Advertisement

Monatsschrift Kinderheilkunde

, Volume 166, Issue 4, pp 317–324 | Cite as

Effekte eines späten Beginns einer Therapie mit Wachstumshormon

Ergebnisse eines Expertenworkshops
  • H.-G. Dörr
  • M. Bettendorf
  • G. Binder
  • J. Dötsch
  • B. Hauffa
  • K. Mohnike
  • H. L. Müller
  • J. Woelfle
Übersichten
  • 520 Downloads

Zusammenfassung

Nach Diagnosestellung sollten kleinwüchsige Kinder im Rahmen der in Deutschland zugelassenen Indikationen auch rechtzeitig mit Wachstumshormon (HGH) behandelt werden. Was passiert aber, wenn die Diagnose spät gestellt wird und die Kinder bei Therapiebeginn schon relativ alt sind? Eine Expertengruppe pädiatrischer Endokrinologen hat sich diese Frage gestellt und für die zugelassenen Indikationen, anhand der Evidenz aus klinischen Studien, die daraus resultierenden Konsequenzen evaluiert. Bei Kindern mit Wachstumshormonmangel (GHD) ist ein später Therapiebeginn in der Regel ab einem Alter über 12 Jahre und nach Pubertätsbeginn der Fall. Die publizierten Daten zeigen insbesondere bei Kindern mit idiopathischem GHD eine deutlich reduzierte Wirksamkeit. Für eine Empfehlung zur Anhebung der HGH-Dosis in der Pubertät bei GHD ist die Evidenz unzureichend. Kinder mit postnatalem Kleinwuchs bei „small for gestational age“ (SGA), die erst nach Einsetzen der Pubertät vorgestellt werden, sollten nur in gut begründeten Ausnahmefällen eine HGH-Therapie erhalten. Bei Mädchen mit Ullrich-Turner-Syndrom konnten bei einem Therapiebeginn nach einem chronologischen Alter über 12 Jahren noch vergleichbare Endgrößen wie bei jüngeren Mädchen erzielt werden. Bei der Indikation Short-stature-homeobox-gene(SHOX)-Syndrom und bei Kindern mit Prader-Willi-Syndrom (PWS) liegen keine aussagekräftigen Daten zu einem späten Therapiebeginn vor. Neue Daten zeigen, dass der Therapiebeginn bei Kindern mit PWS bereits im Säuglingsalter erfolgen soll. Für Patienten mit chronischer Niereninsuffizienz ergibt die begrenzte Datenlage für den HGH-Therapiebeginn in der frühen Pubertät einen vergleichbaren Effekt wie bei einem präpubertären Therapiebeginn. Zusammenfassend muss die Option eines späten HGH-Therapiebeginns individuell, anhand der zu der betreffenden Indikation jeweils verfügbaren Daten, überprüft werden. Weitere Untersuchungen und Analysen sind notwendig, da bei einigen Fragen zum späten HGH-Therapiebeginn die Datenlage noch unbefriedigend ist.

Schlüsselwörter

Kleinwuchs Wachstumshormon Therapiebeginn Pubertät Endgröße 

Effects of a late start to growth hormone therapy

Results of an expert workshop

Abstract

Short statured children usually reach optimal final height within individual target height range if human growth hormone (HGH) therapy is started early. However, what happens if an early diagnosis is missed and the child is relatively old at start of HGH therapy? The consequences of this have been evaluated on an indication-specific basis by an expert panel of German pediatric endocrinologists using evidence from clinical studies. A late start of HGH therapy is assumed in children with growth hormone deficiency (GHD) beyond the age of 12 years and/or after the onset of puberty. The published information shows markedly reduced efficiency, especially in children with idiopathic GHD. Evidence is insufficient to recommend an increased HGH dose in children with GHD during puberty. Small for gestational age (SGA) children – children of postnatal short stature, who are presented after the onset of puberty – should only receive HGH therapy in well-founded, exceptional cases. Comparable final heights were achieved in girls with Ullrich-Turner syndrome when HGH treatment was started at chronological ages before and after 12 years. Children with Prader-Willi syndrome (PWS) can meet the definition for late start of HGH therapy already beyond four years of age. Early therapy is suggested to optimize psychomotoric development and body composition. There is no data on final height in patients with SHOX syndrome. In patients with chronic renal insufficiency, the effect of HGH therapy started in early puberty is comparable with that started before the onset of puberty. However, the availability of data is limited in this case. In summary, the option of a late start to HGH therapy needs to be analyzed on an individual basis using the data available for the relevant indication. Further examinations and analyses are necessary because the availability of data on questions concerning a late start to HGH therapy is still unsatisfactory.

