Rosenbloom AL. The physiology of human growth: a review. Reviews in Endocrinology. July 2008. 36-48.
Rosenbloom AL. Recombinant insulin growth factor I in growth therapy. Preedy VR (ed). Handbook of Growth and Growth Monitoring in Health and Disease Springer. New York: Verlag; 2012. 2743-62.
Woods KA, Camacho-Hubner C, Savage MO, Clark AJ. Intrauterine growth retardation and postnatal growth failure associated with deletion of the insulin-like growth factor I gene. N Engl J Med. 1996 Oct 31. 335(18):1363-7. [QxMD MEDLINE Link].
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 May. 90(5):2855-64. [QxMD MEDLINE Link].
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.
Netchine I, Azzi S, Houang M, Seurin D, Perin L, Ricort JM. Partial primary deficiency of insulin-like growth factor (IGF)-I activity associated with IGF1 mutation demonstrates its critical role in growth and brain development. J Clin Endocrinol Metab. 2009 Oct. 94(10):3913-21. [QxMD MEDLINE Link].
Abuzzahab MJ, Schneider A, Goddard A, et al. IGF-I receptor mutations resulting in intrauterine and postnatal growth retardation. N Engl J Med. 2003 Dec 4. 349(23):2211-22. [QxMD MEDLINE Link].
Rosenbloom AL, Guevara-Aguirre J, Rosenfeld RG, Francke U. Growth hormone receptor deficiency in Ecuador. J Clin Endocrinol Metab. 1999 Dec. 84(12):4436-43. [QxMD MEDLINE Link].
Laron Z, Kopchick JJ. History of Israeli cohort of Laron syndrome patients (1958-2009). Laron syndrome-from Man to Mouse. Berlin-Heidelberg: Springer-Verlag; 2011. 3-7.
Kranzler JH, Rosenbloom AL, Martinez V, Guevara-Aguirre J. Normal intelligence with severe insulin-like growth factor I deficiency due to growth hormone receptor deficiency: a controlled study in a genetically homogeneous population. J Clin Endocrinol Metab. 1998 Jun. 83(6):1953-8. [QxMD MEDLINE Link].
Nadeau K, Hwa V, Rosenfeld RG. STAT5b deficiency: an unsuspected cause of growth failure, immunodeficiency, and severe pulmonary disease. J Pediatr. 2011 May. 158(5):701-8. [QxMD MEDLINE Link].
Goncalves FT, Fridman C, Pinto EM, et al. The E180Splice mutation in the GHR gene causing Laron Syndrome: Witness of a Sephardic Jewish exodus from the Iberian Peninsula to the New World?. Am J Med Genet. 2014. Part A 9999:1-5. [QxMD MEDLINE Link].
Domene HM, Bengolea SV, Martinez AS, et al. Deficiency of the circulating insulin-like growth factor system associated with inactivation of the acid-labile subunit gene. N Engl J Med. 2004 Feb 5. 350(6):570-7. [QxMD MEDLINE Link].
Hwa V, Haeusler G, Pratt KL, et al. Total absence of functional acid labile subunit, resulting in severe insulin-like growth factor deficiency and moderate growth failure. J Clin Endocrinol Metab. 2006 May. 91(5):1826-31. [QxMD MEDLINE Link].
Domene 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 Nov. 92(11):4444-50. [QxMD MEDLINE Link].
Heath KE, Argente J, Barrios V, et al. 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 May. 93(5):1616-24. [QxMD MEDLINE Link].
van Duyvenvoorde HA, Kempers MJ, Twickler TB, et al. Homozygous and heterozygous expression of a novel mutation of the acid-labile subunit. Eur J Endocrinol. 2008 Aug. 159(2):113-20. [QxMD MEDLINE Link].
Fofanova-Gambetti OV, Hwa V, Kirsch S, et al. 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(2):100-10. [QxMD MEDLINE Link].
Fofanova-Gambetti OV, Hwa V, Wit JM, Domene HM, Argente J, Bang P. 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 Sep. 95(9):4184-91. [QxMD MEDLINE Link].
