What are the characteristic signs, symptoms, and recommended treatment strategies for Prader‑Willi syndrome?

Prader-Willi Syndrome: Clinical Features and Management

Core Clinical Presentation

Prader-Willi syndrome presents with a distinctive biphasic pattern: profound hypotonia with feeding failure in infancy, followed by insatiable hyperphagia and obesity in childhood—recognition of these phases is critical for diagnosis and survival. 1

Neonatal Period (Birth to 2 Years)

• Severe hypotonia with poor muscle tone affecting all motor activities 1
• Feeding difficulties requiring specialized nipples (Pigeon feeder, Haberman nipple) or nasogastric tube feeding 1
• Failure to thrive with poor suck reflex and reduced spontaneous arousal for feeding 1, 2
• Hypogonadism manifesting as undescended testes and small phallus in males; clitoral and labia minora hypoplasia in females (may be subtle) 1
• Excessive sleepiness with difficulty awakening for feeds 3

Early Childhood (2-6 Years)

• Persistent hypotonia though gradually improving 2
• Global developmental delay affecting motor, speech, and cognitive milestones 1
• Transition to weight gain without increased appetite initially (Phase 2a begins around age 2 years) 4
• Behavioral rigidity particularly around daily routines, with prolonged temper tantrums 1

Middle Childhood (6-12 Years)

• Hyperphagia onset (typically around age 8 years) with obsessive food-seeking behaviors 1, 3
• Rapid central obesity if food access is not controlled 1, 2
• Food-related behaviors including eating spoiled food, searching garbage, stealing money for food 1
• Compulsive behaviors and perseverant speech become prominent 1
• Poor linear growth despite excessive caloric intake 1

Adolescence and Adulthood (13+ Years)

• Cognitive impairment typically mild intellectual disability 1, 2
• Psychiatric complications including increased risk of psychosis (especially with maternal uniparental disomy), affective disorders, and obsessive-compulsive disorder 5
• Skin-picking requiring behavioral modification 5
• Overconfidence in handling dangerous situations, particularly regarding food-seeking 1

Physical Examination Findings

Characteristic Facial Features (Present in 49% of Cases)

• Narrow bifrontal diameter 2
• Almond-shaped eyes 2
• Thin upper lip 2
• Downturned mouth 2

Additional Physical Signs

• Acromicria (small hands and feet) 6
• Scoliosis (prevalence 15-86%, requires annual screening starting in childhood) 5
• Strabismus (requires annual vision screening with attention to recurrence) 5
• Reduced salivation dramatically increasing dental caries risk 5

Critical Diagnostic Approach

Any infant with unexplained hypotonia and poor suck should undergo immediate chromosome 15q11.2-q13 methylation testing—this is the first-line diagnostic test. 3, 2

Age-Specific Testing Triggers

• Birth to 2 years: Significant hypotonia with poor suck and difficulty with weight gain 1
• 2-6 years: Congenital hypotonia with history of poor suck PLUS global developmental delay 1, 2
• 6-12 years: History of hypotonia/poor suck PLUS global developmental delay PLUS excessive eating with central obesity 1, 2
• 13+ years: Cognitive impairment PLUS excessive eating with central obesity PLUS hypogonadism and/or typical behavior problems 1, 2

Life-Threatening Complications

Without strict weight control, death occurs in the fourth decade from obesity-related complications; with meticulous management, patients can live into their seventh decade. 1, 7

Fatal Complications Without Intervention

• Massive obesity leading to diabetes mellitus 1, 7
• Obstructive sleep apnea (affects >50% of patients) 5, 3
• Right-sided heart failure 1, 7
• Gastric necrosis from binge-eating (vomiting after binge-eating is an ominous sign requiring immediate evaluation) 5

Essential Management Strategies

Environmental Food Control (Most Critical Intervention)

Lock all food storage areas with keys kept by caregivers only—unsupervised food access can lead to fatal binge-eating with intestinal necrosis. 5

• Maintain scrupulous mealtime routines to instill confidence that meals will arrive on schedule 1, 5
• Limit environmental exposures that trigger food thoughts (e.g., birthday treats visible during school day) 1, 5
• Educate all family members, teachers, and social contacts that "sneaking" food undermines treatment and the child's wellbeing 1, 5

