, which is usually focal (eg, staring spells) [10]. Scoliosis is frequently seen among patients with PWS, with reported prevalence of 37 percent; 13 percent of patients require brace treatment or surgery [11]. (See 'Evaluation and management of comorbidities' below.)

Adulthood — In the past, survival after age 50 for individuals with PWS was uncommon; many of the deaths in adults are attributable to obesity and its complications, including cardiovascular problems, diabetes mellitus, and sleep apnea [12]. Advances in the care of these patients have improved life expectancy somewhat. One case series describes 12 individuals older than 50 years of age [13]. Most of these individuals had experienced decline in physical and psychological function with advancing age. A separate case series of 26 individuals older than 40 years of age found evidence of dementia in four (15 percent) [14]. All four patients with early-onset dementia were female, had a long history of psychotic illness, and had maternal uniparental disomy. One study described shorter telomere length in adults with PWS, suggesting that this may be a mechanism for this pattern of accelerated biologic aging [15]; this association may be mediated by sleep apnea [16,17].

BEHAVIOR CHARACTERISTICS — Behavioral problems and learning difficulties are commonly seen in PWS. Young children manifest temper tantrums, stubbornness, and obsessive-compulsive behaviors that can impede school performance. Some of these behaviors are similar to those found in autism spectrum disorder. In a systematic review, behaviors meeting criteria for autism spectrum disorder were found in 27 percent of individuals with PWS [18]. One publication has linked autistic-type behaviors to mutation of the MAGEL2 gene located within the Prader-Willi syndrome locus [19]. Other studies suggest that these behaviors are particularly common in PWS caused by uniparental disomy [18,20-22] (see 'Genetic testing' below). Rectal gouging and skin-picking behavior is common and may respond to treatment with N-acetylcysteine [23-26]. In some cases, the rectal picking leads to rectal bleeding and ulceration sufficient to cause anemia or mimic colitis [27]. A variety of psychiatric symptoms and disorders have been reported among adults, including mood disorders and florid psychotic states [9,25,28].

A mild to moderate degree of cognitive impairment is a commonly associated characteristic. In one study, the mean intelligence quotient (IQ) of individuals with PWS was 40 points below the population mean [29]. The range of IQs is normally distributed; thus, approximately 5 percent of individuals with PWS will have IQs in the low-normal range (>85) and 5 percent will have severe intellectual disability (mental retardation) [30].

Food-seeking behaviors may include eating garbage, eating frozen food, and stealing resources to obtain food. Decreased ability to vomit and increased tolerance of pain can promote binging on spoiled foods and delay treatment for gastrointestinal disease. After episodes of binge eating (eg, at holidays), both thin and obese individuals with PWS have developed abdominal discomfort with acute gastric dilation seen on radiography [31]. Choking episodes, typically associated with voracious eating habits, have been reported as the cause of death among 8 percent of patients in one series of sudden death cases [32].

The mechanism that causes impaired satiety in individuals with PWS is unknown. However, levels of ghrelin, an orexigenic peptide, are persistently elevated in individuals with PWS as compared with weight-matched controls, providing a possible mechanism for the increased appetite in these patients [33,34]. Because this does not appear to be the case for young, lean patients with PWS, some authors have proposed that a surge in ghrelin might precede the hyperphagia and obesity observed in older children [35]. To date, the role of ghrelin as a primary or secondary factor in the satiety defect is unclear. Brain-derived neurotropic factor (BDNF) is another potential mediator of hyperphagia in PWS; this neurohormone is decreased among individuals with PWS [36]. Other possible mediators include pancreatic polypeptide [37,38].

DIAGNOSIS

Clinical suspicion — The diagnosis of PWS is suspected in patients who have characteristic clinical features and is confirmed by genetic testing. Clinical diagnostic criteria were developed in 1993 [39]. For children three years of age or younger, the diagnosis of PWS is highly likely if five points are scored from among these criteria (four from major criteria). In children older than three years of age and adults, eight points are required (five or more from among the major criteria).

●Major criteria (one point each) – Neonatal and infantile hypotonia, feeding problems during infancy, excessive weight gain after infancy, characteristic facial features, hypogonadism, global developmental delay or mild to moderate intellectual disability, and hyperphagia.

●Minor criteria (one-half point each) – Decreased fetal movement, characteristic behavior problems (usually multiple), sleep disturbance or sleep apnea, short stature, hypopigmentation, small hands and/or feet, narrow hands with straight ulnar border, eye abnormalities (esotropia, myopia), thick viscous saliva with crusting at corners of mouth, speech articulation defects, and skin picking.

However, now that definitive testing is available, it is appropriate to use less rigid clinical criteria to determine who should undergo genetic testing.

