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Growth Hormone Insensitivity

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Pediatric Endocrinology

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Abstract

Growth hormone insensitivity (GHI) or resistance is the absence of growth or metabolic response to endogenous GH produced by the liver, or to recombinant human (rh) GH administered in physiologic doses. Genetic disorders that result in GHI are rare and include GH receptor deficiency (GHRD, Laron syndrome), as well as those due to mutations affecting genes of serum transducers and activators of transcription 5B (STAT5b), protein tyrosine phosphatase non-receptor type 11 (PTPN11), acid labile subunit (ALS), insulin-like growth factor-I (IGF-I), the IGF-I receptor, and pappalysin 2 (PAPP-A2).

Mutation of cell surface GH binding protein, IGF-I, IGF-I binding protein, and other intracellular growth factors seldom occurs, whereas secondary GH insensitivity due to undernutrition, renal failure, and disease states is common.

Limited experience with rhIGF-I therapy in GHRD demonstrates restoration of growth that is less than seen with rhGH replacement in GH deficiency, probably due to the absence of direct effects of GH in bone and muscle.

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References

  1. Rosenbloom AL. Physiology and disorders of the growth hormone receptor (GHR) and GH-GHR signal transduction. Endocrine. 2000;12:107–19.

    Article  CAS  PubMed  Google Scholar 

  2. Godowski PJ, Leung DW, Meacham LR, et al. Characterization of the human growth hormone receptor gene and demonstration of a partial gene deletion in two patients with Laron-type dwarfism. Proc Natl Acad Sci U S A. 1989;86:8083–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Postel-Vinay M-C, Kelly PA. Growth hormone receptor signaling. Baillieres Clin Endocrinol Metab. 1996;10:323–6.

    Article  CAS  PubMed  Google Scholar 

  4. de Vos AM, Ultsch M, Kossiakoff AA. Human growth hormone and extracellular domain of its receptor: crystal structure of the complex. Science. 1992;255:306–12.

    Article  PubMed  Google Scholar 

  5. Rajaram S, Baylink DJ, Mohan S. Insulin-like growth factor-binding proteins in serum and other biological fluids: regulation and functions. Endocr Rev. 1997;18:801–31.

    CAS  PubMed  Google Scholar 

  6. Baxter RG, Binoux MA, Clemmons DR, Conover CA, Drop SLA, Holly JMP, et al. Recommendations for nomenclature of the insulin-like growth factor binding proteins superfamily. J Clin Endocrinol Metab. 1998;83:3213.

    Article  CAS  PubMed  Google Scholar 

  7. Dai B, Ruan B, Wang J, Shang P, Sun W, Li X, Dou K, Wang D, Li Y. Int J Clin Exp Pathol. 2014;7(9):5645–54.

    CAS  PubMed  PubMed Central  Google Scholar 

  8. Lewit MS, Dent M, Hall K. The insulin-like growth factor system in obesity, insulin resistance and T2DM. J Clin Med. 2014;3:1561–74.

    Article  Google Scholar 

  9. Lee PDK, Durham S, Martínez V, Vásconez O, Powell D, Guevara-Aguirre J. Kinetics of IGF and IGFBP responses to a single dose of GH. JCEM. 1997;82:2266–74.

    CAS  PubMed  Google Scholar 

  10. Guevara-Aguirre J, Rosenbloom A, Balasubramanian P, Teran E, Guevara-Aguirre M, Guevara C, Procel P, Alfara I, DeCabo R, Narvaez L, Saavedra J, Longo V. GH receptor deficiency in Ecuadorian adults is associated with obesity and enhanced insulin sensitivity. J Clin Endocrinol Metab. 2015;100:2589–96.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Yau S, Azar WJ, Sabin MA, Werther GA, Russo VC. IGFBP-2 – taking the lead in growth, metabolism and cancer. J Cell Commun Signal. 2015;9(2):125–42.

    Article  PubMed  PubMed Central  Google Scholar 

  12. Daughaday WH, Rotwein P. Insulin-like growth factors I and II: peptide, messenger ribonucleic acid and gene structures, serum and tissue concentrations. Endocr Rev. 1989;10:68–91.

    Article  CAS  PubMed  Google Scholar 

  13. Vaccarello MA, Diamond FB Jr, Guevara-Aguirre J, et al. Hormonal and metabolic effects and pharmacokinetics of recombinant human insulin-like growth factor-I in growth hormone receptor deficiency/Laron syndrome. J Clin Endocrinol Metab. 1993;77:273–80.

