AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

INTRODUCTION

Section 2 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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 PWS as an adolescent girl with mental impairment, short stature, hypogonadism, and obesity and attributed these symptoms to polysarcia. In 1956, Prader et al reported a series of patients with similar phenotypes.¹ In 1981, Ledbetter et al identified microdeletions within chromosome 15 and determined it to be the site for PWS.²

Pathophysiology

PWS 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. PWS 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.

Most cases of PWS that involve deletions, unbalanced translocations, and uniparental (maternal) disomy are sporadic. Monozygotic twins are concordantly affected. Approximately 70% of PWS cases arise from deletion of band 15q11-13 on chromosome 15. Maternal uniparental disomy caused by chromosomal nondisjunction accounts for 28% of PWS cases. Less than 1% of patients have mutations isolated to the imprinting center, which carries a risk of recurrence. 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.³

Several genes have been mapped to the 15q11.2-13 region, including the SNRPN gene, P gene (type II oculocutaneous albinism), 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). Mutations associated with the maternal UBE3A gene result in Angelman syndrome.

The role of ghrelin in the satiety defect found in PWS is a subject of active investigation. In 2002, Cummings et al reported significantly elevated ghrelin levels (4.5-fold higher) in individuals with PWS.⁴ Haqq et al reported improvement in ghrelin levels after octreotide infusion but no significant improvement in postprandial suppression of ghrelin levels.⁵ After correction of relative hypoinsulinemia, Goldstone et al reported a residual 1.3- to 1.6-fold elevation in fasting ghrelin levels and a 1.2- to 1.5-fold elevation in postprandial ghrelin levels in adults with PWS.⁶

Frequency

United States

Most cases of PWS are sporadic. Burd et al reported a prevalence rate of 1 per 16,062 population.⁷ Butler reported a prevalence rate of 1 per 25,000 population.⁸

International

PWS has been reported worldwide. Reported prevalence rates for PWS range from 1 per 8000 population in rural Sweden to 1 per 16,000 population in western Japan.^{9, 10} 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.¹¹

Mortality/Morbidity

Complications due to obesity (eg, slipped capital femoral epiphyses, sleep apnea, cor pulmonale, diabetes mellitus type II) and behavioral problems are major contributors to morbidity and mortality in individuals with PWS (see Complications). Lamb et al reported premature development of atherosclerosis with severe coronary artery disease in an patient aged 26 years with PWS, morbid obesity, and non–insulin-dependent diabetes mellitus.¹²

Wharton et al described a series of 6 patients with PWS with dramatic acute gastric distention preceded by symptoms of gastroenteritis.¹³ 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. 

In a series of 152 patients with PWS, choking episodes were reported as the cause of death in 7.9%.¹⁴

Race

Differences in prevalence rates between racial groups have not been consistently reported. However, in a study of 10 African Americans with PWS, Hudgins et al (1998) suggested that clinical features in African American patients differ from those of white patients.¹⁵ In African American patients, growth is less affected, hand lengths are usually normal, and the facies are less typical.

Sex

PWS 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

PWS is a genetic disorder with lifelong implications.

CLINICAL

Section 3 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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). Neonatal hypotonia is one of the hallmark features of this disorder and is a valuable clue to initiate diagnostic testing.
• Toddlers with PWS 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.
• Sleep disturbances, ranging from central or obstructive sleep apnea to narcolepsy, are common. Exacerbation of obstructive sleep apnea shortly after initiation of growth hormone therapy is a recent concern.
• Most patients with PWS have growth hormone deficiency, as determined with provocative testing.
• Pubic and axillary hair may grow prematurely in children with PWS, but other features of PWS are generally delayed or incomplete.
• 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.
• Patients with PWS often exhibit behavioral problems.
  
