Prader–Willi syndrome

Overview

Prader–Willi syndrome (PWS) is a complex genetic disorder that affects multiple body systems. It is characterized by hypotonia (low muscle tone), feeding difficulties in infancy, followed by excessive appetite (hyperphagia) and obesity in early childhood, intellectual disability, behavioral challenges, and short stature. PWS is caused by abnormalities on chromosome 15 and is considered one of the most common genetic causes of life-threatening obesity in children. The syndrome affects approximately 1 in 10,000 to 30,000 live births and occurs equally in males and females.

Causes

Prader–Willi syndrome is caused by a lack of expression of specific genes in the paternal copy of the 15q11-q13 region of chromosome 15. There are three main genetic mechanisms by which this can occur:

• Paternal deletion (about 70% of cases): A segment of the father’s chromosome 15 is missing, including genes that are normally active only on the paternal side.

• Maternal uniparental disomy (UPD, about 25% of cases): The child inherits two copies of chromosome 15 from the mother and none from the father.

• Imprinting defect (less than 5% of cases): A defect in the imprinting center prevents the paternal genes from being activated, even though they are present.

The result in all cases is the absence of active paternal genes in the critical region of chromosome 15, leading to the clinical features of the syndrome.

Symptoms

Prader–Willi syndrome presents with distinct features that evolve over time. Symptoms may vary but generally follow a predictable progression:

Infancy

• Severe hypotonia (low muscle tone)

• Poor sucking reflex and feeding difficulties

• Failure to thrive and delayed developmental milestones

Childhood and Beyond

• Hyperphagia and obesity: Uncontrollable appetite begins around age 2-4 and can lead to morbid obesity if not managed

• Short stature: Often due to growth hormone deficiency

• Developmental delays: Including speech and motor skills

• Intellectual disability: Usually mild to moderate

• Behavioral problems: Including temper outbursts, stubbornness, compulsive behaviors, and skin picking

• Hypogonadism: Underdeveloped sex organs, delayed or incomplete puberty, and infertility

• Distinct facial features: Narrow forehead, almond-shaped eyes, thin upper lip, and downturned mouth

• Sleep disturbances: Including sleep apnea and excessive daytime sleepiness

Diagnosis

Early diagnosis of PWS is crucial for timely intervention. Diagnostic evaluation includes:

• Clinical assessment: Based on physical findings and feeding problems in infancy

• Genetic testing: Essential for confirming the diagnosis

• Methylation analysis: Detects absence of paternal gene expression in the 15q11-q13 region (identifies >99% of cases)

• FISH (fluorescence in situ hybridization): Can detect deletions in the paternal chromosome

• Chromosomal microarray: Identifies deletions and can assist in differentiating between PWS and other conditions

• DNA polymorphism analysis: Used to determine uniparental disomy or imprinting defects

Treatment

There is no cure for Prader–Willi syndrome, but a comprehensive treatment plan can significantly improve outcomes. Management typically involves a multidisciplinary team, including pediatricians, endocrinologists, nutritionists, therapists, and behavioral specialists.

Medical Interventions

• Growth hormone therapy: Improves height, body composition, and muscle tone

• Sex hormone replacement: For delayed or incomplete puberty

• Monitoring for complications: Including diabetes, scoliosis, sleep apnea, and hypothyroidism

Nutritional Management

• Strict dietary supervision to prevent obesity

• Low-calorie diet with restricted access to food

• Supervised meal times and environmental controls (e.g., locking pantries)

Developmental and Behavioral Support

• Early intervention with physical, occupational, and speech therapy

• Special education plans tailored to individual needs

• Behavioral therapy to manage emotional and compulsive behaviors

• Psychological support for both patients and caregivers

Prognosis

The prognosis for individuals with Prader–Willi syndrome depends largely on the management of obesity and associated complications. With early diagnosis and comprehensive care, many individuals can achieve a good quality of life and participate in school, community, and supported work environments. However, without appropriate interventions, severe obesity can lead to life-threatening complications such as type 2 diabetes, cardiovascular disease, and respiratory failure. Lifelong monitoring and support are essential. Continued research and advances in genetic therapies may offer improved outcomes in the future.