    CAS  PubMed  Google Scholar 

  14. Guevara-Aguirre J, Rosenbloom AL. Obesity, diabetes and cancer: insight into the relationship from a cohort with growth hormone receptor deficiency. Diabetologia. 2015:58–37. https://doi.org/10.1007/s00125-0143397-3.

  15. Rosenbloom AL. Growth hormone insensitivity: physiologic and genetic basis, phenotype, and treatment. J Pediatr. 1999;135:280–9.

    Article  CAS  PubMed  Google Scholar 

  16. Rivarola MA, Phillips JA III, Migeon CJ, Heinrich JJ, Hjelle BJ. Phenotypic heterogeneity in familial isolated growth hormone deficiency type I-A. J Clin Endocrinol Metab. 1984;59:34–40.

    Article  CAS  PubMed  Google Scholar 

  17. Powell DR. Effects of renal failure on the growth hormone-insulin-like growth factor axis. J Pediatr. 1997;131:S13–516.

    Article  CAS  PubMed  Google Scholar 

  18. Guevara-Aguirre J, Guevara-Aguirre M, Hwa V, et al. Intrauterine and postnatal growth failure with normal GH/IGF1 axis and insulin-resistant diabetes in a consanguineous kinship. Eur J Endocrinol. 2012;166:521–9.

    Article  CAS  PubMed  Google Scholar 

  19. Ayling RM, Ross R, Towner P, et al. A dominant-negative mutation of the growth hormone receptor causes familial short stature. Nat Genet. 1997;16:13–4.

    Article  CAS  PubMed  Google Scholar 

  20. Metherell LA, Akker SA, Munroe PB, et al. Pseudoexon activation as a novel mechanism for disease resulting in atypical growth hormone insensitivity. Am J Hum Genet. 2001;69:641–6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  21. Iida K, Takahashi Y, Kaji H, et al. Growth hormone (GH) insensitivity syndrome with high serum GH binding protein levels caused by a heterozygous splice site mutation of the GH receptor gene producing a lack of intracellular domain. J Clin Endocrinol Metab. 1998;83:531–7.

    CAS  PubMed  Google Scholar 

  22. Iida K, Takahashi Y, Kaji H, et al. Functional characterization of truncated growth hormone (GH) receptor (1-277) causing partial GH insensitivity syndrome with high GH-binding protein. J Clin Endocrinol Metab. 1999;84:1011–6.

    CAS  PubMed  Google Scholar 

  23. Dastot F, Sobrier ML, Duquesnoy P, Duriez B, Goosens M, Amselem S. Alternative spliced forms in the cytoplasmic domain of the human growth hormone (GH) receptor regulate its ability to generate a soluble GH binding protein. Proc Natl Acad Sci U S A. 1996;93:10723–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Rosenfeld RG, Belgorosky A, Camacho-Hubner C, Savage MO, Wit JM, Hwa V. Defects in growth hormone receptor signaling. Trends Endocrinol Metab. 2007;18:134–41.

    Article  CAS  PubMed  Google Scholar 

  25. Cofanova-Gambetti OV, Hwa V, Jorge AAL, et al. Heterozygous STAT5b gene mutations: impact on clinical phenotype. Endocr Soc Ann Mtg. June 19–22 2010, San Diego, abstract P1–661.

    Google Scholar 

  26. Woods KA, Camacho-Hübner C, Savage MO, Clark AJL. Intrauterine growth retardation and postnatal growth failure associated with deletion of the insulin-like growth factor I gene. N Engl J Med. 1996;335:1363–7.

    Article  CAS  PubMed  Google Scholar 

  27. Bonapace G, Concolino D, Formicola S, Strisciuglio P. A novel mutation in a patient with insulin-like growth factor 1 (IGF1) deficiency. J Med Genet. 2003;40:913–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. Walenkamp MJ, Karperien M, Pereira AM, et al. Homozygous and heterozygous expression of a novel insulin-like growth factor-I mutation. J Clin Endocrinol Metab. 2005;90:2855–64.

    Article  CAS  PubMed  Google Scholar 

  29. Netchine I, Azzi S, Houang M, et al. Partial primary deficiency of insulin-like growth factor (IGF)-I activity associated with IGF-I mutation demonstrates its critical role in growth and brain development. J Clin Endocrinol Metab. 2009;94:3913–21.

    Article  CAS  PubMed  Google Scholar 

  30. Guevara-Aguirre J. IGF-I –An important intrauterine growth factor. N Engl J Med. 1996;335:1389–91.

    Article  CAS  PubMed  Google Scholar 

  31. Domené HM, Bengolea SV, Martínez AS, Ropelato MG, Pennisi P, Scaglia P. Deficiency of the circulating insulin-like growth factor system associated with inactivation of the acid-labile subunit gene. N Engl J Med. 2004;350:570–7.