Indications for genetic testing — Based on a retrospective review of the clinical characteristics of 90 patients with genetically confirmed PWS, molecular testing should be performed in patients who have all of the following clinical features for their age if they are otherwise unexplained [40,41]:

●Birth to 2 years

•Hypotonia with poor suck and poor weight gain as well as cryptorchidism in males

●2 to 6 years

•Hypotonia with history of poor suck

•Global developmental delay

•Short stature and/or growth failure associated with accelerated weight gain

●6 to 12 years

•History of hypotonia with poor suck (hypotonia often persists)

•Global developmental delay

•Excessive eating (hyperphagia: obsession with food), with obesity if food intake is uncontrolled

●13 years through adulthood

•Cognitive impairment (usually mild intellectual disability)

•Excessive eating (hyperphagia: obsession with food), with central obesity if uncontrolled

•Hypogonadotropic or hypergonadotropic hypogonadism (eg, delayed puberty) and/or typical behavior problems (including temper tantrums and obsessive-compulsive features)

Occasionally, prenatal genetic testing may be performed based on suspicious findings on prenatal ultrasound [1] (see 'Prenatal' above) or for pregnancies in a family with a child who has PWS caused by certain mutations. (See "Epidemiology and genetics of Prader-Willi syndrome", section on 'Risk of recurrence in future pregnancies'.)

Genetic testing — PWS is caused by absence of expression of the paternally active genes on the long arm of chromosome 15, either due to deletions from the paternal chromosome, maternal disomy, or (rarely) defects in the imprinting center (table 1).

Testing is done in a sequence that allows identification of all potential genetic defects (algorithm 1) [40,42]. A standard diagnostic panel for PWS begins with karyotype and methylation studies, followed by fluorescence in situ hybridization (FISH), and then microsatellite probes to detect maternal uniparental disomy. Molecular testing for PWS is highly sensitive, and standard panels with a methylation analysis will detect more than 99 percent of cases [4]. (See "Epidemiology and genetics of Prader-Willi syndrome".)

Further testing and genetic counseling may be necessary in families with a child who has a mutation affecting the imprinting center or a parental chromosome translocation. While these mutations are rare, they are associated with a risk of recurrence in future pregnancies.

MANAGEMENT OF FEEDING AND OBESITY

Neonates and infants — Patients with PWS frequently require medical care for a variety of issues, beginning initially with assistance with management of hypotonia and poor feeding. Oromotor evaluation, swallow study, and thickened high-calorie feedings are commonly used early in life; patients with significant reflux or swallowing dysfunction may require gastrostomy or fundoplication. Of note, fundoplication should be considered with caution, given potential adverse effects on swallowing and esophageal clearance and given these individuals' tendency to overeat later in life. Caloric goals should be guided by a dietitian and designed to promote moderate rates of weight gain, with appropriate intake of protein and micronutrients. Excessive caloric restriction prior to three years of age (unless deemed medically necessary because of significant obesity) might limit brain myelination and cognitive development, while excessively rapid growth may increase the long-term predisposition to obesity. Growth standards (PWS-specific growth curves) have been developed for infants and toddlers with PWS [43]. The standards were developed using a sample of 186 White infants with PWS who were living in the United States and not treated with recombinant human growth hormone (rhGH).

Other interventions are offered to optimize cognitive and physical development. Intensive physical and occupational therapies can assist with muscle tone and strength. Speech therapy may assist with development of swallowing, communication, and enunciation.

Older children and adults — Controlling obesity through strict limitation of food intake is the cornerstone of effective management of PWS. To achieve and maintain a healthy body weight, caloric goals must often be set well below those predicted for children without PWS. With these low-calorie diets, vitamin and mineral (calcium) supplementation is usually required to meet daily requirements. Consultation with a pediatric dietitian is important to set appropriate goals for body weight and nutrition. Growth charts have been developed for children 3 to 18 years of age with PWS [44]. The standards were developed using a sample of 133 White children and adolescents with PWS who were not treated with rhGH.

Some behavioral modification techniques have been helpful in engaging the cooperation of the patient. However, strict limitation of access to food using physical barriers (locks) and close supervision is generally necessary. Coordination of efforts between the patient's family, school, and a multidisciplinary care team is valuable. Stealing and hoarding food are common behaviors, even when the individual is otherwise well behaved. For some patients, a specialized highly structured group home environment is used to manage PWS-associated obesity.

In spite of concerted efforts by the families and caregivers, many children and adults with PWS will continue to have severe obesity and associated medical problems. More invasive approaches to treatment of PWS-associated obesity have been attempted, but literature provides minimal evidence on which to evaluate the safety or efficacy of these approaches.

Pharmacotherapy — Treatment with anorectic agents such as phentermine and fenfluramine has not been effective in controlling appetite in patients with PWS. Selective serotonin reuptake inhibitors (SSRIs) may be effective for many of the behavioral symptoms in patients with PWS, but there is little evidence that these drugs have specific effects on binge eating or weight gain [23]. Similarly, topiramate did not decrease appetite, food intake, or weight status of adults with PWS in a brief open-label trial, although it may decrease self-injurious behaviors [25,45]. Other classes of psychotropic drugs including neuroleptics may be useful in treatment of behavioral symptoms, but their benefits must be weighed against their potential weight-promoting side effects [23,45].

