Background: How to define poor growth response in the management of short growth hormone (GH)-treated children is controversial. Aim: Assess various criteria of poor response. Subjects and Methods: Short GH-treated prepubertal children [n = 456; height (Ht) SD score (SDS) ≤–2] with idiopathic GH deficiency (IGHD, n = 173), idiopathic short stature (ISS, n = 37), small for gestational age (SGA, n = 54), organic GHD (OGHD, n = 40), Turner syndrome (TS, n = 43), skeletal dysplasia (n = 15), other diseases (n = 46) or syndromes (n = 48) were evaluated in this retrospective multicenter study. Median age at GH start was 6.3 years and Ht SDS –3.2. Results: Median [25–75 percentile] first-year gain in Ht SDS was 0.65 (0.40–0.90) and height velocity (HtV) 8.67 (7.51–9.90) cm/year. Almost 50% of IGHD children fulfilled at least one criterion for poor responders. In 28% of IGHD children, Ht SDS gain was <0.5 and they had lower increases in median IGF-I SDS than those with Ht SDS >0.5. Only IGHD patients with peak stimulated growth hormone level <3 µg/l responded better than those with ISS. A higher proportion of children with TS, skeletal dysplasia or born SGA had Ht SDS gain <0.5. Conclusion: Many children respond poorly to GH therapy. Recommendations defining a criterion may help in managing short stature patients.

1.
Wit JM, Bang P: European perspective on treatment approaches for growth failure. Pediatr Endocrinol Rev 2008;5(suppl 3):862–868.
2.
Hernández LM, Lee PD, Camacho-Hübner C: Isolated growth hormone deficiency. Pituitary 2007;10:351–357.
3.
Wilton P: Adverse events reported in KIGS; in Ranke MB, Price DA, Reiter EO (eds): Growth Hormone Therapy in Pediatrics – 20 years of KIGS. Basel, Karger, 2007, pp 432–441.
4.
Chernausek SD, Backeljauw PF, Frane J, Kuntze J, Underwood LE, GH Insensitivity Syndrome Collaborative Group: Long-term treatment with recombinant insulin-like growth factor (IGF)-I in children with severe IGF-I deficiency due to growth hormone insensitivity. J Clin Endocrinol Metab 2007;92:902–910.
5.
Midyett LK, Rogol AD, Van Meter QL, Frane J, Bright GM, on behalf of the MS301 Study Group: Recombinant insulin-like growth factor (IGF)-I treatment in short children with low IGF-I levels: first-year results from a randomized clinical trial. J Clin Endocrinol Metab 2010;95:611–619.
6.
Midyett LK, Reiner B, Rogol AD, Geffner ME, Frane JW, Bright GM: Preliminary results of a phase II, randomized, open-label, active-treatment controlled trial of rhGH and rhIGF-1 combination therapy in prepubertal children with short stature associated with low IGF-1. Presentation at the ESPE/LWPES 2009, abstract FC10-006 (study site: http://clinicaltrials.gov/ct2/show/NCT00572156?term=MS+316&rank=1).
7.
Cohen P, Rogol AD, Howard CP, Bright GM, Kappelgaard AM, Rosenfeld RG, American Norditropin Study Group: Insulin growth factor-based dosing of growth hormone therapy in children: a randomized, controlled study. J Clin Endocrinol Metab 2007;92:2480–2486 [comment in Nat Clin Pract Endocrinol Metab 2007;3:682–683 and J Clin Endocrinol Metab 2007;92:2436–2438].
8.
Kriström B, Aronson AS, Dahlgren J, Gustafsson J, Halldin M, Ivarsson SA, Nilsson NO, Svensson J, Tuvemo T, Albertsson-Wikland K: Growth hormone dosing during catch-up growth guided by individual responsiveness decreases growth response variability in prepubertal children with growth hormone deficiency or idiopathic short stature. J Clin Endocrinol Metab 2009;94:483–490.
9.