    Article  PubMed  Google Scholar 

  32. Hwa V, Haeusler G, Pratt KL, Little BM, Frisch H, Koller D. Total absence of functional acid labile subunit, resulting in severe insulin-like growth factor deficiency and moderate growth failure. J Clin Endocrinol Metab. 2006;91:1826–31.

    Article  CAS  PubMed  Google Scholar 

  33. Domené HM, Scaglia PA, Lteif A, et al. Phenotypic effects of null and haploinsufficiency of acid-labile subunit in a family with two novel IGFALS gene mutations. J Clin Endocrinol Metab. 2007;92:4444–50.

    Article  PubMed  CAS  Google Scholar 

  34. Heath KE, Argente J, Barrios V, Pozo J, Díaz-González F, Martos-Moreno GA. Primary acid-labile subunit deficiency due to recessive IGFALS mutations results in postnatal growth deficit associated with low circulating insulin growth factor (IGF)-I, IGF binding protein-3 levels, and hyperinsulinemia. J Clin Endocrinol Metab. 2008;93:1616–24.

    Article  CAS  PubMed  Google Scholar 

  35. van Duyvenvoorde HA, Kempers MJ, Twickler TB, van Doorn J, Gerver WJ, Noordam C. Homozygous and heterozygous expression of a novel mutation of the acid-labile subunit. Eur J Endocrinol. 2008;159:113–20.

    Article  PubMed  CAS  Google Scholar 

  36. Fofanova-Gambetti OV, Hwa V, Kirsch S, Pihoker C, Chiu HK, Högler W. Three novel IGFALS gene mutations resulting in total ALS and severe circulating IGF-I/IGFBP-3 deficiency in children of different ethnic origins. Horm Res. 2009;71:100–10.

    CAS  PubMed  Google Scholar 

  37. Fofanova-Gambetti OV, Hwa V, Wit JM, et al. Impact of heterozygosity for acid-labile subunit (IGFALS) gene mutations on stature: results from the international acid-labile subunit consortium. J Clin Endocrinol Metab. 2010;95:4184–91.

    Article  CAS  PubMed  Google Scholar 

  38. Domené HM, Martínez AS, Frystyk J, et al. Normal growth spurt and final height despite low levels of all forms of circulating insulin-like growth factor-I in a patient with acid-labile subunit deficiency. Horm Res. 2007;67:243–9.

    PubMed  Google Scholar 

  39. Abuzzahab MJ, Schneider A, Goddard A, Grigorescu F, Lautier C, Keller E. IGF-I receptor mutations resulting in intrauterine and postnatal growth retardation. N Engl J Med. 2003;349:2211–22.

    Article  CAS  PubMed  Google Scholar 

  40. Kawashima Y, Kanzaki S, Yang F, Kinoshita T, Hanaki K, Nagaishi J. Mutation at cleavage site of insulin-like growth factor receptor in a short-stature child born with intrauterine growth retardation. J Clin Endocrinol Metab. 2005;90:4679–87.

    Article  CAS  PubMed  Google Scholar 

  41. Walenkamp MJ, van der Kamp HJ, Pereira AM, Kant SG, van Duyvenvoorde HA, Kruithof MF. A variable degree of intrauterine and postnatal growth retardation in a family with a missense mutation in the insulin-like growth factor I receptor. J Clin Endocrinol Metab. 2006;91:3062–70.

    Article  CAS  PubMed  Google Scholar 

  42. Inagaki K, Tiulpakov A, Rubtsov P, Sverdlova P, Peterkova V, Yakar S. A familial insulin-like growth factor-I receptor mutant leads to short stature: clinical and biochemical characterization. J Clin Endocrinol Metab. 2007;92:1542–8.

    Article  CAS  PubMed  Google Scholar 

  43. Walenkamp MJ, de Muinck Keizer-Schrama SM, de Mos M, Kalf ME, van Duyvenvoorde HA, Boot AM. Successful long-term growth hormone therapy in a girl with haploinsufficiency of the insulin-like growth factor-I receptor due to a terminal 15q26.2->qter Deletion detected by multiplex ligation probe amplification. J Clin Endocrinol Metab. 2008;93:2421–5.

