Clinical and Experimental Pediatrics

The Korean Pediatric Society (대한소아청소년과학회)
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Endocrine problems in children with Prader-Willi syndrome: special review on associated genetic aspects and early growth hormone treatment

  • Jin, Dong-Kyu (Department of Pediatrics, Samsung Medical Center, Sungkyunkwan University School of Medicine)
  • Received : 2012.04.13
  • Accepted : 2012.05.07
  • Published : 2012.07.15
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Abstract

Prader-Willi syndrome (PWS) is a complex multisystem genetic disorder characterized by hypothalamic-pituitary dysfunction. The main clinical features include neonatal hypotonia, distinctive facial features, overall developmental delay, and poor growth in infancy, followed by overeating with severe obesity, short stature, and hypogonadism later in development. This paper reviews recent updates regarding the genetic aspects of this disorder. Three mechanisms (paternal deletion, maternal disomy, and deficient imprinting) are recognized. Maternal disomy can arise because of 4 possible mechanisms: trisomy rescue (TR), gamete complementation (GC), monosomy rescue (MR), and postfertilization mitotic nondisjunction (Mit). Recently, TR/GC caused by nondisjunction at maternal meiosis 1 has been identified increasingly, as a result of advanced maternal childbearing age in Korea. We verified that the d3 allele increases the responsiveness of the growth hormone (GH) receptor to endogenous GH. This paper also provides an overview of endocrine dysfunctions in children with PWS, including GH deficiency, obesity, sexual development, hypothyroidism, and adrenal insufficiency, as well as the effects of GH treatment. GH treatment coupled with a strictly controlled diet during early childhood may help to reduce obesity, improve neurodevelopment, and increase muscle mass. A more active approach to correct these hormone deficiencies would benefit patients with PWS.

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References

  1. Smith A, Egan J, Ridley G, Haan E, Montgomery P, Williams K, et al. Birth prevalence of Prader-Willi syndrome in Australia. Arch Dis Child 2003;88:263-4. https://doi.org/10.1136/adc.88.3.263
  2. Vogels A, Van Den Ende J, Keymolen K, Mortier G, Devriendt K, Legius E, et al. Minimum prevalence, birth incidence and cause of death for Prader-Willi syndrome in Flanders. Eur J Hum Genet 2004;12:238-40. https://doi.org/10.1038/sj.ejhg.5201135
  3. Cassidy SB, Dykens E, Williams CA. Prader-Willi and Angelman syndromes: sister imprinted disorders. Am J Med Genet 2000;97:136-46. https://doi.org/10.1002/1096-8628(200022)97:2<136::AID-AJMG5>3.0.CO;2-V
  4. Glenn CC, Driscoll DJ, Yang TP, Nicholls RD. Genomic imprinting: potential function and mechanisms revealed by the Prader-Willi and Angelman syndromes. Mol Hum Reprod 1997;3:321-32. https://doi.org/10.1093/molehr/3.4.321
  5. Glenn CC, Saitoh S, Jong MT, Filbrandt MM, Surti U, Driscoll DJ, et al. Gene structure, DNA methylation, and imprinted expression of the human SNRPN gene. Am J Hum Genet 1996;58:335-46.
  6. Kubota T, Das S, Christian SL, Baylin SB, Herman JG, Ledbetter DH. Methylation-specific PCR simplifies imprinting analysis. Nat Genet 1997; 16:16-7. https://doi.org/10.1038/ng0597-16
  7. Burman P, Ritzen EM, Lindgren AC. Endocrine dysfunction in Prader- Willi syndrome: a review with special reference to GH. Endocr Rev 2001; 22:787-99. https://doi.org/10.1210/er.22.6.787
  8. Butler MG, Meaney FJ. Standards for selected anthropometric measurements in Prader-Willi syndrome. Pediatrics 1991;88:853-60.
  9. Eiholzer U, Bachmann S, l'Allemand D. Is there growth hormone deficiency in prader-willi Syndrome? Six arguments to support the presence of hypothalamic growth hormone deficiency in Prader-Willi syndrome. Horm Res 2000;53 Suppl 3:44-52.
