Overview
Prader-Willi Syndrome (PWS)
1. Clinical Overview
Summary
Prader-Willi Syndrome (PWS) is a complex genetic disorder caused by Loss of Expression of Paternally Inherited Genes on Chromosome 15q11-q13. It is characterised by a distinctive Biphasic Clinical Presentation: In infancy, Severe Hypotonia and Feeding Difficulties predominate; in childhood, Hyperphagia (Insatiable Appetite) and Obesity develop if food intake is not strictly controlled. PWS is the Most Common Genetic Cause of Life-Threatening Obesity. Additional features include Hypogonadism, Short Stature, Intellectual Disability, Distinctive Facial Features, and Characteristic Behavioural Problems (Temper tantrums, Stubbornness, Obsessive-compulsive traits, Skin picking). PWS affects approximately 1 in 10,000-25,000 live births. Diagnosis is confirmed by DNA Methylation Analysis of the 15q11-q13 region. Management requires Multidisciplinary Care focusing on Strict Dietary Control, Growth Hormone Therapy, Management of Behavioural Difficulties, and Surveillance for Complications (Sleep apnoea, Type 2 DM, Scoliosis). [1,2,3]
Clinical Pearls
"Floppy Infant → Hungry Child": Biphasic presentation. Hypotonia and poor feeding in infancy; Hyperphagia and obesity from early childhood.
"Food Security is Essential": Strict environmental control of food access. Locked cupboards. Structured mealtimes.
"Growth Hormone for All": GH therapy improves body composition, Height, Muscle tone, And cognition.
"Methylation Test is Diagnostic": DNA methylation analysis of 15q11-q13 detects >99% of cases.
2. Epidemiology
Demographics
| Factor | Notes |
|---|---|
| Incidence | ~1 in 10,000-25,000 live births. |
| Sex | Equal. |
| Ethnicity | All ethnic groups. |
Genetics
| Mechanism | Proportion |
|---|---|
| Paternal Deletion (15q11-q13) | ~65-75%. |
| Maternal Uniparental Disomy (UPD) | ~20-30%. Child inherits two copies of chromosome 15 from mother, None from father. |
| Imprinting Centre Defect | ~1-3%. |
| Chromosomal Rearrangement | Rare. |
Genomic Imprinting: The 15q11-q13 region is imprinted. Normally, Only the paternal copy is expressed. Loss of paternal expression causes PWS. (Loss of maternal expression causes Angelman Syndrome).
3. Pathophysiology
Genetic Basis
- Loss of Paternal Gene Expression at 15q11-q13.
- Key genes include SNORD116 (Critical for hyperphagia phenotype), SNRPN, And others.
Hypothalamic Dysfunction
- Hypothalamus regulates appetite, Satiety, Temperature, And endocrine function.
- Loss of PWS region genes → Hypothalamic dysfunction:
- Absent Satiety: Hyperphagia (Never feel full).
- Hypogonadism: Hypogonadotropic (Hypothalamic) and Primary.
- Growth Hormone Deficiency: Short stature, Poor muscle mass.
- Thermoregulation Issues: May not mount fever.
- High Pain Threshold: Risk of undetected injury/Illness.
4. Clinical Presentation
Biphasic Presentation
| Phase | Age | Features |
|---|---|---|
| Phase 1: Infancy | Birth to ~2 years | Severe Hypotonia ("Floppy baby"), Poor feeding (NG tube often needed), Weak cry, Lethargy, Failure to thrive. |
| Phase 2: Childhood-Adulthood | ~2 years onwards | Hyperphagia (Insatiable hunger), Food-seeking behaviour, Rapid weight gain → Obesity if not controlled. Behavioural difficulties. |
Major Clinical Features
| Feature | Notes |
|---|---|
| Hypotonia (Neonatal) | Severe. Improves with age but some persists. |
| Feeding Difficulties (Neonatal) | Poor suck. Often needs NG feeding. |
| Hyperphagia (Childhood) | Onset ~2-4 years. Constant hunger. Will eat non-food items (Pica). |
| Obesity | Develops rapidly without strict dietary control. Leading cause of morbidity/Mortality. |
| Hypogonadism | Cryptorchidism (Males). Hypoplastic labia (Females). Incomplete puberty. Infertility. |
| Short Stature | GH deficiency. Improves with GH therapy. |
| Intellectual Disability | Mild-Moderate. Mean IQ ~60-70. Learning difficulties. |
| Behavioural Problems | Temper tantrums. Stubbornness. Obsessive-compulsive traits. Skin picking. Rigidity. Anxiety. Emotional dysregulation. |
| Dysmorphic Features | Almond-shaped eyes. Narrow bifrontal diameter. Thin upper lip. Down-turned mouth. Small hands and feet. |
| Sleep Disorders | Obstructive sleep apnoea (OSA). Central apnoea. Excessive daytime sleepiness. |
| Scoliosis | Common (~40%). Requires monitoring. |
| High Pain Threshold | May not report illness/Injury. |
| Temperature Dysregulation | May not mount fever during illness. |
Diagnostic Criteria (Holm et al. – For Clinical Suspicion)
| Age | Major Criteria | Minor Criteria |
|---|---|---|
| 0-3 years | Hypotonia, Feeding problems | Decreased fetal movement, Sleep disturbance |
| 3 years – Adult | + Hyperphagia, Obesity, Hypogonadism, Short stature, Behaviour, Facial features, Intellectual disability | + Speech problems, Skin picking, Eye abnormalities, Thermoregulation |
Definitive Diagnosis: Genetic testing.
