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Atlas of Genetics and Cytogenetics in Oncology and Haematology OPEN ACCESS JOURNAL AT INIST-CNRS Cancer Prone Disease Section Review Prader Willi syndrome Maria Piccione, Giovanni Corsello Dipartimento Materno Infantile, University of Palermo, Italy (MP, GC) Published in Atlas Database: April 2008 Online updated version : http://AtlasGeneticsOncology.org/Kprones/PraderWilliID10114.html DOI: 10.4267/2042/44461 This work is licensed under a Creative Commons Attribution-Noncommercial-No Derivative Works 2.0 France Licence. © 2009 Atlas of Genetics and Cytogenetics in Oncology and Haematology At 1-3 years hyperphagia appears with rapid weight gain and obesity. The leptine levels are normal and ghrelin levels are significantly elevated, 3-4 fold higher in children with PWS than in general population. Craniofacial characteristics: High prominent forehead, narrow bifrontal diameter, telecanthus, downlated fissures, downturned corners of the mouth, micrognathia, dysplasic ears and diminished mimic activity due to muscular hypotonia (fig.1). Dermatological anomalies: Hypopigmentation-fair skin and severe skin-picking. Limbs and skeletal anomalies: Small hands and feet (acromicria), bracydactyly, clynodactyly of fifth finger, delayed bone age especially in the limbs, related to growth hormone function and diminished bone mineral density. Hypothalamic dysfunction: Hypogonadropic hypogonadism with cryptorchidism and micropenis, delayed or incomplete gonadal maturation with delayed pubertal findings, short stature secondary to growth hormone deficiency, hyperphagia with absence of satiety and obesity (fig.2), temperature instability, central adrenal insufficiency. Performance and behavioural problems: Hypotonia, sleep disorders, obsessive compulsive behaviour, possessiveness, stubbornness and mild to moderate mental retardation. Tumors: Myeloid leukaemia cases are 40 fold higher in PWS patients than in the general population. There have also been cases of lymphoblastic leukaemia, seminoma, adult ovarian teratoma, hepatic tumours, Hodgkin lymphoma and type 1 multiple endocrine neoplasia. Occasional abnormalities Skeletal findings: Scoliosis, kyphosis and hip dysplasia. Central nervous system: Ventriculomegaly, decreased volume of the parietal-occipital lobe, sylvian fissure polymicrogyria and incomplete insular closure. Identity Note The Prader Willi syndrome (PWS) is characterized by diminished fetal activity, dysmorphic facial features, small hands and feet, marked hypotonia, neonatal feeding problems, thick saliva, hyperphagia and weight gain between the ages of 1 and 6, poor linear growth, short stature, hypothalamic dysfunction (obesity, absence of satiety, hypogonadism with cryptorchidism, abnormal temperature control and GH deficiency), cognitive difficulties and characteristic behavioural traits. Inheritance It is sporadic and familial cases are rare. The incidence is 1:10.000-15.000 births. Etiology PWS is genetically heterogeneous. The absent expression of the paternal activity in the critical region on chromosome 15 has been found in patients with PWS. In 70-75% of patients there is a deletion of the paternal 15q11-q13 chromosome (del15) and in about 25% there is a maternal uniparental disomy 15 (UDP15), and a small percentage of patients may have an imprinting center mutation or translocations involving chromosome15. In the 15q11-q13 region a lot of candidate genes are present. The C/D box small nucleolar RNA (snoRNA) gene cluster HBII-85, IPW, PAR1, MAGEL2 and SNRPN genes is not expressed in patients with PWS and may be involved in the phenotype. Clinics Phenotype and clinics Abnormalities Growth: Intrauterine growth retardation, short stature due to a growth hormone deficiency. Atlas Genet Cytogenet Oncol Haematol. 2009; 13(4) 319 Prader Willi syndrome Piccione M, Corsello G Congenital and acquired hypothyroidism. References Cassidy SB. Prader-Willi syndrome. Characteristics, management, and etiology. Ala J Med Sci. 1987 Apr;24(2):16975 Cassidy SB. Prader-Willi syndrome. J Med Genet. 1997 Nov;34(11):917-23 Boccaccio I, Glatt-Deeley H, Watrin F, Roëckel N, Lalande M, Muscatelli F. The human MAGEL2 gene and its mouse homologue are paternally expressed and mapped to the Prader-Willi region. Hum Mol Genet. 1999 Dec;8(13):2497-505 Carrel AL, Myers SE, Whitman BY, Allen DB. Growth hormone improves body composition, fat utilization, physical strength and agility, and growth in Prader-Willi syndrome: A controlled study. J Pediatr. 1999 Feb;134(2):215-21 Hauffa BP, Schlippe G, Roos M, Gillessen-Kaesbach G, Gasser T. Spontaneous growth in German children and adolescents with genetically confirmed Prader-Willi syndrome. Acta Paediatr. 2000 Nov;89(11):1302-11 Fig 1: Dysmorphic facial features: high prominent forehead, narrow bifrontal diameter, downturned corners of the mouth, micrognathia. Lee S, Wevrick R. Identification of novel imprinted transcripts in the Prader-Willi syndrome and Angelman syndrome deletion region: further evidence for regional imprinting control. Am J Hum Genet. 