AUTHOR INFORMATION

Section 1 of 11

Authored by Ann Scheimann, MD MBA, Assistant Professor, Department of Pediatrics, Section of Nutrition and Gastroenterology, Baylor College of Medicine and Johns Hopkins Medical Institution

Ann Scheimann, MD MBA, is a member of the following medical societies: North American Society for Pediatric Gastroenterology and Nutrition

Edited by Michael Fasullo, PhD, Associate Professor, Center for Immunology and Microbial Disease, Albany Medical College; Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine.com, Inc; Robert Anthony Saul, MD, Senior Clinical Geneticist, Greenwood Genetic Center; Clinical Professor, Department of Pediatrics, University of South Carolina; Paul D Petry, DO, FACOP, FAAP, Clinical Assistant Professor of Pediatrics, University of North Dakota, School of Medicine and Health Sciences; Consulting Staff, Altru Health System; and Bruce A Buehler, MD, Professor, Department of Pathology and Microbiology, Chairman, Department of Pediatrics, Director, Hattie B Munroe Center for Human Genetics, University of Nebraska Medical Center

Author's Email:	Ann Scheimann, MD MBA
Editor's Email:	Michael Fasullo, PhD

eMedicine Journal, March 30 2006, VOLUME 7, Number 3

INTRODUCTION

Section 2 of 11

Background: Prader-Willi syndrome (PWS) is a chromosomal microdeletion/disomy disorder arising from deletion or disruption of genes in the proximal arm of chromosome 15 or maternal disomy of 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 labeled her as having polysarcia. Prader et al reported a series of patients with similar phenotypes in 1956. In 1981, Ledbetter et al identified microdeletions within chromosome 15 as the site for PWS.

Pathophysiology: PWS is the first human disorder attributed to genomic imprinting. In disorders attributed to genomic imprinting, genes are expressed differentially based upon the parent of origin. An imprinting center has been identified within 15q11-13; gene expression may be regulated by DNA methylation at cytosine bases. 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.

Most cases of PWS involving deletions, unbalanced translocations, and uniparental (maternal) disomy occur sporadically. Monozygotic twins are concordantly affected. Approximately 70% of cases of PWS arise from deletion of band 15q11-13 on chromosome 15. Twenty-eight percent of cases of PWS arise from maternal uniparental disomy caused by chromosomal nondisjunction. Fewer than 1% of patients have mutations isolated to the imprinting center, which does have a risk of recurrence. Research by Buiting et al has suggested that deletions solely localized to the imprinting center may arise from a failure to erase the maternal imprint during spermatogenesis.

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. Haqq et al reported improvement in ghrelin levels after infusion of octreotide but no significant improvement in postprandial suppression of ghrelin levels. After correction for relative hypoinsulinemia, Goldstone et al reported a residual 1.3 to 1.6-fold elevation in fasting and 1.2 to 1.5-fold elevation in postprandial ghrelin levels in adults with PWS.

Frequency:

• In the US: Most cases of PWS are sporadic in occurrence. Rate of prevalence has been reported to be 1 per 16,062 by Burd et al and 1 per 25,000 by Butler.

• Internationally: Cases of PWS have been reported worldwide. Reported prevalence rates for PWS range from 1 per 8000 in rural Sweden to 1 per 16,000 in Western Japan. Recent data from Whittington et al in the United Kingdom estimates a lower limit of population prevalence of 1 in 52,000 with a proposed true prevalence of 1 in 45,000.

Mortality/Morbidity: Complications from obesity (eg, slipped capital femoral epiphyses, sleep apnea, cor pulmonale, type II diabetes mellitus) and behavioral problems are major contributors to morbidity and mortality of PWS (see Complications). Lamb et al previously reported premature development of atherosclerosis with severe coronary artery disease in an individual aged 26 years with PWS, morbid obesity, and non–insulin-dependent diabetes mellitus. Wharton et al described a series of 6 patients with PWS with dramatic acute gastric distention preceded by symptoms of "gastroenteritis" with rapid progression in one half of the cases to massive gastric dilatation and gastric necrosis. One patient died of overwhelming sepsis and disseminated intravascular coagulation. In 2 children, gastric dilatation resolved spontaneously. Gastrectomy was performed in 2 patients; in 1 patient, gastrectomy was subtotal and distal, whereas in the other patient, gastrectomy was combined with partial duodenectomy and pancreatectomy.

