Overview
Definition:
Prader-Willi syndrome (PWS) is a complex genetic disorder characterized by a spectrum of symptoms including intellectual disability, behavioral problems, endocrine deficiencies, and a relentless appetite leading to hyperphagia and obesity.
Epidemiology:
PWS is one of the most common genetic causes of obesity
The incidence is estimated to be between 1 in 10,000 to 1 in 30,000 live births
It affects males and females equally and has no racial predilection.
Clinical Significance:
Understanding PWS is crucial for pediatricians due to the multisystemic nature of the disorder
Early diagnosis and comprehensive management, especially of endocrine and behavioral aspects, significantly impact patient outcomes and quality of life.
Clinical Presentation
Symptoms:
Infancy: Hypotonia, poor feeding, failure to thrive
Childhood: Insatiable appetite (hyperphagia), rapid weight gain leading to obesity, developmental delay, intellectual disability, behavioral problems (tantrums, stubbornness, skin picking), characteristic facial features (almond-shaped eyes, narrow forehead, downturned mouth)
Behavioral issues can worsen in adolescence
Sleep disturbances: excessive daytime sleepiness, obstructive sleep apnea.
Signs:
Generalized hypotonia in infancy
Short stature
Characteristic facial dysmorphia
Acromicria (small hands and feet)
Undescended testes in males
Obesity
Scoliosis
Dental crowding
Evidence of endocrine deficiencies (see management).
Diagnostic Criteria:
Diagnosis is primarily based on clinical features and confirmed by genetic testing (methylation-sensitive DNA analysis or FISH for deletion/duplication)
Clinical criteria typically include presence of hypotonia and feeding problems in infancy AND characteristic features like hyperphagia, obesity, developmental delay, and specific physical features.
Diagnostic Approach
History Taking:
Detailed history of infant feeding difficulties, growth pattern, developmental milestones, and presence of behavioral issues
Family history of genetic disorders
History of sleep disturbances
Inquire about compulsive behaviors like skin picking
Assess for any history of endocrine issues.
Physical Examination:
Assess for generalized hypotonia
Measure height, weight, and head circumference
Evaluate for characteristic facial features and acromicria
Examine for signs of endocrine dysfunction (genitalia, thyroid, adrenal)
Assess for skeletal abnormalities (scoliosis).
Investigations:
Genetic testing is the gold standard: Methylation analysis of the PWS region on chromosome 15 (most common cause is deletion on paternal chromosome 15, followed by maternal uniparental disomy and imprinting defects)
Endocrine evaluation: Growth hormone levels, IGF-1, thyroid function tests (TSH, free T4), adrenal function (cortisol, ACTH), gonadotropins (LH, FSH), and assessment for diabetes mellitus
Polysomnography for sleep apnea
Skeletal survey for scoliosis.
Differential Diagnosis:
Other genetic syndromes causing hypotonia and developmental delay (e.g., Angelman syndrome - reversed genetic defect, Down syndrome)
Other causes of childhood obesity (e.g., Bardet-Biedl syndrome, leptin deficiency)
Hypothalamic dysfunction
Prader-Labhart-Willi syndrome.
Management
Initial Management:
Early diagnosis is paramount
Multidisciplinary team approach involving pediatric endocrinologists, geneticists, developmental pediatricians, psychiatrists, dietitians, and therapists
Nutritional counseling to manage hyperphagia and prevent obesity
Early intervention programs for developmental delays.
Medical Management:
Growth Hormone (GH) replacement therapy: Initiated in infancy or early childhood to improve linear growth, reduce fat mass, and increase lean body mass
Dosage typically 0.2-0.3 mg/kg/week divided into daily subcutaneous injections
Behavioral management: Pharmacological interventions may be used for severe aggression, self-injury, or obsessive-compulsive symptoms (e.g., SSRIs, atypical antipsychotics)
Management of endocrine deficiencies: Hormone replacement for hypothyroidism, adrenal insufficiency, and hypogonadism
Management of diabetes mellitus if present.
Surgical Management:
Bariatric surgery is generally not recommended in individuals with PWS due to behavioral issues and potential complications
Surgical management for obstructive sleep apnea (e.g., tonsillectomy and adenoidectomy) may be considered
Corrective surgery for severe scoliosis if indicated.
Supportive Care:
Strict dietary control with structured meal plans and restricted access to food is essential
Behavioral therapy and parent education on managing challenging behaviors
Physical and occupational therapy to improve motor skills
Speech therapy
Regular monitoring for obesity-related complications (diabetes, cardiovascular disease, sleep apnea)
Dental care is crucial due to increased risk of dental problems.
Complications
Early Complications:
Failure to thrive in infancy due to poor feeding
Obstructive sleep apnea leading to hypoxemia and poor sleep quality
Hypoglycemia
Gastroesophageal reflux
Undescended testes (cryptorchidism).
Late Complications:
Severe obesity and associated morbidities: Type 2 diabetes mellitus, cardiovascular disease, hypertension, dyslipidemia
Psychological and behavioral issues: severe aggression, self-mutilation, compulsive behaviors
Hypogonadism leading to delayed puberty and infertility
Scoliosis
Gastric dilatation and rupture due to rapid food intake
Gallstones.
Prevention Strategies:
Aggressive weight management through strict dietary control and regular exercise
Early diagnosis and treatment of endocrine deficiencies
Proactive management of behavioral issues
Regular sleep studies and management of sleep apnea
Monitoring for diabetes and cardiovascular risk factors
Genetic counseling for affected families.
Prognosis
Factors Affecting Prognosis:
Early diagnosis and consistent multidisciplinary management, including GH therapy and strict weight control, significantly improve prognosis
The severity of behavioral problems and associated comorbidities also play a role.
Outcomes:
With optimal management, individuals with PWS can achieve better growth, improved body composition, and a reduction in behavioral issues
However, hyperphagia and the tendency towards obesity remain lifelong challenges
Life expectancy can be reduced due to obesity-related complications and behavioral crises.
Follow Up:
Lifelong follow-up with a multidisciplinary team is essential
Regular endocrine assessments, growth monitoring, weight management, behavioral assessments, and screening for complications like diabetes, cardiovascular disease, and sleep apnea are crucial
Genetic counseling for family planning is also important.
Key Points
Exam Focus:
Key features: Hypotonia, hyperphagia, obesity, developmental delay, characteristic facial features, endocrine deficiencies
Genetic basis: Deletion/duplication or uniparental disomy of chromosome 15 (paternal origin)
Management: GH therapy for growth and body composition, strict dietary control for hyperphagia, behavioral interventions
Differentiate from Angelman syndrome.
Clinical Pearls:
Insatiable hunger is a core feature and requires constant vigilance and structured environmental controls
GH therapy can improve body composition and growth but does not cure hyperphagia
Behavioral issues are often related to frustration from hunger and can be managed with consistent routines and positive reinforcement
Always suspect PWS in a child with unexplained obesity and developmental delay.
Common Mistakes:
Underestimating the severity of hyperphagia and its impact on family life and long-term health
Inconsistent dietary enforcement, allowing access to food
Delayed diagnosis due to failure to consider genetic causes of hypotonia and obesity
Inadequate management of behavioral issues, leading to escalation of problems
Neglecting endocrine evaluations, especially GH deficiency and hypogonadism.