    Article  CAS  PubMed  Google Scholar 

  44. Fang P, Schwartz ID, Johnson BD, Derr MA, Roberts CT Jr, Hwa V. Familial short stature caused by haploinsufficiency of the insulin-like growth factor i receptor due to nonsense-mediated messenger ribonucleic acid decay. J Clin Endocrinol Metab. 2009;94:1740–7.

    Article  CAS  PubMed  Google Scholar 

  45. Dauber A, Munoz-Calvo MT, Barrios V, et al. Mutations in pregnancy-associated plasma protein A2 cause short stature due to low IGF-I availability. EMBO Mol Med. 2016;8:363–74.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Velez C, Palamara P, Guevara-Aguirre J, Hao L, Parafet T, Guevara-Aguirre M, Pearlman A, Oddoux C, Hammer M, Burns E, Pe’er I, Atzmon G, Ostrer H. The Impact of Converso Jews on the genome of modern Latin Americans. Hum Genet. 2012;131(2):251–63.

    Article  CAS  PubMed  Google Scholar 

  47. Laron Z, Pertzelan A, Mannheimer S. Genetic pituitary dwarfism with high serum concentration of growth hormone – a new inborn error of metabolism? Isr J Med Sci. 1966;2:152–5.

    CAS  PubMed  Google Scholar 

  48. Rosenbloom AL, Guevara-Aguirre J, Rosenfeld RG, Fielder PJ. The little women of Loja. Growth hormone receptor-deficiency in an inbred population of southern Ecuador. N Engl J Med. 1990;323:1367–74.

    Article  CAS  PubMed  Google Scholar 

  49. Guevara-Aguirre J, Rosenbloom AL, Fielder PJ, Diamond FB Jr, Rosenfeld RG. Growth hormone receptor deficiency in Ecuador: clinical and biochemical phenotype in two populations. J Clin Endocrinol Metab. 1993;76:417–23.

    CAS  PubMed  Google Scholar 

  50. Rosenbloom AL, Francke U, Rosenfeld RG, Guevara-Aguirre J. Growth hormone receptor deficiency in Ecuador. J Clin Endocrinol Metab. 1999;84:4436–43.

    CAS  PubMed  Google Scholar 

  51. Jorge AA, Souza SC, Arnhold IJ, Mendonca BB. Poor reproducibility of IGF-I and IGF binding protein-3 generation test in children with short stature and normal coding region of the GH receptor gene. J Clin Endocrinol Metab. 2002;87:469–72.

    Article  CAS  PubMed  Google Scholar 

  52. Guevara-Aguirre J, Guevara-Aguirre M, Saavedra J. Low serum levels of IGF-I, BP3 and ALS are associated to severe short stature, obesity, premature aging, increased cardiovascular mortality and absence of cancer in the Ecuadorian cohort of Laron syndrome subjects. Pediatric Academic Societies Ann Mtg, Toronto Canada 2007. Abstract #327.

    Google Scholar 

  53. Guevara-Aguirre J, Balasubramanian P, Guevara-Aguirre M, Wei M, Madia F, Cheng C, Hwang D, Martín-Montalvo A, Saavedra J, Ingles S, Cohen P, Longo V. Growth hormone receptor deficiency is associated with a major reduction in pro-aging signaling, cancer and diabetes in humans. Sci Transl Med. 2011;3:70ra13.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  54. Collett-Solberg PF, Misra M, Drug and Therapeutics Committee of the Lawson Wilkins Pediatric Endocrine Society. The role of recombinant human insulin-like growth factor-I in treating children with short stature. J Clin Endocrinol Metab. 2008;93:10–8.

    Article  CAS  PubMed  Google Scholar 

  55. Rosenfeld RG, Rosenbloom AL, Guevara-Aguirre J. Growth hormone (GH) insensitivity due to primary GH receptor deficiency. Endocr Rev. 1994;15:369–90.

    Article  CAS  PubMed  Google Scholar 

  56. Rudling M, Norstedt G, Olivecrona H, Reihnér E, Gustafsson J-A, Angelin B. Importance of growth hormone for the induction of hepatic low density lipoprotein receptors. Proc Natl Acad Sci. 1992;89:6983–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  57. Rosenbloom AL, Guevara-Aguirre J, Rosenfeld RG, Pollock BH. Growth in growth hormone insensitivity. Trends Endocrinol Metab. 1994;5:296–303.

    Article  CAS  PubMed  Google Scholar 

  58. Rosenbloom AL. Recombinant human insulin like factor-1 treatment: prime time or timeout? [Commentary on “Recombinant Human Insulin Like Growth Factor-1Treatment: Ready for Prime Time” by Bright GM, Mendoza JR, Rosenfeld RG. Endocrinol Metab Clin N Am 2009; 38:625–38] International J Pediatr Endocrinol. 2009;2009:Article ID 429684. doi:10.1155/2009/429684.

