Prader-Willi syndrome

Rare genetic imprinting disorder (loss of paternal 15q11.2–q13) causing infantile hypotonia with poor feeding, followed by hyperphagia leading to obesity, developmental delays, and endocrine dysfunction.

• PWS is the most common syndromic form of life-threatening obesity and is a classic example of genomic imprinting. Early diagnosis allows intervention (dietary control, growth hormone therapy) to prevent severe obesity and manage complications like type 2 diabetes and respiratory failure.

• Infancy: profound hypotonia ("floppy baby"), weak suck and feeding difficulties (failure to thrive), often requiring gavage feeding; hypogonadism (cryptorchidism in males, small labia in females) is common.
• Early childhood: around age 2–4, hyperphagia (insatiable appetite) emerges, leading to rapid weight gain and obesity by school age unless food access is strictly controlled.
• Later childhood/adolescence: short stature (due to growth hormone deficiency), intellectual disability (mild to moderate), and behavioral problems (temper tantrums, stubbornness, skin picking, obsessive tendencies) become evident. Distinctive dysmorphic features include almond-shaped eyes, narrow forehead, and small hands and feet.

1. Recognize PWS in a hypotonic infant with feeding difficulties or an older child with voracious appetite, obesity, and developmental delays.
2. Confirm the diagnosis with genetic testing: DNA methylation analysis of 15q11-q13 will show abnormal imprinting (maternal-only pattern), which is present in >99% of cases. Follow up with FISH or microarray to distinguish a paternal deletion from maternal uniparental disomy.
3. Address endocrine issues: screen for and treat growth hormone deficiency (GH therapy improves height and lean mass) and hypogonadism (e.g. hormone replacement at puberty). Monitor thyroid function and risk of adrenal insufficiency as needed.

1. Nutritional: Strict dietary supervision (calorie restriction, locked food storage) and regular exercise from early childhood to prevent excessive weight gain.
2. Endocrine: Growth hormone therapy (started in infancy or early childhood to improve stature, muscle mass, and fat distribution). At adolescence, sex hormone replacement (testosterone or estrogen/progesterone) to induce puberty and support bone health. Monitor and treat hypothyroidism or adrenal insufficiency if present.
3. Behavioral: Structured environment and behavioral therapy for food-seeking and obsessive behaviors. Address skin picking (e.g., with SSRIs or N-acetylcysteine) and provide developmental support (special education, occupational therapy).
4. Others: Surgical correction of cryptorchidism in infancy; evaluation and management of sleep apnea and scoliosis are essential. In adulthood, supervised living arrangements may be needed to ensure ongoing dietary control and health monitoring.

• Prader = Paternal Deletion (father's allele lost); AngelMan = Maternal (mother's allele lost). Think "Papa is missing in Prader-Willi, Mama is missing in Angelman."
• PWS patients have abnormally high ghrelin levels, the hunger-stimulating hormone, which may explain their insatiable appetite.

• Acute gastric distension: PWS patients have decreased vomiting and can develop life-threatening gastric dilation/rupture after binge eating. Sudden abdominal pain or bloating in PWS is an emergency requiring immediate evaluation.
• Obesity complications: High risk of type 2 diabetes, obstructive sleep apnea, pulmonary embolism, and heart failure. Uncontrolled hyperphagia can lead to rapid, morbid obesity with early mortality.
• Behavioral crises: Severe tantrums or impulsive behaviors may occur, and new-onset psychosis has been reported in some adolescents/adults with PWS. Any abrupt change in mental status or behavior warrants prompt psychiatric assessment.

1. Suspect PWS (genomic imprinting disorder) in a hypotonic infant or hyperphagic obese child with developmental delay.
2. Order DNA methylation analysis for 15q11-q13: if it shows maternal-only imprinting (no paternal contribution) → diagnosis of PWS is confirmed. Optionally perform FISH/microarray to identify deletion vs uniparental disomy.
3. After diagnosis, initiate multidisciplinary management: strict diet and activity plan to prevent obesity, growth hormone therapy, endocrine consultations (for puberty induction, thyroid/adrenal monitoring), and developmental/behavioral support services.

• Newborn with floppy tone, weak cry, poor feeding, and undescended testes → suspect Prader-Willi syndrome (paternal 15q deletion).
• An obese 8-year-old with insatiable appetite, short stature, small hands/feet, mild intellectual disability, and temper outbursts → Prader-Willi syndrome.