Prader-Willi Syndrome

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 microdeletions within chromosome 15 and determined it to be the site for Prader-Willi syndrome.3,4

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
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

Race

Differences in prevalence rates between racial groups have not been consistently reported. However, in a study of 10 blacks with Prader-Willi syndrome, Hudgins et al (1998) suggested that clinical features in black patients differ from those of white patients.25 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.
Clinical
History

* Infants with Prader-Willi syndrome (PWS) commonly exhibit hypotonia, poor suck (with requirement of gavage feedings), weak cry, and genital hypoplasia (eg, cryptorchidism, scrotal hypoplasia, clitoral hypoplasia).26 Neonatal hypotonia is one of the hallmark features of this disorder and is a valuable clue to initiate diagnostic testing.
* Toddlers with Prader-Willi syndrome demonstrate late acquisition of major motor milestones (eg, sitting at age 12 mo, walking at age 24 mo).
* Children aged 1-6 years present with symptoms of hyperphagia with progressive development of obesity.
* Short stature is generally present during childhood; a minority of patients present later with lack of pubertal growth spurt.27
* Sleep disturbances, ranging from central or obstructive sleep apnea to narcolepsy, are common.28 Exacerbation of obstructive sleep apnea shortly after initiation of growth hormone therapy is a recent concern.
* Most patients with Prader-Willi syndrome have growth hormone deficiency, as determined with provocative testing.27
* Pubic and axillary hair may grow prematurely in children with Prader-Willi syndrome, but other features of Prader-Willi syndrome are generally delayed or incomplete.27
* Testicular descent has occurred as late as in adolescence; menarche may occur as late as age 30 years in the presence of significant weight loss.27
* Patients with Prader-Willi syndrome often exhibit behavioral problems.29
o Young children exhibit temper tantrums, stubbornness, and obsessive-compulsive behaviors.
o Behavioral issues often compromise the level of academic performance. Obsessive-compulsive behaviors and perseveration are challenging for children with Prader-Willi syndrome in the classroom setting.30
o Features of psychosis are present in 5-10% of young adults with Prader-Willi syndrome.31
o Food-seeking behaviors may include eating garbage, eating frozen food, and stealing resources to obtain food. High thresholds for vomiting and pain tolerance can complicate binging on spoiled foods and delay treatment for GI disease. Death due to choking episodes has been reported.23 After episodes of binge eating (eg, at holidays), both thin and obese individuals with Prader-Willi syndrome have developed abdominal discomfort, with acute gastric dilation observed using radiography. Some patients have developed gastric necrosis.22
* Mild mental retardation is common.30
* Obesity complications (eg, sleep apnea, cor pulmonale, diabetes mellitus, atherosclerosis), hypogonadism (osteoporosis), and behavioral issues are common problems in adults with Prader-Willi syndrome.32

Physical

Holm et al established the following diagnostic criteria for Prader-Willi syndrome.33 Based on these guidelines, the diagnosis of Prader-Willi syndrome is highly likely in children younger than 3 years with 5 points (3 from major criteria) or in those older than 3 years with 8 points (4 from major criteria).

* Major criteria (1 point each)
o CNS - Infantile central hypotonia
o GI - Infantile feeding problems and/or failure to thrive
o Nutrition - Rapid weight gain in children aged 1-6 years
o Craniofacial - Characteristic facial features such as narrow bifrontal diameter, almond-shaped palpebral fissures, narrow nasal bridge, and down-turned mouth
o Endocrine - Hypogonadism
o Developmental - Developmental delay and/or mental retardation
* Minor criteria (one half point each)
o Neurologic - Decreased fetal movement and/or infantile lethargy
o Pulmonary - Sleep disturbance and/or sleep apnea
o Endocrine - Short stature for predicted height by mid adolescence
o Dermatologic - Hypopigmentation
o Orthopedic - Small hands and feet
o Orthopedic - Narrow hands with straight ulnar border
o Ophthalmologic – Esotropia and/or myopia
o Dental - Thick viscous saliva
o Otolaryngology - Speech articulation defects
o Psychiatric - Skin picking (Some patients with Prader-Willi syndrome have become anemic from chronic rectal bleeding secondary to skin picking.)
* Supportive criteria (no points)
o Neurology - High pain threshold and normal neuromuscular evaluation for hypotonia
o Gastroenterology - Decreased vomiting
o Endocrinology - Ineffective thermoregulation, early adrenarche, and/or osteoporosis, adrenal insufficiency27
o Orthopedics – Scoliosis or kyphosis34
o Developmental - Jigsaw puzzle proficiency33
Causes

* Prader-Willi syndrome is due to the loss of the paternal copy of chromosome 15q11.2-13.4
* Most cases of Prader-Willi syndrome are sporadic. More than 70% of patients have a deletion of the paternal copy; approximately 25% of patients with Prader-Willi syndrome have maternal uniparental disomy in chromosome 15. The remainder of patients with this disorder have a translocation or other structural alteration in chromosome 15.
* Most manifestations of Prader-Willi syndrome are attributable to hypothalamic dysfunction.