Ann Pediatr Endocrinol Metab.  2014 Mar;19(1):1-7. 10.6065/apem.2014.19.1.1.

Growth hormone treatment in non-growth hormone-deficient children

• Loche S
• Carta L
• Ibba A
• Guzzetti C

• KMID: 1702656
• DOI: http://doi.org/10.6065/apem.2014.19.1.1

Abstract

Until 1985 growth hormone (GH) was obtained from pituitary extracts, and was available in limited amounts only to treat severe growth hormone deficiency (GHD). With the availability of unlimited quantities of GH obtained from recombinant DNA technology, researchers started to explore new modalities to treat GHD children, as well as to treat a number of other non-GHD conditions. Although with some differences between different countries, GH treatment is indicated in children with Turner syndrome, chronic renal insufficiency, Prader-Willi syndrome, deletions/mutations of the SHOX gene, as well as in short children born small for gestational age and with idiopathic short stature. Available data from controlled trials indicate that GH treatment increases adult height in patients with Turner syndrome, in patients with chronic renal insufficiency, and in short children born small for gestational age. Patients with SHOX deficiency seem to respond to treatment similarly to Turner syndrome. GH treatment in children with idiopathic short stature produces a modest mean increase in adult height but the response in the individual patient is unpredictable. Uncontrolled studies indicate that GH treatment may be beneficial also in children with Noonan syndrome. In patients with Prader-Willi syndrome GH treatment normalizes growth and improves body composition and cognitive function. In any indication the response to GH seems correlated to the dose and the duration of treatment. GH treatment is generally safe with no major adverse effects being recorded in any condition.

Keyword

Child; Growth; Growth hormone; Insulin-like growth factor I

MeSH Terms

Adult
Body Composition
Child*
DNA, Recombinant
Genes, vif
Gestational Age
Growth Hormone*
Humans
Insulin-Like Growth Factor I
Noonan Syndrome
Prader-Willi Syndrome
Renal Insufficiency, Chronic
Turner Syndrome
DNA, Recombinant
Growth Hormone
Insulin-Like Growth Factor I

Reference

1. Bondy CA. Turner Syndrome Study Group. Care of girls and women with Turner syndrome: a guideline of the Turner Syndrome Study Group. J Clin Endocrinol Metab. 2007; 92:10–25. PMID: 17047017.

2. Davenport ML. Approach to the patient with Turner syndrome. J Clin Endocrinol Metab. 2010; 95:1487–1495. PMID: 20375216.

3. Rao E, Weiss B, Fukami M, Rump A, Niesler B, Mertz A, et al. Pseudoautosomal deletions encompassing a novel homeobox gene cause growth failure in idiopathic short stature and Turner syndrome. Nat Genet. 1997; 16:54–63. PMID: 9140395.

4. Soucek O, Zapletalova J, Zemkova D, Snajderova M, Novotna D, Hirschfeldova K, et al. Prepubertal girls with Turner syndrome and children with isolated SHOX deficiency have similar bone geometry at the radius. J Clin Endocrinol Metab. 2013; 98:E1241–E1247. PMID: 23666967.

5. Baxter L, Bryant J, Cave CB, Milne R. Recombinant growth hormone for children and adolescents with Turner syndrome. Cochrane Database Syst Rev. 2007; (1):CD003887. PMID: 17253498.

6. Stephure DK. Canadian Growth Hormone Advisory Committee. Impact of growth hormone supplementation on adult height in turner syndrome: results of the Canadian randomized controlled trial. J Clin Endocrinol Metab. 2005; 90:3360–3366. PMID: 15784709.

7. Ross JL, Quigley CA, Cao D, Feuillan P, Kowal K, Chipman JJ, et al. Growth hormone plus childhood low-dose estrogen in Turner's syndrome. N Engl J Med. 2011; 364:1230–1242. PMID: 21449786.

