Prader-Willi Syndrome (PWS) is a rare genetic disorder characterized by a distinctive biphasic clinical presentation. It affects an estimated one in 10,000 to 30,000 people globally and is the most common genetic cause of life-threatening obesity in children. Affected infants initially struggle with poor muscle tone and feeding difficulties. This is followed by the onset of an insatiable appetite, known as hyperphagia, in early childhood. PWS was only formally recognized in the mid-20th century, though isolated cases had been observed for decades.
Early Clinical Observations
Before PWS was defined as a distinct entity, medical literature contained scattered accounts of individuals exhibiting some of its recognized characteristics. As early as 1887, British physician John Langdon Down described a 14-year-old girl with mental impairment, small hands and feet, and significant weight issues. This is likely the first recorded documentation of a person with PWS. These early observations were fragmented, and clinicians did not yet connect the various symptoms into a single medical pattern.
Characteristics like profound low muscle tone (hypotonia) in infancy, developmental delays, and short stature were noted in individual case reports. However, the combination of these signs with the later development of excessive hunger was not understood as a single syndrome. These isolated reports merely documented unusual medical presentations rather than establishing a new clinical diagnosis.
The Defining 1956 Publication
The formal discovery of the syndrome is attributed to a landmark paper published in 1956 by a team of Swiss physicians. Andrea Prader, Heinrich Willi, and Alex Labhart, along with their colleagues, were the first to formally describe a consistent pattern of symptoms in a group of nine children. Their publication established a new clinical entity.
The doctors observed that the affected children shared a two-stage presentation. They all experienced severe hypotonia and feeding problems during infancy, often requiring feeding assistance. This initial phase was followed by the onset of hyperphagia and rapid weight gain in early childhood. The physicians grouped this combination of infantile hypotonia, intellectual disability, small hands and feet, obesity, and hypogonadism as a single, recognizable syndrome.
Locating the Genetic Origin
For decades after the 1956 description, the underlying cause of the condition remained a mystery, relying solely on clinical diagnosis. A major scientific breakthrough occurred in the early 1980s when researchers identified a genetic abnormality in people with the syndrome. They determined that a small section of genetic material was deleted from chromosome 15 in a significant percentage of patients.
The specific region involved is the long arm of chromosome 15, designated 15q11-q13. Studies in the 1980s and 1990s revealed the genetic mechanism behind the condition, known as genomic imprinting. This phenomenon means that certain genes are active only if they are inherited from a specific parent. In PWS, the genes in the 15q11-q13 region must be expressed from the copy inherited from the father.
The syndrome develops when the paternal copy of this specific region is missing or inactive. This loss of active paternal genes accounts for about 70% of cases, primarily due to a deletion. The remaining cases are often caused by maternal uniparental disomy. This occurs when a person inherits both copies of chromosome 15 from the mother, leaving no active paternal genes to express.
Evolution of Diagnosis and Management
The identification of specific genetic markers on chromosome 15 fundamentally changed the approach to diagnosis and care. Before this discovery, diagnosis relied purely on observing clinical symptoms, often delayed until the onset of hyperphagia and obesity. The genetic knowledge allowed for the development of specific diagnostic tests that confirm the condition with high accuracy.
Today, the standard diagnostic method is DNA methylation analysis, which detects all three molecular causes of PWS, including deletion and uniparental disomy. This testing enables diagnosis in newborns who present with only the initial symptom of profound hypotonia. An earlier diagnosis allows for immediate intervention, such as the prescription of recombinant growth hormone therapy. This therapy improves muscle mass, physical activity, and linear growth in children with the syndrome.