  10. Eiholzer U, l'Allemand D. Growth hormone normalises height, prediction of final height and hand length in children with Prader-Willi syndrome after 4 years of therapy. Horm Res 2000;53:185-92. https://doi.org/10.1159/000023565
  11. Festen DA, de Lind van Wijngaarden R, van Eekelen M, Otten BJ, Wit JM, Duivenvoorden HJ, et al. Randomized controlled GH trial: effects on anthropometry, body composition and body proportions in a large group of children with Prader-Willi syndrome. Clin Endocrinol (Oxf) 2008;69:443-51. https://doi.org/10.1111/j.1365-2265.2008.03228.x
  12. Lin HY, Lin SP, Tsai LP, Chao MC, Chen MR, Chuang CK, et al. Effects of growth hormone treatment on height, weight, and obesity in Taiwanese patients with Prader-Willi syndrome. J Chin Med Assoc 2008;71:305-9. https://doi.org/10.1016/S1726-4901(08)70127-8
  13. Angulo MA, Castro-Magana M, Lamerson M, Arguello R, Accacha S, Khan A. Final adult height in children with Prader-Willi syndrome with and without human growth hormone treatment. Am J Med Genet A 2007;143A:1456-61. https://doi.org/10.1002/ajmg.a.31824
  14. Myers SE, Carrel AL, Whitman BY, Allen DB. Sustained benefit after 2 years of growth hormone on body composition, fat utilization, physical strength and agility, and growth in Prader-Willi syndrome. J Pediatr 2000; 137:42-9. https://doi.org/10.1067/mpd.2000.105369
  15. Carrel AL, Moerchen V, Myers SE, Bekx MT, Whitman BY, Allen DB. Growth hormone improves mobility and body composition in infants and toddlers with Prader-Willi syndrome. J Pediatr 2004;145:744-9. https://doi.org/10.1016/j.jpeds.2004.08.002
  16. 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;143:443-8.
  17. Tauber M, Diene G, Molinas C, Hebert M. Review of 64 cases of death in children with Prader-Willi syndrome (PWS). Am J Med Genet A 2008; 146:881-7.
  18. Grugni G, Crino A, Bosio L, Corrias A, Cuttini M, De Toni T, et al. The Italian National Survey for Prader-Willi syndrome: an epidemiologic study. Am J Med Genet A 2008;146:861-72.
  19. Sacca L, Cittadini A, Fazio S. Growth hormone and the heart. Endocr Rev 1994;15:555-73. https://doi.org/10.1210/edrv-15-5-555
  20. Hauffa BP, Knaup K, Lehmann N, Neudorf U, Nagel B. Effects of growth hormone therapy on cardiac dimensions in children and adolescents with Prader-Willi syndrome. Horm Res Paediatr 2011;75:56-62. https://doi.org/10.1159/000319612
  21. Festen DA, Wevers M, Lindgren AC, Bohm B, Otten BJ, Wit JM, et al. Mental and motor development before and during growth hormone treatment in infants and toddlers with Prader-Willi syndrome. Clin Endocrinol (Oxf) 2008;68:919-25. https://doi.org/10.1111/j.1365-2265.2007.03126.x
  22. Carrel AL, Myers SE, Whitman BY, Eickhoff J, Allen DB. Long-term growth hormone therapy changes the natural history of body composition and motor function in children with prader-willi syndrome. J Clin Endocrinol Metab 2010;95:1131-6. https://doi.org/10.1210/jc.2009-1389
  23. Yamauchi T, Nio Y, Maki T, Kobayashi M, Takazawa T, Iwabu M, et al. Targeted disruption of AdipoR1 and AdipoR2 causes abrogation of adiponectin binding and metabolic actions. Nat Med 2007;13:332-9. https://doi.org/10.1038/nm1557
  24. Matsuzawa Y. The metabolic syndrome and adipocytokines. FEBS Lett 2006;580:2917-21. https://doi.org/10.1016/j.febslet.2006.04.028
  25. Tilg H, Moschen AR. Adipocytokines: mediators linking adipose tissue, inflammation and immunity. Nat Rev Immunol 2006;6:772-83. https://doi.org/10.1038/nri1937
  26. Alberti L, Gilardini L, Girola A, Moro M, Cavagnini F, Invitti C. Adiponectin receptors gene expression in lymphocytes of obese and anorexic patients. Diabetes Obes Metab 2007;9:344-9. https://doi.org/10.1111/j.1463-1326.2006.00614.x
  27. Vuorela P, Ala-Mello S, Saloranta C, Penttinen M, Poyhonen M, Huoponen K, et al. Molecular analysis of the CHD7 gene in CHARGE syndrome: identification of 22 novel mutations and evidence for a low contribution of large CHD7 deletions. Genet Med 2007;9:690-4. https://doi.org/10.1097/GIM.0b013e318156e68e
  28. Butler MG, Fischer W, Kibiryeva N, Bittel DC. Array comparative genomic hybridization (aCGH) analysis in Prader-Willi syndrome. Am J Med Genet A 2008;146:854-60.
