Prader-Willi Syndrome

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 by Anusha Vasamsetti on March 23, 2023.

Disease Entity

8 year-old with Prader-Willi Syndrome[1]. Reproduced from Wikipedia under the Creative Commons Attribution 4.0 International license.


Prader-Willi Syndrome

  • ICD-10-CM Q87.11 Prader-Willi Syndrome


Prader-Willi syndrome is caused by an absence of expression of paternally active genes in the 15q11.2-13 region on the long arm of chromosome 15, either due to deletions from the paternal chromosome or maternal disomy[2][3]. The dependence on the sex of parental origin is known as “genomic imprinting[2][3]." Most cases of Prader-Willi syndrome occur sporadically.


Prader-Willi syndrome affects about 1 in 25,000 live births, with males and females equally affected. The vast majority of cases are sporadic rather than familial[4].

Currently, Prader-Willi syndrome affects about 350,000 - 400,000 individuals worldwide[5]. Prevalence estimates do differ among studies, however it is likely due to different testing methods rather than increased risk in specific populations or countries.

The risk of recurrence in siblings is very low unless a deletion affecting the imprinting center is present, accounting for less than 1 percent of cases[6].


Prader-Willi Syndrome occurs with the loss of the paternal copy of chromosome region 15q11-q13[7]. The process by which gene expression depends on the sex of the parent donating the gene is called genomic imprinting[7]. Loss of the maternal copy of 15q11-q13, in contrast, manifests as Angelman syndrome, a related but otherwise distinct disease entity[7].

Deletion of the paternal copy of 15q11-q13 is found in 70% of cases of Prader-Willi[7]. Alternatively, 25% of cases are associated with maternal uniparental disomy 15[7]. Imprinting defects and other chromosome 15 abnormalities account for the remaining cases[7].

The 15q11-q13 region is home to about 100 nonredundant genes or transcripts, and among these 12 or more are imprinted and paternally expressed[7]. Paternally expressed genes are candidates for causing Prader-Willi Syndrome while the imprinted maternally expressed genes UBE3A and ATP10A are candidates for causing Angelman syndrome[7]. Kemp et al. succinctly described the relationship of genomic imprinting as follows: “a child must receive the paternally derived gene at 15q12 to not develop Prader-Willi syndrome and must receive the maternally derived gene at 15q12 to not develop Angelman syndrome[8]." Paternally expressed genes in the 15q11-q13 region include SNURF-SNRPN, NDN, MKRN3, MAGEL2, and multiple copies of small untranslated nucleolar RNAs (snoRNAs or SNORDs)[7]. Genes in this region are known to have effects on axonal nerve growth, circadian rhythm, behavior, and fertility[7].

Clinical Features

Systemic Manifestations

Neonatal hypotonia is a classic feature of this disorder, which can lead to asphyxia. These infants can have feeding difficulties, leading to failure to thrive. Other common features include a weak cry, genital hypoplasia, and hypopigmentation of the skin, iris, and hair[9][10]. Toddlers with Prader-Willi syndrome have delayed major motor milestones, such as walking at an average of 27 months and talking at an average of 39 months[4]. Toddlers with Prader-Willi syndrome also start to commonly show hyperphagia with subsequent obesity. Prader-Willi syndrome toddlers can have abnormal body composition with increased fat mass and reduced lean body mass compared with normal and obese controls[11][12]. Resting energy use is also reduced lower than normal[13]. Children with Prader-Willi syndrome usually have short stature and most fail to have a pubertal growth spurt, since most patients with Prader-Willi syndrome have growth hormone deficiency[14].

Secondary sexual characteristics generally are delayed or incomplete [15]. Obesity complications, such as sleep apnea, diabetes mellitus, and atherosclerosis are common problems for adolescents and adults with Prader-Willi syndrome. Prader-Willi syndrome patients also can have epilepsy and scoliosis[16][17].

Behavioral problems and learning difficulties similar to those found in autism spectrum disorder are commonly seen in Prader-Willi syndrome[18]. Patients can also exhibit rectal gouging and skin-picking behavior that may respond to N-acetylcysteine treatment[19]. Mood disorders and psychotic states among other psychiatric symptoms and disorders have been reported among adults[20]. Cognitive impairment is also commonly associated with Prader-Willi syndrome[21]. Abnormal food-seeking behaviors among Prader-Willi syndrome patients include stealing food, eating garbage, and eating frozen food. Decreased vomiting ability and increased pain tolerance have been associated with Prader-Willi syndrome[22].