  
  • Young children exhibit temper tantrums, stubbornness, and obsessive-compulsive behaviors.
  • Behavioral issues often compromise the level of academic performance. Obsessive-compulsive behaviors and perseveration provide challenges for the child with PWS in the classroom setting.
  • Features of psychosis are present in 5-10% of young adults with PWS.
  • 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 gastrointestinal disease. Death due to choking episodes has been reported. After episodes of binge eating (eg, at holidays), both thin and obese individuals with PWS have developed abdominal discomfort with acute gastric dilation observed using radiography. Some patients have developed gastric necrosis.
• Mild mental retardation is common.
• Obesity complications (eg, sleep apnea, cor pulmonale, diabetes mellitus, atherosclerosis), hypogonadism (osteoporosis), and behavioral issues are common problems in adults with PWS.

Physical

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

Causes

• PWS is due to the loss of the paternal copy of chromosome 15q11.2-13.
• Most cases of PWS are sporadic. More than 70% of patients have a deletion of the paternal copy; approximately 25% of patients with PWS 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 PWS are attributable to hypothalamic dysfunction.

DIFFERENTIALS

Section 4 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Other Problems to be Considered

Angelman syndrome
Scoliosis
Hypotonia
Bardet-Biedl syndrome
Cohen syndrome
Albright hereditary osteodystrophy

WORKUP

Section 5 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Lab Studies

• Genetic testing
• • Genetic testing for Prader-Willi syndrome (PWS) includes chromosomal analysis and assessment for methylation patterns in the PWS region.
  • Methylation patterns can be determined with Southern blot hybridization or polymerase chain reaction (PCR) using DNA primers that can detect methylated cytosine.
  • Analysis for underlying uniparental disomy requires samples from both parents and the child with PWS.
  • Fluorescent in situ hybridization (FISH) can be used to confirm prenatal diagnosis when a deletion in the 15q region is suspected after chorionic villus sampling or amniocentesis.
  • In a patient with an imprinting center mutation, test both biological parents for the presence of asymptomatic mutations in the imprinting center; such mutations indicate a higher risk for recurrence.
• Hypogonadism
• • Most patients with PWS have hypothalamic dysfunction that manifests as short stature, central obesity, hypogonadism, and osteoporosis.
  • Fasting measurements of serum insulinlike growth factor-1 (IGF-1) and insulinlike growth factor binding protein-3 (IGFBP-3) levels are good screening measurements for underlying growth hormone deficiency.
  • Refer patients with diminished growth velocity and abnormal levels of IGF-1 and IGFBP-3 to a pediatric endocrinologist for provocative growth hormone stimulation testing.
  • Assess thyroid and adrenal status in patients when clinically warranted.
  • Hypopituitarism has been reported in some patients with PWS.
• Obesity
  
  
  • Measure glycosylated hemoglobin inpatients with PWS who are obese to assess for the development of diabetes mellitus type II as clinically warranted, especially if the patient is taking growth hormone supplementation.
  • Evaluate patients with PWS for biochemical evidence of pickwickian syndrome (eg, hypercarbia, polycythemia) as clinically warranted.
  • If symptoms suggest sleep apnea or narcolepsy, perform a sleep study with multiple sleep latency testing.

Imaging Studies

• Individuals with PWS are at risk for pathologic fractures secondary to underlying osteoporosis. A high pain tolerance may allow for minimal symptoms of discomfort with obvious deformity. Patients with PWS may require the following imaging studies:
  
  
  • MRI of the head (to evaluate for hypopituitarism)
  • Serial dual energy x-ray absorptiometry (DEXA) scanning (for detection and monitoring of osteoporosis)
  • Scoliosis films
  • Chest radiography (if cor pulmonale is suspected)
  • Other imaging modalities as clinically dictated (eg, extremity film for limp evaluation)

• In patients who suddenly develop abdominal distension, abdominal pain, or a decrease in appetite, imaging including plain abdominal radiography, abdominal ultrasonography, or CT scanning and gastrointestinal series may be warranted to screen for possible conditions such as acute gastric dilation, cholelithiasis, or pancreatitis.