The use of glucagon-like peptide-1 (GLP-1) receptor agonists (liraglutide, exenatide) for individuals PWS has been described in case reports, but existing evidence is insufficient to recommend their use in this population, pending results of a randomized trial (NCT02527200). Moreover, the safety of these drugs in the PWS population requires further investigation because they are known to delay gastric emptying, which could theoretically increase the risk for gastric rupture [46]. In individuals without PWS, GLP-1 agonists are an effective treatment for type 2 diabetes and also induce modest weight loss. The evidence for the use of these drugs in patients with PWS is summarized in a systematic review that included 23 patients (16 of whom also had type 2 diabetes) [46]. Ten participants experienced improvement in body mass index (change from baseline ranged from -1.5 to -16 kg/m²), and 19 had improvement in hemoglobin A1c. Some improvement in appetite control was reported by all five of the studies that measured this parameter. Some patients experienced transient nausea, but no serious adverse events were reported. A meta-analysis of the data was not performed, due to substantial heterogeneity among the studies.

Other drugs under investigation include intranasal carbetocin, an oxytocin analog with improved specificity for oxytocin receptors. In phase 2 studies, administration of carbetocin to individuals with PWS improved hyperphagia and some other behavioral measures [47]. Further study is needed to determine efficacy and optimal dosing, after equivocal results of a phase 3 study (NCT03649477). By contrast, small trials of oxytocin in patients with PWS have produced conflicting results and a possible worsening of behavioral symptoms [48,49]. Other medications targeting hyperphagia are under investigation, including ghrelin analogs, controlled-release diazoxide, setmelanotide, and tesofensine-metoprolol [50,51].

Treatment of patients with somatostatin or octreotide has also been explored because these agents are predicted to suppress ghrelin and its orexigenic properties [52-54]. However, this approach has not been beneficial in patients with PWS [55].

Surgical weight loss procedures — There are scattered reports of surgical weight loss procedures in patients with PWS, including gastric bypass, biliopancreatic diversion, and gastric-restrictive procedures. The literature in this area consists of case reports, most with follow-up of less than two years, and results are inconsistent [56,57]. Some of the reports are more than 20 years old and describe surgical techniques that are no longer used. However, it appears that there may be fewer benefits and greater risks of weight loss surgery for individuals with PWS as compared with other individuals with obesity.

In a retrospective review of PWS patients undergoing weight loss surgery, 63 percent of those undergoing gastric bypass had poor weight loss [58]. There may be some long-term efficacy for the most malabsorptive of these procedures (biliopancreatic diversion) [56], but these operations also confer increased risks because of chronic malabsorption of micronutrients and electrolytes. Patients with PWS may be at particularly high risk after operations causing malabsorption because they already have an increased risk for osteoporosis [58] (see 'Osteoporosis' below). Furthermore, surgical procedures that restrict the stomach may be particularly risky for patients with PWS since there are reports of gastric dilation and necrosis after gastric restrictive procedures. A case series describes outcomes of sleeve gastrectomy in 24 children and adolescents with PWS, with promising results in weight loss and comorbidity improvement after three to five years of follow-up [59]. However, cautious interpretation of these results is warranted due to limited experience with weight loss surgery in this population [60]. (See "Surgical management of severe obesity in adolescents", section on 'Special populations'.)

Until more is known about the long-term efficacy and safety of surgical interventions in patients with PWS, these procedures cannot be generally recommended [55].

EVALUATION AND MANAGEMENT OF COMORBIDITIES — Additional diagnostic evaluation should be considered in individuals with PWS because of their increased risk for hypogonadism and weight-related complications.

Hypothalamic and pituitary dysfunction — Most patients exhibit evidence of hypothalamic and pituitary dysfunction manifested as short stature, central obesity, hypogonadism, and osteoporosis [61].

Growth hormone deficiency — Children with PWS should be closely monitored for linear growth by measuring length/height at least every three months and calculating linear growth velocity. A subnormal velocity usually is the first and most sensitive sign of growth failure (see "Diagnostic approach to children and adolescents with short stature", section on 'Is the child's height velocity impaired?'). If they have evidence of growth failure, they are likely to have growth hormone (GH) deficiency. However, other causes of growth failure should be excluded, including hypothyroidism and undernutrition (if the child is young and failing to thrive or on a low-calorie diet). Because GH deficiency is very common in PWS, it is generally not necessary to do a formal evaluation for GH deficiency before considering treatment with recombinant human growth hormone (rhGH). (See 'Recombinant growth hormone treatment' below.)

GH deficiency appears to be a primary abnormality of PWS rather than a consequence of obesity [61-65]. This is suggested by the low insulin-like growth factor 1 (IGF-1) levels in patients with PWS, in contrast with the low GH secretion and normal IGF-1 that is typically found in cases of exogenous obesity.

GH has beneficial effects on body composition as well as linear growth. However, rhGH therapy must be managed with caution because patients with PWS and severe obesity or respiratory impairment may be at increased risk for life-threatening adverse effects of rhGH treatment and also have an increased risk of type 2 diabetes and worsening scoliosis, which could be exacerbated by rhGH therapy. (See 'Recombinant growth hormone treatment' below.)