    Article  CAS  Google Scholar 

  59. Tanner JM, Davies PSW. Clinical longitudinal standards for height and height velocity for North American children. J Pediatr. 1985;107:317–29.

    Article  CAS  PubMed  Google Scholar 

  60. Guevara-Aguirre J, Vasconez O, Martinez V, et al. A randomized, double blind, placebo controlled trial on safety and efficacy of recombinant human insulin-like growth factor-I in children with growth hormone receptor deficiency. J Clin Endocrinol Metab. 1995;80:1393–8.

    CAS  PubMed  Google Scholar 

  61. Crosnier H, Gourmelen M, Prëvot C, Rappaport R. Effects of nutrient intake on growth, insulin-like growth factors, and their binding proteins in a Laron-type dwarf. J Clin Endocrinol Metab. 1993;76:248–50.

    CAS  PubMed  Google Scholar 

  62. Laron Z, Lilos P, Klinger B. Growth curves for Laron syndrome. Arch Dis Child. 1993;68:768–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Rose SR, Municchi G, Barnes KM, Kamp GA, Uriarte MM, Ross JL, Cassorla F, Cutler GB Jr. Spontaneous growth hormone secretion increases during puberty in normal girls and boys. J Clin Endocrinol Metab. 1991;73:428–35.

    Article  CAS  PubMed  Google Scholar 

  64. Guevara-Aguirre J, Rosenbloom AL, Vasconez O, Martinez V, Gargosky SE, Rosenfeld RG. Two-year treatment of growth hormone receptor deficiency (GHRD) with recombinant insulin-like growth factor-I in 22 children: comparison of two dosage levels and to GH treated GH deficiency. J Clin Endocrinol Metab. 1997;82:629–33.

    CAS  PubMed  Google Scholar 

  65. Ranke MB, Savage MO, Chatelain PG, Preece MA, Rosenfeld RG, Wilton P. Long-term treatment of growth hormone insensitivity syndrome with IGF-I. Results of the European Multicentre Study. The Working Group on Growth Hormone Insensitivity Syndromes. Horm Res. 1999;51:128–34.

    CAS  PubMed  Google Scholar 

  66. Schaefer GB, Rosenbloom AL, Guevara-Aguirre J, et al. Facial morphometry of Ecuadorian patients with growth hormone receptor deficiency/Laron syndrome. J Med Genet. 1994;31:635–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Rosenbloom AL, Selman-Almonte A, Brown MR, Fisher DA, Baumbach L, Parks JS. Clinical and biochemical phenotype of familial anterior hypopituitarism from mutation of the PROP-1 gene. J Clin Endocrinol Metab. 1999;84:50–7.

    CAS  PubMed  Google Scholar 

  68. Rosenbloom AL, Guevara-Aguirre J, Fielder PJ, Gargosky S, Rosenfeld RG, Diamond FB Jr, Vaccarello MA. Growth hormone receptor deficiency/Laron syndrome in Ecuador: clinical and biochemical characteristics. Pediatr Adolesc Endocrinol. 1993;24:34–52.

    Google Scholar 

  69. Bachrach LB, Marcus R, Ott SM, Rosenbloom AL, Vasconez O, Martinez V, Martinez AL, Rosenfeld RG, Guevara-Aguirre J. Bone mineral, histomorphometry, and body composition in adults with growth hormone receptor deficiency. J Bone Miner Res. 1998;13:415–21.

    Article  CAS  PubMed  Google Scholar 

  70. Bandeira F, Camargo K, Caldas G, Rosenbloom AL, Stabler B, Underwood LE. Primary growth hormone insensitivity: case report. Arq Bras Endocrinol Metabol. 1997;41:198–200.

    Google Scholar 

  71. Frankel JJ, Laron Z. Psychological aspects of pituitary insufficiency in children and adolescents with special reference to growth hormone. Isr J Med Sci. 1968;4:953–61.

    CAS  PubMed  Google Scholar 

  72. Galatzer A, Aran O, Nagelberg N, Rubitzek J, Laron Z. Cognitive and psychosocial functioning of young adults with Laron syndrome. Pediatr Adolesc Endocrinol. 1993;24:53–60.

    Google Scholar 

  73. Woods KA, Dastot F, Preece MA, et al. Extensive personal experience. Phenotype: genotype relationships in growth hormone insensitivity syndrome. J Clin Endocrinol Metab. 1997;82:3529–35.