2000 Mar;66(3):848-58 Ming JE, Blagowidow N, Knoll JH, Rollings L, Fortina P, McDonald-McGinn DM, Spinner NB, Zackai EH. Submicroscopic deletion in cousins with Prader-Willi syndrome causes a grandmatrilineal inheritance pattern: effects of imprinting. Am J Med Genet. 2000 May 1;92(1):19-24 Olander E, Stamberg J, Steinberg L, Wulfsberg EA. Third Prader-Willi syndrome phenotype due to maternal uniparental disomy 15 with mosaic trisomy 15. Am J Med Genet. 2000 Jul 31;93(3):215-8 Tauber M, Barbeau C, Jouret B, Pienkowski C, Malzac P, Moncla A, Rochiccioli P. Auxological and endocrine evolution of 28 children with Prader-Willi syndrome: effect of GH therapy in 14 children. Horm Res. 2000;53(6):279-87 Burman P, Ritzén EM, Lindgren AC. Endocrine dysfunction in Prader-Willi syndrome: a review with special reference to GH. Endocr Rev. 2001 Dec;22(6):787-99 Fulmer-Smentek SB, Francke U. Association of acetylated histones with paternally expressed genes in the Prader--Willi deletion region. Hum Mol Genet. 2001 Mar 15;10(6):645-52 Fig 2: Obesity in a 5-year-old patient. Evolution 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 Nov;108(5):E92 Multidisciplinary management (paediatrician, endocrinologist, orthopaedic specialist, dietologist, cardiologist, psychiatrist etc.) is necessary. Growth hormone treatment and strict diet control have been reported to significantly modify the life of children with PWS. Testosterone therapy has resulted in the enlargement of the micropenis to normal size for age and hormonal substitutive therapy with testosterone or estrogens allows a complete pubertal development. Meguro M, Mitsuya K, Nomura N, Kohda M, Kashiwagi A, Nishigaki R, Yoshioka H, Nakao M, Oishi M, Oshimura M. Large-scale evaluation of imprinting status in the Prader-Willi syndrome region: an imprinted direct repeat cluster resembling small nucleolar RNA genes. Hum Mol Genet. 2001 Feb 15;10(4):383-94 Wirth J, Back E, Hüttenhofer A, Nothwang HG, Lich C, Gross S, Menzel C, Schinzel A, Kioschis P, Tommerup N, Ropers HH, Horsthemke B, Buiting K. A translocation breakpoint cluster disrupts the newly defined 3' end of the SNURFSNRPN transcription unit on chromosome 15. Hum Mol Genet. 2001 Feb 1;10(3):201-10 Prognosis The patients have an increased mortality of 3% across all age groups but, if strict weight control is achieved, survival is improved. 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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 Myers SE, Whitman BY, Carrel AL, Moerchen V, Bekx MT, Allen DB. Two years of growth hormone therapy in young children with Prader-Willi syndrome: physical and neurodevelopmental benefits. Am J Med Genet A. 2007 Mar 1;143(5):443-8 Kato M, Mugishima H, Chin M, Urakami T, Harada K. Acute lymphoblastic leukemia in a patient with Prader-Willi syndrome under growth hormone therapy. Pediatr Int. 2005 Jun;47(3):336-7 Reddy LA, Pfeiffer SI. Behavioral and emotional symptoms of children and adolescents with Prader-Willi Syndrome. J Autism Dev Disord. 2007 May;37(5):830-9 Caixàs A, Giménez-Palop O, Giménez-Pérez G, Potau N, Berlanga E, González-Glemente JM, Arroyo J, Laferrère B, Mauricio D. Postprandial adiponectin levels are unlikely to contribute to the pathogenesis of obesity in Prader-Willi syndrome. Horm Res. 2006;65(1):39-45 Savopoulos C, Hatzitolios A, Panagopoulou P, Kosmidou M, Tsirogianni E, Konstantinou V. Hypothyroidism in Prader-Willi syndrome: a case report and review of the literature. J Endocrinol Invest. 2007 Oct;30(9):804-5 Craig ME, Cowell CT, Larsson P, Zipf WB, Reiter EO, Albertsson Wikland K, Ranke MB, Price DA. Growth hormone Atlas Genet Cytogenet Oncol Haematol. 2009; 13(4) 321 Prader Willi syndrome Piccione M, Corsello G Yamada K, Miyamoto K, Hosoe H, Mizutani M, Shimizu K. Scoliosis associated with Prader-Willi syndrome. Spine J. 2007 May-Jun;7(3):345-8 Cappa M, Caselli G, Cerioni V, Delvecchio M, Giardino D, Iannì F, Memo L, Pilotta A, Pomara C, Radetti G, Sacco M, Sanzari A, Sartorio A, Tonini G, Vettor R, Zaglia F, Chiumello G. The Italian National Survey for Prader-Willi syndrome: an epidemiologic study. Am J Med Genet A. 2008 Apr 1;146(7):861-72 Bacheré N, Diene G, Delagnes V, Molinas C, Moulin P, Tauber M. Early diagnosis and multidisciplinary care reduce the hospitalization time and duration of tube feeding and prevent early obesity in PWS infants. Horm Res. 2008;69(1):45-52 Tauber M, Diene G, Molinas C, Hébert M. Review of 64 cases of death in children with Prader-Willi syndrome (PWS). Am J Med Genet A. 2008 Apr 1;146(7):881-7 Butler MG, Fischer W, Kibiryeva N, Bittel DC. Array comparative genomic hybridization (aCGH) analysis in PraderWilli syndrome. Am J Med Genet A. 2008 Apr 1;146(7):854-60 Webb T, Maina EN, Soni S, Whittington J, Boer H, Clarke D, Holland A. In search of the psychosis gene in people with Prader-Willi syndrome. Am J Med Genet A. 2008 Apr 1;146(7):843-53 de Lind van Wijngaarden RF, Otten BJ, Festen DA, Joosten KF, de Jong FH, Sweep FC, Hokken-Koelega AC. High prevalence of central adrenal insufficiency in patients with Prader-Willi syndrome. J Clin Endocrinol Metab. 2008 May;93(5):1649-54 This article should be referenced as such: Piccione M, Corsello G. 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