Hypogonadism — Hypogonadism is a nearly universal feature of PWS [66]. It is characterized by low luteinizing hormone (LH) and inhibin B and high follicle-stimulating hormone (FSH), features suggesting both hypothalamic and peripheral abnormalities [67]. The vast majority of patients with PWS are sterile, but pregnancy has been reported in just a few women [61]. Approximately two-thirds of boys display cryptorchidism.

For cryptorchidism, treatment with human chorionic gonadotropin (hCG) is sometimes effective and a trial should be suggested prior to surgical treatment [68]. In one series of boys with PWS treated with hCG for six weeks, almost one-quarter of testes reached a stable scrotal position and thus did not require orchiopexy [69].

Treatment for hypogonadism may include administration of hCG or sex steroids, but protocols specific to PWS patients have not been established [61,67]. Until systematic studies of sex hormone replacement are reported, we suggest that sex hormone therapy be offered, in consultation with an endocrinologist if possible, if there are symptoms of hypogonadism, including lack of secondary sexual development or decreased bone density. An expert panel has suggested annual monitoring of sex steroids and bone mineral density in adolescents and adults, with hormone replacement as indicated [41]. Because of concerns about hormonal effects on mood and behavior, replacement doses should be minimized and titrated to the individual's response. PWS males are generally thought to be infertile, and there have been no known reports of PWS males fathering children. Fertility is also markedly reduced in females with PWS, with case reports describing a few pregnancies, with a substantial risk for Angelman syndrome in the offspring [70].

Osteoporosis — Dual-energy x-ray absorptiometry (DXA) scans should be obtained on all patients with PWS beginning at five years of age and every two to three years thereafter. These scans are useful in monitoring bone density as well as body composition. In addition, calcium and vitamin D intake should be monitored through periodic dietary recalls and supplemented as necessary to meet daily recommended intakes for both of these nutrients. (See "Measurement of body composition in children" and "Screening for osteoporosis in postmenopausal women and men", section on 'Bone mineral density'.)

Patients with low bone density as determined by DXA scanning should have further evaluation for other causes of osteopenia, including inadequate intake of vitamin D and calcium, and hypothyroidism. Low bone density may respond to sex hormone replacement therapy and/or rhGH treatment [61].

Hypothyroidism — Thyroid status should be evaluated in patients with PWS by measuring thyroid-stimulating hormone (TSH) and free thyroxine (T4) annually. Screening for hypothyroidism is also appropriate in any child with growth failure or decreased bone density and in those in whom there is an inadequate response to rhGH therapy.

Thyroid hormone concentrations may be normal in PWS, but in our experience, up to 30 percent of patients have central hypothyroidism [66,71,72]. These observations could be confounded by the presence of obesity, which can cause a mild, reversible elevation of TSH.

Adrenal insufficiency — It is unclear whether individuals with PWS are at increased risk for central adrenal insufficiency. Studies report conflicting results for cortisol response to testing [73-76]. In a study of 25 children and adolescents, 60 percent had an abnormal response to a test of corticotropin (ACTH) secretory ability (metyrapone test), suggesting that they might be at risk for acute adrenal insufficiency under stress conditions [73]. In a large case series of adults with PWS, fewer than 2 percent were diagnosed with central adrenal insufficiency, using either metyrapone or insulin-induced hypoglycemia testing [77]. Whether subclinical adrenal dysfunction is responsible for some of the unexplained deaths observed in patients with PWS remains to be determined.

In our practice, we screen for adrenal insufficiency prior to a first procedure requiring general anesthesia and also if there are clinical symptoms suggesting the possibility of adrenal insufficiency. We screen by measuring 8 AM cortisol and proceed to ACTH stimulation testing if results are abnormal or if there is a high level of suspicion. (See "Clinical manifestations and diagnosis of adrenal insufficiency in children", section on 'Initial evaluation'.)

Obesity-related problems — Patients with PWS who develop obesity are at high risk for all obesity-related medical problems. In addition to addressing the obesity itself, providers should actively investigate for obesity-related comorbidities to minimize morbidity and mortality. (See "Overview of the health consequences of obesity in children and adolescents".)

Type 2 diabetes mellitus — Children and adolescents with PWS who have a body mass index >95^th percentile should be screened for the development of type 2 diabetes by measuring fasting blood glucose and/or performing oral glucose tolerance tests. The risk of glucose intolerance and diabetes is increased if the patient is taking GH, which can exacerbate insulin resistance. The reported prevalence of type 2 diabetes mellitus in adults with PWS is between 9 and 22 percent, with generally higher percentages in those living in non-PWS group home settings without nutrition supervision and exercise programs; annual screening with glycated hemoglobin is advised [66,78]. (See "Epidemiology, presentation, and diagnosis of type 2 diabetes mellitus in children and adolescents" and "Overview of the health consequences of obesity in children and adolescents", section on 'Type 2 diabetes mellitus'.)