8. Davenport ML, Crowe BJ, Travers SH, Rubin K, Ross JL, Fechner PY, et al. Growth hormone treatment of early growth failure in toddlers with Turner syndrome: a randomized, controlled, multicenter trial. J Clin Endocrinol Metab. 2007; 92:3406–3416. PMID: 17595258.

9. Linglart A, Cabrol S, Berlier P, Stuckens C, Wagner K, de Kerdanet M, et al. Growth hormone treatment before the age of 4 years prevents short stature in young girls with Turner syndrome. Eur J Endocrinol. 2011; 164:891–897. PMID: 21398400.

10. Menke LA, Sas TC, de Muinck Keizer-Schrama SM, Zandwijken GR, de Ridder MA, Odink RJ, et al. Efficacy and safety of oxandrolone in growth hormone-treated girls with turner syndrome. J Clin Endocrinol Metab. 2010; 95:1151–1160. PMID: 20061421.

11. Gault EJ, Perry RJ, Cole TJ, Casey S, Paterson WF, Hindmarsh PC, et al. Effect of oxandrolone and timing of pubertal induction on final height in Turner's syndrome: randomised, double blind, placebo controlled trial. BMJ. 2011; 342:d1980. PMID: 21493672.

12. Quigley CA, Crowe BJ, Anglin DG, Chipman JJ. Growth hormone and low dose estrogen in Turner syndrome: results of a United States multi-center trial to near-final height. J Clin Endocrinol Metab. 2002; 87:2033–2041. PMID: 11994337.

13. van Pareren YK, de Muinck Keizer-Schrama SM, Stijnen T, Sas TC, Jansen M, Otten BJ, et al. Final height in girls with turner syndrome after long-term growth hormone treatment in three dosages and low dose estrogens. J Clin Endocrinol Metab. 2003; 88:1119–1125. PMID: 12629094.

14. Mehls O, Wuhl E, Tonshoff B, Schaefer F, Nissel R, Haffner D. Growth hormone treatment in short children with chronic kidney disease. Acta Paediatr. 2008; 97:1159–1164. PMID: 18624988.

15. Hodson EM, Willis NS, Craig JC. Growth hormone for children with chronic kidney disease. Cochrane Database Syst Rev. 2012; 2:CD003264. PMID: 22336787.

16. Haffner D, Schaefer F, Nissel R, Wuhl E, Tonshoff B, Mehls O. German Study Group for Growth Hormone Treatment in Chronic Renal Failure. Effect of growth hormone treatment on the adult height of children with chronic renal failure. N Engl J Med. 2000; 343:923–930. PMID: 11006368.

17. Nissel R, Lindberg A, Mehls O, Haffner D. Pfizer International Growth Database (KIGS) International Board. Factors predicting the near-final height in growth hormone-treated children and adolescents with chronic kidney disease. J Clin Endocrinol Metab. 2008; 93:1359–1365. PMID: 18198222.

18. Mehls O, Lindberg A, Nissel R, Haffner D, Hokken-Koelega A, Ranke MB. Predicting the response to growth hormone treatment in short children with chronic kidney disease. J Clin Endocrinol Metab. 2010; 95:686–692. PMID: 20008024.

19. Cassidy SB, Schwartz S, Miller JL, Driscoll DJ. Prader-Willi syndrome. Genet Med. 2012; 14:10–26. PMID: 22237428.

20. Butler MG. Prader-Willi Syndrome: Obesity due to Genomic Imprinting. Curr Genomics. 2011; 12:204–215. PMID: 22043168.

21. Cappa M, Grossi A, Borrelli P, Ghigo E, Bellone J, Benedetti S, et al. Growth hormone (GH) response to combined pyridostigmine and GH-releasing hormone administration in patients with Prader-Labhard-Willi syndrome. Horm Res. 1993; 39:51–55. PMID: 8406340.

22. Tauber M, Barbeau C, Jouret B, Pienkowski C, Malzac P, Moncla A, et al. Auxological and endocrine evolution of 28 children with Prader-Willi syndrome: effect of GH therapy in 14 children. Horm Res. 2000; 53:279–287. PMID: 11146368.