  29. Colmenares A, Pinto G, Taupin P, Giuseppe A, Odent T, Trivin C, et al. Effects on growth and metabolism of growth hormone treatment for 3 years in 36 children with Prader-Willi syndrome. Horm Res Paediatr 2011;75:123-30. https://doi.org/10.1159/000319709
  30. 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;93: 1012-6. https://doi.org/10.1136/adc.2007.123836
  31. Nagai T, Obata K, Ogata T, Murakami N, Katada Y, Yoshino A, et al. Growth hormone therapy and scoliosis in patients with Prader-Willi syndrome. Am J Med Genet A 2006;140:1623-7.
  32. Odent T, Accadbled F, Koureas G, Cournot M, Moine A, Diene G, et al. Scoliosis in patients with Prader-Willi Syndrome. Pediatrics 2008;122: e499-503. https://doi.org/10.1542/peds.2007-3487
  33. Ahl T, Albertsson-Wikland K, Kalen R. Twenty-four-hour growth hormone profiles in pubertal girls with idiopathic scoliosis. Spine (Phila Pa 1976) 1988;13:139-42. https://doi.org/10.1097/00007632-198802000-00001
  34. Skogland LB, Miller JA. Growth related hormones in idiopathic scoliosis. An endocrine basis for accelerated growth. Acta Orthop Scand 1980;51:779-80. https://doi.org/10.3109/17453678008990874
  35. Willner S, Nilsson KO, Kastrup K, Bergstrand CG. Growth hormone and somatomedin A in girls with adolescent idiopathic scoliosis. Acta Paediatr Scand 1976;65:547-52. https://doi.org/10.1111/j.1651-2227.1976.tb04930.x
  36. de Lind van Wijngaarden RF, de Klerk LW, Festen DA, Duivenvoorden HJ, Otten BJ, Hokken-Koelega AC. Randomized controlled trial to investigate the effects of growth hormone treatment on scoliosis in children with Prader-Willi syndrome. J Clin Endocrinol Metab 2009; 94:1274-80. https://doi.org/10.1210/jc.2008-1844
  37. Redline S, Tishler PV, Schluchter M, Aylor J, Clark K, Graham G. Risk factors for sleep-disordered breathing in children. Associations with obesity, race, and respiratory problems. Am J Respir Crit Care Med 1999; 159(5 Pt 1):1527-32. https://doi.org/10.1164/ajrccm.159.5.9809079
  38. Richards A, Quaghebeur G, Clift S, Holland A, Dahlitz M, Parkes D. The upper airway and sleep apnoea in the Prader-Willi syndrome. Clin Otolaryngol Allied Sci 1994;19:193-7. https://doi.org/10.1111/j.1365-2273.1994.tb01213.x
  39. Schluter B, Buschatz D, Trowitzsch E, Aksu F, Andler W. Respiratory control in children with Prader-Willi syndrome. Eur J Pediatr 1997; 156:65-8. https://doi.org/10.1007/s004310050555
  40. Holm VA, Cassidy SB, Butler MG, Hanchett JM, Greenswag LR, Whitman BY, et al. Prader-Willi syndrome: consensus diagnostic criteria. Pediatrics 1993;91:398-402.
  41. Eiholzer U. Deaths in children with Prader-Willi syndrome. A contribution to the debate about the safety of growth hormone treatment in children with PWS. Horm Res 2005;63:33-9. https://doi.org/10.1159/000082745
  42. Fillion M, Deal C, Van Vliet G. Retrospective study of the potential benefits and adverse events during growth hormone treatment in children with Prader-Willi syndrome. J Pediatr 2009;154:230-3. https://doi.org/10.1016/j.jpeds.2008.07.058
  43. Nixon GM, Rodda CP, Davey MJ. Longitudinal association between growth hormone therapy and obstructive sleep apnea in a child with Prader- Willi syndrome. J Clin Endocrinol Metab 2011;96:29-33. https://doi.org/10.1210/jc.2010-1445
  44. Dos Santos C, Essioux L, Teinturier C, Tauber M, Goffin V, Bougneres P. A common polymorphism of the growth hormone receptor is associated with increased responsiveness to growth hormone. Nat Genet 2004;36:720-4. https://doi.org/10.1038/ng1379
  45. Park SW, Lee ST, Sohn YB, Kim SH, Cho SY, Ko AR, et al. A polymorphism in the growth hormone receptor is associated with height in children with Prader-Willi syndrome. Am J Med Genet A 2011;155A:2970-3.
