Prader-Willi syndrome: Management

INTRODUCTION — Prader-Willi syndrome (PWS) is a neurodevelopmental condition attributed to genetic imprinting and caused by absence of expression of the paternally active genes on the long arm of chromosome 15 (15q11.2-q13). The vast majority of cases occur sporadically. It is a hypothalamic disease and the most common syndromic form of obesity.

The management of PWS will be reviewed here. The clinical features and diagnosis of this disorder are discussed separately. (See "Prader-Willi syndrome: Clinical features and diagnosis".)

FEEDING AND OBESITY — PWS is characterized by an initial phase of hypotonia and poor feeding during infancy, followed by hyperphagia and rapid weight gain beginning during early childhood. Obesity ensues if food intake is not rigorously restricted (table 1). The different phases of appetite and weight gain are shown in the figure (figure 1).

Infants and children <2 years

●Poor feeding – Mainly due to the muscular hypotonia, infants with PWS frequently have problems with suck and feeding, with associated hypotonia and poor weight gain. Management includes oromotor evaluation with use of specialized feeding strategies, videofluoroscopic swallow study, and high-calorie feedings. The average duration of tube feeding during the neonatal period is six weeks, which can generally be handled with nasogastric tube use [1]. Speech therapy may assist with development of swallowing, communication, and enunciation.

●Caloric goals – Goals for energy intake should be guided by a dietitian and designed to promote moderate rates of weight gain, with appropriate balance of protein and micronutrients with frequent need for vitamin supplementation.

Adequate energy intake is important to optimize brain growth and cognitive development (especially prior to three years of age), while excessive energy intake may increase the long-term predisposition to obesity.

●Gastroesophageal reflux – Infants and children with significant gastroesophageal reflux should be managed primarily with lifestyle measures (eg, thickened feeds and positioning) and occasionally pharmacotherapy (acid suppression), similar to individuals without PWS. We advise against surgical intervention (fundoplication) because of potential adverse effects on swallowing, which might exacerbate the risk of choking after hyperphagia develops later in life. (See "Gastroesophageal reflux in infants", section on 'Treatment options'.)

Children and adults — Increased appetite typically develops between the ages of three and five years after a period of normal eating and weight gain and subsequently progresses to marked hyperphagia by approximately eight years (figure 1). The hyperphagia includes a strong obsession with eating, a feeling of persistent hunger, and decreased satiety. The hyperphagia continues throughout life, leading to a strong predisposition to obesity.

Restriction of food intake — Controlling obesity through a food-secure environment and a strict limitation of food intake is a central focus of effective management of PWS.

●Nutritional goals – Individuals with PWS have reduced energy needs, likely related to their abnormal body composition, with relatively increased body fat and decreased lean body mass. To achieve and maintain a healthy body weight, caloric goals must often be set well below those predicted for individuals without PWS, typically 70 percent of the needs for individuals without PWS matched for age, sex, and body mass index (BMI) [2].

With these low-calorie diets, vitamin and mineral (calcium) supplementation is usually needed to meet daily requirements. Consultation with a dietitian is important to set appropriate goals for body weight and nutrition to ensure adequate protein intake despite calorie restriction. Gummy vitamin supplements should be avoided due to poor mineral composition and added calories.

Monitoring growth and PWS-specific growth charts are discussed below. (See 'Monitoring growth' below.)

●Management of hyperphagia – Food security (restriction) is essential to prevent excessive weight gain and also to reduce the risk of acute complications of hyperphagia, including choking and gastric dilation/rupture (see 'Acute complications of hyperphagia' below). Food security using physical barriers (locks) and close supervision is often necessary. Some behavioral modification techniques have been helpful in engaging the cooperation of the patient and in reducing the associated anxiety and distress [3], but these are not sufficient to control food intake.

Common behaviors include stealing and hoarding food, even when the individual is otherwise well behaved; some may even eat frozen foods or garbage. Coordination of efforts between the patient's family, caregivers, school, work, and a multidisciplinary care team is valuable. Food security practices should also be employed in the school and work setting. This requires continuing education of teachers and supervisors to maintain food security, avoid using food for behavioral reinforcement, and ensure that activities do not include food preparation and cleanup. For most adults, a specialized and highly structured group home environment is helpful in managing the PWS-associated hyperphagia and obesity.

●Psychosocial consequences – The characteristic hyperphagia of PWS has significant impacts on quality of life and educational/vocational and social functioning. Restriction of food often triggers temper outbursts and is also an important source of burden and stress for the family and caregivers [4,5]. In spite of concerted efforts, many children and adults with PWS will develop or continue to have severe obesity and associated medical problems, which contribute to the emotional and financial burden of the condition.

