Growth Hormone Therapy in Children with Prader-Willi Syndrome

  • Aaron L. Carrel
  • David B. Allen


Prader-Willi syndrome (PWS) , initially described by Prader, Willi, and Labhart in 1956, is characterized by obesity, hypotonia, hyperphagia, delayed motor skill acquisition, short stature, mental retardation, hypothalamic dysfunction, and hypogonadism. This article reviews causes of and potential treatments for impaired growth, body composition, and physical function observed in children with PWS. Growth failure due to PWS is an approved indication for recombinant human growth hormone (hGH) therapy, with disordered body composition being an additional hGH indication in Europe. Treatment of these children has not only improved stature but has also raised awareness of non-height effects of hGH therapy – improvements in body composition and increased physical strength and function and increased energy expenditure – which may exceed linear growth promotion in importance. hGH treatment benefits must be weighed against potential adverse effects, including rare occurrences of sudden death. This review summarizes recent evidence relevant to an informed benefit-risk analysis of hGH therapy in children with PWS.


Prader-Willi syndrome Growth hormone Body composition Strength Physical function Sleep-disordered breathing Cognitive development Imprinting 



The authors wish to thank the important research collaboration of Drs. Susan Meyers and Barbara Whitman, as well as the invaluable help of our study coordinator, Heidi Luebke MS. This work has supported in part by NIH grant M01 RR03186-13S1 as well as funding from Pharmacia, Genentech Foundation for Growth and Development, and Pfizer.


