Prader-Willi Syndrome: An Update and Review for the Primary Pediatrician

Abstract

Prader-Willi syndrome, the first known human genomic imprinting disorder, is one of the most common micro-deletion syndromes. Prader-Willi syndrome is caused by the absence of certain paternally inherited genes on the long arm of chromosome 15, resulting in a complete absence of the active copy of the genetic information in this region. It is most commonly known for its food-related characteristics of hyperphagia, food-seeking behavior, and consequent obesity. Primary care physicians play an important role in the care of children with Prader-Willi syndrome, from recognizing the presenting signs and symptoms at its various stages to understanding their unique medical, developmental, behavioral, and dietary issues. They can also serve as a valuable source of support and advocacy for the family. This article reviews the current state of knowledge about Prader-Willi syndrome and discusses up-to-date understanding of the management of this condition.

Keywords

Prader-Willi syndrome obesity growth hormone hypotonia developmental delay.

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References

Clarke DJ , Boer H. Genetic and behavioural aspects of Prader-Willi syndrome: a review with a translation of the original paper. Ment Handicap Res. 1995;8:38-53.

Ledbetter DH , Riccardi VM , Airhart SD , Strobel RJ , Keenen SB , Crawford JD Deletions of chromosome 15 as a cause of the Prader-Willi syndrome. N Engl J Med. 1981;304:325-329.

Hawkey CJ , Smithies A. The Prader-Willi syndrome with a 15/15 translocation: case report and review of the literature. J Med Genet. 1976;13:152-156.

Knoll Jhm , Nichols RD , Magenis RE , Graham JM Jr , Lalande M. , Latt SA Angelman and Prader-Willi syndromes share a common chromosome 15 deletion but differ in parental origin of the deletion. Am J Med Genet. 1989;32:285-290.

Driscoll DJ , Waters MF , Williams CA , et al. A DNA methylation imprint, determined by the sex of the parent, distinguishes the Angelman and the Prader-Willi syndromes. Genomics. 1992;13:917-924.

Nicholls RD Genomic imprinting and uniparental disomy in Angelman and Prader-Willi syndrome: a review. Am J Med Genet. 1993;46:16-25.

Nicholls RD , Knoll Jhm , Butler MG , Karam S. , Lalande M. Genetic imprinting suggested by maternal heterodisomy in non-deletion Prader-Willi syndrome. Nature. 1989;342:281-285.

Robinson WP , Bottani A. , Yagang X. , et al. Molecular, cytogenetic and clinical investigations of Prader-Willi syndrome patients. Am J Hum Genet. 1991;49:1219-1234.

Robinson WP , Bottani A. , Xie YG , et al. The frequency of uniparental disomy in Prader-Willi syndrome. N Engl J Med. 1992;326:1599-1607.

10.

Cassidy SB , Lai LW , Erickson RP , et al. Trisomy 15 with loss of the paternal 15 as a cause of Prader-Willi syndrome due to maternal disomy. Am J Hum Genet. 1992; 51:701-708.

11.

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. 1994;9:395-400.

12.

Saitoh S. , Buiting K. , Cassidy SB , et al. Clinical spectrum and molecular diagnosis of Angelman and Prader-Willi syndrome imprinting mutation patients. Am J Med Genet. 1997;68:195-206.

13.

Buiting K. , Gross S. , Lich C. , Gillessen-Kaesbach G. , el-Maarri O. , Horsthemke B. Epimutations in Prader-Willi and Angelman syndromes: a molecular study of 136 patients with an imprinting defect. Am J Hum Genet. 2003;72:571-577.

14.

Clayton-Smith J. , Pembrey ME Angelman syndrome. J Med Genet. 1992;29:412-415.

15.

Williams CA , Angelman H. , Clayton-Smith J. , et al. Angelman syndrome: consensus for diagnostic criteria. Am J Med Genet. 1995;56:237-238.

16.

Malzac P. , Webber H. , Moncla A. , et al. Mutation analysis of UBE3A in Angelman syndrome patients. Am J Hum Genet. 1998;62:1353-1360.