Other interventions for obesity — Several pharmacotherapies or surgical approaches to treatment of hyperphagia and PWS-associated obesity have been attempted, but due to the rarity of the disease, evidence is limited and the development of many pharmacologic substances terminated in early study phases. The pathophysiologic pathway of the regulation of hunger and satiety in PWS is very complex, and identification of a single substance or specific management that will completely erase hyperphagia might not be realistic.

●Pharmacotherapy – Glucagon-like peptide-1 receptor agonists (GLP-1 RA) are established treatments for adolescent and adult patients with obesity and particularly those with type 2 diabetes mellitus. (See "Glucagon-like peptide 1-based therapies for the treatment of type 2 diabetes mellitus" and "Obesity in adults: Drug therapy", section on 'GLP-1 receptor agonists'.)

In patients with PWS, GLP-1 RA appear to be somewhat less effective for hemoglobin A1c (A1C) and weight outcomes compared with populations without PWS, but the evidence is limited because of the small size and heterogeneity of the cohorts studied and variable outcomes. A systematic review that included 23 adolescents and adults with PWS and type 2 diabetes mellitus suggested that daily injections of exenatide or liraglutide may reduce BMI and A1C but with marked heterogeneity of response [6]. BMI decreased between 1.5 to 16 kg/m² in 10 patients, and A1C decreased 0.3 to 7.5 percent in 19 patients, but not all of the patients responded to the treatment. In contrast, a 16-week randomized trial with liraglutide in 55 children and adolescents with PWS reported no effect on BMI or other weight-related parameters [7]. On the other hand, an improvement in hyperphagia scores was observed during an open-label extension through 52 weeks. Limitations of this trial included a relatively small number of participants and variable treatment exposure time. In a case report of a man with PWS and diabetes, treatment with semaglutide (weekly injections) was associated with a decrease in A1C and weight, whereas liraglutide had not been effective for this individual [8]. The long-term safety of treatment with GLP-1 RA in PWS is not known. In the studies described above, the safety profile was comparable with that in cohorts without PWS. However, GLP-1 RA are known to delay gastric emptying, which is already a problem in PWS, and delayed gastric emptying might theoretically increase the risk of gastric rupture.

Intranasal carbetocin, an oxytocin analog with improved specificity for oxytocin receptors, is under investigation. In phase 2 studies, administration of carbetocin to individuals with PWS improved hyperphagia and some other behavioral measures [9]. The results of a phase 3 study showed beneficial effects of carbetocin at a dose of 3.2 mg on hyperphagia scores, anxiety, and caregiver impression of change [10]. However, the outcomes during long-term follow-up with carbetocin did not reach significance. Previous small trials of oxytocin in patients with PWS have produced conflicting results and a possible worsening of behavioral symptoms [11,12].

Other medications targeting hyperphagia are under investigation, including ghrelin analogs, controlled-release diazoxide, setmelanotide, and tesofensine-metoprolol [13,14].

Drugs that are probably not useful for this population include anorectic agents such as phentermine and fenfluramine, which were shown not to control appetite; selective serotonin reuptake inhibitors, which do not have effects on hyperphagia or obesity [15]; and topiramate and ghrelin analogs, which do not have effects on obesity [16,17]. In addition, somatostatin analogs that suppress ghrelin were not effective [18-21]. Studies of beloranib, an angiogenesis inhibitor, showed a significant decrease in hyperphagia and weight, but the studies were terminated because of fatal side effects (pulmonary embolism) [22].

●Surgical weight loss procedures – Bariatric surgery is considered a treatment option in patients with PWS with extreme obesity and severe complications in whom other treatments have failed.

Metabolic weight loss surgery, such as gastric bypass or vertical sleeve gastrectomy, has a limited role in managing obesity in patients with PWS as they do not change the eating behavior (hyperphagia). The limited evidence from small case series suggests modest weight loss during the first year after weight loss surgery, followed by weight regain so that there was little or no effect in long-term follow-up [23,24]. A few series have reported better outcomes, including durable results of weight loss surgery in patients who also received high-intensity home care [25,26].

Patients with PWS also may have increased risks after weight loss surgery:

•Gastric-restrictive procedures may be particularly risky for patients with PWS because of their innate hyperphagia and their predisposition to gastric distention and necrosis. These complications have been reported in patients who underwent intragastric balloon placement or adjustable gastric banding, not after other weight loss surgery procedures [27-29].

•Malabsorptive operations result in a lifelong need for supplementation with vitamins and minerals and may have a particularly high risk for patients with PWS because they already have an increased risk for decreased bone mineral density [27] (see 'Low bone mineral density' below). This is clearly true for biliopancreatic diversion (which is rarely performed because of high risks for malabsorption); whether gastric bypass has significant nutritional risks in this population has not been established.

