What are the clinical features, diagnostic approach, and management recommendations for Prader‑Willi syndrome?

Prader-Willi Syndrome: Clinical Features, Diagnosis, and Management

Clinical Features

Prader-Willi syndrome presents in a characteristic biphasic pattern that evolves dramatically with age, beginning with profound hypotonia and feeding failure in infancy, then transitioning to insatiable hyperphagia and rapid obesity in early childhood. 1, 2

Infancy (Birth to 2 Years)

• Severe hypotonia with poor suck reflex and inability to awaken spontaneously for feeding, requiring specialized feeding support or nasogastric tube feeding 1, 2, 3
• Failure to thrive despite normal caloric intake due to weak muscle tone and reduced spontaneous arousal 1, 3
• Hypogonadism manifesting as undescended testes, small phallus in males, or small clitoris in females 1
• Excessive sleepiness with failure to awaken for feeding, distinguishing this from simple hypotonia 2, 3

Early Childhood (2-6 Years)

• Transition to hyperphagia begins, marking the critical shift from failure to thrive to excessive eating 2, 3
• Global developmental delay becomes increasingly apparent 2, 3
• Persistent hypotonia with history of poor suck continues 2

School Age (6-12 Years and Beyond)

• Insatiable hyperphagia with obsessive food-seeking behaviors becomes the dominant feature 2, 3
• Central obesity develops rapidly without strict caloric restriction 2, 3
• Behavioral rigidity with temper tantrums, obsessive-compulsive features, and compulsive skin-picking 2, 4
• Short stature despite excessive caloric intake 5, 6
• Intellectual disability with characteristic behavioral problems including oppositionality and aggression 4, 5

Adolescence and Adulthood

• Increased risk of psychotic disorders and affective illness, particularly in those with maternal uniparental disomy rather than deletion 2, 4
• Multiple endocrinopathies including growth hormone deficiency (nearly universal), hypogonadotropic hypogonadism (>90%), and hypothyroidism (up to 30%) 2, 5
• Sleep disorders affecting over 50% of patients, including obstructive sleep apnea, central sleep apnea, and narcolepsy-like phenotypes 2, 3

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Diagnostic Approach

When PWS is suspected based on neonatal hypotonia with poor feeding or later hyperphagia with developmental delay, immediately proceed with methylation analysis of chromosome 15q11-q13 as the first-line diagnostic test—this single test confirms PWS in all three genetic subtypes. 1, 2

Initial Diagnostic Testing

• Methylation analysis using SNRPN or PW71B probes detects parent-of-origin-specific methylation patterns and confirms PWS when only maternal alleles are present 1
• This test has >99% sensitivity for PWS and differentiates it from Angelman syndrome (which shows only paternal alleles) 1, 5

Subsequent Genetic Subtyping (for Genetic Counseling)

Once PWS is confirmed by methylation analysis, determine the specific genetic mechanism:

• FISH analysis using SNRPN probe with centromeric control probe distinguishes deletion (70% of cases) from other mechanisms 1
• PCR-based microsatellite analysis identifies uniparental disomy (20% of cases) when FISH shows no deletion 1
• Imprinting defects (1-3% of cases) are diagnosed when biparental inheritance is present but methylation is abnormal 1, 5

Clinical Importance of Genetic Subtyping

• Maternal uniparental disomy carries significantly higher risk of psychotic disorders in adolescence and adulthood compared to deletion 2, 4
• Deletion cases may have more severe cognitive impairment 4
• Genetic subtype determines recurrence risk for future pregnancies (imprinting defects may have up to 50% recurrence) 1

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Management Recommendations

Critical Safety Measures: Food Access Control

Lock all food storage areas with keys kept exclusively by caregivers—unsupervised food access can lead to fatal binge-eating with gastric rupture and intestinal necrosis. 2, 3

• Implement strict environmental controls from the moment hyperphagia begins (typically age 2-6 years) 2, 3
• Educate all family members, teachers, and social contacts that "sneaking" food undermines treatment and endangers the patient's life 2
• Maintain scrupulous mealtime routines to instill confidence that the next meal will arrive on schedule, reducing food-seeking anxiety 2
• Recognize that vomiting after eating is an ominous sign requiring immediate emergency evaluation for gastric rupture or intestinal necrosis 2