  46. Miller JL, Lynn CH, Driscoll DC, Goldstone AP, Gold JA, Kimonis V, et al. Nutritional phases in Prader-Willi syndrome. Am J Med Genet A 2011;155A:1040-9.
  47. McAllister CJ, Whittington JE, Holland AJ. Development of the eating behaviour in Prader-Willi Syndrome: advances in our understanding. Int J Obes (Lond) 2011;35:188-97. https://doi.org/10.1038/ijo.2010.139
  48. Brandau DT, Lund M, Cooley LD, Sanger WG, Butler MG. Autistic and dysmorphic features associated with a submicroscopic 2q33.3-q34 interstitial deletion detected by array comparative genomic hybridization. Am J Med Genet A 2008;146A:521-4. https://doi.org/10.1002/ajmg.a.32153
  49. Sahoo T, Bacino CA, German JR, Shaw CA, Bird LM, Kimonis V, et al. Identification of novel deletions of 15q11q13 in Angelman syndrome by array-CGH: molecular characterization and genotype-phenotype correlations. Eur J Hum Genet 2007;15:943-9. https://doi.org/10.1038/sj.ejhg.5201859
  50. Santamaria R, Blanco M, Chabas A, Grinberg D, Vilageliu L. Identification of 14 novel GLB1 mutations, including five deletions, in 19 patients with GM1 gangliosidosis from South America. Clin Genet 2007;71:273-9. https://doi.org/10.1111/j.1399-0004.2007.00767.x
  51. Butler JV, Whittington JE, Holland AJ, McAllister CJ, Goldstone AP. The transition between the phenotypes of Prader-Willi syndrome during infancy and early childhood. Dev Med Child Neurol 2010;52:e88-93. https://doi.org/10.1111/j.1469-8749.2009.03530.x
  52. Siemensma EP, de Lind van Wijngaarden RF, Otten BJ, de Jong FH, Hokken- Koelega AC. Testicular failure in boys with Prader-Willi syndrome: longitudinal studies of reproductive hormones. J Clin Endocrinol Metab 2012;97:E452-9. https://doi.org/10.1210/jc.2011-1954
  53. Eldar-Geva T, Hirsch HJ, Rabinowitz R, Benarroch F, Rubinstein O, Gross-Tsur V. Primary ovarian dysfunction contributes to the hypogonadism in women with Prader-Willi Syndrome. Horm Res 2009; 72:153-9. https://doi.org/10.1159/000232489
  54. Unanue N, Bazaes R, Iniguez G, Cortes F, Avila A, Mericq V. Adrenarche in Prader-Willi syndrome appears not related to insulin sensitivity and serum adiponectin. Horm Res 2007;67:152-8. https://doi.org/10.1159/000096742
  55. Crino A, Di Giorgio G, Schiaffini R, Fierabracci A, Spera S, Maggioni A, et al. Central precocious puberty and growth hormone deficiency in a boy with Prader-Willi syndrome. Eur J Pediatr 2008;167:1455-8. https://doi.org/10.1007/s00431-008-0679-0
  56. Vaiani E, Herzovich V, Chaler E, Chertkoff L, Rivarola MA, Torrado M, et al. Thyroid axis dysfunction in patients with Prader-Willi syndrome during the first 2 years of life. Clin Endocrinol (Oxf) 2010;73:546-50.
  57. Festen DA, Visser TJ, Otten BJ, Wit JM, Duivenvoorden HJ, Hokken- Koelega AC. Thyroid hormone levels in children with Prader-Willi syndrome before and during growth hormone treatment. Clin Endocrinol (Oxf) 2007;67:449-56. https://doi.org/10.1111/j.1365-2265.2007.02910.x
  58. Nagai T, Obata K, Tonoki H, Temma S, Murakami N, Katada Y, e al. Cause of sudden, unexpected death of Prader-Willi syndrome patients with or without growth hormone treatment. Am J Med Genet A 2005; 136:45-8.
  59. Einfeld SL, Kavanagh SJ, Smith A, Evans EJ, Tonge BJ, Taffe J. Mortality in Prader-Willi syndrome. Am J Ment Retard 2006;111:193-8. https://doi.org/10.1352/0895-8017(2006)111[193:MIPS]2.0.CO;2
  60. Corrias A, Grugni G, Crino A, Di Candia S, Chiabotto P, Cogliardi A, et al. Assessment of central adrenal insufficiency in children and adolescents with Prader-Willi syndrome. Clin Endocrinol (Oxf) 2012;76:843-50. https://doi.org/10.1111/j.1365-2265.2011.04313.x

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