Prader-Willi syndrome

Peter Humphreys MD (Dr. Humphreys of the University of Ottawa and Children's Hospital of Eastern Ontario has no relevant financial relationships to disclose.)
Harvey B Sarnat MD FRCPC MS, editor. (Dr. Sarnat of the University of Calgary has no relevant financial relationships to disclose.)
Originally released January 24, 1994; last updated November 28, 2016; expires November 28, 2019

This article includes discussion of Prader-Willi syndrome, HHHO, Prader-Labhart-Willi syndrome, and hypotonia-hypomentia-hypogonadism-obesity syndrome. The foregoing terms may include synonyms, similar disorders, variations in usage, and abbreviations.

Overview

Prader-Willi syndrome is a sporadic condition characterized by neonatal hypotonia, hypogonadism, obesity, mental retardation, small hands and feet, and characteristic facies. 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 advanced understanding of genetic diseases. In this update, the most intriguing development reported by the author is the increasing evidence that, among the several paternally expressed genes at 15q11-q13 that have been hypothesized to play varying roles in the pathogenesis of Prader-Willi syndrome, the most important may be the small nucleolar cluster SNORD116. Mutations confined to SNORD116 have been found to result in a typical Prader-Will syndrome phenotype in humans. A Snord116-null mouse model has now been developed that also manifests the Prader-Willi phenotype. In fact, the same phenotype can also be reproduced by selectively deleting Snord116 in neuropeptide Y (NPY) neurons. From the clinical standpoint, the most exciting addition is a study reporting a significant improvement in social and food-related behavior in children aged 10 and under who had been treated with twice daily intranasal oxytocin for 4 weeks. The latter study reproduced the findings in a previously published study employing a mouse model.

Key points

 

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

 

• Prader-Willi syndrome has a characteristic clinical presentation consisting of severe neonatal hypotonia and feeding difficulties followed, after 1 year of age, by insatiable hyperphagia, developmental delay, and behavioral disturbances.

 

• As a result of hypothalamic dysfunction, individuals with Prader-Willi syndrome demonstrate impaired pituitary function manifested, variously, as hypogonadism, growth failure, and adrenocortical insufficiency.

 

• Typically a sporadic disorder, Prader-Willi syndrome results from lack of function in 1 or more paternally inherited genes located at 15q11-q13, either as a result of deletion of the paternal copy or due to maternal uniparental disomy (in which both copies of the 15q11-q13 region are of maternal origin and inactivated).

 

• Extreme obesity in Prader-Willi syndrome may be avoided by strict control of dietary intake; the marked restriction in linear growth responds well to growth hormone supplementation.

Historical note and terminology

Prader-Willi syndrome, a condition characterized by infantile hypotonia, mental retardation, hyperphagia with obesity, hypogonadism, and characteristic dysmorphic features, was first described by Prader, Labhart, and Willi in 1956 (Prader et al 1956).

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 (Ledbetter et al 1981). However, the identification of patients without this deletion and the fact that Angelman syndrome, a distinct condition, shared the same deleted region (Magenis et al 1987) confused the issue, prompting some to doubt the importance of the cytogenetic deletion in this condition (Zellweger et al 1987).

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 (Hall 1990; Magenis et al 1990). 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 (Nicholls et al 1999; Hanel and Wevrick 2001).

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