Prader-Willi Syndrome: The More We Know, the Less We Know

Abstract

Prader-Willi syndrome (PWS) is a complex genetic neurodevelopmental disorder with multisystem impact and a unique behavior profile that evolves over the life span. Beyond the primary care needs of all children and adults, the unique medical concerns and management needs of those with PWS are best served in a multidisciplinary academic center. Our PWS center has provided care for individuals with PWS and their families since 1981. Our growth hormone studies contributed to growth hormone supplementation becoming standard of care in this country. Here, in collaboration with the primary care provider, early childhood intervention programs, schools and local parent organizations, solid, patient-centered care for affected individuals and their families can be provided across the life-span. The purpose of this article is to provide a brief overview of PWS and the attendant medical and behavior management challenges attendant to the disorder.

Introduction

Prader-Willi syndrome, first described in 1956 by Prader, Labhart and Willi, is characterized by lifelong, unremitting hyperphagia with accompanying endocrine disorders, cognitive deficits, sensory abnormalities, and behavior difficulties.¹ Unlike other hyperphagic syndromes in which hyperphagia is present from birth and usually remits by adolescence,² the late onset, escalating severity and lifelong nature of hyperphagia in PWS is unique—and remains the cardinal syndrome symptom. Seven decades of research has yielded a delineation of the complex underlying genetics, a broadened knowledge of the phenotypic spectrum, and a greater understanding of the accompanying syndrome-related medical issues, yet the pathophysiology driving the hyperphagia and resulting obesity remains unspecified.³ Thus, hyperphagia remains a central, often dramatic management focus for affected individuals. To date, treatment/management remains externally restricted food access with caloric reduction; and, when poorly managed, can result in life-threatening obesity and obesity related complications.⁴

Medical texts describe PWS as primarily hypothalamic/pituitary in origin.⁵ However, separate from the hyperphagia, a well described range of intractable behaviors, neurocognitive deficits, and neuroimaging underscores that PWS reflects a distributed central nervous system dysfunction that has yet to be fully described, resulting in a characteristic behavior profile including an increased risk for behavior disorders and psychiatric problems. From this broadened perspective, the centrally driven hyperphagia and accompanying food-related behavioral constellation, albeit dramatic, is just one aspect of the neurobehavioral profile attendant to this disorder; and, when appropriately addressed, is perhaps the easiest of the syndrome abnormalities to manage.⁶

At the same time, PWS remains one of the most difficult disorders for affected individuals and their families to manage. Compounding this difficulty, many families report that medical professionals, school personnel, and other service providers frequently are hurtfully judgmental, implying that both the hyperphagia and the difficult syndromic behaviors are the result of poor parenting.^7,8 To understand the complex management challenges presented by PWS, we turn first to the epidemiology and genetics of the disorder, followed by a review of the food-related behavior constellation, an overview of the unique behavior concerns, and finally a review of the multiple medical challenges.

Epidemiology, Genetics and Early Diagnosis

Prader-Willi syndrome is the most common syndromic cause of obesity with prevalence estimates between 1:10,000 to 1:30,000 yielding 350,000 to 400,000 affected individuals worldwide. Males and females are equally affected.

Credited as the first identified human disorder evidencing genomic imprinting, PWS results from a failed expression of paternally active genes on chromosome #15q11.2q13 either due to deletions on the paternal chromosome, a maternal disomy, or an imprinting center defect. Most cases occur sporadically.⁹ Among those with a deletion, there are two recognized “typical deletions” based on size. The larger 15q11-q13 Type 1 deletion is approximately 6 Mb in size involving a proximal breakpoint (BP1) while the Type II deletion is slightly smaller and involves a separate proximal breakpoint (BP2). The region between BP1 and BP2 contains four non-imprinted protein coding genes involved in brain development that are missing in those with a Type I deletion but preserved in those with a Type II deletion and may account for the wide variability of phenotypic expression among those with a deletion.¹⁰

Those with a uniparental disomy (UPD) have two copies of the maternal chromosome #15 and a complete absence of a paternal chromosome. While both genetic mechanisms result in the “core” genotype, there are some mild phenotypic differences. Higher body mass index, scoliosis, and more severe behavior problems are described in those with a deletion. Those with maternal disomy generally have less distinct physical features and milder behavior problems than those with a deletion but are more likely to exhibit autistic behaviors and are more at risk for psychosis.²

Most infants with PWS present with severe to profound hypotonia resulting in a poor suck, poor feeding, and a weak cry following a pregnancy characterized by reduced fetal activity, small-for-gestational age, frequently polyhydramnios, breech positioning, and either early or late delivery. Genital hypoplasia and other phenotypic features may be present at birth or develop soon after. As a result of increased awareness, most youngsters are now identified in infancy and are provided with specialized feeding techniques and enrolled in early childhood special education programs. Most youngsters with PWS will have delayed acquisition of motor and language skills coupled with evolving cognitive deficits.