  1. 1.
    Prader A, Labhart A, Willi H. Ein syndrom von adipositas, kleinwuchs, kryptorchismus and oligophrenie. Schweiz Med Wochenschr. 1956;86:1260–1.Google Scholar
  2. 2.
    Butler MG, Thompson T. Prader-Willi syndrome: clinical and genetic findings. Endocrinologist. 2000;10(supp 1):3S–16S.CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Goldstone AP, Holland AJ, Hauffa BP, Hokken-Koelega A, Tauber M. Recommendations for the diagnosis and management of Prader-Willi syndrome. J Clin Endocrinol Metab. 2008;93(11):4183–97.CrossRefPubMedGoogle Scholar
  4. 4.
    Colmers WF, Wevrick R. Leptin signaling defects in a mouse model of Prader-Willi syndrome: an orphan genetic obesity syndrome no more? Rare Dis (Austin, Tex). 2013;1:e24421.CrossRefGoogle Scholar
  5. 5.
    Mercer RE, Michaelson SD, Chee MJ, Atallah TA, Wevrick R, Colmers WF. Magel2 is required for leptin-mediated depolarization of POMC neurons in the hypothalamic arcuate nucleus in mice. PLoS Genet. 2013;9(1):e1003207.CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Angulo M, Castro-Magana M, Uy J. Pituitary evaluation and growth hormone treatment in Prader-Willi syndrome. J Pediatr Endocrinol. 1991;4:167–73.CrossRefGoogle Scholar
  7. 7.
    Brambilla P, Bosio L, Manzoni P. Peculiar body composition in patients with Prader-Labhart-Willi syndrome. Am J Clin Nutr. 1997;65:1369–74.CrossRefPubMedGoogle Scholar
  8. 8.
    Bekx MT, Carrel AL, Shriver TC, Li Z, Allen DB. Decreased energy expenditure is caused by abnormal body composition in infants with Prader-Willi syndrome. J Pediatr. 2003;143:372–6.CrossRefPubMedGoogle Scholar
  9. 9.
    Corrias A, Bellone J, Beccaria L, Bosio L. GH/IGF-I axis in Prader-Willi syndrome: evaluation of IGF-I levels and of the somatotroph responsiveness to various provocative stimuli. J Endocrinol Investig. 2000;23(2):84–9.CrossRefGoogle Scholar
  10. 10.
    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;134(2):215–21.CrossRefPubMedGoogle Scholar
  11. 11.
    Carrel AL, Myers SE, Whitman BY, Allen DB. Benefits of long-term GH therapy in Prader-Willi syndrome: a 4-year study. J Clin Endo Metabol. 2002;87:1581–5.CrossRefGoogle Scholar
  12. 12.
    Haqq AM, Stadler DD, Jackson RH, Rosenfeld RG, Purnell JQ, LaFranchi SH. Effects of growth hormone on pulmonary function, sleep quality, behavior, cognition, growth velocity, body composition, and resting energy expenditure in Prader-Willi syndrome. J Clin Endo Metabol. 2003;88(5):2206–12.CrossRefGoogle Scholar
  13. 13.
    Eiholzer U, Gisin R, Weinmann C, et al. Treatment with human growth hormone in patients with Prader-Labhart-Willi syndrome reduces body fat and increases muscle mass and physical performance. Eur J Pediatr. 1998;157(5):368–77.CrossRefPubMedGoogle Scholar
  14. 14.
    Bakker NE, Kuppens RJ, Siemensma EP, et al. Eight years of growth hormone treatment in children with Prader-Willi syndrome: maintaining the positive effects. J Clin Endocrinol Metab. 2013;98(10):4013–22.CrossRefPubMedGoogle Scholar
  15. 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.CrossRefPubMedGoogle Scholar
  16. 16.
    Eiholzer U, L’Allemand D, Schlumpf M, Rousson V, Gasser T, Fusch C. Growth hormone and body composition in children younger than 2 years with Prader-Willi syndrome. J Pediatr. 2004;144(6):753–8.PubMedGoogle Scholar
  17. 17.
    Butler MG, Lee J, Cox DM, et al. Growth charts for Prader-Willi syndrome during growth hormone treatment. Clin Pediatr (Phila). 2016;55(10):957–74.CrossRefGoogle Scholar
  18. 18.
    Butler MG, Lee J, Manzardo AM, et al. Growth charts for non-growth hormone treated Prader-Willi syndrome. Pediatrics. 2015;135(1):e126–35.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Williams T, Berelowitz M, Joffe SN, et al. Impaired growth hormone response to growth-hormone releasing factor in obesity. N Engl J Med. 1984;311:1403–7.CrossRefPubMedGoogle Scholar
  20. 20.
    Dieguez C, Casanueva FF. Influence of metabolic substrates and obesity on growth hormone secretion. Trends Endocrinol Metab. 1995;6(2):55–9.CrossRefPubMedGoogle Scholar
  21. 21.
    Lindgren AC, Hagenas L, Ritzen EM. Growth hormone treatment of children with Prader-Willi syndrome: effects on glucose and insulin homeostasis. Swedish National Growth Hormone Advisory Group. Horm Res. 1999;51(4):157–61.PubMedGoogle Scholar
  22. 22.
    Bakker NE, van Doorn J, Renes JS, Donker GH, Hokken-Koelega AC. IGF-1 levels, complex formation, and IGF bioactivity in growth hormone-treated children with Prader-Willi syndrome. J Clin Endocrinol Metab. 2015;100(8):3041–9.CrossRefPubMedGoogle Scholar
  23. 23.
    Angulo M, Castro-Magana M, Mazur BCJ, 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.CrossRefPubMedGoogle Scholar
  24. 24.
    de Lind van Wijngaarden RF, Siemensma EP, Festen DA, et al. Efficacy and safety of long-term continuous growth hormone treatment in children with Prader-Willi syndrome. J Clin Endo Metabol. 2009;94(11):4205–15.CrossRefGoogle Scholar
  25. 25.
    Tauber M, Hokken-Koelega AC, Hauffa BP, Goldstone AP. About the benefits of growth hormone treatment in children with Prader-Willi syndrome. J Pediatr. 2009;154(5):778; author reply 779CrossRefPubMedGoogle Scholar
  26. 26.
    Takeda A, Cooper K, Bird A. Recombinant human growth hormone for the treatment of grwoth disorders in children: a sytematic review and economic evaluation. Health Technol Assess. 2010;14:1–209.CrossRefPubMedGoogle Scholar
  27. 27.
    Colmenares A, Pinto G, Taupin P, Giuseppe A, Odent T, Trivin C. 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.CrossRefPubMedGoogle Scholar