Kawashima Y, Kanzaki S, Yang F, et al. 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 Aug. 90(8):4679-87. [QxMD MEDLINE Link].
Walenkamp MJ, van der Kamp HJ, Pereira AM, et al. 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 Aug. 91(8):3062-70. [QxMD MEDLINE Link].
Inagaki K, Tiulpakov A, Rubtsov P, et al. A familial insulin-like growth factor-I receptor mutant leads to short stature: clinical and biochemical characterization. J Clin Endocrinol Metab. 2007 Apr. 92(4):1542-8. [QxMD MEDLINE Link].
Walenkamp MJ, de Muinck Keizer-Schrama SM, de Mos M, et al. 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 Jun. 93(6):2421-5. [QxMD MEDLINE Link].
Fang P, Schwartz ID, Johnson BD, et al. 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 May. 94(5):1740-7. [QxMD MEDLINE Link].
Kruis T, Klammt J, Galli-Tsinopoulou A, Wallborn T, Schlicke M, Muller E. Heterozygous mutation within a kinase-conserved motif of the insulin-like growth factor I receptor causes intrauterine and postnatal growth retardation. J Clin Endocrinol Metab. 2010 Mar. 95(3):1137-42. [QxMD MEDLINE Link].
Wallborn T, Wuller S, Klammt J, Kruis T, Kratzsch J, Schmidt G. A heterozygous mutation of the insulin-like growth factor-I receptor causes retention of the nascent protein in the endoplasmic reticulum and results in intrauterine and postnatal growth retardation. J Clin Endocrinol Metab. 2010 May. 95(5):2316-24. [QxMD MEDLINE Link].
Choi JH, Kang M, Kim GH, et al. Clinical and functional characteristics of a novel heterozygous mutation of the IGF1R gene and IGF1R haploinsufficiency due to terminal 15q26.2->qter deletion in patients with intrauterine growth retardation and postnatal catch-up growth failure. J Clin Endocrinol Metab. 2011 Jan. 96(1):E130-4. [QxMD MEDLINE Link].
Fang P, Cho YH, Derr MA, Rosenfeld RG, Hwa V, Cowell CT. Severe short stature caused by novel compound heterozygous mutations of the insulin-like growth factor 1 receptor (IGF1R). J Clin Endocrinol Metab. 2012 Feb. 97(2):E243-7. [QxMD MEDLINE Link].
Mohn A, Marcovecchio ML, de Giorgis T, Pfaeffle R, Chiarelli F, Kiess W. An insulin-like growth factor-I receptor defect associated with short stature and impaired carbohydrate homeostasis in an Italian pedigree. Horm Res Paediatr. 2011. 76(2):136-43. [QxMD MEDLINE Link].
Kawashima Y, Higaki K, Fukushima T, et al. Novel missense mutation in the IGF-I receptor L2 domain results in intrauterine and postnatal growth retardation. Clin Endocrinol (Oxf). 2012 Aug. 77(2):246-54. [QxMD MEDLINE Link].
Laron Z, Pertzelan A, Mannheimer S. Genetic pituitary dwarfism with high serum concentation of growth hormone--a new inborn error of metabolism?. Isr J Med Sci. 1966 Mar-Apr. 2(2):152-5. [QxMD MEDLINE Link].
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 Feb. 76(2):417-23. [QxMD MEDLINE Link].
Guevara-Aguirre J, Balasubramanian P, Guevara-Aguirre M, et al. Growth hormone receptor deficiency is associated with a major reduction in pro-aging signaling, cancer, and diabetes in humans. Sci Transl Med. 2011 Feb 16. 3(70):70ra13. [QxMD MEDLINE Link]. [Full Text].
Gannage-Yared MH, Klammt J, Chouery E, et al. Homozygous mutation of the IGF1 receptor gene in a patient with severe pre- and postnatal growth failure and congenital malformations. Eur J Endocrinol. 2013 Jan. 168(1):K1-7. [QxMD MEDLINE Link].
Rosenbloom AL, Guevara-Aguirre J. Lessons from the genetics of laron syndrome. Trends Endocrinol Metab. 1998 Sep. 9(7):276-83. [QxMD MEDLINE Link].
