Prader-Willi syndrome

Prader-Willi syndrome (PWS; also known as Prader-Labhart-Willi syndrome) is a rare, complex, multisystem, neurological disorder caused by loss of paternally expressed genes on chromosome 15q11-q13.

Diagnosis is by identification of characteristic features with confirmation by genetic testing. Signs and symptoms may be extensive and wide-ranging; in general, however, consider genetic testing in an infant or young child with hypotonia, difficulty feeding, and/or hypogonadism. Depending on the age of the patient, other presenting features may include weight gain, hyperphagia, developmental delay, cognitive disability, sleep abnormalities, characteristic behaviours, and psychiatric disorders.

PWS presents less commonly in adolescence or early adulthood, with features including new-onset type 2 diabetes, constant hunger and food-seeking behaviours, short stature, obesity, learning difficulties, speech articulation problems, and autistic spectrum behaviours.

Features of acute illness may be subtle or atypical.

Management throughout the patient's life requires a multidisciplinary approach.

Patients with PWS have a shorter life expectancy than the general population, mainly due to complications of hyperphagia and obesity. However, with effective weight control management, patients with PWS may live into their seventh decade.

PWS (also known as Prader-Labhart-Willi syndrome) is a rare, genetically inherited complex neurological disorder caused by absence of expression of paternally inherited imprinted genes on chromosome 15q11-q13.[1]Duis J, van Wattum PJ, Scheimann A, et al. A multidisciplinary approach to the clinical management of Prader-Willi syndrome. Mol Genet Genomic Med. 2019 Mar;7(3):e514. https://onlinelibrary.wiley.com/doi/10.1002/mgg3.514 http://www.ncbi.nlm.nih.gov/pubmed/30697974?tool=bestpractice.com [2]McCandless SE, Committee on Genetics. Clinical report - health supervision for children with Prader-Willi syndrome. Pediatrics. 2011 Jan;127(1):195-204. https://publications.aap.org/pediatrics/article/127/1/195/30016/Health-Supervision-for-Children-With-Prader-Willi http://www.ncbi.nlm.nih.gov/pubmed/21187304?tool=bestpractice.com ​ The syndrome typically occurs due to one of three genetic mechanisms: paternal deletion of involved genes, maternal uniparental disomy, or imprinting centre defects.[2]McCandless SE, Committee on Genetics. Clinical report - health supervision for children with Prader-Willi syndrome. Pediatrics. 2011 Jan;127(1):195-204. https://publications.aap.org/pediatrics/article/127/1/195/30016/Health-Supervision-for-Children-With-Prader-Willi http://www.ncbi.nlm.nih.gov/pubmed/21187304?tool=bestpractice.com [3]International Prader-Willi Syndrome Organisation. Guides for doctors: consensus documents. [internet publication]. https://ipwso.org/information-for-medical-professionals/guides-for-doctors-consensus-documents ​ PWS is the most common known genetic cause of life-threatening obesity in humans.[4]Butler MG. Prader-Willi syndrome: current understanding of cause and diagnosis. Am J Med Genet. 1990 Mar;35(3):319-32. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5493042 http://www.ncbi.nlm.nih.gov/pubmed/2309779?tool=bestpractice.com Patients with PWS have a shorter life expectancy than the general population, which is mainly due to complications of hyperphagia and obesity.[5]Proffitt J, Osann K, McManus B, et al. Contributing factors of mortality in Prader-Willi syndrome. Am J Med Genet A. 2019 Feb;179(2):196-205. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6349475 http://www.ncbi.nlm.nih.gov/pubmed/30569567?tool=bestpractice.com [6]Butler MG, Manzardo AM, Heinemann J, et al. Causes of death in Prader-Willi syndrome: Prader-Willi Syndrome Association (USA) 40-year mortality survey. Genet Med. 2017 Jun;19(6):635-42. https://www.gimjournal.org/article/S1098-3600(21)02257-7/fulltext http://www.ncbi.nlm.nih.gov/pubmed/27854358?tool=bestpractice.com [7]Lionti T, Reid SM, Rowell MM. Prader-Willi syndrome in Victoria: mortality and causes of death. J Paediatr Child Health. 2012 Jun;48(6):506-11. http://www.ncbi.nlm.nih.gov/pubmed/22697408?tool=bestpractice.com [8]Grugni G, Crinò A, Bosio L, et al. The Italian National Survey for Prader-Willi syndrome: an epidemiologic study. Am J Med Genet A. 2008 Apr 1;146A(7):861-72. http://www.ncbi.nlm.nih.gov/pubmed/18203198?tool=bestpractice.com [9]Schrander-Stumpel CT, Curfs LM, Sastrowijoto P, et al. Prader-Willi syndrome: causes of death in an international series of 27 cases. Am J Med Genet A. 2004 Feb 1;124A(4):333-8. http://www.ncbi.nlm.nih.gov/pubmed/14735579?tool=bestpractice.com [10]Stevenson DA, Anaya TM, Clayton-Smith J, et al. Unexpected death and critical illness in Prader-Willi syndrome: report of ten individuals. Am J Med Genet A. 2004 Jan 15;124A(2):158-64. http://www.ncbi.nlm.nih.gov/pubmed/14699614?tool=bestpractice.com