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  • Updated 05.10.2024
  • Released 01.24.1994
  • Expires For CME 05.10.2027

Prader-Willi syndrome

Introduction

Overview

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.

Key points

• Prader-Willi syndrome is a neurodevelopmental disorder characterized by infantile hypotonia, hypogonadism, obesity with hyperphagia, and characteristic facies.

• Prader-Willi syndrome is the most common genetic cause of severe obesity.

• Prader-Willi syndrome is an example of a genetic imprinting disorder resulting from lack of function in paternally inherited genes located at 15q11-q13.

• Management of Prader-Willi syndrome requires dietary, hormonal, developmental, and behavioral interventions.

Historical note and terminology

The first patient with Prader-Willi syndrome was described by John Langdon Down (who also described Down syndrome) in 1864. Prader, Labhart, and Willi published the first case series, describing nine children with infantile hypotonia, intellectual disability, hyperphagia with obesity, hypogonadism, and characteristic dysmorphic features in 1956 (138).

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 (102). However, the identification of patients without this deletion and the fact that Angelman syndrome, a distinct condition, shared the same deleted region (110) confused the issue.

In the mid 1980s, this dilemma was reconciled by the discovery of genomic imprinting–the concept that certain genes can be expressed differently depending on their parent of origin. Prader-Willi syndrome and Angelman syndrome became the first disorders identified as being caused by imprinting and have since been established as human models of the role of genomic imprinting in human disease (130). 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 two copies of a gene from one 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; 80).

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