5. Investigations
Genetic Testing
| Test | Notes |
|---|---|
| DNA Methylation Analysis | First-Line Diagnostic Test. Detects >99% of PWS (All mechanisms). Abnormal methylation pattern = PWS. |
| FISH / Microarray (CMA) | Detects 15q11-q13 deletion. Does NOT detect UPD or imprinting defects. |
| UPD Studies (Microsatellites) | If methylation abnormal but no deletion. Detects maternal UPD. |
| Parental Karyotype / Methylation | For imprinting centre defects. Recurrence risk counselling. |
Other Investigations
| Investigation | Purpose |
|---|---|
| Growth Hormone Stimulation Tests | Most have GH deficiency. Not always needed before GH therapy in PWS. |
| Sleep Study (Polysomnography) | Before and during GH therapy. OSA screening. |
| Body Composition (DEXA) | Baseline and monitoring. |
| Scoliosis X-Ray | Baseline and regular monitoring. |
| Thyroid Function | Screen for hypothyroidism. |
| HbA1c / Fasting Glucose | Monitor for Type 2 Diabetes (Obesity). |
| Sex Hormones, LH, FSH | Assessment of hypogonadism. |
6. Management
Management Algorithm
PWS DIAGNOSED
(DNA Methylation Positive for PWS)
↓
MULTIDISCIPLINARY TEAM (MDT)
- Paediatrician / Geneticist
- Dietitian
- Endocrinologist
- Psychologist / Psychiatrist
- Physiotherapist / OT
- Speech Therapist
- Social Worker
- Respiratory / Sleep Medicine
- Orthopaedics (Scoliosis)
↓
AGE-SPECIFIC MANAGEMENT
┌────────────────┴────────────────┐
INFANCY CHILDHOOD / ADOLESCENCE /
(0-2 years) ADULTHOOD
↓ ↓
INFANCY MANAGEMENT
┌──────────────────────────────────────────────────────────┐
│ **Hypotonia / Feeding** │
│ - NG tube feeding often required initially │
│ - Monitor growth, Avoid overfeeding │
│ - Physiotherapy for muscle tone │
│ │
│ **Cryptorchidism (Males)** │
│ - hCG injections or Orchidopexy │
│ │
│ **Early GH Therapy (Before Age 2)** │
│ - Recommended. Improves muscle tone, Body composition. │
│ - Sleep study before starting. │
│ │
│ **Developmental Support** │
│ - Early intervention services │
│ - Speech and language therapy │
└──────────────────────────────────────────────────────────┘
↓
CHILDHOOD / ADOLESCENCE / ADULT MANAGEMENT
┌──────────────────────────────────────────────────────────┐
│ **DIETARY CONTROL (CRITICAL)** │
│ - Strict calorie restriction (Often 60-80% of normal) │
│ - Structured mealtimes, No snacking │
│ - **Environmental Control of Food**: │
│ - Locked cupboards, Fridges, Pantries │
│ - Supervision at all times around food │
│ - School/Carers must understand this │
│ - Dietitian involvement essential │
│ - Balanced, Low-calorie, High-protein, High-fibre diet │
│ │
│ **GROWTH HORMONE THERAPY** │
│ - Recommended for almost all individuals with PWS │
│ - Benefits: Improves body composition (↓Fat, ↑Muscle), │
│ Height, Bone density, Muscle tone, Cognition, QoL │
│ - Continue into adulthood (Metabolic benefits) │
│ - Monitor: Sleep study (OSA can worsen initially), │
│ Scoliosis, IGF-1 levels │
│ │
│ **BEHAVIOURAL MANAGEMENT** │
│ - Structured, Predictable routines │
│ - Clear expectations and consequences │
│ - Avoid food-related triggers │
│ - Psychology / Psychiatry input for severe behaviours │
│ - SSRIs for anxiety, OCD traits, Skin picking │
│ │
│ **HYPOGONADISM** │
│ - Testosterone replacement (Males) at puberty │
│ - Oestrogen replacement (Females) at puberty │
│ - Monitor bone health │
│ │
│ **SLEEP DISORDERS** │
│ - Polysomnography baseline and during GH therapy │
│ - CPAP for OSA │
│ - Tonsillectomy/Adenoidectomy if indicated │
│ │
│ **SCOLIOSIS MONITORING** │
│ - Regular spinal X-rays │
│ - Orthopaedic referral if progressive │
│ │
│ **TRANSITION TO ADULT SERVICES** │
│ - Plan early │
│ - Lifelong care needed │
└──────────────────────────────────────────────────────────┘
Key Medications
| Medication | Use |
|---|---|
| Growth Hormone (Somatropin) | Standard therapy. |
| Sex Hormone Replacement | Testosterone / Oestrogen. |
| SSRIs | Anxiety, OCD traits, Skin picking. |
| Melatonin | Sleep disturbance. |
7. Complications
| Complication | Notes |
|---|---|
| Morbid Obesity | Most serious. Leading cause of morbidity/Mortality. Prevented by strict diet. |
