Prader-Willi syndrome

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Prader-Willi Syndrome is a genetic disorder in which seven genes (or some subset thereof) on chromosome 15 are missing or unexpressed (chromosome 15q partial deletion). It was identified in 1956 by Andrea Prader, Heinrich Willi, Alexis Labhart, and Guido Fanconi of Switzerland. The incidence of PWS is between 1 in 12,000 and 1 in 15,000 live births.

Originally, PWS was diagnosed by clinical presentation and diagnosis was typically made later in life. Currently, infants are diagnosed through genetic testing. In fact, genetic testing for PWS is recommended for newborns with pronounced hypotonia. Early diagnosis of PWS allows for early intervention as well as the early prescription of growth hormone. Daily recombinant growth hormone (GH) shots are indicated for children with PWS. GH can be given from birth.

Traditionally, PWS is characterized by hyperphagia and food preoccupations, as well as small stature and mental retardation [link]. Early diagnosis and the administration of growth hormone appears to be having a dramatic effect, however, on clinical presentation of individuals with the syndrome. In 2000, the US Food and Drug Administration (FDA) approved the use of growth hormone treatment for treating symptoms related to PWS. Consequently, the cohort of infants treated with PWS from birth are at best kindergarten age. This group appears to be quite different from individuals who are untreated. While these differences have not yet been documented in a peer-reviewed study, anecdotal reports suggest that the three main characteristics of food preoccupation, mental retardation, and small stature may not become manifest when GH therapy is initiated in the first year of life.

Contents

1 Diagnosis/testing
2 PWS phenotype
3 Genetics
4 Neuro-cognitive
5 Endocrine
6 References
7 External links

Diagnosis/testing

PWS should be considered when presented with a hypotonic (floppy) newborn. Accurate consensus clinical diagnostic criteria exist, but the mainstay of diagnosis is genetic testing, specifically DNA-based methylation testing to detect the absence of the paternally contributed Prader-Willi syndrome/Angelman syndrome (PWS/AS) region on chromosome 15q11-q13. Such testing detects over 99% of patients. Methylation-specific testing is important to confirm the diagnosis of PWS in all individuals, but especially those who are too young to manifest sufficient features to make the diagnosis on clinical grounds or in those individuals who have atypical findings.

PWS phenotype

The classic PWS presentation includes:

short stature
small hands and feet
hypotonia and poor muscle development
excess fat, especially in the central portion of the body
narrow forehead
almond shaped eyes with thin, down-turned lips
light skin and hair relative to other family members
lack of complete sexual development in adolescence

Genetics

PWS is caused by absence of the paternally derived PWS/AS region of chromosome 15 (15q11-13) by one of several genetic mechanisms, including uniparental disomy, imprinting mutations, chromosome translocations, and gene deletions. The genes responsible for Prader-Willi syndrome are expressed only on the paternal chromosome. (Interestingly, a deletion on the maternal chromosome causes Angelman syndrome.) This is the first known instance of imprinting in humans, and is a fascinating model of this genetic phenomena.

The risk to the sibling of an affected child of having PWS depends upon the genetic mechanism which caused the disorder. The risk to siblings is <1% if the affected child has a gene deletion or uniparental disomy, up to 50% if the affected child has a mutation of the imprinting control center, and up to 25% if a parental chromosomal translocation is present. Prenatal testing is possible for any of the known genetic mechanisms.

Neuro-cognitive

Individuals with PWS are at risk for learning and attention difficulties.

Endocrine

There are several aspects of PWS that support the concept of growth hormone deficiency in individuals with PWS. Specifically, individuals with PWS have short stature, are obese with abnormal body composition, have reduced fat free mass (FFM), have reduced LBM and total energy expenditure, and have decreased bone density.

PWS is characterized by sex hormome deficiency. This is manifestd as undescended testes in males and benign premature adrenarchy in females. Testes may descend with time or can be managed with surgery or testosterone replacement. Adrenarchy may be treated with hormone replacement therapy.

References

Prader A, Labhart A, Willi H. Ein Syndrom von Adipositas, Kleinwuchs, Kryptorchismus und Oligophrenie nach Myatonieartigem Zustand im Neugeborenenalter (German: a syndrome of obesity, short stature, cryptorchism and oligophrenia after decreased muscle tone in an infant). Schweiz Med Wschr 1956;86:1260-1.

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