119  Prada-Willi Syndrome

119.1 Introduction

Prader-Willi Syndrome (PWS) is a complex and rare genetic disorder that affects multiple systems in the body, leading to developmental, cognitive, and behavioral challenges. It is characterized by hypotonia (low muscle tone), feeding difficulties in infancy, hyperphagia (excessive hunger) in childhood and adulthood, and obesity-related complications. With proper management, individuals with PWS can lead healthier and more fulfilling lives.

119.2 Definition

Prader-Willi Syndrome is a genetic disorder caused by the loss of function of specific genes on the paternal copy of chromosome 15 (15q11-q13). It is considered the most common genetic cause of life-threatening obesity. Individuals with PWS often exhibit a characteristic phenotype, including short stature, intellectual disability, behavioral issues, and endocrine abnormalities.

119.3 Genetics

Prader-Willi Syndrome is most commonly caused by the absence of expression of paternally inherited genes on chromosome 15. Three main genetic mechanisms are responsible for PWS:

  1. Paternal Deletion (about 70% of cases): A segment of the paternal chromosome 15 is deleted, preventing normal gene expression.
  2. Maternal Uniparental Disomy (UPD) (about 25% of cases): The individual inherits two copies of chromosome 15 from the mother and none from the father.
  3. Imprinting Defects (1-3% of cases): Errors in genomic imprinting prevent proper gene activation. The region affected includes genes responsible for hypothalamic regulation, which plays a significant role in developing key features of the syndrome.

119.4 Clinical Features

Prader-Willi Syndrome presents a wide spectrum of clinical features that evolve throughout an individual’s life.

  1. Neonatal and Infancy:
    • Severe hypotonia (low muscle tone)
    • Poor feeding and weak suck, often requiring feeding support
    • Failure to thrive
    • Delayed developmental milestones
  2. Childhood and Adulthood:
    • Hyperphagia (uncontrollable hunger)
    • Rapid weight gain, leading to obesity if not managed
    • Short stature
    • Hypogonadism (underdeveloped sexual characteristics)
    • Intellectual disabilities and learning difficulties
    • Behavioral issues, such as temper tantrums and obsessive-compulsive tendencies
  3. Physical Features:
    • Almond-shaped eyes
    • Narrow forehead
    • Small hands and feet
    • Soft, fair skin
  4. Endocrine Abnormalities:
    • Growth hormone deficiency
    • Hypothyroidism
    • Insulin resistance
  5. Cognitive and Behavioral Features:
    • Mild to moderate intellectual disability
    • Obsessive-compulsive behaviors
    • Anxiety and mood instability
    • Sleep disturbances

119.5 Investigations

Clinical evaluation and genetic testing are essential for diagnosing Prader-Willi Syndrome.

  1. Genetic Testing:

    • Methylation Analysis: Detects all known causes of PWS by identifying the absence of paternal gene expression.
    • Fluorescence In Situ Hybridization (FISH): Detects deletions on chromosome 15.
    • DNA Microarray Analysis: Helps identify chromosomal abnormalities.
    • Uniparental Disomy Testing: Confirms cases due to maternal UPD.

  2. Hormonal Assessment:

    • Evaluation of growth hormone and thyroid function
    • Assessment of sex hormone levels

  3. Developmental and Cognitive Testing:

    • Psychological assessments for intellectual and behavioral evaluations

  4. Imaging Studies:

    • Brain MRI in cases with unusual neurological presentations

119.6 Treatment

Management of Prader-Willi Syndrome requires a comprehensive, multidisciplinary approach.

  1. Nutritional and Weight Management:

    • Controlled dietary intake to prevent obesity
    • Structured meal plans and avoidance of access to food
    • Close monitoring of weight and metabolic parameters

  2. Growth Hormone Therapy (GHT):

    • Improves growth, body composition, muscle tone, and possibly cognitive function

  3. Hormonal Replacement:

    • Testosterone for males and estrogen/progesterone for females to induce secondary sexual characteristics
    • Thyroid hormone replacement if needed

  4. Behavioral and Psychological Interventions:

    • Behavioral therapy for tantrums and obsessive-compulsive behaviors
    • Psychological counseling for anxiety and emotional instability

  5. Educational Support:

    • Special education services tailored to individual needs
    • Speech and occupational therapy for communication and motor skill development

  6. Physical Activity:

    • Encouragement of regular physical exercise to maintain muscle strength and control weight

  7. Sleep Management:

    • Treatment for sleep apnea, often present in individuals with obesity

  8. Pharmacological Treatments:

    • Medications for mood stabilization, anxiety, or behavioral management when necessary

119.7 Counseling

Genetic counseling plays a crucial role in supporting affected families and individuals.

  1. Diagnosis Counseling: Parents are guided through the genetic basis of the condition and its clinical implications.

  2. Reproductive Counseling:

    • Discussion of recurrence risks (less than 1% in most cases but higher if imprinting errors are present)
    • Prenatal testing options, such as chorionic villus sampling (CVS) and amniocentesis

  3. Psychosocial Support:

    • Addressing emotional and mental health challenges faced by families
    • Providing connections to support groups and advocacy organizations

119.8 Conclusion

Prader-Willi Syndrome is a complex genetic disorder that poses numerous challenges throughout an individual’s life. However, advances in genetic testing, growth hormone therapy, and behavioral interventions have greatly improved outcomes for affected individuals. A structured, multidisciplinary approach to care ensures that individuals with PWS can achieve their developmental potential and maintain better health. Ongoing research and awareness efforts remain essential to further understanding and improving the management of this rare condition.