eMedicine Specialties > Pediatrics: Genetics and Metabolic Disease > Genetics

Prader-Willi Syndrome

Author: Ann Scheimann, MD, MBA, Associate Professor, Department of Pediatrics, Section of Nutrition and Gastroenterology, Baylor College of Medicine and Johns Hopkins Medical Institution
Contributor Information and Disclosures

Updated: Jul 27, 2009

Introduction

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
    • Young children exhibit temper tantrums, stubbornness, and obsessive-compulsive behaviors.
    • 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
    • Features of psychosis are present in 5-10% of young adults with Prader-Willi syndrome.31
    • 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)
    • 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 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 Prader-Willi syndrome 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, adrenal insufficiency27
    • Orthopedics – Scoliosis or kyphosis34
    • 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.

More on Prader-Willi Syndrome

Overview: Prader-Willi Syndrome
Differential Diagnoses & Workup: Prader-Willi Syndrome
Treatment & Medication: Prader-Willi Syndrome
Follow-up: Prader-Willi Syndrome
Multimedia: Prader-Willi Syndrome
References
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References

  1. Down JL. Mental Affections of Childhood and Youth. 1887:172.

  2. 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.

  3. 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].

  4. Ledbetter DH, Riccardi VM, Airhart SD, et al. Deletions of chromosome 15 as a cause of the Prader-Willi syndrome. N Engl J Med. Feb 5 1981;304(6):325-9. [Medline].

  5. Nicholls RD, Knoll JH, Butler MG, Karam S, Lalande M. Genetic imprinting suggested by maternal heterodisomy in nondeletion Prader-Willi syndrome. Nature. Nov 16 1989;342(6247):281-5. [Medline].

  6. Nicholls RD. Genomic imprinting and uniparental disomy in Angelman and Prader-Willi syndromes: a review. Am J Med Genet. Apr 1 1993;46(1):16-25. [Medline].

  7. Robinson WP, Langlois S, Schuffenhauer S, et al. Cytogenetic and age-dependent risk factors associated with uniparental disomy 15. Prenat Diagn. Sep 1996;16(9):837-44. [Medline].

  8. 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. Mar 2003;72(3):571-7. [Medline].

  9. 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. Apr 1995;9(4):395-400. [Medline].

  10. 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. Jan 7 1993;361(6407):72-6. [Medline].

  11. MacDonald HR, Wevrick R. The necdin gene is deleted in Prader-Willi syndrome and is imprinted in human and mouse. Hum Mol Genet. Oct 1997;6(11):1873-8. [Medline].

  12. Cummings DE, Clement K, Purnell JQ, et al. Elevated plasma ghrelin levels in Prader Willi syndrome. Nat Med. Jul 2002;8(7):643-4. [Medline].

  13. 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. Aug 2003;88(8):3573-6. [Medline].

  14. 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. May 2005;90(5):2681-90. [Medline].

  15. Burd L, Vesely B, Martsolf J, Kerbeshian J. Prevalence study of Prader-Willi syndrome in North Dakota. Am J Med Genet. Sep 1990;37(1):97-9. [Medline].

  16. 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. Jan 11 1996;61(2):188-90. [Medline].

  17. Akefeldt A, Gillberg C, Larsson C. Prader-Willi syndrome in a Swedish rural county: epidemiological aspects. Dev Med Child Neurol. Aug 1991;33(8):715-21. [Medline].

  18. Ehara H, Ohno K, Takeshita K. Frequency of the Prader-Willi syndrome in the San-in district, Japan. Brain Dev. Sep-Oct 1995;17(5):324-6. [Medline].

  19. 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. Nov 2001;38(11):792-8. [Medline].

  20. Lamb AS, Johnson WM. Premature coronary artery atherosclerosis in a patient with Prader-Willi syndrome. Am J Med Genet. Dec 1987;28(4):873-80. [Medline].

  21. 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. Dec 31 1997;73(4):437-41. [Medline].

  22. Stevenson DA, Heinemann J, Angula M, et al. Gastric Rupture and Necrosis in Prader-Willi Syndrome. J Pediatr Gastroenterol Nutr. 2007;45:272-4. [Medline].

