Prader-Willi syndrome

Disease Description (Causes and Symptoms)

• Definition summary: Prader–Willi syndrome (PWS) is a genetic neuroendocrine and developmental disorder caused by loss of expression of paternally inherited genes in the long arm of chromosome 15 (q11–q13). It is characterized by hyperphagia, obesity, growth and sex hormone deficiencies, hypogonadism, hypotonia, and cognitive and behavioral problems due to hypothalamic dysfunction.
• Causes (pathophysiology summary)
  • Main cause: loss of expression of paternally inherited 15q11–q13 genes
    • Approximately 60–75%: deletion of the paternally inherited 15q11–q13 (mostly occurring spontaneously)
    • Approximately 20–30%: monoparental disomy (maternal uniparental disomy, UPD)
    • A minority: imprinting center mutations or abnormalities in transcriptional regulation
  • As a result, hypothalamus-related circuits (regulating satiety and appetite, body temperature, sleep, sex, and growth hormone) are impaired.
• Main clinical symptoms (key features by age)
  • Neonatal period: hypotonia, feeding difficulties, weak crying, small face and small hands and feet, genital and testicular abnormalities (in boys)
  • Infancy and early childhood: initially low weight, followed by increasing appetite beginning around age 2 → progression to obesity, developmental delay, and language and motor delays
  • Childhood and adolescence: obsessive and defiant behavior, stealing and hiding food, pica, reduced concentration and short-term memory, low average IQ (approximately 65)
  • Adulthood: complications of persistent overweight and obesity (sleep apnea, diabetes, cardiovascular disease), impaired gonadal development and infertility, abnormal temperature regulation, reduced pain sensitivity
• Diagnosis (summary)
  • Genetic testing is recommended when clinical findings raise suspicion: methylation analysis (methylation test) — can detect all causative types (recommended as the initial test). Evaluation for microdeletions: MLPA/microarray/FISH. Confirmation of UPD: molecular genetic testing (microsatellite/multilocus genotype analysis).
  • Multidisciplinary evaluation (including endocrinology, pediatric neurology, and genetic counseling) is recommended.

Treatment Methods

• Overview: There is no curative treatment; multidisciplinary long-term management is used to prevent and manage complications, particularly obesity.
• Endocrine treatment
  • Growth hormone (GH) therapy: when started at a young age, it helps increase height, improve muscle strength and body fat distribution, and increase activity. IGF-1, blood glucose, and sleep apnea should be checked before and during treatment (polysomnography may be considered), and scoliosis should be monitored.
  • Sex hormone replacement (induction and maintenance of puberty): when sex hormone deficiency is present, appropriate hormone therapy (estrogen for females, testosterone for males) induces secondary sexual characteristics and improves bone mineral density.
• Obesity, dietary, and behavioral management
  • Strict calorie-restricted diet, a structured eating environment (controlling access to food, locked storage, scheduled meals), and a regular exercise program.
  • Behavioral therapy and mental health support: cognitive behavioral therapy, family education, and structured school and living environments. Medications should be used cautiously only for specific behavioral or psychiatric symptoms (such as severe compulsions or aggression) (including SSRIs and antipsychotics — beware of metabolic side effects).
• Sleep and respiratory management
  • When sleep apnea is suspected, polysomnography (DSA) and measures such as CPAP may be used.
• Surgical and other treatments
  • Cryptorchidism in childhood: early orchiopexy.
  • Treatment by each relevant specialty is needed for strabismus, dental problems, and orthopedic problems (such as strabismus surgery and fracture treatment).
  • Bariatric surgery may be considered only in limited cases of extreme obesity, but its long-term risks and benefits should be carefully assessed.
• Follow-up and monitoring
  • Regular monitoring of growth (height, weight, and BMI), IGF-1, blood glucose/insulin, lipids, bone mineral density, hormonal status, sleep status, and behavioral assessments.
• Genetic counseling: explanation of recurrence risk according to the causative type (deletion vs. UPD vs. imprinting mutation) and counseling on family planning.

Checklist Before an Outpatient Visit (Including Items to Prepare and Examples of Questions)

• Items to prepare (materials that may help with the consultation)
  • List of currently used medications and supplements (including doses and administration times)
  • Copies of previous diagnostic results and genetic testing reports (methylation, microarray, and UPD tests)
  • Recent growth charts (height and weight records), and food and sleep diaries (if possible)
  • Recent test results (blood tests, polysomnography, blood glucose, lipids, etc.)
  • Photographs (physical features, skin injuries, etc.) or notes on behavioral observations
• Recommended items to record
  • Changes in food intake and the frequency of food-seeking or food-hiding incidents
  • Sleep patterns and suspected abnormal breathing during sleep (apnea) symptoms
  • Situations and frequency of behavioral problems (seizures, aggression, compulsive behaviors)
  • Awareness of pain or history of injuries (suspected fractures)

Examples of General Questions to Ask the Doctor

• What is the expected course and long-term prognosis of this condition?
• Which genetic tests (or additional tests) are recommended, and what do the results mean for the family?
• What are the benefits and risks (side effects) of growth hormone therapy? When should treatment begin, and what is the monitoring plan?
• What dietary, exercise, and behavioral programs do you recommend for obesity management? When should medication or surgery be considered?
• What safety precautions and emergency situations should we be aware of in daily life (for example, what to do when a fracture is suspected because of reduced pain sensitivity)?

Examples of Condition-Specific Questions

• What is our (or the patient's) genetic test result (deletion/UPD/imprinting mutation), and how does this type affect the prognosis, complications, and recurrence risk?
• What baseline tests (for example, polysomnography, IGF-1, and scoliosis evaluation) are needed to start growth hormone therapy, and which tests will be used for monitoring during treatment?

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