(See "Surgical management of severe obesity in adolescents", section on 'Special populations'.)

Acute complications of hyperphagia

Choking episodes — Choking episodes in patients with PWS are common, likely because of hyperphagia and decreased mastication, with impaired oromotor coordination. In a case series of patients who died suddenly, 34 percent of patients had a history of choking episodes and choking was listed as a cause of death in 8 percent of patients [30]. In a systematic review of morbidity and mortality in PWS, 30 of 500 deaths were found to be caused by choking [31]. Training in use of the Heimlich maneuver is recommended for all families and caregivers for PWS patients.

Gastric distension and rupture — Acute gastric distension occasionally develops in individuals with PWS, sometimes with associated necrosis and gastric rupture, as described in several case reports and an autopsy study [32,33]; in two reviews, it was reported to be the cause of death in 10 percent of the patients [31,34].

An episode of gastric distension typically presents with progressive abdominal discomfort, abdominal distention, and vomiting. Patients may only complain of mild abdominal discomfort despite significant gastric necrosis, which is consistent with the difficulties with expressing their well-being and the high pain threshold often reported in patients with PWS. The disorder may be triggered by binge eating episodes, or related to delayed gastric emptying without binge eating, and may be recurrent. The vomiting is often present in the syndrome of acute gastric distension, whereas it is uncommon after episodes of binge eating. A management algorithm was developed by the clinical advisory board of the Prader-Willi Syndrome Association USA.

BEHAVIOR AND NEURODEVELOPMENT

Common behavioral and neurodevelopmental issues and potential interventions are (table 1):

●Motor skills – Intensive physical and occupational therapies can assist with muscle tone and strength. Early initiation of recombinant human growth hormone (rhGH) also improves physical function, strength, and motor development (see 'Recombinant growth hormone treatment' below). Screening for carnitine deficiency and supplementation if present may be beneficial to help with endurance [35]. Due to the lifelong muscular hypotonia, regular physical activity is important at any age. It might be difficult to find physical activity that patients can adhere to, but most like to walk, swim, or ride a bike. Physical activity is also important for training balance and increasing energy expenditure.

●Behaviors – Common behavioral manifestations are temper tantrums; stubbornness; and repetitive, ritualistic, and obsessive-compulsive behaviors that can impede performance in school and at work [36].

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 [37]. One publication has linked autistic-type behaviors to variants of the MAGEL2 gene located within the PWS locus [38]. Other studies suggest that these behaviors are particularly common in PWS caused by uniparental disomy [37,39,40]. (See "Prader-Willi syndrome: Clinical features and diagnosis", section on 'Mutation identification'.)

●Skin picking – Skin picking and rectal gouging behaviors are common and may respond to treatment with N-acetylcysteine [15,17,41]. Guanfacine has shown benefit for skin picking in one study [42]. In some cases, the rectal picking leads to rectal bleeding and ulceration sufficient to cause anemia or mimic colitis [43]. If anxiety or distress appear to be a trigger for these behaviors, treatment with a selective serotonin reuptake inhibitor can be tried.

●Psychiatric disorders – A variety of psychiatric symptoms and disorders have been reported among adults, including mood disorders and florid psychotic states [17,44,45]. Approximately 60 percent of patients with PWS due to uniparental disomy may develop psychotic illness by adulthood. The diagnosis of psychosis and initiation of antipsychotic pharmacotherapy should preferably be made in consultation with a psychiatrist. A lower starting dose of antipsychotics with a gradual dose increase is recommended because it is not known how these drugs act on the neurotransmitter systems in the brains of patients with PWS. Another concern is that most antipsychotics cause metabolic changes and promote weight gain.

●Cognition and learning – 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 60 [46]. 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 [47]. Some patients can have a normal IQ within certain areas and low IQ within others. Common deficits are in executive function and socialization. Adults tend to experience cognitive decline with age; in one study, the brain age was 8.74 years older than chronologic age [48]. (See "Prader-Willi syndrome: Clinical features and diagnosis", section on 'Adulthood' and "Intellectual disability (ID) in children: Management, outcomes, and prevention".)

Most children need individualized education in small classes with limited distraction, although some manage education in common schools, at least during the first few years. Adults usually manage a sheltered or adapted work with low expectancy for delivery and with small demands.

HYPOTHALAMIC AND PITUITARY DYSFUNCTION — PWS is a hypothalamic disease, and most patients exhibit evidence of hypothalamic and pituitary dysfunction that includes growth hormone (GH) deficiency (which contributes to short stature and altered body composition), hypogonadism (causing cryptorchidism and delayed puberty), and hypothyroidism [15,49,50]. Management is outlined below (table 1).