    CAS  PubMed  Google Scholar 

  74. Guevara-Aguirre J, Rosenbloom AL. Psychosocial adaptation of Ecuadorian patients with growth hormone receptor deficiency/Laron syndrome. Pediat Adolesc Endocrinol. 1993;24:61–4.

    Google Scholar 

  75. Kranzler JH, Rosenbloom AL, Martinez V, Guevara-Aguirre J. Normal intelligence with severe IGF-I deficiency due to growth hormone receptor deficiency: a controlled study in genetically homogeneous population. J Clin Endocrinol Metab. 1998;83:1953–8.

    CAS  PubMed  Google Scholar 

  76. Bunn RC, King WD, Winkler MK, Fowlkes JL. Early developmental changes in IGF1, IGFII, BP1, and BP3 in the CSF of children. Pedaitric Research. 2005;58:89–93.

    Article  CAS  Google Scholar 

  77. Laron Z, Ginsberg S, Lilos P, Arbiv M, Vaisman N. Long-term IGF-I treatment of children with Laron syndrome increases adiposity. Growth Horm IGF Res. 2006;16:61–4.

    Article  CAS  PubMed  Google Scholar 

  78. Beck KD, Powell-Braxton L, Widmer H-R, Valverde J, Hofti F. IGF-I gene disruption results in reduced brain size, CNS hypomyelination, and loss of hippocampal granule and striatal parvalbumin-containing neurons. Neuron. 1995;14:717–30.

    Article  CAS  PubMed  Google Scholar 

  79. Zhou Y, BC X, Maheshwari HG, He H, et al. A mammalian model for the Laron syndrome produced by targeted disruption of the mouse growth hormone receptor/binding protein gene (the Laron mouse). Proc Natl Acad Sci U S A. 1997;94:13215–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Buckway CK, Guevara-Aguirre J, Pratt KL, Burren CP, Rosenfeld R. The IGF-I generation test revisited: a marker of GH sensitivity. J Clin Endocrinol Metab. 2001;86:5176–83.

    Article  CAS  PubMed  Google Scholar 

  81. Maheshwari HG, Silverman BI, Dupuis J, Baumann G. Phenotype and genetic analysis of a syndrome caused by an inactivating mutation in the growth hormone-releasing hormone receptor: dwarfism of Sindh. J Clin Endocrinol Metab. 1998;83:4065–74.

    CAS  PubMed  Google Scholar 

  82. Gargosky SE, Wilson KF, Fielder PJ, et al. The composition and distribution of insulin-like growth factors (IGFs) and IGF-binding proteins (IGFBPs) in the serum of growth hormone receptor-deficient patients: effects of IGF-I therapy on IGFBP-3. J Clin Endocrinol Metab. 1993;77:1683–168.

    CAS  PubMed  Google Scholar 

  83. Wilson KF, Fielder PJ, Guevara-Aguirre J, et al. Long-term effects of insulin-like growth factor (IGF)-I treatment on serum IGFs and IGF binding proteins in adolescent patients with growth hormone receptor deficiency. Clin Endocrinol (Oxf). 1995;42:399–407.

    Article  CAS  Google Scholar 

  84. Ranke MB, Savage MO, Chatelain PG, et al. Insulin-like growth factor I improves height in growth hormone insensitivity: two years’ results. Horm Res. 1995;44:253–64.

    Article  CAS  PubMed  Google Scholar 

  85. Rosenbloom AL, Guevara-Aguirre J, Fielder PJ, Gargosky S, Cohen P, Rosenfeld RG. Insulin-like growth factor binding proteins-2 and -3 in Ecuadorian patients with growth hormone receptor deficiency and their parents. Pediatr Adolesc Endocrinol. 1993;24:185–91.

    Google Scholar 

  86. Goddard AD, Covello R, Luoh S-M, et al. Mutations of the growth hormone receptor in children with idiopathic short stature. N Engl J Med. 1995;333:1093–8.

    Article  CAS  PubMed  Google Scholar 

  87. Carlsson LM, Attie KM, Compton PG, Vitangcol RV, Merimee TJ. Reduced concentrations concentration of serum growth hormone-binding protein in children with idiopathic short stature. National Cooperative Growth Study. J Clin Endocrinol Metab. 1994;78:1325–30.

    CAS  PubMed  Google Scholar 

  88. Attie KM, Carlsson LMS, Rundle AC, Sherman BM. Evidence for partial growth hormone insensitivity among patients with idiopathic short stature. J Pediatr. 1995;127:244–50.