Sleep apnea — Patients with PWS are at high risk for sleep-related disturbances including central sleep apnea, obstructive sleep apnea (OSA), and excessive daytime sleepiness with features resembling narcolepsy [79]. Sleep-disordered breathing occurs in at least 70 percent of children and young adults with PWS [80,81] and is associated with increased daytime sleepiness and behavioral disturbances. Clinicians should monitor all patients for sleep-related symptoms, including consistent snoring, pauses in breathing for longer than five seconds, or daytime sleepiness, particularly during intercurrent respiratory illnesses. Patients with severe obesity or any clinical symptoms of sleep apnea should be referred for a polysomnogram (sleep study), if possible, and evaluated for adenotonsillar hypertrophy.

Tonsillectomy, adenoidectomy, or tracheostomy placement may be required in patients with severe OSA. Patients with PWS who undergo adenotonsillectomy are at increased risk for postoperative complications, including respiratory complications during the perioperative period and velopharyngeal insufficiency [82-84]. Detailed preoperative assessment and close postoperative monitoring are essential. OSA often improves after adenotonsillectomy but may not resolve or may recur, so it is important to follow the patients postoperatively with polysomnography [85,86]. Although a series of PWS patients undergoing bariatric surgery reported complete amelioration of symptoms of sleep-disordered breathing after surgery, these results should be interpreted with caution because factors other than obesity contribute to OSA in individuals with PWS [59,60]. Continuous positive airway pressure (CPAP) treatment may also be indicated but is often not well tolerated by the patient. Working with a psychologist may help with mask adherence. Patients with substantial OSA should be evaluated for cor pulmonale. (See "Evaluation of suspected obstructive sleep apnea in children" and "Management of obstructive sleep apnea in children".)

A possible interaction between OSA and rhGH treatment is discussed below. (See 'Safety' below.)

Excessive daytime sleepiness is present in most individuals with PWS [87,88] and is probably due to a combination of OSA and a primary disorder of vigilance [89,90]. The polysomnographic features resemble narcolepsy, but clinical symptoms of cataplexy and sleep paralysis that are typical of narcolepsy are uncommon in individuals with PWS. Accordingly, the excessive daytime sleepiness does not consistently respond to interventions for OSA. Modafinil may have some benefits for daytime sleepiness in these patients [91].

Other — Other obesity-related problems frequently seen in obese patients with PWS include dyslipidemia, cholelithiasis, gastroesophageal reflux, nonalcoholic fatty liver disease, and hypertension [66]. These are generally treated as they would be in other patients with obesity. (See "Overview of the health consequences of obesity in children and adolescents".)

Additional risks

Gastric distension and rupture — Several case reports and an autopsy study have described acute gastric distension and necrosis in patients with PWS [92]. The patient typically presents with progressive abdominal discomfort and vomiting in what may appear to be a flu-like syndrome. Patients may only complain of mild abdominal discomfort despite significant gastric necrosis, consistent with the high pain threshold often reported in patients with PWS. The disorder may or may not be triggered by binge-eating episodes [31]. Vomiting is often present in the syndrome of acute gastric distension, whereas vomiting is uncommon in patients with PWS after episodes of binge eating.

Choking episodes — Choking episodes attributed to oromotor incoordination, hypotonia, hyperphagia, voracious feeding habits, and decreased mastication were reported by the families of 34 percent of patients who died suddenly [32]. Choking was listed as a cause of death in 8 percent of patients. Training in use of the Heimlich maneuver should be considered for all providers and families of PWS patients.

Orthopedic problems — Scoliosis is common in PWS. Scoliosis with Cobb angle >10° affects up to 80 percent of patients, and 20 to 40 percent of patients have clinically significant scoliosis [11,93]. Approximately 30 percent of infants and children are affected, and the prevalence increases with age [11,66]. In patients with obesity, it may be difficult to detect scoliosis with a physical examination, so radiographic evaluation is recommended.

The presence of scoliosis is not a contraindication to rhGH therapy (see 'Safety' below). Serial spinal casting has been used for infants and may avoid or delay the need for surgery [94]. Several case series have reported unusually high complication rates for scoliosis surgery in individuals with PWS [95-97]. The largest series described outcomes of scoliosis surgery among 16 patients with PWS [95]. Nine of these patients experienced severe complications; four of which were the development of severe progressive cervical-thoracic kyphosis above the fusion requiring reoperation, and three of these were further complicated by spinal cord injury.

Patients with PWS are also at increased risk for hip dysplasia and lower limb alignment abnormalities [98,99]. Unlike other children with obesity, they do not appear to have increased risk for slipped capital femoral epiphysis [100].

RECOMBINANT GROWTH HORMONE TREATMENT

Indications and timing — We suggest that recombinant growth hormone (rhGH) treatment be offered to all children with PWS and growth failure. We also suggest it for adults (although this is an off-label use for adults with PWS in the United States unless there is confirmed or reconfirmed GH deficiency). Contraindications to rhGH include severe obesity, uncontrolled diabetes, untreated severe sleep apnea or acute respiratory infection, as well as active cancer or psychosis [55]. Patients should be evaluated for these prior to starting treatment and should be monitored during treatment. (See 'Pretreatment evaluation and monitoring' below.)