Ocular Manifestations

Commonly reported ocular findings of patients with Prader-Willi syndrome include decreased visual acuity, iris and choroid hypopigmentation, refractive error, and strabismus[23][24]. Other ocular findings include cataracts, congenital ocular fibrosis syndrome, diabetic retinopathy, nystagmus and congenital ectropion uvea[23][24]. A study using data from 908 participants in the Vision Survey in the Global PWS Registry found that the prevalence of strabismus of Prader-Willi syndrome is 40%, and that 91% of those with strabismus were diagnosed before 5 years old. 42% of Prader-Willi syndrome patients with strabismus had strabismus surgery[25]. 41% of patients had myopia, 25% had hyperopia, 25% had astigmatism, and 16% had amblyopia[25]. There is also an overlap between Prader-Willi Syndrome and oculocutaneous albinism that is attributed to the deletion of the OCA2 gene found in the PWS critical region[24].

Compared to the general population, the Prader-Willi syndrome population in the Global PWS Registry had considerably higher prevalence of strabismus, amblyopia, and hyperopia[25]. Therefore, it is critical to screen Prader-Willi syndrome patients for ocular issues.


The diagnosis of Prader-Willi syndrome is made after a thorough clinical evaluation resulting in multiple characteristic features and later confirmed with genetic testing[26]. Major clinical features that are consistent with the diagnosis of PWS include hypotonia, developmental delay, hypothalamic hypogonadism, short stature and obesity[27].

The gold standard of genetic testing is methylation analysis (detects 99% of cases), which depends on the differences in methylation patterns in maternally or paternally inherited alleles in the 15q11-q13 region[4].   Fluorescent in-situ hybridization is another effective test however it is limited to the detection of Prader-Willi syndrome caused by a deletion (up to 75% of cases)[28][29].

Newer techniques such as chromosomal microarrays, genotyping with DNA markers, and methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) may also be used for diagnosis and characterization[7].


Prader-Willi often requires multidisciplinary management due to the various pathologies that result from this condition. Treatment options also differ with age. While the management of hypotonia is the main concern for neonates and infants, obesity is the cornerstone of disease management in older patients[30]. Weight loss surgery is a method that has been used in the management of the pathologies associated with obesity in PWS but the results have been far from consistent[31][32].

Management of PWS also includes the screening and treatment of abnormal hypothalamic and pituitary function, growth hormone deficiency, hypogonadism, osteoporosis, hypothyroidism, adrenal insufficiency and sleep apnea[14][33][34][35].

Due to the higher prevalence of strabismus, amblyopia, and hyperopia in patient's with Prader-Willi Syndrome, it is critical to screen these patients for ocular issues.


The life expectancy for patients with Prader-Willi syndrome has been gradually increasing with advances in treatment techniques with many patients living after the age of 50[36][37][38]. The main causes of mortality in patients with PWS include respiratory failure, cardiovascular disease, diabetes mellitus and intellectual disability[36][39][40].

