microsatellite probes or single nucleotide polymorphisms. Both the affected child and the parents DNA are examined. If the study shows that the patient has inherited a chromosome 15 loci from both mother and father, which excluded maternal UPD, then the child is assumed to have an imprinting defect.
The next step would be to categorize the imprinting defect as wither due to an epimutation which carries a low recurrence risk or a small deletion in the imprinting center where the recurrence risk can be as high as 50% if the father also possesses an IC deletion . Further sequencing studies of the imprinting center will determine whether a deletion occurred as well as the risk of recurrence in future pregnancies. Once the specific genetic etiology is determined in an individual with PWS, appropriate genetic counseling and clinical guidance can be provided to the patient and their families.
Growth hormone is the most commonly reported endocrinopathy in the PWS population and is characterized by a dysregulated growth hormone insulin-like growth factor I (IGF-I) axis. The prevalence of growth hormone deficiency in PWS is reported to be between 40 100% based on a number of studies . The discrepancy is attributed to variation in the testing methods used, differences in growth hormone assays, and age of patients at the time of testing.
PWS individuals present clinically with many of the same features that are seen in those with growth hormone deficiency, and this is the therapeutic rationale for the use of recombinant human growth hormone (rhGH) in PWS. These symptoms include short stature, small hands and feet, growth deceleration, excessive body fat, reduced lean body mass, reduced or lack of pubertal growth spurt, and short final adult height [29, 30]. Without treatment, the average height for males is 155 cm and 148 cm or females while the hands and feet grow slowly and are mostly below the fifth percentile by ten years of age . An Australian study found that 53% of infants were born small for their gestational age .
The surveillance recommendation for children with PWS is quarterly monitoring for growth failure with close observation of their linear growth with length and height measurements and a calculated linear growth velocity . Subnormal linear growth velocity is a strong indicator that the child has growth hormone deficiency, however, other causes of growth failure including hypothyroidism and insufficient nutrition due to a low-calorie diet or failure to thrive during infancy should be ruled out. If hypothyroidism and nutrient deficiency can be excluded, then children with PWS growth failure are candidates for recombinant growth hormone therapy and formal testing for growth hormone deficiency is not required.
The precise pathogenesis of growth hormone deficiency in PWS has not been fully elucidated. Reduced growth hormone secretion has been documented in at least 15 studies involving more than 300 affected children showing low peak growth hormone response to stimulation tests, decreased spontaneous growth hormone secretion, and low serum IGF-1 levels . When compared to the low growth hormone secretion and normal IGF-1 levels found in exogenous obesity, the data suggests that growth hormone deficiency is a primary result of PWS and not a result of obesity.
A number of studies have evaluated the effect of growth hormone therapy in PWS. Infants who had been treated with growth hormone were found to have improvement in head circumference, height, BMI, body composition (with improvement of lean muscle mass and delay of fate tissue accumulation), body proportions, acquisition of gross motor skills, language acquisition, and cognitive scores . Two controlled studies showed that growth hormone therapy in children improved growth, body composition, fat utilization, physical strength and agility, and behavior [32, 33]. Another study found a reduction in depressive symptoms and a lack of behavioral deterioration with growth hormone replacement therapy .
While the beneficial effects of growth hormone use in PWS have been demonstrated, the ideal age at which to begin treatment, along with dosing and duration of therapy have not been fully established . The current recommendation from experts is to initiate rhGH therapy before the onset of obesity, typically around two years of age in children with PWS. However, there are some reports of rhGH in infants as young as three to six months of age with benefits in motor and cognitive developments [29, 35].
Current long-term studies on the effects of growth hormone therapy in children with Prader-Willi showed improved body composition with treatment. A multicenter prospective cohort study following 60 prepubertal children for eight years reported the body mass index standard deviation score was significantly lower after eight years of GH treatment than at baseline . Height and head circumference standard deviation score were also normalized. A five-year study in a Japanese cohort also saw improved height velocity, height standard deviation score, final height, and the degree of obesity with GH treatment .
In another study by Carrell et al., PWS children experienced decreases in fat mass, and increases in lean body mass, linear growth, and fat utilization with improved strength and agility function with one to two years of rhGH therapy . Their follow-up study into longer term treatment over two to four years of growth hormone treatment continued to show changes in body composition (fat mass did not increase while lean body mass did) although the rate of change decreased . Growth velocity and resting energy expenditure also improved. Overall, the greatest response seen in children undergoing GH therapy was during the first twelve months.