Ayling RM, Ross R, Towner P, et al. A dominant-negative mutation of the growth hormone receptor causes familial short stature. Nat Genet. 1997 May. 16(1):13-4. [QxMD MEDLINE Link].
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 Feb. 83(2):531-7. [QxMD MEDLINE Link].
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 Sep. 69(3):641-6. [QxMD MEDLINE Link]. [Full Text].
Crosnier H, Gourmelen M, Prevot 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 Jan. 76(1):248-50. [QxMD MEDLINE Link].
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 Apr. 80(4):1393-8. [QxMD MEDLINE Link].
Rosenbloom AL. Mecasermin (recombinant human insulin-like growth factor I). Adv Ther. 2009 Jan. 26(1):40-54. [QxMD MEDLINE Link].
Ekstrom K, Carlsson-Skwirut C, Ritzen EM, Bang P. Insulin-like growth factor-I and insulin-like growth factor binding protein-3 cotreatment versus insulin-like growth factor-I alone in two brothers with growth hormone insensitivity syndrome: effects on insulin sensitivity, body composition and linear growth. Horm Res Paediatr. 2011. 76(5):355-66. [QxMD MEDLINE Link].
Guevara-Aguirre J, Rosenbloom AL, Vasconez O, et al. Two-year treatment of growth hormone (GH) receptor deficiency 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 Feb. 82(2):629-33. [QxMD MEDLINE Link].
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 Feb. 10(1):68-91. [QxMD MEDLINE Link].
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(3):128-34. [QxMD MEDLINE Link].
Chernausek SD, Backeljauw PF, Frane J, Kuntze J, Underwood LE. 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 Mar. 92(3):902-10. [QxMD MEDLINE Link].
Klinger B, Laron Z. Three year IGF-I treatment of children with Laron syndrome. J Pediatr Endocrinol Metab. 1995 Jul-Sep. 8(3):149-58. [QxMD MEDLINE Link].
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 Feb. 98(2):839-45. [QxMD MEDLINE Link].
Rosenbloom AL, Rivkees SA. Off-label use of recombinant igf-I to promote growth: is it appropriate?. J Clin Endocrinol Metab. 2010 Feb. 95(2):505-8. [QxMD MEDLINE Link].
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 Feb. 28(1):20-47. [QxMD MEDLINE Link].
Perry JK, Emerald BS, Mertani HC, Lobie PE. The oncogenic potential of growth hormone. Growth Horm IGF Res. 2006 Oct-Dec. 16(5-6):277-89. [QxMD MEDLINE Link].
Guevara-Aguirre J, Rosenbloom AL, Balasubramanian P, et al. GH receptor deficiency in Ecuadorian adults is associated with obesity and enhanced insulin sensitivity. J Clin Endocrinol Metab. 2015 Jul. 100(7):2589-96. [QxMD MEDLINE Link]. [Full Text].
Rosenbloom AL. Genetic disorders of the hypothalamic-pituitary-GH/IGF-I axis. Preedy VR, ed. Handbook of Growth and Growth Monitoring in Health and Disease. New York: Springer-Verlag; 2012. 2723-41.
Forrest L, Sedmak C, Sikder S, et al. Effects of growth hormone on hepatic insulin sensitivity and glucose effectiveness in healthy older adults. Endocrine. 2019 Jan 7. [QxMD MEDLINE Link].
Boguszewski CL, Barbosa EJL, Svensson PA, Johannsson G, Glad CAM. Mechanisms in Endocrinology: Clinical and pharmacogenetic aspects of the growth hormone receptor polymorphism. Eur J Endocrinol. 2017 Dec. 177(6):R309-R321. [QxMD MEDLINE Link]. [Full Text].
Kurtoglu S, Hatipoglu N. Growth hormone insensitivity: diagnostic and therapeutic approaches. J Endocrinol Invest. 2016 Jan. 39(1):19-28. [QxMD MEDLINE Link].
Gentilin E, Minoia M, Bondanelli M, et al. Growth hormone differentially modulates chemoresistance in human endometrial adenocarcinoma cell lines. Endocrine. 2017 Jun. 56(3):621-32. [QxMD MEDLINE Link].

