Prader-Willi Syndrome

Updated: Dec 24, 2015
  • Author: Ann Scheimann, MD, MBA; Chief Editor: Luis O Rohena, MD  more...
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Overview

Background

Prader-Willi syndrome (PWS) is a disorder caused by a deletion or disruption of genes in the proximal arm of chromosome 15 or by maternal disomy in the proximal arm of chromosome 15. Commonly associated characteristics of this disorder include diminished fetal activity, obesity, hypotonia, mental retardation, short stature, hypogonadotropic hypogonadism, strabismus, and small hands and feet.

In 1887, Langdon Down described the first patient with Prader-Willi syndrome as an adolescent girl with mental impairment, short stature, hypogonadism, and obesity and attributed these symptoms to polysarcia. [1] In 1956, Prader et al reported a series of patients with similar phenotypes. [2] In 1981, Ledbetter et al identified deletions located between bands 15q11 and 15q13 and determined it to be the site for Prader-Willi syndrome. [3, 4]

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Pathophysiology

Prader-Willi syndrome is the first human disorder attributed to genomic imprinting. In such disorders, genes are expressed differentially based on the parent of origin. An imprinting center has been identified within 15q11-13; gene expression may be regulated by DNA methylation at cytosine bases. [5] Prader-Willi syndrome results from the loss of imprinted genomic material within the paternal 15q11.2-13 locus. The loss of maternal genomic material at the 15q11.2-13 locus results in Angelman syndrome. [6]

Most cases of Prader-Willi syndrome that involve deletions, unbalanced translocations, and uniparental (maternal) disomy are sporadic. Monozygotic twins are concordantly affected. Approximately 70% of Prader-Willi syndrome cases arise from deletion of band 15q11-13 on chromosome 15. Maternal uniparental disomy caused by chromosomal nondisjunction accounts for 28% of Prader-Willi syndrome cases. [7] Less than 1% of patients have mutations isolated to the imprinting center, which carries a risk of recurrence. [8] Buiting et al have suggested that deletions solely localized to the imprinting center may be due to a failure to erase the maternal imprint during spermatogenesis. [9]

Several genes have been mapped to the 15q11.2-13 region, including the SNRPN gene, P gene (type II oculocutaneous albinism), [10] UBE3A gene (encodes a ubiquitin-protein ligase involved in intracellular protein turnover), and necdin gene (codes for a nuclear protein expressed exclusively in the differentiated mouse brain). [11] Mutations associated with the maternal UBE3A gene result in Angelman syndrome. [9]

The role of ghrelin in the satiety defect found in Prader-Willi syndrome is a subject of active investigation. In 2002, Cummings et al reported significantly elevated ghrelin levels (4.5-fold higher) in individuals with Prader-Willi syndrome. [12] Haqq et al reported improvement in ghrelin levels after octreotide infusion but no significant improvement in postprandial suppression of ghrelin levels. [13] After correction of relative hypoinsulinemia, Goldstone et al reported a residual 1.3-fold to 1.6-fold elevation in fasting ghrelin levels and a 1.2-fold to 1.5-fold elevation in postprandial ghrelin levels in adults with Prader-Willi syndrome. [14]

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Epidemiology

Frequency

United States

Most cases of Prader-Willi syndrome are sporadic. Burd et al reported a prevalence rate of 1 per 16,062 population. [15] Butler reported a prevalence rate of 1 per 25,000 population. [16]

International

Prader-Willi syndrome has been reported worldwide. Reported prevalence rates for Prader-Willi syndrome range from 1 per 8000 population in rural Sweden to 1 per 16,000 population in western Japan. [17, 18] Despite findings that suggest a prevalence rate of 1 per 52,000 population in the United Kingdom, Whittington et al estimate that the actual prevalence rate is higher and propose a true prevalence rate of 1 per 45,000 population. [19]

Mortality/Morbidity

Complications due to obesity (eg, slipped capital femoral epiphyses, sleep apnea, cor pulmonale, type 2 diabetes mellitus) and behavioral problems are major contributors to morbidity and mortality in individuals with Prader-Willi syndrome (see Complications). Lamb et al reported premature development of atherosclerosis with severe coronary artery disease in an patient aged 26 years with Prader-Willi syndrome, morbid obesity, and non–insulin-dependent diabetes mellitus. [20]

Wharton et al described a series of 6 patients with Prader-Willi syndrome with dramatic acute gastric distention preceded by symptoms of gastroenteritis. [21] One half of the cases rapidly progressed to massive gastric dilatation and gastric necrosis. One patient died of overwhelming sepsis and disseminated intravascular coagulation. Gastric dilatation spontaneously resolved in 2 children. Gastrectomy was performed in 2 patients; in one patient, gastrectomy was subtotal and distal, whereas in the other patient, gastrectomy was combined with partial duodenectomy and pancreatectomy. An autopsy series by Stevenson et al reported gastric rupture and necrosis as the confirmed cause of death in 3% of the patients with Prader-Willi syndrome, with another 4 suspected cases of gastric necrosis. [22]

In a series of 152 patients with Prader-Willi syndrome, choking episodes were reported as the cause of death in 7.9%. [23]

Another series of patients noted 8 children and 2 adults who had unexpected death, with small adrenal glands noted in 3 of 8 children, raising suspicion for underlying adrenal insufficiency. [24] Subsequent studies have disputed the frequency of central adrenal insufficiency proposed by these authors, believing it to be a rare occurrence. [25]

Race

Differences in prevalence rates between racial groups have not been consistently reported. However, in a study of 10 black patients with Prader-Willi syndrome, Hudgins et al (1998) suggested that clinical features in black patients differ from those of white patients. [26] In black patients, growth is less affected, hand lengths are usually normal, and the facies are less typical.

Sex

Prader-Willi syndrome is caused by the loss of the paternal copy in the proximal arm of chromosome 15 in the region of 15p11-13. Differences in prevalence rates between sexes have not been reported.

Age

Prader-Willi syndrome is a genetic disorder with lifelong implications.

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