17.

Fang P. , Lev-Lehman E. , Tsai TF , et al. The spectrum of mutations in UBE3A causing Angelman syndrome . Hum Mol Genet. 1999;8:129-135.

18.

Khan NL , Wood NW Prader-Willi and Angelman syndromes: update on genetic mechanisms and diagnostic complexities. Curr Opin Neurol. 1999;12:149-154.

19.

Ozcelik T. , Leff S. , Robinson W. , et al. Small nuclear ribonucleoprotein polypeptide N (SNRPN), and expressed gene in the Prader-Willi syndrome critical region. Nat Genet. 1992;2:265-269.

20.

Glenn CC , Porter KA , Jong Mtc , Nicholls RD , Driscoll DJ Functional imprinting and epigenetic modification of the human SNRPN gene . Hum Mol Genet. 1993;2: 2001-2005.

21.

Glenn CC , Saitoh S. , Jong Mtc , et al. Gene structure, DNA methylation and imprinted expression of the human SNRPN gene. Am J Hum Genet. 1996 ;58:335-346.

22.

Jay P. , Rougeulle C. , Massacrier A. , et al. The human necdin gene, NDN, is maternally imprinted and located in the Prader-Willi syndrome chromosomal region. Nat Genet. 1997;17:357-361.

23.

Spritz RA , Bailin T. , Nicholls RD , et al. Hypopigmentation in the Prader-Willi syndrome correlates with P gene deletion but not with haplotype of the hemizygous P allele. Am J Hum Genet. 1997;71:57-62.

24.

Cassidy SB , Forsythe M. , Heeger S. , et al. Comparison of phenotype between patients with Prader-Willi syndrome due to deletion 15q and uniparental disomy 15. Am J Med Genet. 1997;68:433-440.

25.

Gillessen-Kaesbach G. , Robinson W. , Lohmann D. , Kaya-Westerloh S. , Passarge E. , Horsthemke B. Genotype-phenotype correlation in a series of 167 deletion and non-deletion patients with Prader-Willi syndrome. Hum Genet. 1995;96:638-643.

26.

Dykens EM

Are jigsaw puzzle skills “spared

” in persons with Prader-Willi syndrome?

J Child Psychol Psychiatry. 2002;43:343-352.

27.

Dykens EM , Cassidy SB , King BH Maladaptive behavior differences in Prader-Willi syndrome due to paternal deletion versus maternal uniparental disomy. Am J Ment Retard . 1999;104:67-77.

28.

Roof E. , Stone W. , MacLean W, Feurer ID, Thompson T, Butler MG. Intellectual characteristics of Prader-Willi syndrome: comparison of genetic subtypes. J Intellect Disabil Res. 2000;44:25-30.

29.

Gunay-Aygun M. , Cassidy SB Delayed diagnosis in Prader-Willi syndrome due to uniparental disomy. Am J Med Genet. 1997;71:106-110.

30.

Holland AJ , Whittington JE , Butler J. , Webb T. , Boer H. , Clarke D. Behavioural phenotypes associated with specific genetic disorders: evidence from a population-based study of people with Prader-Willi syndrome. Psychol Med. 2003;33:141-153.

31.

Veltman MW , Thompson RJ , Roberts SE , Thomas NS , Whittington J. , Bolton PF Prader-Willi syndrome—a study comparing deletion and uniparental disomy cases with reference to autism spectrum disorders. Eur Child Adolesc Psychiatry. 2004;13:42-50.

32.

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;48:172-187.

33.

Hudgins L. , Geer JS , Cassidy SB Phenotypic differences in African-Americans with Prader-Willi syndrome. Genet Med. 1998;1:49-51.

34.

Cassidy SB , Geer JS , Holm VA , Hudgins L. African-Americans with Prader-Willi syndrome are phenotypically different . Am J Hum Genet. 1996;59:A21.

35.

Whittington JE , Holland AJ , Webb T. , Butler J. , Webb T. , Clarke D. Population prevalence and estimated birth incidence and mortality rate for people with Prader-Willi syndrome in one UK Health Region. J Med Genet. 2001;38:792-798.