    Article  CAS  PubMed  Google Scholar 

  89. Park P, Cohen P. Insulin-like growth factor I (IGF-I) measurements in growth hormone (GH) therapy of idiopathic short stature (ISS). Growth Horm IGF Res. 2005;15(Supp A):S13–20.

    Article  CAS  PubMed  Google Scholar 

  90. Moore WV, Dana K, Frane J, Lippe B. Growth hormone responsiveness: peak stimulated growth hormone levels and other variables in idiopathic short stature (ISS): data from the National Cooperative Growth Study. Pediatr Endocrinol Rev. 2008;6:4–7.

    Google Scholar 

  91. Rosenbloom AL. Is there a role for recombinant insulin-like growth factor-I (rhIGF-I) in the treatment of idiopathic short stature? Lancet. 2006;368:612–6.

    Article  CAS  PubMed  Google Scholar 

  92. 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;95:611–9.

    Article  CAS  PubMed  Google Scholar 

  93. Rosenbloom AL, Rivkees SA. Is off label use of recombinant human insulin like growth factor (IGF)-I for growth promotion appropriate? J Clin Endocrinol Metab. 2010;95:505–8.

    Article  CAS  PubMed  Google Scholar 

  94. Guevara-Aguirre J, Rosenbloom AL, Guevara-Aguirre M, et al. Effects of heterozygosity for the E180 splice mutation causing growth hormone receptor deficiency in Ecuador on IGF-I, IGFBP-3, and stature. Growth Horm IGF Res. 2007;17:261–4.

    Article  CAS  PubMed  Google Scholar 

  95. Rosenbloom AL. IGF-I treatment of growth hormone insensitivity. In: Rosenfeld RG, Roberts CT, editors. The IGF system: molecular biology, physiology, and clinical applications. Totowa: Humana Press; 1999. p. 739–69.

    Chapter  Google Scholar 

  96. Heinrichs C, Vis HL, Bergmann P, Wilton P, Bourguignon JP. Effects of 17-month treatment using recombinant insulin-like growth factor-I in two children with growth hormone insensitivity (Laron) syndrome. Clin Endocrinol (Oxf). 1993;38:647–51.

    Article  CAS  Google Scholar 

  97. Martinez V, Vasconez O, Martinez A, Moreno Z, Davila N, Rosenbloom A, Diamond F, Bachrach L, Rosenfeld R, Guevara-Aguirre J. Body changes in adolescent patients with growth hormone receptor deficiency receiving recombinant human insulin-like growth factor I and luteinizing hormone-releasing hormone analog: preliminary results. Acta Paediatr Suppl. 1994;399:133–6.

    Article  CAS  PubMed  Google Scholar 

  98. Klinger B, Laron Z. Three year IGF-I treatment of children with Laron syndrome. J Pediatr Endocrinol Metab. 1995;8:149–58.

    Article  CAS  PubMed  Google Scholar 

  99. Chernausek SD, Backeljauw PF, Frane J, Kuntze J, Underwood LE, GH Insensitivity Syndrome Collaborative Group. Long-term treatment with recombinant IGF-I in children with severe IGF-I deficiency due to growth hormone insensitivity. J Clin Endocrinol Metab. 2007;92:902–10.

    Article  CAS  PubMed  Google Scholar 

  100. Fan Y, Menon RK, Cohen P, et al. Liver-specific deletion of the growth hormone receptor reveals essential role of growth hormone signaling in hepatic lipid metabolism. J Biol Chem. 2009;24(284):19937–44.

    Article  CAS  Google Scholar 

  101. Munoz-Calvo M, Barrios V, Pozo J, Chowen J, Martos-Moreno G, Hawkins F, Dauber A, Domene H, Yakar S, Rosenfeld R, Perez-Jurado L, Oxvig C, Frystyk J, Argente J. Treatment with recombinant human insulin growth factor-1 improves growth in patients with PAPP-A2 deficiency. J Clin Endocrinol Metab. 2016;101:3879–993.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Leonard J, Samuels M, Cotterill AM, Savage MO. Effects of recombinant insulin-like growth factor I on craniofacial morphology in growth hormone insensitivity. Acta Paediatr Suppl. 1994;399:140–1.

    Article  CAS  PubMed  Google Scholar 

  103. Bjerknes R, Vesterhus P, Aarskog D. Increased neutrophil insulin-like growth factor-I (IGF-I) receptor expression and IGF-I-induced functional capacity in patients with untreated Laron syndrome. Eur J Endocrinol. 1997;136:92–5.