Procedures

• Assess the growth hormone axis and adrenal axis under the supervision of an endocrinologist if clinically warranted.

TREATMENT

Section 6 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical Care

• Patients with Prader-Willi syndrome (PWS) require medical care for the following:
  
  
  • Initial management of hypotonia or poor feeding
  • Evaluation for hypogonadism or hypopituitarism
  • Management of obesity
  • Monitoring for scoliosis
  • Therapy for behavioral issues
• On June 20, 2000, the US Food and Drug Administration (FDA) approved the use of growth hormone in children with genetically confirmed PWS and evidence of growth failure.

Surgical Care

• Patients with PWS may require surgical care for treatment of complications of obesity, treatment of cryptorchidism, and scoliosis intervention. They may require urgent surgical attention for abdominal issues. Because of the high pain tolerance and decreased ability to vomit, they may present late with symptoms of cholecystitis, appendicitis, or acute gastric dilation with risk for progression to necrosis.
• Tonsillectomy, adenoidectomy, or tracheostomy placement may be required in patients with obstructive sleep apnea.
• Biliopancreatic diversion and gastric bypass surgery have been ineffective for long-term weight reduction. Significant disruption in the enterohepatic circulation of bile acids may result in deficiencies of fat-soluble vitamins and steatorrhea with anal pruritus due to bile acids. Anal pruritus may exacerbate rectal-picking compulsions. Deficiencies of fat-soluble vitamins may exacerbate the following:
  
  
  • Osteoporosis (vitamin D)
  • Hypochromic anemia (vitamin E)
  • Hyporeflexia (vitamin E)
  • Spinocerebellar ataxia (vitamin E)
  • Coagulopathy (vitamin K)
  • Night blindness (vitamin A)
  • Enhanced susceptibility to infections (vitamin A)

Consultations

Patients with PWS may require the support of the following specialists:

• Geneticist for initial diagnosis and counseling
• Developmental pediatrician for stimulation programs
• Endocrinologist for management of hypogonadism
• Nutritionist for dietary counseling
• Ophthalmologist for management of strabismus
• Pulmonologist for management of sleep apnea
• Psychiatrist, psychologist, or both for management of behavioral issues

Diet

Patients with PWS have hyperphagia (onset in children aged 1-6 y) and diminished basal metabolic rate. Various treatment modalities for weight control, ranging from behavioral modification to anorexic agents, have been largely unsuccessful in curbing hyperphagia. However, these modalities may yield some success when used at group home settings.

• Significant dietary restrictions are not implemented during early childhood to ensure optimal myelination.
• Institution of a balanced hypocaloric diet (1000 calories with supplementation of vitamins and calcium) is generally implemented at early school age with careful monitoring by a dietitian.
• As children with PWS become ambulatory, limitation of access to foods is essential for modulation of weight. Placement of locks on cupboards and refrigerators, use of smaller dishes, and restriction of access to food in the school environment help deter excessive weight gain.
• In patients with morbid obesity, a protein-sparing modified fast with careful medical and nutritional supervision over several weeks may facilitate short-term weight loss.

Activity

Patients with PWS have hypotonia and require supplemental occupational and physical therapy to promote acquisition of gross and fine motor skills and to strengthen spinal musculature in order to minimize scoliosis. Encouragement of physical activity at home, at school (eg, increased physical education periods), and in the community (eg, Special Olympics) is essential for modulation of weight. Care providers should be instructed in the Heimlich maneuver.

MEDICATION

Section 7 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Currently, no medications have been found to effectively modify hyperphagia. Growth hormone therapy in patients with growth hormone deficiency improves lean body mass, corrects osteopenia, does not appear to enhance the development of scoliosis, and anecdotally modulates behavior in some patients. Supplementation of sex steroids does improve secondary sex characteristics but may aggravate behavioral disorders.