36.

Butler JV , Whittington JE , Holland AJ , Boer H. , Clarke D. , Webb T. Prevalence of, and risk factors for, physical ill-health in people with Prader-Willi syndrome: a population-based study. Dev Med Child Neurol. 2002;44:248-255.

37.

Smith A. , Egan J. , Ridley G. , et al. Birth prevalence of Prader-Willi syndrome in Australia. Arch Dis Child. 2003;88:263-264.

38.

Vogels A. , Van Den Ende J. , Keymolen K. , et al. Minimum prevalence, birth incidence and cause of death for Prader-Willi syndrome in Flanders. Eur J Hum Genet. 2004 ;12:238-240.

39.

Cassidy SB , McCandless SE Prader-Willi syndrome. In: Cassidy SB , Allanson JE , eds. Management of Genetic Syndromes . 2nd ed. Hoboken, NJ: John Wiley & Sons, 2005:429-448.

40.

Schrander-Stumpel CT , Curfs L. , Sastrowijoto P. , Cassidy SB , Schrander JU , Fryns JP Prader-Willi syndrome: causes of death in an international series of cases. Am J Med Genet. 2004;124A:333-338.

41.

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. 2004;124A:154-164.

42.

Toth-Fejel S. , Magenis RE , Leff S. , et al. Prenatal diagnosis of chromosome 15 abnormalities in the Prader-Willi/ Angelman syndrome region by traditional and molecular cytogenetics. Am J Med Genet. 1995;55:444-452.

43.

Fong BF, De Vries JI. Obstetric aspects of the Prader-Willi syndrome. Ultrasound Obstet Gynecol. 2003;21:389-392.

44.

Holm VA , Cassidy SB , Butler M. , et al. Prader-Willi syndrome: consensus diagnostic criteria. Pediatrics. 1993;91: 398-402.

45.

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:E92.

46.

Dykens EM , Cassidy SB Prader-Willi syndrome: genetic, behavioral and treatment issues. Child Adolesc Psychiatr Clin North Am. 1996;5:913-927.

47.

Aughton DJ and Cassidy SB Physical features of Prader-Willi syndrome in neonates. Am J Dis Child. 1990;144: 1351-1254.

48.

Crino A. , Schiaffini R. , Ciampalini P. , et al. Hypogonadism and pubertal development in Prader-Willi syndrome . Eur J Pediatr. 2003;162:327-33.

49.

Monaghan KG , Wiktor A. , Van Dyke DL Diagnostic testing for Prader-Willi syndrome and Angelman syndrome: a cost comparison. Genet Med. 2002;4:448-450.

50.

Gunay-Aygun M. , Cassidy SB , Nicholls RD Prader-Willi and other syndromes associated with obesity and mental retardation. Behav Genet. 1997;27:307-324.

51.

DiMario FJ Jr , Dunham B. , Burleson JA , Moskovitz J. , Cassidy SB An evaluation of autonomic nervous system function in patients with Prader-Willi syndrome. Pediatrics. 1994;93:76-81.

52.

Wiesner GL , Bendel CM , Olds DP , et al. Hypopigmentation in the Prader-Willi syndrome. Am J Med Genet. 1987; 40:431-442.

53.

Butler MG Hypopigmentation: a common feature of the Prader-Labhart-Willi syndrome. Am J Hum Genet. 1989;45:140-146.

54.

Creel DJ , Bendel CM , Wiesner GL , Wirtschafter JD , Arthur DC , King RA Abnormalities of the central visual pathways in Prader-Willi syndrome associated with hypopigmentation. N Engl J Med. 1986;314:1606-1609.

55.

Lee Pdk. Endocrine and metabolic aspects of Prader-Willi syndrome. In: Louise Greenswag L , Alexander R , eds. Management of Prader-Willi Syndrome. New York, NY: Springer-Verlag, 1995 :32-57.

56.