Keywords

Short stature Growth hormone Therapy start Puberty Adult height 

Notes

Danksagung

Die Durchführung des Workshops am 10.02.2016 und vor- sowie nachbereitende Arbeiten wurden von der Firma Novo Nordisk Pharma GmbH finanziell und logistisch unterstützt. Den Autoren wurde ein Honorar bezahlt und die Fahrtkosten ersetzt. Wir danken Herrn Dr. med. Detlev Janssen für die redaktionelle Mitarbeit. Herr Janssen erklärt, dass seine Firma Med-i-Scene Concept GmbH, D‑91085 Weisendorf, diesbezüglich eine Unterstützung von der Firma Novo Nordisk Pharma GmbH, D‑55127 Mainz, erhalten hat.

Einhaltung ethischer Richtlinien

Interessenkonflikt

H.-G. Dörr, M. Bettendorf, G. Binder, J. Dötsch, B. Hauffa, K. Mohnike, H.L. Müller und J. Woelfle geben an, dass kein Interessenkonflikt besteht.

Dieser Beitrag beinhaltet keine von den Autoren durchgeführten Studien an Menschen oder Tieren.

Supplementary material

112_2017_267_MOESM1_ESM.pdf (44 kb)
Tab. 1: Daten zum späten HGH-Therapiebeginn bei Patienten mit idiopathischem GHD (iGHD) und SGA
112_2017_267_MOESM2_ESM.pdf (35 kb)
Tab. 2: Daten zum späten HGH-Therapiebeginn bei Patienten mit UTS und SHOX
112_2017_267_MOESM3_ESM.pdf (34 kb)
Tab. 3: Früher versus später HGH-Therapiebeginn beim Prader-Willi-Syndrom
112_2017_267_MOESM4_ESM.pdf (32 kb)
Tab. 4: Ergebnisse aus der KIGS-Datenbank bei 240 Patienten mit chronischer Niereninsuffizienz in Abhängigkeit vom Zeitpunkt des HGH-Therapiebeginns [48]