Drug Category: Growth hormone agents

These agents improve symptoms of growth hormone deficiency.

FOLLOW-UP

Section 8 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Further Inpatient Care

• Patients with Prader-Willi syndrome (PWS) may require inpatient evaluation and treatment for hypotonia and poor feeding during infancy.
• Individuals with PWS and other medical issues, including scoliosis and complications of obesity or pickwickian syndrome, may require inpatient therapy.
• Patients with severe behavioral problems may merit admission to a facility staffed with individuals with long-term experience with PWS.

Further Outpatient Care

• Further outpatient care is targeted toward management of hypogonadism, obesity, and behavioral issues.

Transfer

• Patients with PWS and significant behavioral issues recalcitrant to traditional therapies may benefit from transfer to a center, such as the Children's Institute in Pittsburgh, staffed with individuals with experience in treatment of people with PWS.

Deterrence/Prevention

• Patients with PWS have hyperphagia and require restricted access to foods to minimize weight gain. Binge-eating episodes may predispose patients to development of food poisoning and acute gastric dilation. Caregivers of patients with PWS should be instructed in the Heimlich maneuver.
• Evaluate males with PWS and cryptorchidism for gonadotropin-releasing hormone (GnRH) and orchiopexy.
• Routinely monitor for symptoms of sleep apnea. Obtaining a sleep study within the few months after initiation of growth hormone therapy at the first sign of symptoms.
• Routinely screen children for scoliosis.
• Regularly screen patients with obesity for evidence of diabetes mellitus type II.

Complications

• Patients with PWS can develop complications from the following:
  
  
  • Hypogonadism (osteoporosis/pathologic fractures)
  • Obesity due to hyperphagia and hypometabolism (secondary to hypopituitarism): This predisposes patients to premature death from cardiorespiratory failure.
  • Slipped capital femoral epiphyses
  • Sleep apnea: Patients with PWS have a primary disturbance in central control of the respiratory drive with diminished responsiveness to hypercapnia during quiet sleep.
  • Cor pulmonale
  • Diabetes mellitus type II
  • Neoplasias (eg, Wilms tumors, testicular neoplasias, endocrine [MEN 1] neoplasias, hematologic neoplasias [leukemia]): Various neoplasias have been rarely reported in patients with PWS.
  • Binge-eating episodes: These episodes may predispose patients to choking episodes (which require the Heimlich maneuver), acute gastric dilation with risk of gastric necrosis, and food poisoning from consumption of contaminated food.

Prognosis

• Patients with PWS frequently reach adulthood and are able to function in a group home setting, performing vocational work or attending community college classes.
• 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, diabetes mellitus type II, cor pulmonale) may shorten life expectancy and may affect the quality of life.
• Patients with PWS 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 PWS may enter vocational programs (with avoidance of food preparation). Some adults have attended community colleges.

MISCELLANEOUS

Section 9 of 10  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

Medical/Legal Pitfalls

• Potential medicolegal pitfalls involving care of patients with Prader-Willi syndrome (PWS) include failure to appropriately manage cryptorchidism, failure to appropriately manage obesity and its associated complications, and failure to appropriately investigate reports of pain or emesis.
  
  
• Patients with PWS have a very high threshold for pain and emesis; they can develop ipecac toxicity and have been known to have minimal reports of abdominal discomfort in the presence of significant gastrointestinal pathology such as pancreatitis, acute gastric dilation with necrosis, appendicitis, and cholecystitis.

Special Concerns

• The following Web sites provide excellent resources regarding PWS:

• Prader-Willi Syndrome Association
• Prader-Willi Syndrome Arizona Association
• Ontario Prader-Willi Syndrome Association
• Foundation for Prader-Willi Research (FPWR)
• International Prader-Willi Syndrome Organization

REFERENCES

Section 10 of 10

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• References

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Article Last Updated: Jul 19, 2007