Prader-Willi syndrome is a sporadic condition characterized by neonatal hypotonia, hypogonadism, and obesity. Small hands and feet, characteristic facies, developmental delays, growth hormone deficiency, and behavior problems are strongly associated with Prader-Willi syndrome. The explanation of how both Prader-Willi syndrome and Angelman syndrome could share the same deletion in chromosome 15q11-q13 established these disorders as human models of genomic imprinting and greatly enhanced our understanding of genetic diseases. Management of Prader-Willi syndrome requires a multidisciplinary team approach, including hormone therapies in combination with dietary, developmental, and behavioral interventions. There is no cure for Prader-Willi syndrome; however, clinical outcomes can be improved through targeted therapeutic interventions. Advances in our understanding of the complex genetic and molecular mechanisms underlying the pathophysiology of this condition may lead to new treatment options.
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• Prader-Willi syndrome is a neurodevelopmental disorder characterized by infantile hypotonia, hypogonadism, obesity with hyperphagia, and characteristic facies.
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• Prader-Willi syndrome is the most common genetic cause of severe obesity.
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• Prader-Willi syndrome is an example of a genetic imprinting disorder resulting from lack of function in paternally inherited genes located at 15q11-q13.
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• Management of Prader-Willi syndrome requires dietary, hormonal, developmental, and behavioral interventions.
Historical note and terminology
Prader-Willi syndrome, a condition characterized by infantile hypotonia, intellectual disability, hyperphagia with obesity, hypogonadism, and characteristic dysmorphic features, was first described by Prader, Labhart, and Willi in 1956 (135).
A quarter century later, the demonstration of a deletion in chromosome 15q11-q13 in 60% of patients with Prader-Willi syndrome suggested an etiology for this condition (100). However, the identification of patients without this deletion and the fact that Angelman syndrome, a distinct condition, shared the same deleted region (109) confused the issue, prompting some to doubt the importance of the cytogenetic deletion in this condition (180).
The clarification of this dilemma has been an important advance in our understanding of genetic disease. Prader-Willi syndrome and Angelman syndrome have been established as human models of the role of genomic imprinting in human disease (76; 110). Whether or not a given patient has Prader-Willi syndrome or Angelman syndrome depends on the sex of the parent with whom the deletion originates or on uniparental disomy, the inheritance of 2 copies of a gene from 1 parent. The differential expression of alleles in the 15q11-q13 region is the result of modification of maternal and paternal contributions to the zygote during gametogenesis (131; 78).