Literatur

  1. 1.
    GH Research Society (2000) Consensus guidelines for the diagnosis and treatment of growth hormone (GH) deficiency in childhood and adolescence: summary statement of the GH Research Society. J Clin Endocrinol Metab 85(11):3990–3993Google Scholar
  2. 2.
    Ranke MB et al (2003) Prediction of response to growth hormone treatment in short children born small for gestational age: analysis of data from KIGS (Pharmacia International Growth Database). J Clin Endocrinol Metab 88(1):125–131CrossRefPubMedGoogle Scholar
  3. 3.
    Ranke MB et al (1999) Derivation and validation of a mathematical model for predicting the response to exogenous recombinant human growth hormone (GH) in prepubertal children with idiopathic GH deficiency. KIGS International Board. Kabi Pharmacia International Growth Study. J Clin Endocrinol Metab 84(4):1174–1183CrossRefPubMedGoogle Scholar
  4. 4.
    Ranke MB et al (2000) Therapie des Kleinwuchses mit Wachstumshormon. Monatsschr Kinderheilkd 8(148):746–761CrossRefGoogle Scholar
  5. 5.
    Rohayem J et al (2016) Long-term outcomes, genetics, and pituitary morphology in patients with isolated growth hormone deficiency and multiple pituitary hormone deficiencies: A single-centre experience of four decades of growth hormone replacement. Horm Res Paediatr 86(2):106–116CrossRefPubMedGoogle Scholar
  6. 6.
    Karavanaki K et al (2001) Growth response, pubertal growth and final height in Greek children with growth hormone (GH) deficiency on long-term GH therapy and factors affecting outcome. J Pediatr Endocrinol Metab 14(4):397–405CrossRefPubMedGoogle Scholar
  7. 7.
    Mauras N et al (2000) High dose recombinant human growth hormone (GH) treatment of GH-deficient patients in puberty increases near-final height: a randomized, multicenter trial. Genentech, Inc., Cooperative Study Group. J Clin Endocrinol Metab 85(10):3653–3660PubMedGoogle Scholar
  8. 8.
    Mericq MV et al (2000) Near final height in pubertal growth hormone (GH)-deficient patients treated with GH alone or in combination with luteinizing hormone-releasing hormone analog: results of a prospective, randomized trial. J Clin Endocrinol Metab 85(2):569–573PubMedGoogle Scholar
  9. 9.
    Mauras N et al (2008) Anastrozole increases predicted adult height of short adolescent males treated with growth hormone: a randomized, placebo-controlled, multicenter trial for one to three years. J Clin Endocrinol Metab 93(3):823–831CrossRefPubMedGoogle Scholar
  10. 10.
    Binder G et al (2009) Diagnostik des Wachstumshormonmangels im Kindes- und Jugendalter. Kinder Jugendmed 9:461–464CrossRefGoogle Scholar
  11. 11.
    Maghnie M et al (2013) Magnetic resonance imaging of CNS in 15,043 children with GH deficiency in KIGS (Pfizer International Growth Database). Eur J Endocrinol 168(2):211–217CrossRefPubMedGoogle Scholar
  12. 12.
    Smuel K et al (2015) Growth, development, puberty and adult height before and during treatment in children with congenital isolated growth hormone deficiency. Growth Horm IGF Res 25(4):182–188CrossRefPubMedGoogle Scholar
  13. 13.
    Carel JC et al (2002) Adult height after long term treatment with recombinant growth hormone for idiopathic isolated growth hormone deficiency: observational follow up study of the French population based registry. BMJ 325:7CrossRefGoogle Scholar
  14. 14.
    Ross JL et al (2015) Increased height standard deviation scores in response to growth hormone therapy to near-adult height in older children with delayed skeletal maturation: results from the ANSWER Program. Int J Pediatr Endocrinol 1:9Google Scholar
  15. 15.
    Ross J et al (2010) Factors influencing the one- and two-year growth response in children treated with growth hormone: analysis from an observational study. Int J Pediatr Endocrinol p:7Google Scholar
  16. 16.
    Ross JL et al (2015) Attaining genetic height potential: Analysis of height outcomes from the ANSWER Program in children treated with growth hormone over 5 years. Growth Horm IGF Res 25:8CrossRefGoogle Scholar
  17. 17.
    Lee PA et al (2012) Comparison of response to 2‑years’ growth hormone treatment in children with isolated growth hormone deficiency, born small for gestational age, idiopathic short stature, or multiple pituitary hormone deficiency: combined results from two large observational studies. Int J Pediatr Endocrinol 22(1):1–8Google Scholar
  18. 18.
    Lee PA et al (2011) Identification of factors associated with good response to growth hormone therapy in children with short stature: results from the ANSWER Program(R). Int J Pediatr Endocrinol 6:6CrossRefGoogle Scholar
  19. 19.
    Albertsson-Wikland K et al (2014) Growth hormone dose-dependent pubertal growth: a randomized trial in short children with low growth hormone secretion. Horm Res Paediatr 82(3):158–170CrossRefPubMedGoogle Scholar
  20. 20.
    Coelho R et al (2008) A randomised study of two doses of biosynthetic human growth hormone on final height of pubertal children with growth hormone deficiency. Horm Res 70(2):85–88CrossRefPubMedGoogle Scholar
  21. 21.
    Davenport ML et al (2002) Growth failure in early life: an important manifestation of Turner syndrome. Horm Res 57(5–6):157–164PubMedGoogle Scholar
  22. 22.
    Simm D et al (2008) Chronologisches Alter von Mädchen mit Ullrich-Turner Syndrom bei Diagnosestellung. Klin Padiatr 220(1):16–20CrossRefPubMedGoogle Scholar
  23. 23.
    Massa G et al (2005) Trends in age at diagnosis of Turner syndrome. Arch Dis Child 90(3):267–268CrossRefPubMedCentralPubMedGoogle Scholar
  24. 24.
    Massa G et al (2003) Late or delayed induced or spontaneous puberty in girls with Turner syndrome treated with growth hormone does not affect final height. J Clin Endocrinol Metab 88(9):4168–4174CrossRefPubMedGoogle Scholar
  25. 25.