While rhGH treatments have a promising safety profile, there has been concern about an association between unexpected fatalities in children undergoing rhGH therapy. A review of 64 deaths of children with PWS (42 boys and 22 girls, 28 on GH treatment) suggested that the first nine months after initiation of GH therapy to be a high-risk period for death . Respiratory disorders including respiratory insufficiency or infections were the most common cause of death in this cohort (68% in GH?treated and 55.5% in ?untreated patients) .
Due to the obesity that typically accompanies a PWS diagnosis, there is concern for an adverse metabolic result from growth hormone therapy, especially an impairment in glucose homeostasis, due to the diabetogenic or insulin resistant properties of growth hormone. While the mechanism of action is not yet well described, current hypotheses include changes in free fatty acid metabolism, non-physiologic levels of IGF-1, and chronic basal hyperinsulinemia . Current guidelines include evaluating diabetes risk with HbA1c, fasting glucose, and insulin testing in PWS patients who are obese and/or who are older than twelve years old or who have a family history of diabetes .
Based on expert recommendations and guidelines provided, possible contraindications to be considered with the use of rhGH in the PWS population include severe obesity (BMI > 40 kg/m2), uncontrolled diabetes mellitus, untreated severe obstructive sleep apnea, active cancer and psychosis . Cognitive dysfunction should not be considered a deterrent in initiating growth hormone therapy, but proper informed consent should be obtained beforehand.
Dietary, environmental, and lifestyle interventions should be used in conjunction with rhGH therapy for proper weight maintenance. Therapy should be continued as long as the benefits outweigh the risks.
The challenges facing rhGH therapy in PWS include treating a population that has a cognitive disability, meeting goals that are not dedicated to increasing height alone, and apprehensions about potential life-threatening side effects. Future research is directed towards assessing the long-term effects of rhGH treatment, especially in regard to glucose metabolism and diabetes risk. The effects on sleep and sleep apnea should also be examined. Additional studies should also evaluate the long-term effects of rhGH therapy, especially in adults with PWS.
Individuals with PWS typically display behavioral problems and learning challenges. Characteristic behaviors seen in 70-90% of the PWS population include temper tantrums, stubbornness, controlling and manipulative behavior, obsessive-compulsive behaviors, and difficulty with change in routine [9, 10]. The distinct behavioral phenotype of PWS has some overlap with autism spectrum disorder a neurodevelopmental disorder characterized by restricted or repetitive behaviors and social-communication impairment. A systematic review found that 26.7% of population with PWS met the criteria for autism spectrum disorder with rates differing based on genetic subtype . Rates of autism spectrum disorder were higher in individuals with PWS with uniparental disomy (35.3%) than those with paternally-derived chromosome 15 gene deletions (18.5%) .
Individuals with PWS have been found to have mild to moderate degree of cognitive impairment with a mean intelligence quotient (IQ) of 60-70 . A study in the U.K. found that the mean IQ of persons with PWS was 40 points below the population mean .
Food-seeking behavior also accompanies the hyperphagia exhibited in PWS. These behaviors include eating garbage, eating frozen food, and stealing resources to obtain food . Stealing and hoarding food is also seen. As obesity is a major problem in PWS, preventing and modifying food-seeking behaviors is essential in limiting caloric intake and controlling obesity. Some useful techniques include coordinated efforts from the patients family and caretakers to use physical barriers like locks and close supervision to limit access to food.
Behavioral disturbances exhibited by PWS patients including aggressive reactions, skin picking, and hyperphagia are difficult to manage, and psychotropic medications have been prescribed for symptomatic control. In a review by Bonnot et al., topiramate, an antiepileptic, was suggested for self-injury and impulsive and aggressive behaviors while N-acetyl cysteine seemed to be a promising treatment for skin picking and antidepressants for obsessive compulsive disorder symptoms (OCD) . Risperidone was also identified as a possible treatment for psychotic symptoms associated with uniparental disomy. Selective serotonin reuptake inhibitors (SSRIs) have also been prescribed for PWS patients because SSRIs are known to decrease appetite and are effective for OCD .
However, evidence for many psychotropic medications were derived from primarily retrospective studies, small sample sizes, and case reports and randomized control trials were lacking. Overall, there is a scarcity of well-designed trials of psychotropic medicines in PWS, and the current literature largely encompasses case reports.
Obesity and its related comorbidities are the most significant health problem in individuals with PWS. The marked obesity is attributable to hyperphagia, physical inactivity, a decreased metabolic rate, and a decreased ability to vomit. Other complications of obesity including sleep apnea, cor pulmonale, diabetes mellitus, and atherosclerosis contribute to significant morbidity and mortality in PWS. As such, coordinated care among clinicians, dieticians, and family members along with support from teachers, friends, and caregivers are required to prevent excessive weight gain. Without proper oversight and control of food, many patients weights may be double their ideal body weight .