Angulo M. , Castro-Magana M. , Mazur B. , Canas JA , Vitollo PM , Sarrantonio M. Growth hormone secretion and effects of growth hormone therapy on growth velocity and weight gain in children with Prader-Willi syndrome. J Pediatr Endocrinol Metab. 1996;9:393-400.

57.

Butler MG , Meaney FJ Standards for selected anthropometric measurements in Prader-Willi syndrome . Pediatrics. 1991;88:853-860.

58.

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: 565-567.

59.

Butler MG , Haber L. , Mernaugh R. , Carlson MG , Price R. , Feurer ID Decreased bone mineral density in Prader-Willi syndrome: comparison with obese subjects. Am J Med Genet. 2001;103:216-222.

60.

Hoybye C. , Hilding A. , Jacobsson H. , Thoren M. Metabolic profile and body composition in adults with Prader-Willi syndrome and severe obesity. J Clin Endocrinol Metab. 2002;87:3590-3597.

61.

Zipf WB , Bernston GG Characteristics of abnormal food-intake patterns in children with Prader-Willi syndrome and study of effects of naloxone. Am J Clin Nutr. 1987;46:277-281.

62.

Holland AJ , Treasure J. , Coskeran P. , Dallow J. , Milton N. , Hillhouse E. Measurement of excessive appetite and metabolic changes in Prader-Willi syndrome . Int J Obes. 1993;17:526-532.

63.

Butler MG , Bittel lDC , Talebizadeh Z. Plasma peptide YY and ghrelin levels in infants and children with Prader-Willi syndrome. J Pediatr Endocrinol Metab. 2004 ;17: 1177-1184.

64.

Holm VA , Pipes PL Food and children with Prader-Willi syndrome. Am J Dis Child. 1976;130:1063-1067.

65.

Butler MG , Butler RI , Meaney FJ The use of skinfold measurements to judge obesity during the early phase of Prader-Labhart-Willi syndrome. Int J Obes. 1988;12: 417-422.

66.

Akefeldt A. , Tornhage CJ , Gillberg C. “A woman with Prader-Willi syndrome gives birth to a healthy baby girl” [letter]. Dev Med Child Neurol. 1999;41:789-790.

67.

Schulze A. , Mogensen H. , Hamborg-Petersen B. , et al. Fertility in Prader-Willi syndrome: a case report with Angelman syndrome in the offspring. Acta Paediatr. 2001;90:455-459.

68.

69.

Lewis BA Speech and language disorders associated with Prader-Willi syndrome. In: Butler MG , Lee PDK , Whitman BY , eds. Management of Prader-Willi Syndrome. 3rd ed. New York, NY: Springer-Verlag; 2006:272-283.

70.

Dykens EM , Hodapp RM , Walsh K. , Nash L. Profiles, correlates and trajectories of intelligence in individuals with Prader-Willi syndrome. J Am Acad Child Adolesc Psychiatry. 1992;31:1125-1130.

71.

Curfs LG Psychological profile and behavioral characteristics in Prader-Willi syndrome . In: Cassidy SB , ed. Prader-Willi Syndrome and Other 15q Deletion Disorders. Berlin, Germany: Springer-Verlag, 1992:211-222.

72.

Whittington J. , Holland A. , Webb T. , Butler J. , Clarke D. , Boer H. Academic underachievement by people with Prader-Willi syndrome. J Intellect Disabil Res. 2004;48:188-200.

73.

Greenswag L. , Alexander R. Early diagnosis in Prader-Willi syndrome: implications for managing weight and behavior. Dysmorphol Clin Genet. 1990;4:8-12.

74.

Greenswag LR Adults with Prader-Willi syndrome. A survery of 232 cases. Dev Med Child Neurol. 1987;29: 145-152.

75.

Waters J. Prader-Willi syndrome. In: Profound Mental Retardation and Multiple Impairment, Vol 3: Medical and Physical Care and Management. London, UK: Chapman and Hall; 1990.

76.

Steinhausen HC , Eiholzer U. , Hauffa BP , Malin Z. Behavioural and emotional disturbances in people with Prader-Willi Syndrome. J Intellect Disabil Res. 2004;48: 47-52.