Management of PWS requires a multidisciplinary team to follow the triple trajectories of the hyperphagia and food-related behavior constellation, separately and concurrently the syndrome-related behavior/developmental trajectory, and finally the related medical concerns. We turn first to the evolution of the hyperphagia and the accompanying food related behavior constellation.⁷

Feeding, Eating, and the Evolution of Hyperphagia, and the Food-Related Behavior Constellation

As the early hypotonia improves, sometime between the ages of 18–24 months, weight gain is evident and occurs prior to an increase in food or caloric intake, or an increased interest in food. An increased appetite typically emerges between two to five years of age, progressing to marked hyperphagia by approximately eight years of age.

Physiologically, the hyperphagia is thought to be primarily associated with hypothalamic dysfunction involving both the hunger/satiety circuitry and the main hypothalamic/pituitary axis. Seven distinct nutritional phases have been identified, with five main phases and sub-phases in phases 1 and 2 (Table 1).¹¹

Table 1.

Nutritional Phases of PWS (adapted from Miller et al, 2011)

Phase 0 – in utero	Decreased fetal movements Growth restriction compared to unaffected siblings
Phase 1 (birth)	Hypotonic non-obese infant
Phase 1a (birth to 15 months)	Difficulty feeding Failure to thrive may be present
Phase 1b (5–15 months)	Weight increases at normal rate for individual growth curve
Phase 2 (range 2–4.5 years)	Weight gain
Phase 2a	Weight gain without increase in caloric intake of interest in food
Phase 2b	Weight gain and increased interest in food
Phase 3 (5–13 years)	Lifelong hyperphagia, food seeking, a feeling of persistent hunger coupled with a decreased sensation of satiety
Phase 4	In some individuals there may be some blunting of hyperphagia and a new ability to feel full

As the affected youngster evolves into nutritional phases 2b and 3, the accompanying food-related behavior constellation becomes evident (Table 2).⁶ A number of pharmacologic treatments for hyperphagia and obesity are under investigation; to date the results are highly variable, inconclusive and frequently are coupled with sub-optimal side-effect and safety profiles (see medical issues). Currently, treatment/management of the hyperphagia remains restricted food access including physical barriers (locks) with close supervision and caloric reduction. While many families can achieve a food secure environment at home, the many other environments of life (school, church, neighborhood) often present insurmountable challenges.

Table 2.

Overview of Food related behavior constellation associated with PWS

Behavior Category	Observed Behavior
Hyperphagia	Extreme and constant (over) eating exceeding that needed for nutrition. Can lead to choking episodes due to decreased chewing and to stuffing food when caught eating “illegally”
Food seeking, foraging, sneaking, hiding and hoarding	Sneaking food at home, school or workshop. Stealing food in grocery or convenience stores. Hoarding food and hiding in room. Asking others to give them their food. Taking from others’ food trays at school. Foraging leftovers from food plates, trays, and garbage cans. Looking for food in others’ desks, lockers, purses, backpacks.
Preoccupation with food	Constant need to know when the next food will be available Detailed food-oriented questions: what that food might be, serving size, how will it be cooked An assurance that the food information provided is certain Hypervigilance for food via collection of restaurant advertisements, newspaper and magazine pictures and recipes, and other visual reminders of food
Maladaptive and sometimes illicit/illegal behavior directed at obtaining food	Lying, such as untruthfully telling school personnel that the family failed to provide breakfast or lunch Shoplifting Surreptitiously “borrowing” money from parental wallets for later food purchase Purchasing food via the Internet
Eating unusual food items	Sticks of butter Saved “used” grease Eating garbage Eating frozen food Pet food Decaying or rotten food Food-flavored items such as shampoos

Developmental and Behavioral Trajectory

Beyond the common genetic abnormality, those with PWS are not a homogenous group. Individuals demonstrate a range of personality traits, talents, and interests. At the same time, PWS is associated with an evolving pattern of challenging traits and behaviors that is consistent across those affected but differs in severity between individuals and in a single individual across time. Among those with PWS, studies document an increased rate of behavior disturbances compared with: 1) typically developing individuals; 2) those with other genetic syndromes; 3) those with a similar level of cognitive impairment; and 4) those with a similar level of obesity.