Nutritional Management by Phase

Infancy (Failure to Thrive Phase):

• Use specialized feeding systems with one-way valves to compensate for weak suck 3
• Monitor weight weekly initially and adjust caloric density upward to maintain appropriate growth 1, 3
• Consider nasogastric tube feeding if oral intake insufficient; avoid gastrostomy tubes when possible 3
• Do NOT restrict calories during this phase—focus on achieving adequate weight gain 3

Childhood Through Adulthood (Hyperphagia Phase):

• Restrict calories to approximately 60% of standard requirements (8-10 kcal/cm of height, roughly 800-1200 kcal/day) 5, 3
• Establish daily physical activity routines from early childhood 5
• Work with dietitian to ensure adequate essential nutrients despite severe caloric restriction 3
• Screen hemoglobin, ferritin, and vitamin D levels at least annually 3

Growth Hormone Therapy (FDA-Approved Treatment)

Initiate growth hormone therapy at diagnosis and continue lifelong to improve body composition, metabolic function, and developmental outcomes. 5, 3

• Refer to pediatric endocrinology for GH evaluation in all patients 5
• Perform polysomnography before starting GH to rule out sleep-disordered breathing 5, 3
• Repeat polysomnography 6-10 weeks after GH initiation 3
• Monitor IGF-1 levels at least twice yearly, dosing to keep levels in physiologic range 1, 5
• Monitor head circumference at each visit, as GH can cause abnormal head growth especially if fontanelles are open 1

Endocrine Surveillance

• Evaluate growth hormone deficiency at diagnosis 5
• Screen thyroid function every 2-3 years or when symptomatic (hypothyroidism occurs in up to 30% of patients) 5
• Measure early-morning ACTH and cortisol levels to assess hypothalamic-pituitary axis dysfunction 3
• Consider prophylactic hydrocortisone during critical illness 3

Hypogonadism Management

Trial human chorionic gonadotropin (hCG) before surgery for undescended testes to avoid general anesthesia in hypotonic infants with potential respiratory compromise 1

• Additional hCG benefits include increased scrotal size and partial normalization of phallus length, improving surgical outcomes and facilitating standing micturition 1

Sleep Disorder Management

Screen annually for sleep disorders, as these affect >50% of patients and contribute to behavioral problems, daytime dysfunction, and mortality risk. 5, 3

• Obtain baseline polysomnography in infancy 5
• Repeat polysomnography if symptoms develop or worsen, or when weight changes rapidly 5, 3
• Perform Multiple Sleep Latency Test when excessive daytime sleepiness persists despite treated obstructive sleep apnea 5

Behavioral Management

Implement structured behavioral interventions early, as behavioral rigidity, temper tantrums, skin-picking, and psychiatric disorders worsen with age. 5

• Address skin-picking primarily through behavioral modification 5
• Recognize that hyperphagia represents neurological inability to feel satiety due to hypothalamic dysfunction, not a behavioral choice—requires environmental controls rather than behavioral punishment alone 3, 7

Additional Monitoring

• Scoliosis: Evaluate annually starting in childhood; refer to pediatric orthopedics when detected 5
• Dental care: Refer to pediatric dentist by age 1 year; schedule cleanings every 3-4 months due to reduced salivation 5
• Vision: Screen annually with attention to strabismus recurrence; refer to pediatric ophthalmology if concerns arise 5

Critical Safety Considerations

Patients with PWS have high pain tolerance that masks serious complications and delays treatment—maintain high index of suspicion for acute illness. 5

• Vomiting after binge-eating is an ominous sign requiring immediate evaluation for intestinal necrosis 5
• Avoid prolonged oral feeding time in infancy (usually not >20 minutes per feeding) 1

Genetic Counseling

Confirm diagnosis through chromosome 15q11.2-q13 methylation testing to guide prognosis, as maternal uniparental disomy carries higher psychosis risk than deletion. 5

• Review recurrence risk in subsequent pregnancies and availability of prenatal diagnosis 1
• Discuss implications of molecular testing results with both parents whenever possible 1