Race: Differences in prevalence between racial groups have not been consistently reported, but a study of 10 African Americans with PWS by Hudgins et al (1998) pointed out that the clinical features differ from those of white patients. Growth is less affected, hand lengths usually are normal, and the facies are less typical.

Sex: PWS arises from loss of the paternal copy of the proximal arm of chromosome 15 in the region of 15p11-13. Differences in prevalence between sexes have not been reported.

Age: PWS is a genetic disorder with lifelong implications for the individual who is affected with PWS.

CLINICAL

Section 3 of 11

History:

• Infants with 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 months, walking at age 24 months).



• Children aged 1-6 years manifest 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.



• Most patients with PWS have growth hormone deficiency, as determined by provocative testing.



• Pubic and axillary hair may arise prematurely in children with PWS, but other features of PWS generally are delayed or incomplete.



• Testicular descent has occurred as late as 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 manifest 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.
  
  
  
  • Of young adults with PWS, 5-10% demonstrate features of psychosis.
  
  
  
  • Food seeking behaviors may include eating garbage, eating frozen food, and stealing resources to obtain food. High thresholds for vomiting and tolerance of pain can complicate binging on spoiled foods and delay treatment for gastrointestinal disease. After episodes of binge eating (eg, at holidays), both thin and obese individuals with PWS have developed abdominal discomfort with acute gastric dilation seen on radiography. Some patients have progressed on to develop gastric necrosis.
  
  
  
• Mild mental retardation is a commonly associated characteristic.



• Management of complications of obesity (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 Prader-Willi syndrome. Based upon 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
  
  
  
  • GI - 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/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/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/kyphosis

  • Developmental - Jigsaw puzzle proficiency
  
  
  

Causes:

• PWS results from the loss of the paternal copy of chromosome 15 q11.2-13.



• Most cases of PWS arise sporadically. More than 70% of patients have a deletion of the paternal copy; approximately 25% of patients with PWS have maternal uniparental disomy for 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 11

Failure to Thrive
Fragile X Syndrome
Growth Hormone Deficiency
Hypogonadism
Obesity
Obesity-Hypoventilation Syndrome and Pulmonary Consequences of Obesity
Obstructive Sleep Apnea Syndrome
Osteoporosis
Short Stature
Sleep Apnea

Other Problems to be Considered:

Angelman syndrome
Obsessive-compulsive disorder
Scoliosis
Hypotonia
Bardet-Biedl syndrome
Cohen syndrome
Albright hereditary osteodystrophy
Cryptorchidism

WORKUP

Section 5 of 11

Lab Studies:

• Genetic testing for PWS includes chromosome analysis and assessment for methylation patterns in the PWS region.


• • Methylation patterns can be determined by Southern blot hybridization or by 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 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.
  
  
  
• Evaluation for hypogonadism: Most patients with PWS exhibit hypothalamic dysfunction via short stature, central obesity, hypogonadism, and osteoporosis.


• • Measurements of insulinlike growth factor-1 (IGF-1) and insulinlike growth factor binding protein-3 (IGFBP-3) levels from fasted serum 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 those when clinically warranted.
  
  
  
  • Hypopituitarism has been reported in some patients with PWS.
  
  
  
• Monitoring for complications of obesity


• • Screen obese patients with PWS for the development of type II diabetes mellitus with glycosylated hemoglobin as clinically warranted (especially if the patient is taking growth hormone supplementation).
  
  
  
  • Evaluate the patient with PWS for biochemical evidence of pickwickian syndrome (eg, hypercarbia, polycythemia) as clinically warranted.
  
  
  

Imaging Studies:

• Patients with PWS are at risk for pathologic fractures secondary to underlying osteoporosis. 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 x-ray (if cor pulmonale is suspected)
  
  
  
  • Other imaging modalities may be required as clinically dictated (eg, extremity film for limp evaluation).
  
  
  
  • In patients with sudden development of abdominal distension, complaints of abdominal pain, or decrease in appetite, imaging including plain abdominal radiographs, abdominal ultrasonography, or CT/GI 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 11

Medical Care:

• Patients with PWS require medical care for the following:


• • Initial management of hypotonia/poor feeding
  
  
  
  • Evaluation for hypogonadism/hypopituitarism
  
  
  
  • Management of obesity
  
  
  
  • Monitoring for scoliosis

  • Therapy for behavioral issues
  
  
  
• As of June 20, 2000, the FDA has 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 low pain threshold 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 has 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 produce worsening of 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 and/or psychologist 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, yet these modalities might 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) generally is 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/refrigerators, utilization of smaller dishes, and restriction of access to food in the school environment help deter excessive weight gain.