Additional Resources


  1. Cortés M F, Alliende R MA, Barrios R A, et al. Caracterización Clínico-Genético-molecular de 45 Pacientes Chilenos Con Síndrome de Prader willi. Revista médica de Chile. 2005;133(1). doi:10.4067/s0034-98872005000100005
  2. 2.0 2.1 Lionti T, Reid SM, White SM, Rowell MM. A population-based profile of 160 Australians with Prader-Willi syndrome: trends in diagnosis, birth prevalence and birth characteristics. Am J Med Genet A 2015; 167A:371
  3. 3.0 3.1 Whittington JE, Butler JV, Holland AJ. Changing rates of genetic subtypes of Prader-Willi syndrome in the UK. Eur J Hum Genet 2007; 15:127
  4. 4.0 4.1 4.2 Butler MG. Prader-Willi syndrome: current understanding of cause and diagnosis. Am J Med Genet. 1990 Mar;35(3):319-32. doi: 10.1002/ajmg.1320350306. PMID: 2309779
  5. Butler MG, Hanchett JM, Thompson T. Clinical findings and natural history of Prader-Willi syndrome. In: Management of Prader-willi Syndrome, Butler MG, Lee PDK, Whitman BY (Eds), Springer, New York 2006
  6. Buiting, K, Horsthemke, B. Molecular Genetic Findings in Prader-willi Syndrome in Management of Prader-willi Syndrome, Butler MG, Lee PDK, Whitman BY (Eds), Springer, New York 2006. p.63
  7. 7.00 7.01 7.02 7.03 7.04 7.05 7.06 7.07 7.08 7.09 7.10 Butler MG. Prader-Willi and Angelman Syndromes: Examples of Genomic Imprinting. In: Murray MF, Babyatsky MW, Giovanni MA, Alkuraya FS, Stewart DR. eds. Clinical Genomics: Practical Applications in Adult Patient Care, 1e. McGraw Hill; 2014. Accessed April 06, 2022
  8. Chapter 6. Genetic Disorders. In: Kemp WL, Burns DK, Brown TG. eds. Pathology: The Big Picture. McGraw Hill; 2008. Accessed April 06, 2022
  9. Butler MG. Hypopigmentation: a common feature of Prader-Labhart-Willi syndrome. Am J Hum Genet. 1989 Jul;45(1):140-6. PMID: 2741944; PMCID: PMC1683374.
  10. Cassidy SB, Schwartz S, Miller JL, Driscoll DJ. Prader-Willi syndrome. Genet Med. 2012 Jan;14(1):10-26. doi: 10.1038/gim.0b013e31822bead0. Epub 2011 Sep 26. PMID: 22237428.
  11. Brambilla P, Bosio L, Manzoni P, Pietrobelli A, Beccaria L, Chiumello G. Peculiar body composition in patients with Prader-Labhart-Willi syndrome. Am J Clin Nutr. 1997 May;65(5):1369-74. doi: 10.1093/ajcn/65.5.1369. PMID: 9129464.
  12. Eiholzer U, Blum WF, Molinari L. Body fat determined by skinfold measurements is elevated despite underweight in infants with Prader-Labhart-Willi syndrome. J Pediatr. 1999 Feb;134(2):222-5. doi: 10.1016/s0022-3476(99)70419-1. PMID: 9931533.
  13. van Mil EA, Westerterp KR, Gerver WJ, Curfs LM, Schrander-Stumpel CT, Kester AD, Saris WH. Energy expenditure at rest and during sleep in children with Prader-Willi syndrome is explained by body composition. Am J Clin Nutr. 2000 Mar;71(3):752-6. doi: 10.1093/ajcn/71.3.752. PMID: 10702169.
  14. 14.0 14.1 Burman P, Ritzén EM, Lindgren AC. Endocrine dysfunction in Prader-Willi syndrome: a review with special reference to GH. Endocr Rev. 2001;22(6):787-799. doi:10.1210/edrv.22.6.0447
  15. Whitman BY. Neurodevelopmental and neuropsychological aspects of Prader-Willi syndrome. In: Management of Prader-Willi Syndrome, 3rd ed, Butler M, Lee PDK, Whitman BY (Eds), Springer-Verlag, New York 2006. p.264
  16. Vendrame M, Maski KP, Chatterjee M, Heshmati A, Krishnamoorthy K, Tan WH, Kothare SV. Epilepsy in Prader-Willi syndrome: clinical characteristics and correlation to genotype. Epilepsy Behav. 2010 Nov;19(3):306-10. doi: 10.1016/j.yebeh.2010.07.007. Epub 2010 Aug 21. PMID: 20727826.
  17. de Lind van Wijngaarden RF, de Klerk LW, Festen DA, Hokken-Koelega AC. Scoliosis in Prader-Willi syndrome: prevalence, effects of age, gender, body mass index, lean body mass and genotype. Arch Dis Child. 2008 Dec;93(12):1012-6. doi: 10.1136/adc.2007.123836. Epub 2008 Feb 8. PMID: 18263693.