Nutritional Management by Age

Infancy (Birth to 2 Years): Support Adequate Growth

• Do NOT restrict calories during the hypotonic/failure-to-thrive phase 2, 3
• Use specialized feeding systems with one-way valves to compensate for weak suck 2
• Monitor weight weekly initially and adjust caloric density upward as needed to maintain appropriate growth 2
• Consider nasogastric tube feeding if oral intake is insufficient, but avoid gastrostomy tubes when possible due to permanent cosmetic scarring 2

Childhood Through Adulthood: Prevent Obesity

• Restrict calories to approximately 60% of standard requirements (8-10 kcal/cm of height, roughly 800-1200 kcal/day depending on height) 2, 3
• Work with a dietitian to ensure adequate essential nutrients despite severe caloric restriction 3
• Establish daily physical activity routines from early childhood, aiming for structured exercise programs 2
• Monitor hemoglobin, ferritin, and vitamin D levels at least annually due to restricted diet 2

Growth Hormone Therapy

Initiate growth hormone therapy at diagnosis and continue lifelong—this is the only FDA-approved treatment for PWS and improves body composition, prevents short stature from caloric restriction, and enhances developmental outcomes. 2, 3

• Perform polysomnography before starting GH and repeat 6-10 weeks after initiation to monitor for sleep-disordered breathing 2, 3
• Refer to pediatric endocrinology for GH evaluation in all patients 2
• Monitor IGF-1 levels at least twice yearly, dosing to keep levels in physiologic range 2
• Do not delay GH therapy for sleep study results if testing is not immediately available 3

Sleep Disorder Management

Screen annually for sleep disorders using validated questionnaires, as these affect over 50% of patients and contribute to behavioral problems, daytime dysfunction, and mortality risk. 2, 3

• Obtain baseline polysomnography in infancy and repeat if symptoms develop or worsen 2
• Perform Multiple Sleep Latency Test when excessive daytime sleepiness persists despite treated obstructive sleep apnea 2
• Include sleep specialists in the multidisciplinary team to address sleep disorders that worsen food-seeking behaviors 3

Endocrine Surveillance

Evaluate growth hormone deficiency at diagnosis and screen thyroid function every 2-3 years or when symptomatic, as hypothyroidism occurs in up to 30% of patients. 2

• Measure early-morning ACTH and cortisol levels to assess for central adrenal insufficiency 3
• Consider prophylactic hydrocortisone during critical illness due to risk of adrenal crisis 3
• Monitor for premature adrenarche and delayed puberty requiring hormone replacement 2, 5

Behavioral and Psychiatric Management

Implement structured behavioral interventions early with predictable daily routines, as behavioral rigidity, temper tantrums, skin-picking, and psychiatric disorders worsen with age. 2, 4

• Address skin-picking primarily through behavioral modification rather than physical barriers 2, 4
• Provide extra help with transitions between activities, as this is a common trigger for tantrums 4
• Consider SSRIs for compulsive behaviors (skin-picking, obsessive-compulsive symptoms) and aggressive episodes, though formal drug trials are lacking 4
• Use atypical antipsychotics for psychotic features or extreme aggression and impulsivity, particularly in adolescents and adults with maternal uniparental disomy 4
• Recognize that hyperphagia represents neurological inability to feel satiety, not a behavioral choice requiring punishment 7

Musculoskeletal Monitoring

Evaluate annually for scoliosis starting in childhood, as prevalence ranges from 15-86% and impacts respiratory function. 2

• Refer to pediatric orthopedics when scoliosis is detected 2
• Monitor for progression that may require bracing or surgical intervention 2

Dental Care

Refer to pediatric dentist by age 1 year, as reduced salivation increases caries risk dramatically. 2

• Schedule dental cleanings every 3-4 months rather than standard 6-month intervals 2

Vision and Hearing

Screen vision annually with particular attention to strabismus recurrence. 2

• Refer to pediatric ophthalmology if strabismus or other concerns arise 2

Critical Clinical Pitfall

Educate families that patients with PWS have abnormally high pain tolerance, which masks serious complications like appendicitis, fractures, and intestinal necrosis—maintain high index of suspicion for serious pathology even with minimal symptoms. 2

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Prognosis

Without adequate weight control, death typically occurs in the fourth decade from obesity-related complications (diabetes, obstructive sleep apnea, right-sided heart failure), but with meticulous weight control and comprehensive multidisciplinary management, patients can live into their seventh decade. 1, 2, 7