Rosenthal S, Cohen P, Clayton P, Backeljauw P, Bang P, Ten S: Treatment perspectives in idiopathic short stature with a focus on IGF-I deficiency. Pediatr Endocrinol Rev 2007;4(suppl 2):252–271.
10.
Cohen P, Rogol AD, Deal CL, Saenger P, Reiter EO, Ross JL, Chernausek SD, Savage MO, Wit JM, 2007 ISS Consensus Workshop participants: 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.
11.
Ranke MB, Lindberg A, Price DA, Darendeliler F, Albertsson-Wikland K, Wilton P, Reiter EO: KIGS International Board: Age at growth hormone therapy start and first-year responsiveness to growth hormone are major determinants of height outcome in idiopathic short stature. Horm Res 2007;68:53–62.
12.
Ranke MB, Lindberg A, Chatelain P, Wilton P, Cutfield W, Albertsson-Wikland K, Price DA: KIGS International Board. Kabi International Growth Study. Prediction of long-term response to recombinant human growth hormone in Turner syndrome: development and validation of mathematical models. J Clin Endocrinol Metab 2000;85:4212–4218.
13.
Ranke MB, Lindberg A, Chatelain P, Wilton P, Cutfield W, Albertsson-Wikland K, Price DA: KIGS International Board. Kabi Pharmacia International Growth Study. Derivation and validation of a mathematical model for predicting the response to exogenous recombinant human growth hormone in prepubertal children with idiopathic growth hormone deficiency. J Clin Endocrinol Metab 1999;84:1174–1183.
14.
Ranke MB, Lindberg A, Cowell CT, Albertsson-Wikland K, Reiter EO, Wilton P, Price DA: KIGS International Board: 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 2003;88:125–131.
15.
Albertsson-Wikland K, Kristrom B, Rosberg S, Svensson B, Nierop AF: Validated multivariate models predicting the growth response to GH treatment in individual short children with a broad range in GH secretion capacities. Pediatr Res 2000;48:475–484.
16.
Dahlgren J, Kristrom B, Niklasson A, Nierop AF, Rosberg S, Albertsson-Wikland K: Models predicting the growth response to growth hormone treatment in short children independent of GH status, birth size and gestational age. BMC Med Inform Decis Mak 2007;7:40.
17.
Bakker B, Frane J, Anhalt H, Lippe B, Rosenfeld RG: Height velocity targets from the National Cooperative Growth Study for first-year growth hormone responses in short children. J Clin Endocrinol Metab 2008;93:352–357.
18.
Ranke MB, Lindberg A: KIGS International Board: Observed and predicted growth responses in prepubertal children with growth disorders: guidance of growth hormone treatment by empirical variables. J Clin Endocrinol Metab 2010;95:1229–1237.
19.
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.
20.
Albertsson-Wikland K, Aronson AS, Gustafsson J, Hagenäs L, Ivarsson SA, Jonsson B, Kriström B, Marcus C, Nilsson KO, Ritzén EM, Tuvemo T, Westphal O, Aman J: 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.
21.
Albertsson-Wikland K, Luo ZC, Niklasson A, Karlberg J: Swedish population-based longitudinal reference values from birth to 18 years of age for height, weight and head circumference. Acta Paediatr 2002;91:739–754.
22.
Niklasson A, Albertsson-Wikland K: Continuous growth reference from 24th week of gestation to 24 months by gender. BMC Pediatr 2008;8:8.
23.
Abbassi V: Growth and normal puberty. Pediatrics 1998;102:507–511.
24.
Karlberg J, Luo ZC, Albertsson-Wikland K: Body mass index reference values (mean and SD) for Swedish children. Acta Peadiatr 2001;90:1427–1434 [erratum in Acta Paediatr 2002;91:362].
25.
Fredriks AM, van Buuren S, van Heel WJM, Dijkman-Neerincx RHM, Verloove-Vanhorick SP, Wit JM: Nationwide age references for sitting height, leg length, and sitting height/height ratio, and their diagnostic value for disproportionate growth disorders. Arch Dis Child 2005;90:807–812.
26.