  28. 28.
    Oto Y, Obata K, Matsubara K, Kozu Y, Tsuchiya T, Sakazume S. Growth hormone secretion and its effect on height in pediatric patients with different genotypes of Prader-Willi syndrome. Am J Med Genet. 2012;6(Part A):14.Google Scholar
  29. 29.
    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;134:222–5.CrossRefPubMedGoogle Scholar
  30. 30.
    van Mil EG, Westerterp KR, Gerver WJ, et al. Energy expenditure at rest and during sleep in children with Prader-Willi syndrome is explained by body composition. Am J Clin Nutr. 2000;71(3):752–6.CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Davies PS. Growth hormone therapy in Prader-Willi syndrome. Int J Obes. 2001;25(1):2–7.CrossRefGoogle Scholar
  32. 32.
    Festen DA, de Lind van Wijngaarden R, van Eekelen M, 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. 2008;69(3):443–51.CrossRefGoogle Scholar
  33. 33.
    Gondoni LA, Vismara L, Marzullo P, Vettor R, Liuzzi A, Grugni G. Growth hormone therapy improves exercise capacity in adult patients with Prader-Willi syndrome. J Endocrinol Investig. 2008;31(9):765–72.CrossRefGoogle Scholar
  34. 34.
    Bakker NE, Kuppens RJ, Siemensma EP, et al. Bone mineral density in children and adolescents with Prader-Willi syndrome: a longitudinal study during puberty and 9 years of growth hormone treatment. J Clin Endocrinol Metab. 2015;100(4):1609–18.CrossRefGoogle Scholar
  35. 35.
    Carrel AL, Myers S, Whitman BY, Eickhoff JE, 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 Endo Metabol. 2010;95(3):1131–6.CrossRefGoogle Scholar
  36. 36.
    Reus L, van Vlimmeren LA, Staal JB, Otten BJ, Nijhuis-van der Sanden MW. The effect of growth hormone treatment or physical training on motor performance in Prader-Willi syndrome: a systematic review. Neurosci Biobehav Rev. 2012;36(8):1817–38.CrossRefGoogle Scholar
  37. 37.
    Whitman BY, Myers SE. Prader-Willi syndrome and growth hormone therapy: take a deep breath and weigh the data. J Pediatr. 2013;162(2):224–6.CrossRefGoogle Scholar
  38. 38.
    Wolfgram PM, Carrel AL, Allen DB. Long-term effects of recombinant human growth hormone therapy in children with Prader-Willi syndrome. Curr Opin Pediatr. 2013;25(4):509–14.CrossRefPubMedPubMedCentralGoogle Scholar
  39. 39.
    Haqq AM, DeLorey DS, Sharma AM, et al. Autonomic nervous system dysfunction in obesity and Prader-Willi syndrome: current evidence and implications for future obesity therapies. Clinical obesity. 2011;1(4-6):175–83.CrossRefGoogle Scholar
  40. 40.
    Bruininks RH. Bruininks-Oseretsky test of motor proficiency. Circle Pines: American Guidance Service; 1978.Google Scholar
  41. 41.
    Lo ST, Siemensma EP, Festen DA, Collin PJ, Hokken-Koelega AC. Behavior in children with Prader-Willi syndrome before and during growth hormone treatment: a randomized controlled trial and 8-year longitudinal study. Eur Child Adolesc Psychiatry. 2015;24(9):1091–101.CrossRefPubMedGoogle Scholar
  42. 42.
    Siemensma EP, Tummers-de Lind van Wijngaarden RF, Festen DA, et al. Beneficial effects of growth hormone treatment on cognition in children with Prader-Willi syndrome: a randomized controlled trial anercad longitudinal study. J Clin Endo Metabol. 2012;97:2307–14.CrossRefGoogle Scholar
  43. 43.
    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(Suppl 3):24–6.PubMedGoogle Scholar
  44. 44.
    Bakker B, Maneatis T, Lippe B. Sudden death in Prader-Willi syndrome: brief review of five additional cases. Concerning the article by U. Eiholzer et al.: 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;63:33-39). Horm Res. 2007;67(4):203–4.PubMedGoogle Scholar
  45. 45.
    Van Vliet G, Deal CL, Crock PA, Robitaille Y, Oligny LL. Sudden death in growth hormone treated children with Prader-Willi syndrome. J Pediatr. 2004;144:129–31.CrossRefPubMedGoogle Scholar
  46. 46.
    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. J Pediatr. 2009;154(2):230–3.CrossRefPubMedGoogle Scholar
  47. 47.
    Deal CL, Tony M, Hoybye C, Allen DB, Tauber M, Christiansen JS. GrowthHormone research society workshop summary: consensus guidelines for recombinant human growth hormone therapy in Prader-Willi syndrome. J Clin Endocrinol Metab. 2013;98(6):E1072–87.CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    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. 2008;146:881–7.CrossRefGoogle Scholar
  49. 49.
    Al-Saleh S, Al-Naimi A, Hamilton J, Zweerink A, Iaboni A, Narang I. Longitudinal evaluation of sleep-disordered breathing in children with Prader-Willi syndrome during 2 years of growth hormone therapy. J Pediatr. 2013;162(e1):263–8.CrossRefPubMedGoogle Scholar
  50. 50.
    Katz-Salamon M, Lindgren AC, Cohen G. The effect of growth hormone on sleep-related cardio-respiratory control in Prader-Willi syndrome. Acta Paediatr (Oslo, Norway: 1992). 2012;101:643–8.CrossRefGoogle Scholar
  51. 51.
    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):1649–54.CrossRefGoogle Scholar
  52. 52.
    Reinehr T, Lindberg A, Koltowska-Haggstrom M, Ranke M. Is growth hormone treatment in children associated with weight gain? – longitudinal analysis of KIGS data. Clin Endocrinol. 2014;81(5):721–6.CrossRefGoogle Scholar
  53. 53.
    Hoybye C. Growth hormone treatment of Prader-Willi syndrome has long-term, positive effects on body composition. Acta Paediatr (Oslo, Norway: 1992). 2015;104(4):422–7.CrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of PediatricsUniversity of Wisconsin School of Medicine and Public Health, American Family Children’s HospitalMadisonUSA

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