23. Corrias A, Bellone J, Beccaria L, Bosio L, Trifiro G, Livieri C, et al. Genetic Obesity Study Group of Italian Society of Pediatric Endocrinology and Diabetology. GH/IGF-I axis in Prader-Willi syndrome: evaluation of IGF-I levels and of the somatotroph responsiveness to various provocative stimuli. J Endocrinol Invest. 2000; 23:84–89. PMID: 10800760.

24. Grugni G, Crino A, Pagani S, Meazza C, Buzi F, De Toni T, et al. Growth hormone secretory pattern in non-obese children and adolescents with Prader-Willi syndrome. J Pediatr Endocrinol Metab. 2011; 24:477–481. PMID: 21932585.

25. Diene G, Mimoun E, Feigerlova E, Caula S, Molinas C, Grandjean H, et al. Endocrine disorders in children with Prader-Willi syndrome: data from 142 children of the French database. Horm Res Paediatr. 2010; 74:121–128. PMID: 20395666.

26. Eiholzer U, Stutz K, Weinmann C, Torresani T, Molinari L, Prader A. Low insulin, IGF-I and IGFBP-3 levels in children with Prader-Labhart-Willi syndrome. Eur J Pediatr. 1998; 157:890–893. PMID: 9835431.

27. Bakker NE, Kuppens RJ, Siemensma EP, Tummers-de Lind van Wijngaarden RF, Festen DA, Bindels-de Heus GC, et al. Eight years of growth hormone treatment in children with Prader-Willi syndrome: maintaining the positive effects. J Clin Endocrinol Metab. 2013; 98:4013–4022. PMID: 24001750.

28. 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; 134:215–221. PMID: 9931532.

29. Siemensma EP, Tummers-de Lind van Wijngaarden RF, Festen DA, Troeman ZC, van Alfen-van der Velden AA, Otten BJ, et al. Beneficial effects of growth hormone treatment on cognition in children with Prader-Willi syndrome: a randomized controlled trial and longitudinal study. J Clin Endocrinol Metab. 2012; 97:2307–2314. PMID: 22508707.

30. Deal CL, Tony M, Hoybye C, Allen DB, Tauber M, Christiansen JS, et al. GrowthHormone Research Society workshop summary: consensus guidelines for recombinant human growth hormone therapy in Prader-Willi syndrome. J Clin Endocrinol Metab. 2013; 98:E1072–E1087. PMID: 23543664.

31. 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; 68:919–925. PMID: 18031326.

32. 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; 145:744–749. PMID: 15580194.

33. Tartaglia M, Mehler EL, Goldberg R, Zampino G, Brunner HG, Kremer H, et al. Mutations in PTPN11, encoding the protein tyrosine phosphatase SHP-2, cause Noonan syndrome. Nat Genet. 2001; 29:465–468. PMID: 11704759.

34. Romano AA, Allanson JE, Dahlgren J, Gelb BD, Hall B, Pierpont ME, et al. Noonan syndrome: clinical features, diagnosis, and management guidelines. Pediatrics. 2010; 126:746–759. PMID: 20876176.

35. Roberts AE, Allanson JE, Tartaglia M, Gelb BD. Noonan syndrome. Lancet. 2013; 381:333–342. PMID: 23312968.

36. Limal JM, Parfait B, Cabrol S, Bonnet D, Leheup B, Lyonnet S, et al. Noonan syndrome: relationships between genotype, growth, and growth factors. J Clin Endocrinol Metab. 2006; 91:300–306. PMID: 16263833.

37. Binder G, Neuer K, Ranke MB, Wittekindt NE. PTPN11 mutations are associated with mild growth hormone resistance in individuals with Noonan syndrome. J Clin Endocrinol Metab. 2005; 90:5377–5381. PMID: 15985475.

