Prader-Willi Syndrome (PWS) is a genetic condition affecting development, growth, and metabolism. It is rare, occurring in approximately 1 in 10,000 to 30,000 births worldwide. The syndrome is characterized by physical, cognitive, and behavioral features that evolve throughout an individual’s life. This article explores how PWS came to be understood, from its initial clinical recognition to the identification of its genetic causes.
Early Clinical Observations
The initial clinical description of Prader-Willi Syndrome occurred in 1956. Three Swiss physicians, Andrea Prader, Heinrich Willi, and Alexis Labhart, published a paper describing a distinct set of symptoms observed in nine children. Working at the Zurich Children’s Hospital, their observations led them to identify this as a unique syndrome. Prader and Willi were pediatricians, and Labhart was an endocrinologist.
Key characteristics identified included weak muscle tone (hypotonia) in infancy, often leading to poor feeding and slow development. As these children grew, physicians observed a progression to excessive hunger (hyperphagia) and rapid weight gain, often resulting in obesity. Other features included short stature, small hands and feet, and varying degrees of intellectual disability. These consistent patterns helped establish PWS as a recognizable medical condition.
Identifying the Genetic Cause
While the clinical presentation of Prader-Willi Syndrome was recognized, its specific genetic basis remained unknown for decades. A breakthrough occurred in 1981 when Dr. David Ledbetter and his team discovered that many individuals with PWS had a missing segment of genes on chromosome 15. This deletion, located in the region 15q11-q13, accounts for approximately 70% of PWS cases.
Further research revealed PWS is an example of genomic imprinting, where certain genes are active only when inherited from a specific parent. In PWS, affected genes on chromosome 15 must be inherited from the father to function correctly. If the paternal copy of this region is deleted or inactive, the syndrome manifests because corresponding maternal genes in that region are naturally turned off.
Beyond paternal deletions, other genetic mechanisms can also cause Prader-Willi Syndrome. In 25% to 30% of cases, individuals inherit two copies of chromosome 15 from their mother and none from their father, known as maternal uniparental disomy (UPD). Rarely, the syndrome can also result from other genetic alterations that inactivate paternal genes on chromosome 15. These discoveries provide an understanding of PWS’s genetic origins, allowing for precise diagnostic testing.