Infants and toddlers are typically described as cheerful, compliant, and cooperative. By adolescence, affected individuals are characterized as cognitively and behaviorally inflexible, ritualistic, subject to sudden and intense emotional and behavioral dysregulation with frequent sensory/self-injurious acting out. Studies document a broad behavior phenotype (Table 3) with some genetic subtype differences. Hoarding and over expressions of frustration, anger, and aggression are more common among those with a deletion, while autistic spectrum behaviors and frank psychoses are more common among those with UPD.

Table 3.

Broad Behavior Phenotype

Behavior Category	Observed Behaviors
Cognition and executive functioning	Wide variability of intellectual functioning; most function in the mild to moderate range of intellectual disability. Independent of IQ score, an overlay of learning disabilities, processing deficits and executive function deficits lead most to function in the mildly impaired range. Executive function deficits: concrete thinking; difficulty planning, organizing and learning from experience; impulsive, acts before thinking; attention deficits.
Cognitive and behavioral inflexibility	Insistence on sameness Oppositional, stubborn, uncooperative and often openly disobedient Inability to handle even minor daily transitions or changes Willful, oppositional, argumentative Difficulty with uncertainty and ambiguity Decrease tolerance for, and overreactive to, frustration and stress
Social perception, cognitive deficits	Social immaturity Egocentric, Inability to see the other’s perspective Insistence on having own way regardless of environment or others affected Difficulty recognizing emotions in facial expressions Difficulty recognizing and adhering to ordinary social cues (turn-taking, personal space, appropriate touch) Difficulty being or perceived as being “wrong” or making a mistake Deficits in social attribution Problems detecting and interpreting social information
Ritualistic	Extraordinary insistence on sameness Gets upset or distressed over small changes in routine or environment “Getting stuck”, e.g., perseverative speech and routines Obsession with an idea or activity (or person) Collecting/hoarding non-food items
Subject to sudden, intense emotional and behavioral dysregulation and aggression	Cries easily for no apparent reason, or over small upsets Mood changes rapidly for no apparent reason Verbal and/or physical aggression or abusive behavior Impulsivity; acts before thinking about potential consequences Severe temper tantrums, rages, overt expression of frustration, anger
Sensory/self-stimulating/self-injurious	Sensory deficits leading to inability to experience volume induced discomfort when overeating Under reacts to pain Lack of appropriate fever response Abnormal response to ambient temperature - refusal to remove warm clothing even in excessive heat or conversely the refusal to wear warm clothing even in cold weather. Smells, tastes or licks objects Skin and rectal picking, gouging other body parts

There are few empirical studies of effective behavior management for this population and a concomitant lack of empirically based interventions; nonetheless, collected clinical experience provides guidelines for behavior management.⁶

The use of behavior management medications has become extensive across the age span,^13,14 however it must be noted that there are no randomized controlled trials to guide the use of these medications. Further, the limited empirical evidence available suggests an extremely idiosyncratic response to psychotropic medications with both unrecognized toxicity and frank ineffectiveness common. Use of these medications should be based on clinical judgement and on the individual’s symptoms such as aggression or psychoses.

Trajectory of Medical Issues

As noted, hyperphagia is primarily attributed to hypothalamic dysfunction involving both the hunger/satiety circuitry and the main hypothalamic/pituitary axis. Additional hypothalamic/pituitary manifestations include temperature instability, high pain threshold, an aberrant sleep/wake cycle, and associated endocrine abnormalities including growth and sex hormone deficiency, hypogonadism, and frequently hypothyroidism, central adrenal insufficiency and premature adrenarche.

The early literature frequently suggested that aside from hyperphagia and the resulting obesity-related complications, individuals with PWS were unusually healthy. Such conclusions may have resulted, in part, from an abnormal temperature response to routine illness coupled with an abnormal sensory awareness of pain and discomfort. Clinical research coupled with data from multiple national registries yields a range of commonly encountered medical issues (Table 4). While it is beyond the scope of this publication to detail treatment options (an age anchored medical checklist for managing PWS can be found in Duis et al., 2019),¹⁸ two areas deserve attention here: 1) growth hormone replacement therapy; and 2) pharmacologic and surgical approaches to hyperphagia.