  23. Stevenson DA, Heinemann J, Angulo M, et al. Deaths due to choking in Prader-Willi syndrome. Am J Med Genet A. Mar 1 2007;143(5):484-7. [Medline].

  24. Stevenson Da, Anaya TM, Clayton-Smith J, et al. Unexpected Death and Critical Illness in Prader-Willi Syndrome: Report of Ten Individuals. Amer J Med Genet A. 2004;124A:158-64. [Medline].

  25. Hudgins L, Geer JS, Cassidy SB. Phenotypic differerencss in African Americans with Prader-Willi syndrome. Genet Med. Nov-Dec 1998;1(1):49-51. [Medline].

  26. Cassidy SB, Schwartz S. Prader-Willi and Angelman syndromes. Disorders of genomic imprinting. Medicine (Baltimore). Mar 1998;77(2):140-51. [Medline].

  27. 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.

  28. Kaplan J, Fredrickson PA, Richardson JW. Sleep and breathing in patients with the Prader-Willi syndrome. Mayo Clin Proc. Nov 1991;66(11):1124-6. [Medline].

  29. Martin A, State M, Koenig K, et al. Prader-Willi syndrome. Am J Psychiatry. Sep 1998;155(9):1265-73. [Medline].

  30. Dykens EM, Hodapp RM, Walsh K, Nash LJ. Profiles, correlates, and trajectories of intelligence in Prader-Willi syndrome. J Am Acad Child Adolesc Psychiatry. Nov 1992;31(6):1125-30. [Medline].

  31. Soni S, Whittington J, Holland AJ, et al. The Phenomenology and Diagnosis of Psychiatric Illness in People with Prader-Willi Syndrome. Psychol Med. 2008;38:1505-14. [Medline].

  32. Greenswag LR. Adults with Prader-Willi syndrome: a survey of 232 cases. Dev Med Child Neurol. Apr 1987;29(2):145-52. [Medline].

  33. [Guideline] Holm VA, Cassidy SB, Butler MG, et al. Prader-Willi syndrome: consensus diagnostic criteria. Pediatrics. Feb 1993;91(2):398-402. [Medline].

  34. Gurd AR, Thompson TR. Scoliosis in Prader-Willi syndrome. J Pediatr Orthop. 1981;1(3):317-20. [Medline].

  35. ASHG/ACMG Test and Technology Transfer Committee. Diagnostic testing for Prader-Willi and Angleman syndromes. Am J Hum Genet. May 1996;58(5):1085-8. [Medline].

  36. Goldstone AP, Holland AJ, Hauffa BP, et al. Recommendations for the Diagnosis and Management of Prader-Willi Syndrome. J Clin Endocrinol Metab. 2008;93:4183-97. [Medline].

  37. O'Donoghue FJ, Camfferman D, Kennedy JD, et al. Sleep-disordered breathing in Prader-Willi syndrome and its association with neurobehavioral abnormalities. J Pediatr. Dec 2005;147(6):832-9. [Medline].

  38. Schluter B, Buschatz D, Trowitzsch E, et al. Respiratory control in children with Prader-Willi syndrome. Eur J Pediatr. Jan 1997;156(1):65-8. [Medline].

  39. Reychler A. [Cephalometric analysis]. Acta Stomatol Belg. 1976;73(4):403-21. [Medline].

  40. West LA, Ballock RT. High Incidence of Hip Dysplasia but not Slipped Capital Femoral Epiphysis in Patients With Prader-Willi Syndrome. J Pediatr Orthop. 2004;24:565-7. [Medline].

  41. Miller J, Silverstein J, Shuster J, Driscoll DJ, Wagner M. Short-term effects of growth hormone on sleep abnormalities in Prader-Willi syndrome. J Clin Endcrinol Metabo. Feb 2006;91(2):413-7. [Medline].

  42. Pandey SN, Vaidya RA, Irani A. Growth hormone treatment in a girl with Prader Willi syndrome. Indian J Pediatr. Apr 2003;70(4):351-3. [Medline].

  43. Soper RT, Mason EE, Printen KJ, Zellweger H. Gastric bypass for morbid obesity in children and adolescents. J Pediatr Surg. Feb 1975;10(1):51-8. [Medline].

