Prader-Willi syndrome (PWS) is a rare genetic disorder that affects appetite, metabolism, growth, and cognitive function. The condition presents a wide range of physical and behavioral symptoms that evolve from infancy through adulthood. PWS occurs in approximately one in every 15,000 to 30,000 births, affecting males and females of all ethnicities equally.
Genetic Origins of Prader-Willi Syndrome
Prader-Willi syndrome arises from the loss of function of specific genes located on chromosome 15. These genes are normally expressed only from the chromosome inherited from the father. This is due to a process called genomic imprinting, where certain genes are silenced depending on their parental origin. In PWS, the paternal copies of these genes are non-functional, and the maternal copies are normally silenced, resulting in a complete absence of their expression.
The condition is nearly always the result of a spontaneous genetic error, meaning it is not typically inherited. There are three primary genetic mechanisms that cause PWS. The most common, accounting for 60-70% of cases, is a deletion of the gene region on the paternal chromosome 15.
Another 25-30% of cases are caused by maternal uniparental disomy (UPD), where the individual inherits two copies of chromosome 15 from their mother and none from their father. A much rarer cause is an imprinting center defect, which involves a mutation in the area of chromosome 15 that controls the activation of the paternal genes.
Key Symptoms and Developmental Phases
The clinical presentation of Prader-Willi syndrome unfolds in two distinct phases. The initial phase begins at birth and is characterized by severe hypotonia, or weak muscle tone. Infants with PWS often feel “floppy” when held, have a weak cry, and display a general lethargy. This poor muscle tone impacts their ability to suck, leading to significant feeding difficulties and a failure to thrive, which may require tube feeding.
As the child grows, between the ages of two and six, the second phase begins, marked by a profound change in appetite. The defining symptom of this stage is hyperphagia, a chronic and insatiable feeling of hunger that is believed to stem from a dysfunction in the hypothalamus. Without strict external controls, this leads to overeating, rapid weight gain, and severe obesity. The metabolic rate in people with PWS is also lower than normal, which exacerbates the tendency to gain weight.
Developmental delays are common, with motor milestones and language development often lagging. Most individuals experience some degree of cognitive impairment, ranging from low-normal intelligence with learning disabilities to mild intellectual disability. Behavioral problems are also a common feature, including temper outbursts, stubbornness, and obsessive-compulsive tendencies like skin picking.
Distinctive physical features may also be present. Short stature is typical if not addressed with treatment, and sexual development is usually incomplete, leading to infertility. Other features include:
- Almond-shaped eyes
- A narrow forehead
- A thin upper lip
- Unusually small hands and feet
Diagnosis and Testing
The diagnosis of Prader-Willi syndrome is often first suspected based on its characteristic clinical symptoms, such as profound hypotonia and feeding difficulties in newborns. A definitive diagnosis requires genetic testing to confirm the underlying chromosomal abnormality, as standard chromosome tests are not reliable for detecting PWS.
The most effective initial test is a DNA methylation analysis. This specialized test can identify the abnormal parent-specific imprinting pattern on chromosome 15 that is the hallmark of the disorder. The DNA methylation test is highly accurate, detecting over 99% of all cases, regardless of the specific genetic cause.
While the methylation test confirms a PWS diagnosis, further genetic testing, such as a chromosome microarray or FISH, may be performed. These subsequent tests can determine the specific molecular cause, for example, by identifying whether the syndrome is due to a paternal deletion or maternal uniparental disomy. Knowing the genetic subtype can be useful for genetic counseling.
Management and Therapeutic Approaches
There is currently no cure for Prader-Willi syndrome, so management focuses on treating the symptoms and improving the individual’s quality of life. A primary part of PWS management is a highly structured and controlled nutritional plan to address hyperphagia and prevent obesity. This involves a strict, low-calorie diet and constant supervision to manage food-seeking behaviors. Ensuring food security, such as locking refrigerators and cupboards, is a common strategy for many families.
Growth hormone (GH) therapy is another component of treatment, typically started in infancy or early childhood. Daily injections of GH can significantly improve height, increase muscle mass, and decrease body fat. These changes in body composition can lead to improved muscle strength and physical activity levels. GH therapy may also have positive effects on development and behavior.
A team of specialists provides other therapies to address the wide-ranging symptoms. Physical, occupational, and speech therapy are used to help with developmental delays and coordination. Behavioral and psychological support can help manage challenging behaviors like temper outbursts and obsessive-compulsive tendencies. As individuals with PWS age, ongoing support from dietitians, endocrinologists, and mental health professionals remains part of their lifelong care plan.