Growth hormone deficiency — GH deficiency is present in approximately 80 percent of children and 25 to 70 percent of adults with PWS [15,51,52]. It appears to be a primary abnormality of PWS rather than a biochemical phenomenon, as also occurs in obesity unrelated to PWS [15,53]. This is suggested by the associated hypothalamic dysfunction and low insulin-like growth factor 1 (IGF-1) levels present in patients with PWS [15]. In contrast, in simple obesity unrelated to PWS, IGF-1 levels are usually normal.

Monitoring growth — Children with PWS should be closely monitored for linear growth by measuring length/height at least every three months and calculating height velocity. A subnormal height 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 the child has evidence of growth failure, they are likely to have 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).

Growth charts have been developed for individuals with PWS; these may be helpful for tracking growth relative to other children with and without PWS:

●Children <3 years – Charts depicting growth with recombinant human growth hormone (rhGH) treatment [54] and without rhGH treatment [55]

●Children 3 to 18 years – Charts depicting growth with rhGH treatment [54] and without rhGH treatment [56]

Some clinicians also use standard growth charts for tracking growth in children with PWS during rhGH treatment, while recognizing that these children tend to have somewhat reduced growth potential than children without PWS, even with rhGH treatment.

Recombinant growth hormone treatment — rhGH is routinely included in the management of individuals with PWS because of its potential beneficial effects on linear growth, body composition/obesity, physical function, and cardiovascular risk factors.

Decisions about initiating rhGH should be made collaboratively with the family or guardian. The discussion should include the potential benefits of rhGH for PWS patients, as well as the treatment burden (subcutaneous injections and cost) and potential risks for this population, as discussed in the following sections.

●Indications and timing – We recommend treatment with rhGH for all children with PWS. We also suggest rhGH therapy during the transition period (ie, between late adolescence and young adulthood) and for adults (although this is an off-label use for adults with PWS in most countries unless there is confirmed or reconfirmed GH deficiency) [53]. Contraindications to rhGH include severe obesity, uncontrolled diabetes, untreated severe sleep apnea or acute respiratory infection, as well as active cancer or psychosis [21]. Patients should be evaluated for these prior to starting treatment and should be monitored during treatment, as outlined below.

Formal testing for GH deficiency in children with PWS is not necessary. In contrast, confirming or reconfirming GH deficiency in adolescents and adults is required in most countries before continuing rhGH treatment, although the majority will have GH deficiency if they are tested. Measurement of IGF-1 can help support a diagnosis of GH deficiency if low and is also used for dose titration. Measurement of IGF-binding protein 3 (IGFBP-3) is used by some endocrinologists as evidence of GH deficiency. (See "Growth hormone treatment during the transition period" and "Growth hormone deficiency in adults".)

In children with PWS, treatment with rhGH should be initiated at the time that PWS is first diagnosed, after adequate nutrition is ensured, and, ideally, prior to one year of age [57]. Early initiation of rhGH improves clinical outcomes, as detailed in the following sections. 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 thus a requirement for coverage by many insurance plans [58]. Growth failure in children is typically defined by the standards used for children without PWS (decreased height velocity or decreased height compared with the mid-parental height prediction) (see "Diagnostic approach to children and adolescents with short stature", section on 'Evaluation of growth'). However, 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 rhGH for treatment of the consequences of GH deficiency other than linear growth. Interpretation of tests for GH deficiency can be a challenge due to the possibility of false-positive (low) results in patients with obesity; however, a low IGF-1 in the setting of growth failure with normal or excessive weight is very suggestive of GH deficiency. (See "Diagnosis of growth hormone deficiency in children", section on 'Testing for growth hormone deficiency' and "Growth hormone deficiency in adults".)

●Dose and administration

•Children – The optimal approach to dosing rhGH for PWS has not been fully established. Consensus guidelines suggest body surface area (BSA)-based dosing to avoid using excessive GH doses due to the high prevalence of obesity in PWS [21]. However, weight-based dosing is still very common.

-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 (between +1 to +2 standard deviations for age) [21]. Some individuals with PWS (particularly infants) may require rhGH doses as high as 1.5 mg/m²/day. The child's BSA can be derived from a nomogram or calculator (calculator 1).

-Weight-based dosing – rhGH may be dosed based on body weight, with the recommended dose for infants and children of 0.034 mg/kg/day (0.24 mg/kg/week) [59], although some experts use as much as 0.05 mg/kg/day (0.35 mg/kg/week) [60]. The patient's actual body weight is used even if the patient has obesity. Many clinicians monitor IGF-1 and adjust doses accordingly [60].

GH is given by subcutaneous injection. It is typically administered daily, although longer-acting formulations designed for weekly administration are now available for the treatment of GH deficiency. (See "Treatment of growth hormone deficiency in children", section on 'Growth hormone treatment'.)