Excessive eating behavior may be varied in its nature and severity, but it is present in all genetic subtypes of PWS. The insatiable appetites seen in this population is accompanied by a display of aggressive and obsessive food seeking behaviors including food storage, foraging, and hoarding and stealing of either food or money to buy food. All of these represent a lifelong challenge for patients and families and negatively affect quality of life, social adaptation, work-related performance. PWS individuals therefore are required to live a dependent life in order to have complete care and support in limiting their access to food. Without support, most individuals with PWS will go to great lengths to eat large quantities of food, even if it is spoiled, indigestible, or unpalatable to others.
Overweight and obesity affects nearly all persons with PWS over the course of their lives. The prevalence of obesity in this population ranges from 40% in childhood and adolescence and upwards to 82% to 92% by adulthood [44-46].
PWS was classically divided into two clinical stages: 1.) Neonatal hypotonia with hypogonadism, and feeding difficulties, and 2.) Hyperphagia occurring between 1 and 2 years of age, early onset of childhood obesity, and psychomotor delay . The more recent study by Miller et al. describes a more gradual and complex transition between nutritional phases from hypotonia to hyperphagia . These seven newly recognized nutritional phases begin with Phase 0 which occurs in utero, with decreased fetal movements and growth restriction compared to unaffected siblings. In Phase 1, the infant is hypotonic and not obese, with sub-phase 1a characterized by difficulty feeding with or without failure to thrive (ages: birth -15 months). The following phase is sub-phase 1b where the infant grows steadily along a growth curve and weight is increasing at a normal rate (median age of onset: 9 months). Phase 2 is associated with weight gain. In sub-phase 2a the weight increases without a significant change in appetite or caloric intake (median age of onset: 2 years) while in sub-phase 2b the weight gain is associated with a simultaneous increased interest in food (median age of onset: 4.5 years). Phase 3 is characterized by hyperphagia that is typically accompanied by food-seeking and lack of satiety (median age of onset: 8 years). Phase 4 is for adults who were previously in Phase 3 but is now able to feel full and no longer has an insatiable appetite.
The pathophysiology that underlies hyperphagia in PWS is still not fully understood. Imaging and deletion studies have identified some altered brain structures that may explain the excessive eating behaviors observed in the PWS population. In one study comparing children with PWS, obese children without PWS, and healthy controls, both the PWS and obese groups showed changes in cortical volume with brain deficit patterns identified in the bilateral dorsolateral and medial prefrontal cortices, right anterior cingulate cortex, and bilateral temporal lobe . Further analysis showed reduced fractional anisotropy of white matter fibers in these areas in patients of PWS when compared to the primary obesity group . Brain structure abnormalities were also observed between different genetic subtypes of PWS . Children with maternal uniparental disomy exhibited enlarged lateral ventricles, larger cortical cerebrospinal fluid volume, and increased cortical thickness, signs of early brain atrophy. On the other hand, children with the deletion genetic subtype had a smaller cerebellum, and smaller cortical and subcortical grey matter volumes, signs of stunted development but not cortical atrophy.
Mouse models have been developed for PWS but have largely been unable to encapsulate the various genetic mutations and marked hyperphagia and obesity seen in the PWS population. Current work includes a study from Polex-Wolf et al. which showed that selectively deleting Snord116 in the mediobasal hypothalamus in adult mice models the hyperphagia seen in PWS . However, only a subset, five out of twenty-one, of these mice developed obesity, gaining over 140% of their pre-surgery weights. Magel2 knock out mice is another experimental model developed for PWS that is characterized by overeating. Igarashi et al. showed that this hyperphagia is a result of increased meal size and meal duration and not due to changes in the time interval between meals, which suggests of an impaired ability in Magel2 knock out mice to produce proper satiety-related signals . They also demonstrated that intraperitoneal administration of oleoylethanolamide, a lipid messenger, produced by small-intestinal enterocytes, that controls feeding, body weight, and energy metabolism, in Magel2 knock out mice is able to reduce food intake, probably by mechanisms that underlie satiety control.
Many efforts have been undertaken to decipher the appetite regulatory system in PWS so that the roles of endogenous appetite stimulants and suppressants behind the hyperphagic behavior may be characterized. However, the exact mechanism responsible has not been determined . Current theories on the mechanisms for the etiology of obesity and hyperphagia in PWS include deficits in the ability to generate satiety signals in response to feeding, dysfunctions of hypothalamic centers that control energy homeostasis, abnormally high