From the Guidelines
Prader-Willi syndrome is a genetic disorder caused by the loss of function of specific genes on chromosome 15, primarily affecting the hypothalamus and leading to hypothalamic dysfunction that disrupts multiple body systems. The primary pathology involves the absence of gene expression from the paternal chromosome 15q11-q13 region, which can occur through three main mechanisms: paternal deletion, maternal uniparental disomy, or imprinting defects 1. This genetic abnormality affects the hypothalamus, leading to hypothalamic dysfunction that disrupts multiple body systems, including appetite regulation, growth hormone production, and sexual development.
The syndrome is characterized by:
- Hypotonia and poor feeding in infancy
- Excessive appetite and obesity in childhood
- Cognitive impairment
- Behavioral problems
- Hypogonadism
- Distinctive facial features
- Small hands and feet
- Short stature
The diagnosis of Prader-Willi syndrome should be considered in any infant with significant hypotonia, particularly in the setting of poor feeding, reduced spontaneous arousal for feeding, and hypogonadism 1. In older children, the diagnosis should be considered when there is impaired satiety for food, especially with rapid weight gain. Diagnostic testing for PWS should begin with methylation analysis to confirm the absence of paternally imprinted genes in the PWS region of chromosome 15 1.
Management of Prader-Willi syndrome includes growth hormone therapy, strict dietary control, and behavioral interventions, with early diagnosis and comprehensive management being essential to improve quality of life and prevent complications such as morbid obesity and its associated health problems. The diet must be quite calorically restricted, often to as little as 60% of the calories that similarly sized children without PWS might require for adequate growth, and requires careful attention to the balance of essential nutrients 1.
From the Research
Pathology of Prader-Willi Syndrome
The pathology of Prader-Willi syndrome (PWS) is a complex and multisystemic disorder involving the hypothalamus, caused by the loss of expression of paternally inherited genes in the chromosome 15q11-13 region 2, 3, 4. The estimated incidence of PWS is around 1 in 20,000 births 2.
Clinical Manifestations
The clinical manifestations of PWS change with age and include:
- Hypotonia and poor suck in infancy, resulting in failure to thrive 3, 4
- Short stature, food seeking with excessive weight gain, developmental delay, cognitive disability, and behavioral problems as the individual ages 2, 3, 4
- Hyperphagia, a deficit of satiety, and a high risk of severe obesity 2, 3, 4
- Intellectual disability, comprising cognitive deficit, delayed motor and language development, learning deficits, impaired social skills, and emotional regulation 2
- Behavioral features, including temper outbursts, anxiety, obsessive-compulsive symptoms, and rigidity, which become more apparent with increasing age 2, 5
Genetic Subtypes
There are three main genetic subtypes in PWS:
- Paternal 15q11-q13 deletion (65-75% of cases) 3
- Maternal uniparental disomy 15 (20-30% of cases) 3
- Imprinting defect (1-3% of cases) 3
Endocrine Abnormalities
PWS is associated with multiple endocrine abnormalities, including:
- Growth hormone deficiency 2, 3, 4
- Hypogonadism 2, 3, 4
- Central adrenal insufficiency (rare) 2
- Central hypothyroidism (up to 30% of children with PWS) 2
Treatment and Management
There is no specific treatment for PWS, and care consists of comprehensive management of feeding disorders, a restricted and controlled diet, regular exercise, hormone substitution, and screening and treatment of comorbidities 2. Growth hormone treatment has been shown to improve stature, body composition, and body mass index in PWS patients 6.