Prader-Willi Syndrome

Prader-Willi syndrome (PWS) is a neurodevelopmental disorder due to loss of function of paternally expressed genes in the imprinted 15q11.2-q13 region (including SNRPN, MAGEL2, NDN and the SNORD116 cluster). Incidence is about 1 in 10,000 to 30,000. Mechanisms:

• Paternal deletion of 15q11-q13 (about 60%; type I and type II by breakpoint)
• Maternal uniparental disomy 15 (about 35%; associated with advanced maternal age)
• Imprinting defect (1 to 3%)
• Paternal chromosomal translocation (under 1%)

Hypothalamic dysfunction underlies hyperphagia, growth hormone deficiency, hypogonadism, temperature instability, sleep disorders and high pain threshold.

The course has nutritional phases:

• Phase 0: reduced fetal movements, lower birth weight
• Phase 1a (0 to 9 months): severe hypotonia, poor suck, feeding difficulty, failure to thrive
• Phase 1b (9 to 25 months): improved feeding, normal weight gain
• Phase 2a (2 to 4.5 years): weight gain without increased appetite or calories
• Phase 2b (4.5 to 8 years): increased appetite, weight gain
• Phase 3 (8 years to adulthood): hyperphagia with no satiety, food seeking, obesity if not controlled
• Phase 4 (adults): appetite may become less insatiable

Other features:

• almond shaped eyes, narrow bifrontal diameter, thin upper lip, small hands and feet, short stature
• hypogonadism (cryptorchidism, micropenis, hypoplastic labia, incomplete puberty)
• mild to moderate intellectual disability, learning difficulties, skin picking, temper outbursts, obsessive compulsive features
• psychosis (maternal UPD, in adulthood)
• scoliosis, osteoporosis
• sleep apnoea and excessive daytime sleepiness
• central adrenal insufficiency (up to 60% in some series), hypothyroidism, type 2 diabetes in obesity
• high pain threshold with delayed vomiting reflex

• DNA methylation analysis of the SNRPN locus (above 99% sensitive) is first line, and shows abnormal methylation in all molecular classes.
• Follow with chromosomal microarray or methylation specific MLPA to detect deletion. Then do UPD studies (parental samples) and imprinting centre analysis to define the mechanism for recurrence risk (below 1% for deletion and UPD; up to 50% for imprinting centre microdeletions inherited from a father).
• Clinical suspicion is raised in any hypotonic neonate with poor feeding and in older children with hyperphagia and obesity, developmental delay and hypogonadism.

• Infancy: nasogastric or specialised feeding techniques, high calorie formulas, physiotherapy.
• Growth hormone: recombinant GH 0.5 mg/m2/day initially (about 0.1 mg/kg/week), titrated to 1 mg/m2/day, started early (before 2 years where possible) to improve body composition, muscle tone, height and cognition.
• Growth hormone is contraindicated in severe obesity, uncontrolled diabetes, untreated severe sleep apnoea, active malignancy and active psychosis. Perform a sleep study before and 6 to 10 weeks after starting; monitor IGF-1, glucose, scoliosis and tonsillar and adenoid size.
• Diet: calorie restriction (about 60 to 80% of the needs of healthy peers), regular structured meals, locking food cupboards and refrigerators, limiting access to money, and supervised food environment throughout life.
• Hypogonadism: testosterone enanthate 25 to 50 mg IM monthly increasing in steps to adult dose in boys, oestradiol replacement in girls; hCG for cryptorchidism or orchidopexy.
• Central adrenal insufficiency: stress dose hydrocortisone (30 to 50 mg/m2/day during acute illness, and for surgery or anaesthesia) when the 9 am cortisol is borderline or stimulation testing is abnormal.
• Hypothyroidism: levothyroxine.
• Sleep: polysomnography, CPAP, adenotonsillectomy where indicated, and modafinil for hypersomnolence.
• Behaviour: structured routines, behavioural therapy, SSRIs (fluoxetine, sertraline) for compulsions, topiramate for skin picking, antipsychotics with caution.
• Bone health: vitamin D and calcium, bisphosphonates in selected adults, and scoliosis surveillance.
• Anaesthetic precautions: sensitivity to sedatives and risk of respiratory complications.
• Diabetes mellitus: metformin or GLP-1 receptor agonists in selected patients.