    Bettendorf M et al (2013) Height gain in Ullrich-Turner syndrome after early and late growth hormone treatment start: results from a large retrospective German study and potential basis for an individualized treatment approach. Horm Res Paediatr 80(5):356–362CrossRefPubMedGoogle Scholar
  26. 26.
    Stahnke N, Keller E, Landy H (2002) Favorable final height outcome in girls with Ullrich-Turner syndrome treated with low-dose growth hormone together with oxandrolone despite starting treatment after 10 years of age. J Pediatr Endocrinol Metab 15(2):129–138CrossRefPubMedGoogle Scholar
  27. 27.
    Binder G (2011) Short stature due to SHOX deficiency: genotype, phenotype, and therapy. Horm Res Paediatr 75(2):81–89CrossRefPubMedGoogle Scholar
  28. 28.
    Blum WF et al (2009) Height gains in response to growth hormone treatment to final height are similar in patients with SHOX deficiency and Turner syndrome. Horm Res 71(3):167–172CrossRefPubMedGoogle Scholar
  29. 29.
    Binder G et al (2013) Adult height and epigenotype in children with Silver-Russell syndrome treated with GH. Horm Res Paediatr 80(3):193–200CrossRefPubMedGoogle Scholar
  30. 30.
    Donze SH et al (2015) The growth response to GH treatment is greater in patients with SHOX enhancer deletions compared to SHOX defects. Eur J Endocrinol 173(5):611–621CrossRefPubMedGoogle Scholar
  31. 31.
    Butler MG et al (2015) Growth charts for non-growth hormone treated Prader-Willi syndrome. Pediatrics 135(1):e126–35CrossRefPubMedCentralPubMedGoogle Scholar
  32. 32.
    Butler MG et al (2016) Growth charts for Prader-Willi syndrome during growth hormone treatment. Clin Pediatr (Phila) 55(10):957–974CrossRefGoogle Scholar
  33. 33.
    Nyunt O et al (2009) Benefit of early commencement of growth hormone therapy in children with Prader-Willi syndrome. J Pediatr Endocrinol Metab 22(12):1151–1158CrossRefPubMedGoogle Scholar
  34. 34.
    Lo ST et al (2015) Beneficial effects of long-term growth hormone treatment on adaptive functioning in infants with Prader-Willi syndrome. Am J Intellect Dev Disabil 120(4):315–327CrossRefPubMedGoogle Scholar
  35. 35.
    Reus L et al (2014) Growth hormone therapy, muscle thickness, and motor development in Prader-Willi syndrome: an RCT. Pediatrics 134(6):e1619–e1627CrossRefPubMedGoogle Scholar
  36. 36.
    Carrel AL et al (2010) 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 95(3):1131–1136CrossRefPubMedCentralPubMedGoogle Scholar
  37. 37.
    Carrel AL et al (2004) Growth hormone improves mobility and body composition in infants and toddlers with Prader-Willi syndrome. J Pediatr 145(6):744–749CrossRefPubMedGoogle Scholar
  38. 38.
    Festen DA et al (2008) Mental and motor development before and during growth hormone treatment in infants and toddlers with Prader-Willi syndrome. Clin Endocrinol (Oxf) 68(6):919–925CrossRefGoogle Scholar
  39. 39.
    Deal CL et al (2013) GrowthHormone Research Society workshop summary: consensus guidelines for recombinant human growth hormone therapy in Prader-Willi syndrome. J Clin Endocrinol Metab 98(6):E1072–87CrossRefPubMedCentralPubMedGoogle Scholar
  40. 40.
    Berini J et al (2013) Growth hormone therapy and respiratory disorders: long-term follow-up in PWS children. J Clin Endocrinol Metab 98(9):E1516–23CrossRefPubMedGoogle Scholar
  41. 41.
    Clayton PE et al (2007) 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 92(3):804–810CrossRefPubMedGoogle Scholar
  42. 42.
    Ranke MB, Lindberg A (2010) Height at start, first-year growth response and cause of shortness at birth are major determinants of adult height outcomes of short children born small for gestational age and Silver-Russell syndrome treated with growth hormone: analysis of data from KIGS. Horm Res Paediatr 74:259–266CrossRefPubMedGoogle Scholar
  43. 43.
    Maiorana A, Cianfarani S (2009) Impact of growth hormone therapy on adult height of children born small for gestational age. Pediatrics 124(3):e519–e531CrossRefPubMedGoogle Scholar
  44. 44.
    Dahlgren J, Wikland KA (2005) Final height in short children born small for gestational age treated with growth hormone. Pediatr Res 57(2):216–222CrossRefPubMedGoogle Scholar
  45. 45.
    Carel JC et al (2003) 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 88(4):1587–1593CrossRefPubMedGoogle Scholar
  46. 46.
    Lem AJ et al (2012) 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 97(11):4096–4105CrossRefPubMedGoogle Scholar
  47. 47.
    Harambat J, Cochat P (2009) Growth after renal transplantation. Pediatr Nephrol 24(7):1297–1306CrossRefPubMedGoogle Scholar
  48. 48.
    Nissel R et al (2008) Factors predicting the near-final height in growth hormone-treated children and adolescents with chronic kidney disease. J Clin Endocrinol Metab 93(4):1359–1365CrossRefPubMedGoogle Scholar
  49. 49.
    Mehls O et al (2015) Long-term growth hormone treatment in short children with CKD does not accelerate decline of renal function: results from the KIGS registry and ESCAPE trial. Pediatr Nephrol 30(12):2145–2151CrossRefPubMedGoogle Scholar
  50. 50.
    Hodson EM, Willis NS, Craig JC (2012) Growth hormone for children with chronic kidney disease. Cochrane Database Syst Rev 2:CD003264Google Scholar
  51. 51.
    Wu Y et al (2013) Growth hormone improves growth in pediatric renal transplant recipients – a systemic review and meta-analysis of randomized controlled trials. Pediatr Nephrol 28(1):129–133CrossRefPubMedGoogle Scholar
  52. 52.
    Blum WF et al (2013) 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 98(8):E1383–E1392CrossRefPubMedGoogle Scholar
  53. 53.
    Hauffa BP et al (2001) Stellungnahme zur Wachstumshormontherapie bei Kindern mit Prader-Willi-Syndrom durch die Arbeitsgruppe Pädiatrische Endokrinologie (APE) und der Arbeitsgruppe Adipositas (AGA). Endokrinologie Informationen der DGE, 25. Jahrgang, Bd. 5., S 141–145Google Scholar