Bang P, Eriksson U, Sara V, Wivall I-L, Hall K: Comparison of acid ethanol extraction and acid gel filtration prior to IGF-I and IGF-II radioimmunoassays: improvement of determinations in acid ethanol extracts by the use of truncated IGF-I as radioligand. Acta Endocrinol (Copenh) 1991;124:620–629.
27.
Tanner JM, Whitehouse RH: Clinical longitudinal standards for height, weight, height velocity, weight velocity, and stages of puberty. Arch Dis Child 1976;51:170–179.
28.
EU Summary of Product Characteristics (SPC) for GH therapy in SGA with lack of catch up (www.emea.europa.eu/pdfs/human/referral/norditropin/347803en.pdf).
29.
Spagnoli A, Spadoni GL, Cianfarani S, Pasquino AM, Troiani S, Boscherini B: Prediction of the outcome of growth hormone therapy in children with idiopathic short stature. A multivariate discriminant analysis. J Pediatr 1995;126:905–909.
30.
International conference on harmonisation of technical requirements for registration of pharmaceuticals for human use: ICH harmonised tripartite guideline: statistical principles for clinical trials E9. 1998. Available at http://www.ich.org/LOB/media/MEDIA485.pdf.
31.
Blum WF, Cao D, Hesse V, Fricke-Otto S, Ross JL, Jones C, Quigley CA, Binder G: Height gains in response to growth hormone treatment to final height are similar in patients with SHOX deficiency and Turner syndrome. Horm Res 2009;71:167–172.
32.
Ranke MB, Reiter EO, Price DA: Idiopathic growth hormone deficiency in KIGS: selected aspects; in Ranke MB, Price DA, Reiter EO (eds): Growth Hormone Therapy in Pediatrics – 20 years of KIGS. Basel, Karger, 2007, pp 116–135.
33.
Ranke MB, Lindberg A, Price DA, Darendeliler F, Albertsson-Wikland K, Wilton P, Reiter EO: Short-term and long-term response to GH in ISS: KIGS analysis of factors predicting growth; in Ranke MB, Price DA, Reiter EO (eds): Growth Hormone Therapy in Pediatrics – 20 years of KIGS. Basel, Karger, 2007b, pp 319–325.
34.
Kriström B, Karlberg J, Albertsson-Wikland K: Prediction of the growth response of short prepubertal children treated with growth hormone. Swedish Paediatric Study Group for GH treatment. Acta Paediatr 1995;84:51–57.
35.
Park P, Cohen P: Insulin-like growth factor I measurements in growth hormone therapy of idiopathic short stature. Growth Horm IGF Res 2005;15(suppl A):S13–S20.
36.
Karlberg J, Fryer JG, Engström I, Karlberg P: Analysis of linear growth using a mathematical model. II. From 3 to 21 years of age. Acta Paediatr Scand Suppl 1987;337:12–29.
37.
Gelander L, Karlberg J, Albertsson-Wikland K: Seasonality in lower leg length velocity in prepubertal children. Acta Paediatr 1994;83:1249–1254.
38.
Land C, Blum WF, Stabrey A, Schoenau E: Seasonality of growth response to GH therapy in prepubertal children with idiopathic growth hormone deficiency. Eur J Endocrinol 2005;152:727–733.
39.
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.
40.
Ranke MB, Lindberg A, Price DA, Darendeliler F, Albertsson-Wikland K, Wilton P, Reiter EO: KIGS International Board: Age at growth hormone therapy start and first-year responsiveness to growth hormone are major determinants of height outcome in idiopathic short stature. Horm Res 2007;68:53–62.
41.
Reiter EO, Price DA, Wilton P, Albertsson-Wikland K, Ranke MB. Effect of growth hormone treatment on the near-final height of 1,258 patients with idiopathic growth hormone deficiency: analysis of a large international database. J Clin Endocrinol Metab 2006;91:2047–2054.
42.
Rachmiel M, Rota V, Atenafu E, Daneman D, Hamilton J. Final height in children with idiopathic growth hormone deficiency treated with a fixed dose of recombinant growth hormone. Horm Res 2007;68:236–243.
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.