  44. Scheimann AO, Butler MG, Gourash L, Cuffari C, Klish W. Critical Analysis of Bariatric Procedures in Prader-Willi Syndrome. J Pediatr Gastroenterol Nutr. 2008;46:80-3. [Medline].

  45. Bistrian BR, Blackburn GL, Stanbury JB. Metabolic Aspects of a Protein-Sparing Modified Fast in the Dietary Management of Prader-Willi Obesity. N Eng J Med. 1977;296:774-9. [Medline].

  46. Coppes MJ, Sohl H, Teshima IE, et al. Wilms tumor in a patient with Prader-Willi syndrome. J Pediatr. May 1993;122(5 Pt 1):730-3. [Medline].

  47. Jaffray B, Moore L, Dickson AP. Prader-Willi syndrome and intratubular germ cell neoplasia. Med Pediatr Oncol. Jan 1999;32(1):73-4. [Medline].

  48. Nakajima K, Sakurai A, Kubota T, et al. Multiple endocrine neoplasia type 1 concomitant with Prader-Willi syndrome: case report and genetic diagnosis. Am J Med Sci. May 1999;317(5):346-9. [Medline].

  49. Hall BD. Leukaemia and the Prader-Willi syndrome. Lancet. Jan 5 1985;1(8419):46. [Medline].

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Further Reading

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Keywords

PWS, Prader-Labhart-Willi syndrome, Prader-Willi syndrome, chromosomal microdeletion, disomy disorder, diminished fetal activity, obesity, hypotonia, mental retardation, short stature, hypogonadotropic hypogonadism, strabismus, polysarcia, Angelman syndrome, ghrelin, hypoinsulinemia, slipped capital femoral epiphyses, sleep apnea, cor pulmonale, diabetes mellitus type II, obsessive-compulsive behavior, developmental delay, sleep disturbance, hypopigmentation, hypothalamic dysfunction, treatment, diagnosis

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Contributor Information and Disclosures

Author

Ann Scheimann, MD, MBA, Associate 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
Disclosure: Nothing to disclose.

Medical Editor

Michael Fasullo, PhD, Senior Scientist, Ordway Research Institute; Associate Professor, State University of New York at Albany; Adjunct Associate Professor, Center for Immunology and Microbial Disease, Albany Medical College
Michael Fasullo, PhD is a member of the following medical societies: Radiation Research Society
Disclosure: Nothing to disclose.

Pharmacy Editor

Mary L Windle, PharmD, Adjunct Assistant Professor, University of Nebraska Medical Center College of Pharmacy, Pharmacy Editor, eMedicine
Disclosure: Pfizer Inc Stock Investment from financial planner; Avanir Pharma Stock Investment from financial planner ; WebMD Salary and stock Employment and investment from financial planner

Managing Editor

Robert Anthony Saul, MD, Clinical Professor, Department of Pediatrics, University of South Carolina; Senior Clinical Geneticist, Greenwood Genetic Center
Robert Anthony Saul, MD is a member of the following medical societies: American Academy of Pediatrics, American College of Medical Genetics, and American College of Physician Executives
Disclosure: Nothing to disclose.

CME Editor

Paul D Petry, DO, FACOP, FAAP, Consulting Staff, Freeman Pediatric Care, Freeman Health System
Paul D Petry, DO, FACOP, FAAP is a member of the following medical societies: American Academy of Osteopathy, American Academy of Pediatrics, American College of Osteopathic Pediatricians, and American Osteopathic Association
Disclosure: Nothing to disclose.

Chief Editor

Bruce Buehler, MD, Professor, Department of Pediatrics, Pathology and Microbiology, Executive Director, Hattie B Munroe Center for Human Genetics, University of Nebraska Medical Center
Bruce Buehler, MD is a member of the following medical societies: American Academy for Cerebral Palsy and Developmental Medicine, American Academy of Pediatrics, American Association on Mental Retardation, American College of Medical Genetics, American College of Physician Executives, American Medical Association, and Nebraska Medical Association
Disclosure: Nothing to disclose.

 
 
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