Table 4.

An Overview of Common Medical Issues for those with PWS

Musculo-skeletal issues	Hypotonia – severe in infancy, lifelong Abnormal body composition-decreased lean muscle mass at birth and lifelong – improved with growth hormone therapy but never normal Hip dysplasia Scoliosis – as high as 80%; Kyphosis Lower limb misalignments Gait and balance abnormalities
Gastric issues	Poor oromotor control Abnormal gag reflex – decreased ability to vomit Gastroesophageal reflux and aspiration – particularly in infancy Constipation Gastroparesis Gastric distention and rupture – often following binge eating episode but can be related to delayed gastric emptying without binging
Endocrine issues	Cryptorchidism Slowed energy metabolism with reduced caloric needs and decreased interest in physical activities Growth hormone deficiency resulting in short stature Premature Adrenarche Hypogonadism resulting in delayed and incomplete puberty Central hypothyroid Central adrenal Insufficiency Obesity related Type II diabetes
Sleep and breathing Issues	Abnormal arousal in infants Central apnea with oxygen desaturation Obstructive apnea – increased severity with increasing obesity coupled with oxygen desaturation Abnormal sleep-wake organization with atypical REM cycles Excessive day time sleepiness
Vision issues	Strabismus
Dental issues	Thick, viscous saliva Enamel hypoplasia Increased risk of caries Tooth grinding occasionally severe ultimately requiring dentures
Developmental issues	Early delays in motor development Early delays in speech and language development Cognitive delays and differences coupled with specific learning disabilities Autistic features
Sensory abnormalities	Temperature instability High pain threshold Skin picking – as high as 90%; rectal picking
Neurological issues	Seizures – currently estimated to affect 25% Narcolepsy
Obesity-related co-morbidities	Type II diabetes Pulmonary hypertension and Cor Pulmonale Cardiovascular disease

Recombinant growth hormone treatment (GHT) remains the most extensively studied and only FDA approved intervention for PWS. Randomized trials document that GHT improves linear growth, body composition, bone density, physical function, and motor development.^15,16 GHT for children with PWS should be initiated at the time of diagnosis after adequate nutrition and family stability is ensured, usually between three to four months of age. In adults, continuing or initiating GHT provides benefits to body composition, physical performance, and quality of life. In general, GHT is safe, however, should not be administered in the context of severe obesity, untreated severe obstructive sleep apnea, acute respiratory infection or uncontrolled diabetes.¹⁷

Multiple pharmacologic treatments for hyperphagia and obesity are under investigation including GLP-1 receptor agonists, ghrelin analogs, controlled-release diazoxide, setmelanotide, tesofebsube-metaprolol, and intranasal carbetocin. Previous trials with Phentermine, naltrexone, naltrexone-buprion combination, Orlistat, sibutramine, beloranib, and various serotonin and racepinephrine reuptake inhibitors have been tried.⁴ Negative or inconsistent results coupled with intolerable side effect profiles currently disqualify use or fail to meet FDA approval.

Surgical weight loss procedures in this population remain controversial. Limited research suggests that metabolic surgeries such as gastric bypass or vertical sleeve gastrectomy have little use due to a failure to change the (central) hyperphagia thereby resulting in limited to no weight loss. In addition, gastric restriction surgeries such as banding or balloons may increase risk as again, the hyperphagia remains unchanged and restrictive procedures may predispose to gastric distention and necrosis. Further, post-surgical complications are not insignificant. Finally, some question the ethics of such surgery in the context of intellectual disabilities that may limit the capacity to give informed consent and to cooperate with post-surgical care.^3,4,5

Conclusion

Prader-Willi syndrome is a complex, genetically driven, neurodevelopmental disorder with multisystem impact and a unique behavior profile that evolves over the life span. Beyond the primary care needs of all children and adults, the many medical concerns and unique management needs of those with PWS are best served in an academic-center multidisciplinary clinic where, in collaboration with the primary care provider, early childhood intervention programs, schools, and local parent organizations, and other care providers can provide solid, patient-centered care for affected individuals and their families across the lifespan.