•Adults – In adults with PWS, the starting dose for rhGH is 0.1 to 0.2 mg/day, which is the same starting dose as for adults with GH deficiency without PWS. The dose is then titrated to achieve a serum IGF-1 level between 0 and +2 standard deviations for age and sex [21]. The dosing may also be influenced by the presence of edema, prior rhGH treatment, sensitivity, and concomitant oral estrogen use. After dose titration, the dose for adults with GH deficiency (with or without PWS) is approximately 0.4 mg/day (typical range 0.2 mg to 1.0 mg). Relatively high doses are needed in younger individuals (in particular, young females) and lower doses in older individuals. (See "Growth hormone deficiency in adults", section on 'Treatment protocol'.)

●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/obesity, bone density, physical function, and motor development [61-67].

-Motor development – In a meta-analysis of five randomized trials involving 154 infants and children with PWS (age 1.3 to 3 years), those treated with rhGH scored higher on standardized tests of motor development (standard mean difference 0.71, 95% CI 0.38-1.03) [67]. In a representative trial that enrolled only infants and toddlers (29 participants age six months to three years), rhGH therapy improved motor development during the first year of treatment [68]. Standardized scores for motor development on the Bayley Scales of Infant Development (BSID) increased by an average of 11.2 percent in the rhGH group compared with a decrease of 18.5 percent in the control group.

-Cognitive development – In the trial of rhGH in infants and toddlers described above, rhGH therapy improved cognitive development during the first year of treatment [68]. Standardized BSID scores for mental development increased by an average of 9.3 percent in the rhGH group compared with a 2.9 percent decrease in the control group. In the meta-analysis described above, a separate analysis of six trials involving 165 infants, children, and adolescents with PWS found that cognitive scores were similar in rhGH-treated children and untreated controls (standard mean difference 0.2, 95% CI -0.1 to 0.5) [67]. However, two of the trials in this analysis enrolled children at an older age (the average age in one trial was seven years; in the other, it was 17 years). This may explain the lack of benefit on cognitive outcome in the pooled analysis.

-Growth and body composition – Available studies have consistently shown that rhGH improves linear growth and body composition/obesity regardless of whether it is started in infancy or later in childhood [66]. In a meta-analysis of nine randomized trials (328 patients), rhGH improved height and body mass index (BMI) compared with controls (mean difference in Z-score for height 1.67 [95% CI 1.54-1.81]; mean difference in Z score for BMI -0.67 [95% CI -0.87 to -0.47]) [66]. Additional long-term data are needed to determine whether therapy with rhGH increases adult height. Treatment may also improve lipid profiles [69].

Observational studies and clinical trials have reported similar benefits of rhGH in infants and young children [64,65,70,71]. In a randomized trial involving 22 participants ages 5 to 32 months, rhGH combined with physical therapy increased muscle thickness, which was related to muscle strength and motor performance compared with a control group given physical therapy alone [64,65]. In a third randomized trial (29 participants age 4 to 37 months), those treated with rhGH had greater mobility skill acquisition and improvement in body composition [71]. Initiating treatment before the age of 18 months was associated with accelerated acquisition of mobility skills compared with controls of the same age. These findings support our practice of initiating rhGH at the time of PWS diagnosis, and ideally prior to one year of age, consistent with expert consensus [57].

The response to rhGH in children with PWS is greatest during the first 12 months of therapy [72]. 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 [73]. However, even with long-term rhGH treatment, body composition is not completely normalized.

•Adults – Continuation or initiation of rhGH during adulthood has beneficial effects on body composition similar to those seen in adults without PWS who were treated for GH deficiency [74-76]. The evidence was outlined in a systematic review that included nine randomized trials and 20 observational studies [75]. Meta-analysis of the trial data was not possible, due to substantial heterogeneity in trial designs and outcomes measured. In the included 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. BMI 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. A case series of adults with PWS undergoing long-term rhGH treatment (20 years) noted positive effects on body composition without any serious side effects [77]. A case series reported improvements in a standardized measure of quality of life during rhGH therapy [78]. GH replacement is not considered a weight loss medication.

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 [79-82]. Continuation or resumption of low-dose adult rhGH therapy does not have clinically important adverse effects on glucose homeostasis or cardiovascular risk markers [75,83,84].

●Safety

•Respiratory complications – Limited evidence suggest a short-term risk for respiratory complications in a few patients after initiating rhGH treatment in children with PWS. As of 2006, there were reports of at least 20 fatalities worldwide coinciding with the use of exogenous rhGH treatment in children with PWS [85,86]. The deaths were associated with obesity and respiratory problems and/or were unexpected, and most occurred within the first three months of rhGH treatment. 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.