Copyright information

© Springer Medizin Verlag GmbH 2017

Authors and Affiliations

  • H.-G. Dörr
    • 1
  • M. Bettendorf
    • 2
  • G. Binder
    • 3
  • J. Dötsch
    • 4
  • B. Hauffa
    • 5
  • K. Mohnike
    • 6
  • H. L. Müller
    • 7
  • J. Woelfle
    • 8
  1. 1.Kinder- und JugendklinikUniversitätsklinikum ErlangenErlangenDeutschland
  2. 2.Sektion für Pädiatrische Endokrinologie und DiabetologieUniversitätsklinikum HeidelbergHeidelbergDeutschland
  3. 3.Kinder- und JugendmedizinUniversitätsklinikum TübingenTübingenDeutschland
  4. 4.Klinik und Poliklinik für Kinder- und JugendmedizinUniversitätsklinikum KölnKölnDeutschland
  5. 5.Kinderklinik II, Pädiatrische Endokrinologie und DiabetologieUniversitätsklinikum EssenEssenDeutschland
  6. 6.Otto-von-Guericke-Universität Magdeburg, UniversitätskinderklinikMagdeburgDeutschland
  7. 7.Zentrum für Kinder- und JugendmedizinKlinikum Oldenburg AöR, Medizinischer Campus Universität OldenburgOldenburgDeutschland
  8. 8.Zentrum für Kinderheilkunde, Abteilung für Allgemeine Pädiatrie, Schwerpunkt Pädiatrische Endokrinologie und DiabetologiUniversitätsklinikum BonnBonnDeutschland

Personalised recommendations