• For 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 through the community (eg, Special Olympics) is essential for modulation of weight.

MEDICATION

Section 7 of 11

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 -- Improve symptoms of growth hormone deficiency.

Drug Name	Human growth hormone (Saizen, Genotropin, Humatrope, Norditropin, Nutropin) -- Stimulates growth of linear bone, skeletal muscle, and organs. Stimulates erythropoietin which increases red blood cell mass.
Pediatric Dose	0.15-0.3 mg/kg/wk SC initially; divide into daily or 6 times/wk subcutaneous injections; adjust dose to effect
Contraindications	Documented hypersensitivity; closed epiphyses, actively growing intracranial tumor, any underlying intracranial lesion
Interactions	Glucocorticoids may decrease growth promoting effects
Pregnancy	C - Safety for use during pregnancy has not been established.
Precautions	Caution in diabetes; reconstitute with sterile water for injection if administering to newborns

FOLLOW-UP

Section 8 of 11

Further Inpatient Care:

• Patients with Prader-Willi syndrome 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 and/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 people 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.



• Evaluate males with PWS and cryptorchidism for gonadotropin-releasing hormone (GnRH) and/or orchiopexy.



• Screen children routinely for scoliosis.



• Regularly screen obese patients for evidence of diabetes mellitus type II.

Complications:

• Patients with PWS can develop complications from the following:


• • Hypogonadism (osteoporosis/pathologic fractures)
  
  
  
  • Obesity arising from hyperphagia and hypometabolism (secondary to hypopituitarism) predisposes patients with this disorder to premature death from cardiorespiratory failure.
  
  
  
  • Slipped capital femoral epiphyses
  
  
  
  • Sleep apnea: Patients with PWS have a primary disturbance in central control of 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]) have been reported (rarely) in patients with PWS.
  
  
  
  • Binge eating episodes may predispose patients to choking episodes requiring use of 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 impact on 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 11

Medical/Legal Pitfalls:

• Potential medicolegal pitfalls involving care of patients with Prader-Willi syndrome involve failure to appropriately manage cryptorchidism, failure to appropriately manage obesity and its associated complications, and failure to appropriately investigate complaints 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 complaints of abdominal discomfort in the presence of significant GI pathology such as pancreatitis, acute gastric dilation with necrosis, appendicitis, and cholecystitis.

Special Concerns:

• The following web sites are excellent resources on Prader-Willi syndrome:


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

TEST QUESTIONS

Section 10 of 11

CME Question 1: Which of the following is the most common cause for the development of Prader-Willi syndrome (PWS)?

A: Deletion of 15q11-13
B: Paternal disomy
C: Translocation
D: Trisomy 15q
E: None of the above

The correct answer is A: The most common cause of PWS is deletion of 15q11-13. Maternal disomy of 15q11-13 results in Angelman syndrome. Translocations and trisomy are uncommon causes of PWS.

CME Question 2: Which of the following is not a commonly observed manifestation of Prader-Willi syndrome (PWS) during infancy?

A: Central hypotonia
B: Hyperphagia
C: Cryptorchidism
D: Strabismus
E: Facies with narrow bifrontal diameter and down-turned mouth

The correct answer is B: Infants with PWS frequently have hypotonia, poor oral suck requiring gavage feedings, and small hands and feet. Males with Prader-Willi syndrome commonly present with undescended testicles. Symptoms of hyperphagia manifest in children with this disorder who are aged 1-6 years. Restriction of caloric intake is not instituted during early childhood to allow for growth and myelination.

Pearl Question 1 (T/F): Gastric bypass frequently is successful for long-term management of obesity in the individual with Prader-Willi syndrome (PWS).

The correct answer is False: Surgical treatments for morbid obesity in the patient with PWS may allow for short-term weight loss followed by eventual reaccumulation of weight.

Pearl Question 2 (T/F): A minority of patients with Prader-Willi syndrome (PWS) exhibit gonadal dysfunction.

The correct answer is False: The majority of patients with PWS exhibit gonadal dysfunction manifested by osteoporosis, delayed menarche, and cryptorchidism.

Pearl Question 3 (T/F): Patients with Prader-Willi syndrome (PWS) respond well to appetite suppressive agents.

The correct answer is False: Patients with Prader-Willi syndrome have hypothalamic obesity and generally respond poorly to appetite suppressive therapies.

Pearl Question 4 (T/F): Patients with Prader-Willi syndrome (PWS) commonly present with symptoms of cyclic vomiting.