77.

Dykens EM , Cassidy SB Correlates of maladaptive behavior in children and adults with Prader-Willi syndrome. Am J Med Genet. 1995;60:546-549.

78.

Dykens EM , Leckman JF , Cassidy SB Obsessions and compulsions in Prader-Willi syndrome. J Child Psychol Psychiatry. 1996;37:995-1002.

79.

Boer H. , Holland A. , Whittington J. , Butler J. , Webb T. , Clarke D. Psychotic illness in people with Prader-Willi syndrome due to chromosome 15 maternal uniparental disomy. Lancet. 2002;359:135-136.

80.

Nixon GM , Brouillette RT Sleep and breathing in Prader-Willi syndrome. Pediatr Pulmonol. 2002;34:209-217.

81.

Hertz G. , Cataletto M. , Feinsilver SH , Angulo M. Developmental trends of sleep-disordered breathing in Prader-Willi syndrome: the role of obesity. Am J Med Genet. 1995;56:188-190.

82.

Carrel AL , Lee Pdk , Mogul HR Growth hormone and Prader-Willi syndrome. In: Butler MG , Lee PDK , Whitman BY , eds. Management of Prader-Willi Syndrome. 3rd ed. New York, NY : Springer-Verlag; 2006:201-244.

83.

Eiholzer U. , Schlumpf M. , Nordmann Y. , l'Allemand D. Early manifestations of Prader-Willi syndrome: influence of growth hormone . J Pediatr Endocrinol Metab. 2001;14:1441-1444.

84.

Hoybye C. , Hilding A. , Jacobsson H. , Thoren M. Growth hormone treatment improves body composition in adults with Prader-Willi syndrome. Clin Endocrinol. 2003;58:653-661.

85.

Carrel AL , Myers SE , Whitman BY , Allen DB Sustained benefits of growth hormone on body composition, fat utilization, physical strength and agility, and growth in Prader-Willi syndrome are dose-dependent . J Pediatr Endocrinol Metab. 2001;14:1097-1105.

86.

Carrel AL , Myers SE , Whitman BY , Allen DB Benefits of long-term GH therapy in Prader-Willi syndrome: a 4-year study . J Clin Endocrinol Metab. 2002;87:1582-1585.

87.

Nordmann Y. , Eiholzer U. , l'Allemand D. , Mirjanic S. , Markwalder C.

Sudden death of an infant with Prader-Willi syndrome—not a unique case?

Biol Neonate. 2002;82: 139-142.

88.

Eiholzer U. , Nordmann Y. , l'Allemand D. Fatal outcome of sleep apnoea in PWS during the initial phase of growth hormone treatment. A case report. Horm Res. 2002;58:24-26.

89.

Vliet GV , Deal CL , Crock PA , Robitaille Y. , Oligny LL Sudden death in growth hormone-treated children with Prader-Willi syndrome . J Pediatr. 2004;144:129-131.

90.

Burman P. , Ritzen EM , Lindgren AC Endocrine dysfunction in Prader-Willi syndrome: a review with special reference to GH. Endocr Rev. 2001;22:787-799.

91.

Brice JA Behavioral and psychotropic interventions in persons with Prader-Willi syndrome . Endocrinologist. 2000;10:27S-30S.

92.

Benjamin E. , Buot-Smith T. Naltrexone and fluoxetine in Prader-Willi syndrome. J Am Acad Child Adolesc Psychiatry. 1993;32:870-873.

93.

Desh B. , Budow L. The use of fluoxetine in an adolescent with Prader-Willi syndrome. J Am Acad Child Adolesc Psychiatry. 1991;30:298-302.

94.

Durst R. , Rubin-Jobotinsky K. , Raskin S. , Katz G. , Zislin J. Risperidone in treating behavioural disturbances of Prader-Willi syndrome . Acta Psychiatr Scand. 2000;102:461-465.

95.

Cassidy SB , Devi A. , Mukaida C. Aging in Prader-Willi syndrome: 232 patients over age 30 years. Proc Greenwood Genet Center. 1994;13:102-103.