The increased short-term risks for obstructive sleep apnea (OSA) during treatment with rhGH tend to occur in children with baseline obstructive symptoms or intercurrent upper respiratory tract infections [87]. No changes in sleep-disordered breathing were attributable to rhGH treatment. This was also seen in another study of 64 children with PWS 0 to 2.5 years old, in whom OSA appeared to develop independently of GH treatment [88]. Respiratory complications have not been reported in adults with PWS treated with rhGH [89].

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 have severe obesity or severe respiratory impairment [90-92].

•Scoliosis – The risk of scoliosis generally increases with height velocity and might be increased in patients treated with rhGH. 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 [21,89,93]. (See 'Orthopedic problems' below.)

●Pretreatment evaluation and monitoring – Patients with PWS should not begin rhGH therapy if any of the following are present [21]:

•Severe obesity – eg, >225 percent of ideal body weight in children or BMI >40 kg/m² in adults with uncontrolled comorbidities

•Acute respiratory infection – Initiation of rhGH therapy should be delayed until the patient has fully recovered

•Uncontrolled severe OSA, diabetes, hypothyroidism, or adrenal insufficiency

•Active cancer or psychosis

•Severe malnutrition – Delay initiation of rhGH until nutrition status is stabilized

Accordingly, pretreatment evaluation and monitoring include [21]:

•Respiratory – Prior to starting rhGH treatment, all children with PWS should undergo evaluation for upper airway obstruction, ideally with polysomnography or, at a minimum, sleep oximetry [21]. In those with severe 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. The rhGH doses administered in adults with PWS are much lower than those in children with PWS, and rhGH treatment has not been associated with adverse severe respiratory outcomes or polysomnographic findings in adults [21,69,94].

•Endocrine – For older children or adults with obesity, evaluate for type 2 diabetes mellitus prior to rhGH treatment and continue to monitor during therapy [21]. One of the physiologic effects of GH is induction of insulin resistance to varying degrees, so all patients should be monitored for development or progression of glucose intolerance during rhGH treatment. If rhGH therapy is undertaken in a patient with diabetes, glycemia should be well controlled prior to starting rhGH therapy and the patient should also be monitored for retinopathy and albuminuria.

Therapy with rhGH in PWS does not have known effects on the underlying risk for hypothyroidism or adrenal insufficiency. Nonetheless, pretreatment testing and ongoing monitoring for hypothyroidism are suggested [21]. Pretreatment testing for adrenal insufficiency is not required when there are no clinical signs but should be done immediately if suggestive symptoms develop (unexplained nausea, vomiting, or hypotension, especially under physical stress conditions). (See 'Hypothyroidism' below and 'Central adrenal insufficiency' below.)

•Orthopedic – Scoliosis is not a contraindication to rhGH therapy but should be monitored closely for signs of progression [21]. (See 'Orthopedic problems' below.)

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

Hypogonadism — Hypogonadism is a nearly universal feature of PWS [95]. It can be of primary (peripheral) or secondary (hypothalamic) origin or a combination of these mechanisms. It is characterized by low levels of luteinizing hormone and inhibin B combined with high follicle-stimulating hormone [95].

Manifestations of hypogonadism are:

●Cryptorchidism – Approximately two-thirds of boys have cryptorchidism. Treatment of cryptorchidism with human chorionic gonadotropin (hCG) is sometimes effective, and a trial can be attempted in the hope of avoiding surgical treatment [96]. 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 [97].

●Pubertal delay – Most children with PWS have pubertal delay. An expert panel has suggested annual monitoring of sex steroids and bone mineral density in adolescents and adults, with hormone replacement as indicated [58]. We suggest consultation with an endocrinologist to discuss initiating sex hormone therapy. After puberty, sex hormones are important for secondary sex characteristics, mood, bone mineral density, and body composition. Decisions about initiation and dosing of sex hormone therapy should include considerations about potential adverse effects of sex hormones on mood, behavior, and epiphyseal closure. (See "Approach to the patient with delayed puberty".)

●Fertility – Males with PWS are considered infertile, and there have been no known reports of PWS males fathering children. Females with PWS have markedly reduced fertility, with case reports describing a few pregnancies. If the mother's PWS is caused by uniparental disomy, there is substantial risk for Angelman syndrome in the offspring [98].

Low bone mineral density — 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 reviewed 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, decreased physical activity, hypogonadism, GH deficiency, and hypothyroidism. Although bone density is improved by rhGH treatment, it often remains below that of children without PWS and may benefit from age-appropriate sex hormone replacement therapy [15,99]. In addition, adults with severe osteoporosis might need treatment with bone resorption inhibitors [100].