The correct answer is False: Patients with PWS have a high threshold for pain and rarely vomit, which frequently delays the diagnosis of organic disease.

BIBLIOGRAPHY

Section 11 of 11

• Akefeldt A, Gillberg C, Larsson C: Prader-Willi syndrome in a Swedish rural county: epidemiological aspects. Dev Med Child Neurol 1991 Aug; 33(8): 715-21[Medline].
• Buiting K, Saitoh S, Gross S, et al: Inherited microdeletions in the Angelman and Prader-Willi syndromes define an imprinting centre on human chromosome 15. Nat Genet 1995 Apr; 9(4): 395-400[Medline].
• Buiting K, Gross S, Lich C, et al: Epimutations in Prader-Willi and Angelman syndromes: a molecular study of 136 patients with an imprinting defect. Am J Hum Genet 2003 Mar; 72(3): 571-7[Medline].
• Burd L, Vesely B, Martsolf J, Kerbeshian J: Prevalence study of Prader-Willi syndrome in North Dakota. Am J Med Genet 1990 Sep; 37(1): 97-9[Medline].
• Butler MG: Molecular diagnosis of Prader-Willi syndrome: comparison of cytogenetic and molecular genetic data including parent of origin dependent methylation DNA patterns. Am J Med Genet 1996 Jan 11; 61(2): 188-90[Medline].
• Cassidy SB, Schwartz S: Prader-Willi and Angelman syndromes. Disorders of genomic imprinting. Medicine (Baltimore) 1998 Mar; 77(2): 140-51[Medline].
• Coppes MJ, Sohl H, Teshima IE, et al: Wilms tumor in a patient with Prader-Willi syndrome. J Pediatr 1993 May; 122(5 Pt 1): 730-3[Medline].
• Cummings DE, Clement K, Purnell JQ, et al: Elevated plasma ghrelin levels in Prader Willi syndrome. Nat Med 2002 Jul; 8(7): 643-4[Medline].
• Diagnostic testing for Prader-Willi and Angleman syndromes: Report of the ASHG/ACMG Test and Technology Transfer Committee. Am J Hum Genet 1996 May; 58(5): 1085-8[Medline].
• Down JL: Mental Affections of Childhood and Youth. 1887:172.
• Dykens EM, Hodapp RM, Walsh K, Nash LJ: Profiles, correlates, and trajectories of intelligence in Prader-Willi syndrome. J Am Acad Child Adolesc Psychiatry 1992 Nov; 31(6): 1125-30[Medline].
• Ehara H, Ohno K, Takeshita K: Frequency of the Prader-Willi syndrome in the San-in district, Japan. Brain Dev 1995 Sep-Oct; 17(5): 324-6[Medline].
• Glenn CC, Saitoh S, Jong MT, et al: Gene structure, DNA methylation, and imprinted expression of the human SNRPN gene. Am J Hum Genet 1996 Feb; 58(2): 335-46[Medline].
• Goldstone AP, Patterson M, Kalingag N, et al: Fasting and postprandial hyperghrelinemia in Prader-Willi syndrome is partially explained by hypoinsulinemia, and is not due to peptide YY3-36 deficiency or seen in hypothalamic obesity due to craniopharyngioma. J Clin Endocrinol Metab 2005 May; 90(5): 2681-90[Medline].
• Greenswag LR: Adults with Prader-Willi syndrome: a survey of 232 cases. Dev Med Child Neurol 1987 Apr; 29(2): 145-52[Medline].
• Gurd AR, Thompson TR: Scoliosis in Prader-Willi syndrome. J Pediatr Orthop 1981; 1(3): 317-20[Medline].
• Hall BD: Leukaemia and the Prader-Willi syndrome. Lancet 1985 Jan 5; 1(8419): 46[Medline].
• Haqq AM, Stadler DD, Rosenfeld RG, et al: Circulating ghrelin levels are suppressed by meals and octreotide therapy in children with Prader-Willi syndrome. J Clin Endocrinol Metab 2003 Aug; 88(8): 3573-6[Medline].
• Holm VA, Cassidy SB, Butler MG, et al: Prader-Willi syndrome: consensus diagnostic criteria. Pediatrics 1993 Feb; 91(2): 398-402[Medline].
• Hudgins L, Greer JS, Cassidy SB: Phenotypic differences in African Americans with Prader-Willi syndrome. Genetic Medicine 1998; 1: 49-51[Medline].