  18. Bennett JA, Germani T, Haqq AM, Zwaigenbaum L. Autism spectrum disorder in Prader-Willi syndrome: A systematic review. Am J Med Genet A. 2015 Dec;167A(12):2936-44. doi: 10.1002/ajmg.a.37286. Epub 2015 Aug 29. PMID: 26331980.
  19. Bonnot O, Cohen D, Thuilleaux D, Consoli A, Cabal S, Tauber M. Psychotropic treatments in Prader-Willi syndrome: a critical review of published literature. Eur J Pediatr. 2016 Jan;175(1):9-18. doi: 10.1007/s00431-015-2670-x. Epub 2015 Nov 19. PMID: 26584571.
  20. Sinnema M, Boer H, Collin P, Maaskant MA, van Roozendaal KE, Schrander-Stumpel CT, Curfs LM. Psychiatric illness in a cohort of adults with Prader-Willi syndrome. Res Dev Disabil. 2011 Sep-Oct;32(5):1729-35. doi: 10.1016/j.ridd.2011.02.027. Epub 2011 Mar 31. PMID: 21454045.
  21. Whittington J, Holland A, Webb T, Butler J, Clarke D, Boer H. Cognitive abilities and genotype in a population-based sample of people with Prader-Willi syndrome. J Intellect Disabil Res. 2004 Feb;48(Pt 2):172-87. doi: 10.1111/j.1365-2788.2004.00556.x. PMID: 14723659.
  22. Wharton RH, Wang T, Graeme-Cook F, Briggs S, Cole RE. Acute idiopathic gastric dilation with gastric necrosis in individuals with Prader-Willi syndrome. Am J Med Genet. 1997 Dec 31;73(4):437-41. doi: 10.1002/(sici)1096-8628(19971231)73:4<437::aid-ajmg12>;2-s. PMID: 9415471.
  23. 23.0 23.1 Libov AJ, Maino DM. Prader-Willi syndrome. J Am Optom Assoc. 1994 May;65(5):355-9. PMID: 8071507
  24. 24.0 24.1 24.2 Hamid, M.A., Mehta, M.C. & Kuppermann, B.D. Multimodal imaging in a patient with Prader–Willi syndrome. Int J Retin Vitr 4, 45 (2018).
  25. 25.0 25.1 25.2 Bohonowych, J.E., Vrana-Diaz, C.J., Miller, J.L. et al. Incidence of strabismus, strabismus surgeries, and other vision conditions in Prader-Willi syndrome: data from the Global Prader-Willi Syndrome Registry. BMC Ophthalmol 21, 296 (2021).
  26. Goldstone AP, Holland AJ, Hauffa BP, Hokken-Koelega AC, Tauber M; speakers contributors at the Second Expert Meeting of the Comprehensive Care of Patients with PWS. Recommendations for the diagnosis and management of Prader-Willi syndrome [published correction appears in J Clin Endocrinol Metab. 2010 Dec;95(12):5465]. J Clin Endocrinol Metab. 2008;93(11):4183-4197. doi:10.1210/jc.2008-0649
  27. Gunay-Aygun M, Schwartz S, Heeger S, O'Riordan MA, Cassidy SB. The changing purpose of Prader-Willi syndrome clinical diagnostic criteria and proposed revised criteria. Pediatrics. 2001;108(5):E92. doi:10.1542/peds.108.5.e92
  28. Driscoll DJ, Miller JL, Schwartz S, et al. Prader-Willi Syndrome. 1998 Oct 6 [Updated 2017 Dec 14]. In: Adam MP, Ardinger HH, Pagon RA, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2022. Available from:
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  35. de Lind van Wijngaarden RF, Otten BJ, Festen DA, et al. High prevalence of central adrenal insufficiency in patients with Prader-Willi syndrome. J Clin Endocrinol Metab. 2008;93(5):1649-1654. doi:10.1210/jc.2007-2294
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  37. Sinnema M, Schrander-Stumpel CT, Maaskant MA, Boer H, Curfs LM. Aging in Prader-Willi syndrome: twelve persons over the age of 50 years. Am J Med Genet A. 2012;158A(6):1326-1336. doi:10.1002/ajmg.a.35333
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  39. Butler, Merlin G., et al. "Causes of death in Prader-Willi syndrome: Prader-Willi Syndrome Association (USA) 40-year mortality survey." Genetics in Medicine 19.6 (2017): 635-64
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