38. Noordam C, Peer PG, Francois I, De Schepper J, van den Burgt I, Otten BJ. Long-term GH treatment improves adult height in children with Noonan syndrome with and without mutations in protein tyrosine phosphatase, nonreceptor-type 11. Eur J Endocrinol. 2008; 159:203–208. PMID: 18562489.

39. Chacko EM, Rapaport R. Short stature and its treatment in Turner and Noonan syndromes. Curr Opin Endocrinol Diabetes Obes. 2012; 19:40–46. PMID: 22157403.

40. Dahlgren J. GH therapy in Noonan syndrome: Review of final height data. Horm Res. 2009; 72(Suppl 2):46–48. PMID: 20029237.

41. Romano AA, Dana K, Bakker B, Davis DA, Hunold JJ, Jacobs J, et al. Growth response, near-adult height, and patterns of growth and puberty in patients with noonan syndrome treated with growth hormone. J Clin Endocrinol Metab. 2009; 94:2338–2344. PMID: 19401366.

42. Munns CJ, Haase HR, Crowther LM, Hayes MT, Blaschke R, Rappold G, et al. Expression of SHOX in human fetal and childhood growth plate. J Clin Endocrinol Metab. 2004; 89:4130–4135. PMID: 15292358.

43. Binder G. Short stature due to SHOX deficiency: genotype, phenotype, and therapy. Horm Res Paediatr. 2011; 75:81–89. PMID: 21325865.

44. Rosilio M, Huber-Lequesne C, Sapin H, Carel JC, Blum WF, Cormier-Daire V, et al. Genotypes and phenotypes of children with SHOX deficiency in France. J Clin Endocrinol Metab. 2012; 97:E1257–E1265. PMID: 22518848.

45. Blum WF, Crowe BJ, Quigley CA, Jung H, Cao D, Ross JL, et al. Growth hormone is effective in treatment of short stature associated with short stature homeobox-containing gene deficiency: two-year results of a randomized, controlled, multicenter trial. J Clin Endocrinol Metab. 2007; 92:219–228. PMID: 17047016.

46. Blum WF, Ross JL, Zimmermann AG, Quigley CA, Child CJ, Kalifa G, et al. GH treatment to final height produces similar height gains in patients with SHOX deficiency and Turner syndrome: results of a multicenter trial. J Clin Endocrinol Metab. 2013; 98:E1383–E1392. PMID: 23720786.

47. Saenger P, Czernichow P, Hughes I, Reiter EO. Small for gestational age: short stature and beyond. Endocr Rev. 2007; 28:219–251. PMID: 17322454.

48. Clayton PE, Cianfarani S, Czernichow P, Johannsson G, Rapaport R, Rogol A. Management of the child born small for gestational age through to adulthood: a consensus statement of the International Societies of Pediatric Endocrinology and the Growth Hormone Research Society. J Clin Endocrinol Metab. 2007; 92:804–810. PMID: 17200164.

49. Maiorana A, Cianfarani S. Impact of growth hormone therapy on adult height of children born small for gestational age. Pediatrics. 2009; 124:e519–e531. PMID: 19706577.

50. Van Pareren Y, Mulder P, Houdijk M, Jansen M, Reeser M, Hokken-Koelega A. Adult height after long-term, continuous growth hormone (GH) treatment in short children born small for gestational age: results of a randomized, double-blind, dose-response GH trial. J Clin Endocrinol Metab. 2003; 88:3584–3590. PMID: 12915640.

51. Carel JC, Chatelain P, Rochiccioli P, Chaussain JL. Improvement in adult height after growth hormone treatment in adolescents with short stature born small for gestational age: results of a randomized controlled study. J Clin Endocrinol Metab. 2003; 88:1587–1593. PMID: 12679443.

52. Dahlgren J, Wikland KA. Swedish Study Group for Growth Hormone Treatment. Final height in short children born small for gestational age treated with growth hormone. Pediatr Res. 2005; 57:216–222. PMID: 15585685.