Growth failure in children is typically defined by the standards used for children without PWS (decreased height velocity or decreased height in comparison to the mid-parental height prediction) (see "Diagnostic approach to children and adolescents with short stature", section on 'Evaluation of growth'). Formal testing for GH deficiency is generally not necessary for patients with PWS, provided that they meet criteria for growth failure, although most individuals with PWS will have GH deficiency if they are tested. Measurements of insulin-like growth factor 1 (IGF-1) and IGF-binding protein 3 (IGFBP-3) are used by some endocrinologists for anecdotal evidence of GH deficiency and are sometimes used to target rhGH doses.

Early initiation of rhGH treatment (eg, before two years of age) improves clinical outcomes, as detailed in the following section. However, early initiation of rhGH could be difficult in the United States where growth failure is stipulated as part of the indication for rhGH treatment in PWS and is also a requirement for coverage by many insurance plans [41]. For infants and children with PWS who do not meet criteria for growth failure, formal testing for GH deficiency may assist the pediatric endocrinologist and family in making decisions about early initiation of treatment. Interpretation of tests for GH deficiency is limited by the possibility of false-positive (low) results, especially in patients with obesity. (See "Diagnosis of growth hormone deficiency in children", section on 'Testing for growth hormone deficiency'.)

Decisions about initiating rhGH should be made collaboratively with the family. The discussion should include the potential benefits of rhGH for PWS patients on short stature, body composition, and bone density, as well as the potential risks for this population, as discussed in the following sections. (See 'Potential benefits' below and 'Safety' below.)

Potential benefits

●Children – The efficacy of rhGH in children with PWS is supported by many observational studies and a few small randomized trials that consistently demonstrated improvements in linear growth, body composition, bone density, physical function, and motor development [101-107]. Treatment may also improve lipid profiles [108]. It is uncertain whether rhGH improves cognitive function in children with PWS. While some studies have demonstrated improvements in cognitive function during rhGH treatment [109-111], a meta-analysis of six randomized trials (165 patients) did not detect a significant difference in cognitive performance between rhGH-treated children and controls [112].

These benefits are seen in infants as well as children, and most experts suggest initiating rhGH therapy early in life [105,108,111,113]. The optimal age to begin treatment, dosing, and duration of therapy have not been fully established.

The response to rhGH in children with PWS is greatest during the first 12 months of therapy [114]. Nevertheless, patients have had continued improvement in linear growth, bone density, and body composition when rhGH has been administered in sufficient doses for as long as five years [115]. Even with long-term rhGH treatment, body composition is not completely normalized.

rhGH has generally been used in children with PWS older than the age of two years. However, some studies have demonstrated beneficial effects in younger children [101,116]. In one report, administration of rhGH to children with PWS who were younger than two years of age resulted in significantly increased lean body mass and delayed fat tissue accumulation compared with a group that received coenzyme Q [116]. Similar improvements in body composition with rhGH therapy were reported in a randomized, placebo-controlled trial of 29 infants and toddlers with PWS (aged 4 to 37 months) [101]. Initiating treatment before the age of 18 months was associated with accelerated acquisition of mobility skills compared with controls of the same age. Additional long-term observation will be required to determine whether therapy with rhGH increases adult height. The high cost of treatment with rhGH and the possibility of side effects also are important issues for parents and clinicians to consider.

●Adults – Continuation or initiation of rhGH during adulthood has modest beneficial effects on body composition [117,118]. This was shown in a systematic review that included nine randomized trials and 20 observational studies [118]. Meta-analysis of the trial data was not possible, due to substantial heterogeneity in trial designs and outcomes measured. In the trials that examined body composition outcomes at 12 months, all three reported reduced fat mass (range 2.9 to 4.2 kg) and increased lean body mass (range 1.5 to 2.3 kg). Similar findings were noted in the observational studies. Body mass index slightly decreased in two trials, although the difference was not statistically significant. There were no apparent differences in bone mineral density, low-density lipoprotein cholesterol, or cognition.

Additional support for the efficacy of rhGH in adult patients with PWS comes from the observation that discontinuation of rhGH treatment after epiphyseal closure leads to adverse changes in body composition [119-122]. Continuation or resumption of rhGH therapy does not have clinically important adverse effects on glucose homeostasis or cardiovascular risk markers [118,123,124].

Dosing

●Children – The optimal approach to dosing rhGH for PWS has not been fully established, but both of the following approaches are supported by some clinical studies and expert opinion:

•Weight-based dosing – rhGH may be dosed based on body weight, with recommended doses for infants and children of 0.034 mg/kg/day (0.24 mg/kg/week) [125], although some experts use 0.05 mg/kg/day (0.35 mg/kg/week) [126]. The patient's actual body weight is used even if the patient is obese. Some providers monitor IGF-1 and adjust doses accordingly, although routine monitoring of IGF-1 is not thought to be necessary [126].