• Jaffray B, Moore L, Dickson AP: Prader-Willi syndrome and intratubular germ cell neoplasia. Med Pediatr Oncol 1999 Jan; 32(1): 73-4[Medline].
• Kaplan J, Fredrickson PA, Richardson JW: Sleep and breathing in patients with the Prader-Willi syndrome. Mayo Clin Proc 1991 Nov; 66(11): 1124-6[Medline].
• Kubota T, Aradhya S, Macha M, et al: Analysis of parent of origin specific DNA methylation at SNRPN and PW71 in tissues: implication for prenatal diagnosis. J Med Genet 1996 Dec; 33(12): 1011-4[Medline].
• Lamb AS, Johnson WM: Premature coronary artery atherosclerosis in a patient with Prader- Willi syndrome. Am J Med Genet 1987 Dec; 28(4): 873-80[Medline].
• Ledbetter DH, Riccardi VM, Airhart SD, et al: Deletions of chromosome 15 as a cause of the Prader-Willi syndrome. N Engl J Med 1981 Feb 5; 304(6): 325-9[Medline].
• Ledbetter DH, Engel E: Uniparental disomy in humans: development of an imprinting map and its implications for prenatal diagnosis. Hum Mol Genet 1995; 4 Spec No: 1757-64[Medline].
• Lee PD: Endocrine and metabolic aspects of Prader-willi syndrome. In: Greenswag LR, Alexander RC, eds. Management of Prader-willi Syndrome. 2nd ed. New York, NY: Springer-Verlag; 1995:32-57.
• MacDonald HR, Wevrick R: The necdin gene is deleted in Prader-Willi syndrome and is imprinted in human and mouse. Hum Mol Genet 1997 Oct; 6(11): 1873-8[Medline].
• Martin A, State M, Koenig K, et al: Prader-Willi syndrome. Am J Psychiatry 1998 Sep; 155(9): 1265-73[Medline].
• Nakajima K, Sakurai A, Kubota T: Multiple endocrine neoplasia type 1 concomitant with Prader-Willi syndrome: case report and genetic diagnosis. Am J Med Sci 1999 May; 317(5): 346-9[Medline].
• Nicholls RD, Knoll JH, Butler MG, et al: Genetic imprinting suggested by maternal heterodisomy in nondeletion Prader-Willi syndrome. Nature 1989 Nov 16; 342(6247): 281-5[Medline].
• Nicholls RD: Genomic imprinting and uniparental disomy in Angelman and Prader-Willi syndromes: a review. Am J Med Genet 1993 Apr 1; 46(1): 16-25[Medline].
• Pandey SN, Vaidya RA, Irani A: Growth hormone treatment in a girl with Prader Willi syndrome. Indian J Pediatr 2003 Apr; 70(4): 351-3[Medline].
• Prader A, Labhart A, Willi H: Ein Syndrom von Adipositas, Kleinwuchs, Kryptorchismus und Oligophrenie nach Myatonieartigem Zustand im Neugeborenenalter. Schweiz Med Wschr 1956; 86: 1260-1.
• Reychler A: [Cephalometric analysis]. Acta Stomatol Belg 1976; 73(4): 403-21[Medline].
• Rinchik EM, Bultman SJ, Horsthemke B, et al: A gene for the mouse pink-eyed dilution locus and for human type II oculocutaneous albinism. Nature 1993 Jan 7; 361(6407): 72-6[Medline].
• Robinson WP, Langlois S, Schuffenhauer S, et al: Cytogenetic and age-dependent risk factors associated with uniparental disomy 15. Prenat Diagn 1996 Sep; 16(9): 837-44[Medline].
• Schluter B, Buschatz D, Trowitzsch E, et al: Respiratory control in children with Prader-Willi syndrome. Eur J Pediatr 1997 Jan; 156(1): 65-8[Medline].
• Soper RT, Mason EE, Printen KJ, Zellweger H: Gastric bypass for morbid obesity in children and adolescents. J Pediatr Surg 1975 Feb; 10(1): 51-8[Medline].
• Wharton RH, Wang T, Graeme-Cook F, et al: Acute idiopathic gastric dilation with gastric necrosis in individuals with Prader-Willi syndrome. Am J Med Genet 1997 Dec 31; 73(4): 437-41[Medline].
• Whittington JE, Holland AJ, Webb T, et al: Population prevalence and estimated birth incidence and mortality rate for people with Prader-Willi syndrome in one UK Health Region. J Med Genet 2001 Nov; 38(11): 792-8[Medline].

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