Hypothyroidism — Up to 17 percent of patients with PWS have central hypothyroidism, which may be congenital or can develop at any time after birth [101,102]. These observations could be confounded by the presence of obesity, which can cause a mild, reversible elevation of thyroid-stimulating hormone (TSH). As in the general population, primary hypothyroidism (peripheral thyroid dysfunction) may also occur in PWS.

Thyroid status should be evaluated in patients with PWS by measuring free thyroxine (fT4) and TSH. We suggest testing every few months during the first year of life, then annually thereafter. Testing 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. Routine measurement of fT4 is important to detect central hypothyroidism. TSH levels are also helpful in diagnosing primary hypothyroidism, which is less common than central hypothyroidism in PWS patients.

Evaluation and management of hypothyroidism are discussed separately. (See "Clinical features and detection of congenital hypothyroidism" and "Treatment and prognosis of congenital hypothyroidism" and "Acquired hypothyroidism in childhood and adolescence" and "Central hypothyroidism".)

Central adrenal insufficiency — Central adrenal insufficiency is not considered a part of PWS, but studies report conflicting results for cortisol response to testing [103-105]. In a study of 25 children and adolescents, 60 percent had a low 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 [103]. 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 [106]. Whether subclinical adrenal dysfunction is responsible for some of the unexplained deaths observed in patients with PWS remains to be determined.

However, because PWS is a hypothalamic disease, there is at least a theoretical risk for an association with central adrenal insufficiency. In our practice, we screen for adrenal insufficiency if there are clinical symptoms suggesting the possibility of adrenal insufficiency (unexplained nausea, vomiting, or hypotension, especially under physical stress conditions). We screen by measuring 8 AM cortisol and proceed to ACTH stimulation testing if the cortisol result is abnormal or if there is a high level of suspicion. (See "Clinical manifestations and diagnosis of adrenal insufficiency in children", section on 'Initial evaluation'.)

TYPE 2 DIABETES MELLITUS — Individuals with PWS who have obesity (body mass index [BMI] ≥95^th percentile for children and BMI ≥30 kg/m² for adults) should be screened annually for type 2 diabetes mellitus by measuring fasting blood glucose and hemoglobin A1c (A1C) and/or performing an oral glucose tolerance test [107]. (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' and "Overweight and obesity in adults: Health consequences".)

The reported prevalence of type 2 diabetes mellitus in adults with PWS is between 9 and 22 percent, with generally higher percentages in those with obesity and those living in less structured environments without nutrition supervision and exercise programs. Patients with PWS diagnosed with type 2 diabetes mellitus should be treated according to general guidelines. Glucagon-like peptide 1 receptor agonists (GLP-1 RA) may be a valuable therapeutic option because of their beneficial effects on body weight, although their effects are not well studied in patients with PWS. These drugs should be approached with extreme caution among those with history of slow gastric emptying, vomiting, or gastric dilation. (See 'Other interventions for obesity' above and "Management of type 2 diabetes mellitus in children and adolescents" and "Initial management of hyperglycemia in adults with type 2 diabetes mellitus".)

Further, the risk of glucose intolerance and type 2 diabetes mellitus is increased if a patient with obesity is taking growth hormone (GH) therapy, which can exacerbate insulin resistance.

OTHER OBESITY-RELATED COMORBIDITIES — Other obesity-related problems frequently seen in patients with PWS include dyslipidemia, cholelithiasis, gastroesophageal reflux, nonalcoholic fatty liver disease, and, in children, idiopathic intracranial hypertension [108]. These comorbidities are generally treated as they would be in patients with obesity who do not have PWS. (See "Overview of the health consequences of obesity in children and adolescents" and "Overweight and obesity in adults: Health consequences".)

SLEEP AND RESPIRATORY DISORDERS — Patients with PWS are at high risk for several types of sleep disorders [109,110]:

●Obstructive sleep apnea (OSA) – Sleep-disordered breathing occurs in at least 70 percent of children and young adults with PWS [111,112] 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 [113-115]. 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 patients postoperatively with polysomnography [116,117]. Although one series of PWS patients undergoing bariatric surgery reported complete amelioration of symptoms of sleep-disordered breathing after weight loss, these results should be interpreted with caution because factors other than obesity contribute to OSA in individuals with PWS [25,118]. Continuous positive airway pressure treatment may also be indicated but is often not well tolerated or accepted by the patient. Working with a psychologist may help with mask adherence. Patients with severe OSA should be evaluated for cor pulmonale. (See "Evaluation of suspected obstructive sleep apnea in children" and "Management of obstructive sleep apnea in children" and "Management of obstructive sleep apnea in adults".)

A possible interaction between OSA and recombinant human growth hormone (rhGH) treatment is discussed above. (See 'Recombinant growth hormone treatment' above.)