•Body surface area (BSA)-based dosing – Consensus guidelines suggest a starting rhGH dose of 0.5 mg/m²/day for infants and children based on BSA, with subsequent adjustments up to approximately 1 mg/m²/day as needed to achieve a target IGF-1 level in the upper part of the normal range for age (+1 to +2 standard deviations for age) [55]. Some individuals with PWS (particularly infants) may require rhGH doses as high as 1.5 mg/m²/day [114]. The child's BSA can be derived from a nomogram or calculator (calculator 1).

●Adults – When rhGH is used for adults with PWS, the typically recommended the same starting dose range as that for non-PWS adults with GH deficiency, ie, 0.1 to 0.2 mg/day, with further dose adjustments targeted to achieve a serum IGF-1 level between 0 and +2 standard deviations for age and gender [55]. The dosing may also be influenced by the presence of edema, prior rhGH treatment and sensitivity, and concomitant oral estrogen use. The final doses for adults with GH deficiency with or without PWS after titration are typically between 0.2 and 1.6 mg/day. (See "Growth hormone deficiency in adults", section on 'Treatment protocol'.)

Safety — As of 2006, there were reports of at least 20 fatalities worldwide coinciding with the use of exogenous rhGH treatment in children with PWS [127,128]. The deaths were associated with respiratory problems and/or were unexpected, and most occurred within the first three months of rhGH treatment. The patients had one or more of the following risk factors: severe obesity, sleep apnea, or respiratory infection. A separate study confirmed that respiratory complications are most likely to occur during the first few weeks after initiation of rhGH therapy and in patients with severe obesity and that most children do not experience these adverse effects [129].

Whether the deaths were directly related to the use of rhGH therapy is unknown since children with PWS have an increased risk of sudden unexpected death independent of treatment with rhGH [130,131].

rhGH is postulated to have mixed effects on sleep-disordered breathing:

●rhGH therapy may worsen obstructive apnea by stimulating adenotonsillar hypertrophy via IGF-1 signaling. This mechanism is supported by case reports that correlate worsening obstructive apnea in some patients with higher IGF-1 levels [132].

●Conversely, central hypoventilation may improve because of direct effects of rhGH on hypothalamic function. This mechanism is consistent with observations that, in the majority of patients with PWS, rhGH improves sleep-disordered breathing and/or pulmonary function [132-134].

The increased short-term risks for obstructive sleep apnea during treatment with rhGH tend to occur in patients with baseline obstructive symptoms or intercurrent upper respiratory tract infections. As an example, in a study of young patients with PWS (under 21 months of age), there was an increased frequency of obstructive events associated with upper respiratory tract infections or gastroesophageal reflux [135]. In contrast, there were no changes in sleep-disordered breathing attributable to rhGH treatment.

Because of these concerns, the US Food and Drug Administration has added labeling to rhGH products stating that rhGH therapy is contraindicated in patients with PWS who are severely obese or have severe respiratory impairment [136-138].

Because the risk of scoliosis generally increases with height velocity, the risk of scoliosis might be increased in patients treated with rhGH (as was shown for patients with Turner syndrome treated with rhGH [139]). However, studies have suggested that rhGH therapy does not increase the risk or severity of scoliosis in patients with PWS, and the presence of scoliosis is not a contraindication to rhGH therapy [55,114,140,141]. (See 'Orthopedic problems' above.)

Pretreatment evaluation and monitoring — Patients with PWS should not begin rhGH therapy if any of the following are present [55]:

●Severe obesity (eg, >225 percent of ideal body weight in children or body mass index >40 in adults with uncontrolled comorbidities)

●Uncontrolled diabetes

●Untreated severe obstructive sleep apnea

●Active cancer

●Psychosis

●Acute respiratory infection – If the patient has an acute respiratory infection, initiation of rhGH therapy should be delayed until the patient has fully recovered

●Untreated or undertreated hypothyroidism and adrenal insufficiency

Accordingly, pretreatment evaluation and monitoring includes [55]:

●Respiratory – Prior to starting rhGH treatment, all patients with PWS should undergo evaluation for upper airway obstruction, ideally with polysomnography or, at a minimum, sleep oximetry [55]. In those with severe obstructive sleep apnea (OSA), rhGH treatment should not be initiated until the sleep-disordered breathing is effectively treated by weight loss in those with severe obesity and/or by adenotonsillectomy or other surgical intervention to treat the airway obstruction. Those with significant abnormalities on a polysomnogram should have follow-up studies approximately one month after beginning rhGH treatment.

During rhGH treatment, patients should be clinically reevaluated if they develop intercurrent upper respiratory tract infections or increased obstructive symptoms. rhGH treatment should be interrupted if patients develop signs of upper respiratory obstruction (including onset of or increased snoring) and/or new onset of sleep apnea. Particular care should be taken in managing this issue in infants and toddlers, who appear to be at the highest risk for respiratory compromise because of underlying hypotonia. For these children, monitoring oxygen saturation during sleep for the first one to two months after starting rhGH treatment should be considered.