| Type 2 Diabetes Mellitus | Related to obesity. |
| Obstructive Sleep Apnoea (OSA) | Common. Worsened by obesity and hypotonia. GH may initially worsen. |
| Cardiovascular Disease | Related to obesity. |
| Scoliosis | ~40%. May require bracing/Surgery. |
| Osteoporosis | Hypogonadism. GH and sex hormones protective. |
| Gastric Distension / Rupture | Rare. May occur with binge eating. Reduced pain perception. |
| Respiratory Failure | Central and Obstructive apnoea. |
| Behavioural Crises | Severe tantrums. May require psychiatric input. |
| Skin Infections | From skin picking. |
8. Prognosis and Outcomes
| Factor | Notes |
|---|---|
| Life Expectancy | Reduced if obesity uncontrolled. Normal or near-normal if weight managed. |
| Quality of Life | Significantly improved with early diagnosis, GH, And strict dietary control. |
| Independent Living | Most require supervised living. Some achieve semi-independence. |
| Fertility | Most are infertile. Rare pregnancies reported. |
| Mortality | Historically ~3% per year in untreated. Much lower with modern management. Leading causes: Respiratory failure, Cardiovascular disease. |
9. Evidence and Guidelines
Key Guidelines
| Guideline | Organisation | Key Recommendations |
|---|---|---|
| PWS Management | Consensus Guidelines (McCandless et al.) | GH therapy. Strict dietary control. MDT. Sleep studies. |
10. Patient and Layperson Explanation
What is Prader-Willi Syndrome?
PWS is a rare genetic condition that affects many parts of the body. It is caused by missing genetic information from the father's chromosome 15.
What are the main features?
- As a baby: Very floppy (Hypotonic), Difficulty feeding.
- As a child and adult: Constant hunger (Hyperphagia) that can lead to severe obesity if food is not strictly controlled. Learning difficulties. Behavioural challenges.
Why is food control so important?
People with PWS never feel full. They have an overwhelming drive to eat. Without strict control of food access (Locked cupboards, Supervised mealtimes), Life-threatening obesity can develop.
What treatment is available?
- Growth Hormone: Given from early childhood. Helps with growth, Muscle tone, And body composition.
- Strict Diet: Essential. Lower calorie intake with healthy foods.
- Support for Behaviour: Structured routines. Sometimes medication.
- Regular Monitoring: For sleep problems, Spine curvature, Diabetes.
What is the outlook?
With good management, Many people with PWS live fulfilling lives. Most need some support throughout life. Keeping weight under control is the most important factor for long-term health.
11. References
Primary Sources
- Cassidy SB, Schwartz S, Miller JL, Driscoll DJ. Prader-Willi syndrome. Genet Med. 2012;14(1):10-26. PMID: 22237428.
- McCandless SE, Committee on Genetics. Clinical Report – Health Supervision for Children With Prader-Willi Syndrome. Pediatrics. 2011;127(1):195-204. Re-affirmed 2017. PMID: 21187304.
- Driscoll DJ, Miller JL, Schwartz S, Cassidy SB. Prader-Willi Syndrome. GeneReviews. 2017 (Updated 2023).
12. Examination Focus
Common Exam Questions
- Genetic Mechanism: "What is the most common genetic cause of PWS?"
- Answer: Paternal Deletion of 15q11-q13 (~65-75%).
- Diagnostic Test: "What is the first-line diagnostic test for PWS?"
- Answer: DNA Methylation Analysis of the 15q11-q13 region.
- Biphasic Presentation: "Describe the biphasic clinical presentation of PWS."
- Answer: Infancy: Hypotonia, Poor feeding. Childhood/Adulthood: Hyperphagia, Obesity.
- Treatment: "What is a key therapy for children with PWS?"
- Answer: Growth Hormone Therapy (Improves body composition, Height, Muscle tone, Cognition).
Viva Points
- Genomic Imprinting: Paternal genes at 15q11-q13 are normally expressed. Loss causes PWS. Loss of maternal expression = Angelman Syndrome.
- Food Security: Locked cupboards. Absolutely critical to prevent obesity.
- High Pain Threshold: May not report illness/Injury.
- Sleep Study Before GH: OSA can worsen initially.
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