●Excessive daytime sleepiness – Excessive daytime sleepiness is present in most individuals with PWS [119] and is probably due to a combination of OSA and a primary disorder of vigilance [120,121]. The polysomnographic features resemble narcolepsy, but clinical symptoms of cataplexy and sleep paralysis that are typical of narcolepsy are uncommon in individuals with PWS [110,122]. The excessive daytime sleepiness does not consistently respond to interventions for OSA. Modafinil may have some benefits for daytime sleepiness in these patients.

●Insomnia – Paradoxically, patients with PWS are also at risk for chronic insomnia [110,123].

ORTHOPEDIC PROBLEMS — Scoliosis is common in PWS. Scoliosis with a Cobb angle >10° affects up to 80 percent of patients, 20 to 40 percent of patients have clinically significant scoliosis, and 13 percent of patients require brace treatment or surgery [124]. Approximately 30 percent of infants and children are affected, and the prevalence increases with age [124]. In patients with obesity, it may be difficult to detect scoliosis with a physical examination, so radiographic evaluation is recommended. In our practice, we monitor for scoliosis with a clinical examination until early school age (approximately age six years), then initiate monitoring with spine radiographs every one to two years thereafter until growth is complete.

The presence of scoliosis is not a contraindication to recombinant human growth hormone (rhGH) therapy (see 'Recombinant growth hormone treatment' above). Serial spinal casting has been used for infants and may avoid or delay the need for surgery [125]. Several case series have reported unusually high complication rates for scoliosis surgery in individuals with PWS [126,127]. The largest series described outcomes of scoliosis surgery among 16 patients with PWS [126]. 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 [128,129]. Protocols for radiographic monitoring have been suggested but not widely implemented [128]. Unlike other children with obesity, they do not appear to have increased risk for slipped capital femoral epiphysis [130].

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 (941)-312-0400

●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

●General approach – Prader-Willi syndrome (PWS) is a multisymptomatic disease and must be understood as a whole for treatment and management to be effective. Most patients with PWS have difficulties communicating how they feel as well as their medical needs, and they might understate or exaggerate their symptoms. Management of feeding, obesity, and comorbidities is summarized in the table (table 1).

●Management of feeding and obesity

•A secured food environment and restriction of food intake are critical parts of care for patients with PWS, together with regular physical activity. 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. Food security practices should also be employed in the school and work setting, requiring continuing education of teachers and supervisors. (See 'Feeding and obesity' above.)

•No pharmacologic agent has been shown to be consistently helpful in controlling appetite or binge eating. Glucagon-like peptide-1 receptor agonists (GLP-1 RA) are established treatments for adolescent and adult patients with obesity (without PWS) and particularly those with type 2 diabetes mellitus. In patients with PWS, they may have some effects on body weight and hyperphagia, based on limited data, but should be approached with extreme caution among those with history of slow gastric emptying, vomiting, or gastric dilation. 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 PWS patients. (See 'Other interventions for obesity' above and "Glucagon-like peptide 1-based therapies for the treatment of type 2 diabetes mellitus".)

•Acute severe complications of hyperphagia include choking episodes and acute abdominal distension, both of which can be life-threatening. (See 'Acute complications of hyperphagia' above.)

●Endocrine abnormalities – Individuals with PWS have increased risk for growth hormone (GH) deficiency, hypogonadism, type 2 diabetes mellitus, low bone mineral density, and central hypothyroidism and should have routine monitoring for these disorders. (See 'Hypothalamic and pituitary dysfunction' above and 'Type 2 diabetes mellitus' above.)

●Recombinant human growth hormone (rhGH) therapy – We recommend treatment with rhGH for all children with PWS (Grade 1B); we also suggest rhGH for most adults with PWS (Grade 2C). In children, rhGH improves linear growth, body composition, and neuromotor development. In adults, continuing or initiating rhGH has benefits on body composition, physical performance, and quality of life. rhGH treatment of children with PWS has significantly changed the clinical characteristics of the syndrome.

In general, rhGH is a safe therapy. Contraindications to initiating rhGH therapy at any age include severe obesity, untreated severe obstructive sleep apnea (OSA), acute respiratory infection, and uncontrolled diabetes. 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, in particular type 2 diabetes mellitus. (See 'Recombinant growth hormone treatment' above.)

Treatment with rhGH is optimally initiated before one year of age because of benefits on early motor and cognitive development; however, cost and insurance constraints may limit the feasibility of early initiation in some countries. 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.)

●Sleep disorders – PWS is associated with increased risks for OSA, excessive daytime sleepiness (similar to narcolepsy), and insomnia. Management includes routine monitoring and surgical or medical intervention as indicated. (See 'Sleep and respiratory disorders' above.)