●Endocrine

•Diabetes – Prior to starting rhGH treatment, all PWS patients with obesity should be screened for diabetes mellitus. The minimum screen is hemoglobin A1c, along with fasting insulin and glucose; patients with risk factors (acanthosis nigricans or family history of diabetes) should have an oral glucose tolerance test [55]. Therapy with rhGH should be approached with caution in patients with diabetes mellitus because it tends to worsen glycemic control. If rhGH therapy is undertaken in a patient with diabetes mellitus, glycemic control should be well controlled prior to starting rhGH therapy. During rhGH treatment, all patients should be monitored for adverse progression of glucose tolerance.

•Hypothyroidism – We suggest monitoring for hypothyroidism before and during rhGH therapy by measuring thyroid-stimulating hormone (TSH) and free thyroxine (T4) [55].

•Adrenal insufficiency – It is also recommended that patients be monitored for central adrenal insufficiency before and during treatment with rhGH [55]. This is most practically accomplished by measuring plasma adrenocorticotropic hormone (ACTH) and serum cortisol around 8 AM. The exact frequency of testing on treatment is uncertain but should be done immediately if there are suggestive symptoms of adrenal insufficiency (unexplained nausea, vomiting, or hypotension, especially under physical stress conditions). (See 'Adrenal insufficiency' above and "Clinical manifestations and diagnosis of adrenal insufficiency in children".)

●Orthopedic – Prior to starting rhGH treatment, patients should be evaluated for scoliosis with a spine radiograph. Scoliosis is not a contraindication to rhGH therapy, but should be monitored closely for signs of progression [55]. (See 'Orthopedic problems' above.)

●Neurologic – Evaluate for pseudotumor cerebri if suspicious symptoms develop before or during rhGH therapy (headache, visual changes, nausea).

RESOURCES AND INFORMATION — The following organizations provide information and support for families affected by PWS, including detailed medical information about PWS and crisis support for families and clinicians:

●Prader-Willi Syndrome Association USA – Phone (800)-926-4797

●International Prader-Willi Syndrome Organisation

●Foundation for Prader-Willi Research

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Obesity in children" and "Society guideline links: Growth hormone deficiency and other growth disorders".)

SUMMARY AND RECOMMENDATIONS — Prader-Willi syndrome (PWS) is the most common syndromic form of obesity but is still rare in comparison with nonsyndromic obesity.

●Clinical presentation – PWS is associated with key clinical characteristics that help to distinguish this disorder from simple obesity and guide selection of candidates for genetic testing:

•Prominent clinical features in infants and toddlers are hypotonia and feeding problems, sometimes leading to failure to thrive. Hypotonic infants with PWS are also at risk for asphyxia. (See 'Clinical manifestations' above.)

•Common clinical features in older children, adolescents, and adults are voracious appetite (with obesity if food is not restricted), decreased cognition, and hypogonadism. Short stature relative to genetic background usually becomes apparent during childhood or puberty. (See 'Clinical manifestations' above.)

●Diagnosis – Genetic testing for PWS is highly sensitive (>99 percent sensitivity) using disease-specific test panels and is the gold standard for making the diagnosis of PWS. Clinical screening is designed to determine which patients should have genetic testing. (See 'Indications for genetic testing' above and 'Genetic testing' above.)

●Comorbidities and complications – Care of the patient with PWS includes monitoring and management of comorbid conditions. Important comorbidities that can be acutely life-threatening include sleep apnea, diabetes mellitus, and gastric distension and rupture. Other comorbid conditions associated with obesity are common. (See 'Evaluation and management of comorbidities' above.)

●Recombinant human growth hormone (rhGH) therapy – We suggest treatment with rhGH for children and adolescents with PWS who have clinical evidence of growth failure (Grade 2B) and for most adults with PWS (Grade 2C). In children, rhGH improves linear growth, body composition, and motor development; continuing or initiating rhGH during adulthood appears to have modest benefits on body composition. Contraindications to initiating rhGH therapy at any age include severe obesity, untreated severe obstructive sleep apnea, uncontrolled diabetes, active cancer, psychosis, and acute respiratory infection. Patients should be evaluated for these prior to starting treatment and should be monitored during treatment for development of respiratory obstruction and/or endocrine abnormalities. (See 'Recombinant growth hormone treatment' above.)

Treatment with rhGH is optimally initiated before two years of age to impact early motor development; however, cost and insurance constraints may limit the feasibility of early initiation. If treatment cannot be started early, it should be started as soon as the child has evidence of growth failure. (See 'Recombinant growth hormone treatment' above.)

●Management of obesity

•Management of feeding and obesity is a critical part of care for patients with PWS. Patients tend to do best in a highly structured living environment in which access to food is strictly limited through close supervision and physical barriers. (See 'Management of feeding and obesity' above.)

•No pharmacologic agent, including phentermine, topiramate, or selective serotonin reuptake inhibitors (SSRIs), has been shown to be helpful in controlling appetite or binge eating. Psychotropic drugs are often used for behavior control. (See 'Pharmacotherapy' above.)

•Weight loss surgery for patients with PWS has been reported but not well studied. There are concerns about both efficacy and safety of the procedure in these patients. Until better information is available, we advise against weight loss surgery for patients with PWS, except possibly in the context of a disease-specific research protocol. (See 'Surgical weight loss procedures' above.)