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. Characteristics that are commonly associated with this disorder include diminished fetal activity, obesity, hypotonia, intellectual disability, short stature, hypogonadotropic hypogonadism, strabismus, and small hands and feet. [1, 2]
Pathophysiology
Prader-Willi syndrome is the first human disorder to be attributed to genomic imprinting. In such conditions, 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. [3] Prader-Willi syndrome results from the loss of imprinted genomic material within the paternal 15q11.2-13 locus. [4] The loss of maternal genomic material at the 15q11.2-13 locus results in Angelman syndrome. [5]
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. [6, 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]
A report by Butler et al suggested that individuals with Prader-Willi syndrome have decreased mitochondrial function, with basal respiration, maximal respiratory capacity, and adenosine triphosphate (ATP)–linked respiration in the study differing significantly between Prader-Willi syndrome patients and healthy controls. [12]
The role of ghrelin in the satiety defect found in Prader-Willi syndrome is a subject of active investigation. Cummings et al reported significantly elevated ghrelin levels (4.5-fold higher) in individuals with Prader-Willi syndrome. [13] Haqq et al reported improvement in ghrelin levels after octreotide infusion but no significant improvement in postprandial suppression of ghrelin levels. [14] 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. [15]
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. [16] Butler reported a prevalence rate of 1 per 25,000 population. [17]
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. [18, 19] Despite findings that suggest a prevalence rate of 1 per 52,000 population in the United Kingdom, Whittington et al estimated that the actual prevalence rate is higher and proposed a true prevalence rate of 1 per 45,000 population. [20]
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 a patient aged 26 years with Prader-Willi syndrome. [21]
A study by Brito et al reported that in pediatric subjects with Prader-Willi syndrome, total heart rate variability during slow-wave sleep was lower than in obese-matched controls and sex- and age-matched lean controls. The investigators stated that during slow-wave sleep, the children with Prader-Willi syndrome experienced impaired cardiac autonomic balance as a result of reduced parasympathetic modulation. The study suggested that in patients with Prader-Willi syndrome, cardiovascular disease risk is greater even at an early age, with an underlying cause that exists independent of the effects of obesity. [22]
Wharton et al described a series of six patients with Prader-Willi syndrome with dramatic acute gastric distention preceded by symptoms of gastroenteritis. [23] 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 two children. Gastrectomy was performed in two 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 patients with Prader-Willi syndrome, with another four suspected cases of gastric necrosis. [24]
In a series of 152 patients with Prader-Willi syndrome, choking episodes were reported as the cause of death in 7.9%. [25]
Another series of patients noted eight children and two adults who had unexpected death, with small adrenal glands noted in three of eight children, raising suspicion for underlying adrenal insufficiency. [26] Subsequent studies have disputed the frequency of central adrenal insufficiency proposed by these authors, believing it to be a rare occurrence. [27]
Assessing a 40-year mortality survey from the Prader-Willi Syndrome Association (USA), Manzardo et al found measurable increases in survival in Prader-Willi syndrome with regard to cardiovascular- and gastrointestinal (GI)-related problems. The investigators said the change was probably the result of "earlier diagnosis and proactive interventions to prevent morbid obesity." [28]
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 suggested that clinical features in Black patients differ from those of White patients. [29] 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.
Prognosis
Patients with Prader-Willi syndrome frequently reach adulthood and are able to function in a group home setting.
Diminished sensitivity to pain and diminished capacity to vomit may delay the diagnosis of underlying disease (eg, appendicitis).
Complications from hypogonadism (eg, osteoporosis/pathologic fracture), behavioral issues (eg, temper tantrums, stubbornness, psychoses), and morbid obesity (eg, type 2 diabetes mellitus, cor pulmonale) may shorten life expectancy and may affect the quality of life.
Patients with Prader-Willi syndrome can be mainstreamed into the classroom environment. They require additional speech therapy to enhance verbal skills and should have additional physical activity periods in place of rest periods. These individuals require a structured environment and may need a smaller classroom size for individual attention.
Older children with Prader-Willi syndrome may enter vocational programs (with avoidance of food preparation). Some adults have attended community college.
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Severe typical scoliosis.