53. van Dijk M, Bannink EM, van Pareren YK, Mulder PG, Hokken-Koelega AC. Risk factors for diabetes mellitus type 2 and metabolic syndrome are comparable for previously growth hormone-treated young adults born small for gestational age (sga) and untreated short SGA controls. J Clin Endocrinol Metab. 2007; 92:160–165. PMID: 17062774.

54. 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; 36:720–724. PMID: 15208626.

55. Willemsen RH, Arends NJ, Bakker-van Waarde WM, Jansen M, van Mil EG, Mulder J, et al. Long-term effects of growth hormone (GH) treatment on body composition and bone mineral density in short children born smallfor-gestational-age: six-year follow-up of a randomized controlled GH trial. Clin Endocrinol (Oxf). 2007; 67:485–492. PMID: 17561977.

56. Schweizer R, Martin DD, Schonau E, Ranke MB. Muscle function improves during growth hormone therapy in short children born small for gestational age: results of a peripheral quantitative computed tomography study on body composition. J Clin Endocrinol Metab. 2008; 93:2978–2983. PMID: 18505766.

57. Lem AJ, van der Kaay DC, de Ridder MA, Bakker-van Waarde WM, van der Hulst FJ, Mulder JC, et al. Adult height in short children born SGA treated with growth hormone and gonadotropin releasing hormone analog: results of a randomized, dose-response GH trial. J Clin Endocrinol Metab. 2012; 97:4096–4105. PMID: 22904179.

58. Cohen P, Rogol AD, Deal CL, Saenger P, Reiter EO, Ross JL, et al. Consensus statement on the diagnosis and treatment of children with idiopathic short stature: a summary of the Growth Hormone Research Society, the Lawson Wilkins Pediatric Endocrine Society, and the European Society for Paediatric Endocrinology Workshop. J Clin Endocrinol Metab. 2008; 93:4210–4217. PMID: 18782877.

59. Loche S, Casini MR, Ubertini GM, Cappa M. Growth hormone treatment in non-growth hormone-deficient short children. J Endocrinol Invest. 2005; 28:193–198. PMID: 15887870.

60. Hindmarsh PC, Brook CG. Effect of growth hormone on short normal children. Br Med J (Clin Res Ed). 1987; 295:573–577.

61. Hopwood NJ, Hintz RL, Gertner JM, Attie KM, Johanson AJ, Baptista J, et al. Growth response of children with non-growth-hormone deficiency and marked short stature during three years of growth hormone therapy. J Pediatr. 1993; 123:215–222. PMID: 8345416.

62. Ranke MB. Treatment of children and adolescents with idiopathic short stature. Nat Rev Endocrinol. 2013; 9:325–334. PMID: 23609338.

63. McCaughey ES, Mulligan J, Voss LD, Betts PR. Randomised trial of growth hormone in short normal girls. Lancet. 1998; 351:940–944. PMID: 9734940.

64. Leschek EW, Rose SR, Yanovski JA, Troendle JF, Quigley CA, Chipman JJ, et al. Effect of growth hormone treatment on adult height in peripubertal children with idiopathic short stature: a randomized, double-blind, placebo-controlled trial. J Clin Endocrinol Metab. 2004; 89:3140–3148. PMID: 15240584.

65. Albertsson-Wikland K, Aronson AS, Gustafsson J, Hagenas L, Ivarsson SA, Jonsson B, et al. Dose-dependent effect of growth hormone on final height in children with short stature without growth hormone deficiency. J Clin Endocrinol Metab. 2008; 93:4342–4350. PMID: 18728172.

66. Deodati A, Cianfarani S. Impact of growth hormone therapy on adult height of children with idiopathic short stature: systematic review. BMJ. 2011; 342:c7157. PMID: 21398350.

67. Kemp SF, Kuntze J, Attie KM, Maneatis T, Butler S, Frane J, et al. Efficacy and safety results of long-term growth hormone treatment of idiopathic short stature. J Clin Endocrinol Metab. 2005; 90:5247–5253. PMID: 15998780.