    Article  CAS  PubMed  Google Scholar 

  104. Diamond F, Martinez V, Guevara-Aguirre J, et al. Immune function in patients with growth hormone receptor deficiency (GHRD). Proc Endocrine Soc 78th Ann Mtg. 1996;1:276.

    Google Scholar 

  105. Le Roith D, Blakesley VA. The yin and the yang of the IGF system: immunological manifestations of GH resistance. Eur J Endocrinol. 1997;136:33–4.

    Article  PubMed  Google Scholar 

  106. Han JC, Balagopal P, Sweeten S, Darmaun D, Mauras N. Evidence for hypermetabolism in boys with constitutional delay of growth and maturation. J Clin Endocrinol Metab. 2006;91:2081–6.

    Article  CAS  PubMed  Google Scholar 

  107. Boschetti M, Larizza D, Calcaterra V, et al. Effect of environment on growth: auxological and hormonal parameters in African and Italian children. Growth Horm IGF Res. 2009;19:238–41.

    Article  CAS  PubMed  Google Scholar 

  108. Gelander L, Blum WF, Larsson L, Rosberg S, Albertsson-Wikland K. Monthly measurements of insulin-like growth factor I (IGF-I) and IGF-binding protein-3 in healthy prepubertal children: characterization and relationship with growth: the 1-year growth study. Pediatr Res. 1999;45:377–83.

    Article  CAS  PubMed  Google Scholar 

  109. Vasconez O, Martinez V, Martinez AL, Hidalgo F, Diamond FB, Rosenbloom AL, Rosenfeld RG, Guevara-Aguirre J. Heart rate increase in patients with growth hormone receptor deficiency treated with insulin-like growth factor I. Acta Paediatr Suppl. 1994;399:137–9.

    Article  CAS  PubMed  Google Scholar 

  110. Klinger B, Anin S, Sibergeld A, Eshet R, Laron Z. Development of hyperandrogenism during treatment with insulin-like growth factor-I (IGF-I) in female patients with Laron syndrome. Clin Endocrinol (Oxf). 1998;48:81–7.

    Article  CAS  Google Scholar 

  111. Samani AA, Yakar S, LeRoith D, Brodt P. The role of the IGF system in cancer growth and metastasis: overview and recent insights. Endocr Rev. 2007;28:20–47.

    Article  CAS  PubMed  Google Scholar 

  112. Guevara-Aguirre J, Rosenbloom AL, Guevara-Aguirre M, Saavedra J, Procel P. Recommended IGF-I dosage causes greater fat accumulation and osseous maturation than lower dosage and may compromise long-term growth effects. J Clin Endocrinol Metab. 2013;98:839–45.

    Article  CAS  PubMed  Google Scholar 

  113. Ho SC, Clayton P, Vasudevan P, Greening J, Wardhaugh B, Shawn N, Kelnar C, Kirk J, Hogler W. Recombinant human GH therapy in children with chromosome 15q26 deletion. Horm Res Paediatr. 2015;83:424–30.

    Article  CAS  Google Scholar 

  114. Jeong I, Kang E, Cho JH, et al. Long-term efficacy of recombinant human growth hormone therapy in short statured patients with Noonan’s syndrome. Ann Pediatric Endocrinol Metab. 2016;21:26–30.

    Article  Google Scholar 

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Authors and Affiliations

  1. Department of Pediatrics, University of Florida College of Medicine, Children’s Medical Services Center, Gainesville, FL, USA

    Arlan L. Rosenbloom MD

  2. Diabetology and Endocrinology, College of Medicine, Universidad San Francisco de Quito, Ecuador, Instituto de Endocrinología IEMYR, San Ignacio, Quito, Ecuador

    Jaime Guevara-Aguirre MD

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  1. Arlan L. Rosenbloom MD
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  2. Jaime Guevara-Aguirre MD
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Correspondence to Arlan L. Rosenbloom MD .

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Editors and Affiliations

  1. Department of Pediatrics, Robert Wood Johnson Medical School, New Brunswick, New Jersey, USA

    Sally Radovick

  2. Pediatric Endocrinology, Massachusetts General Hospital for Children, Boston, Massachusetts, USA

    Madhusmita Misra

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Rosenbloom, A.L., Guevara-Aguirre, J. (2018). Growth Hormone Insensitivity. In: Radovick, S., Misra, M. (eds) Pediatric Endocrinology. Springer, Cham. https://doi.org/10.1007/978-3-319-73782-9_2

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  • DOI: https://doi.org/10.1007/978-3-319-73782-9_2

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