Media Gallery

Diagram of the hypothalamic-pituitary-GH/IGF-I axis, showing mutational targets beginning with the GH-releasing hormone receptor (GHRHR), indicated in bold and italicized.
A 50-year-old woman with GHRD (right) and her 75-year-old mother, indicating premature aging appearance. Photos were taken at the same distance, emphasizing the small size of the subject and relative foreshortening of the facies.
A 10-year-old Ecuadorian girl with GHRD/Laron syndrome, who was performing at the top of the class, with her classmates.
15 Ecuadorian children with GHRD due to homozygosity for the E180 splice mutation of the GH receptor, lined up according to descending age from 15 years to 2 years, with 3 normal children standing behind age mates. Note general but not consistent statural correlation with age, most dramatic for the 11-year-old boy, 4th from the left, and his 8-year-old brother holding the ball who is almost the same height.
A 21-year-old woman and her 23-year-old brother with GHRD/Laron syndrome demonstrating variable effects on growth of the same mutation and the correlation with low levels of IGF-I in IGFBP3. Her height is 100 cm, -11.2 SDS and his height is 134 cm, -6.3 SDS, his IGF-I level is 4 times hers, and his IGFBP3 level is twice hers.
Adult with GHRD standing with 3 of his fellow police officers, his affected brother, a visiting US physician (Dr Frank Diamond) and the seated chief.
Six-month, placebo-controlled, double-blind study of rhIGF-I in 16 Ecuadorian children with GHRD, followed by 6 months open label rhIGF-I therapy of the entire group.
Treatment with rhIGF-I for 1-2 year of children with GH insensitivity. Data are from the references noted as well as package inserts.
Four subjects with growth hormone (GH) receptor deficiency due to the E180 splice mutation on the GH receptor gene. From left to right, the first woman, age 22 years, was treated from age 4 years, when she had a height standard deviation score (SDS) of -8, to age 14 years with insulinlike growth factor-1 at a dose of 80 µg/kg body weight bid; adult height is -4.3 SDS and body fat percent is 39.8. The other 3 women were treated for 3 years with 120 µg/kg bid and are aged 30, 23, and 27 years with body fat content of 49.3%, 49%, and 54.6% and with heights of 120.7 cm, 120.8 cm, and 118.5 cm, respectively. Females with GH insufficiency who had comparable baseline characteristics and were treated with 120 µg/kg twice daily to adult height in the US trial only reached 112 cm, 121.2 cm, and 120.8 cm. These observations suggest no greater statural attainment with prolonged high-dose therapy than with short-term, high-dose treatment, consistent with the observation of disproportionate advancement of osseous maturation by the higher dose. Courtesy of The Journal of Clinical Endocrinology and Metabolism (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 98: 839–845, 2013).

of 9

Table. Features of GH Resistance Causes

Table. Features of GH Resistance Causes

Condition	Growth failure	GH	GH binding protein	IGF-I	IGFBP3
Genetic
GHRD - Recessive forms	Severe	Elevated	Absent-low*	Very low	Very low
GHRD - Dominant negative forms	Mild-moderate	Elevated	Increased	Very low	Low-normal
STAT5b mutation	Severe	Elevated	Normal	Very low	Very low
ALS mutation	None-moderate	Normal	Normal	Very low	Very low
IGF-I gene mutation	Severe	Elevated	Normal	Absent-high**	Low-normal
IGF-I receptor mutation	Mild-moderate	Normal-elevated	Normal	Normal-elevated	Normal-elevated
Acquired
GH inhibiting antibodies	Severe	Absent	Normal	Very low	Low
Malnutrition	None-mild	Elevated	Decreased	Variable	Variable
Diabetes mellitus	None-mild	Elevated	Decreased	Decreased	Increased
Renal disease	Mild-severe	Normal	Decreased	Normal	Increased
Hepatic disease	Mild-severe	Elevated	Normal-increased	Decreased	Normal
Increased in mutations of or near the transmembrane domain of the GH receptorAbsent with partial IGF1* gene deletion; very high with abnormal IGF-I

Back to List

Author

Arlan L Rosenbloom, MD Adjunct Distinguished Service Professor Emeritus of Pediatrics, University of Florida College of Medicine; Fellow of the American Academy of Pediatrics; Fellow of the American College of Epidemiology

Arlan L Rosenbloom, MD is a member of the following medical societies: American Academy of Pediatrics, American College of Epidemiology, American Pediatric Society, Endocrine Society, Pediatric Endocrine Society, Society for Pediatric Research, Florida Chapter of The American Academy of Pediatrics, Florida Pediatric Society, International Society for Pediatric and Adolescent Diabetes

Disclosure: Nothing to disclose.

Coauthor(s)

Jaime Guevara-Aguirre, MD Professor, Department of Diabetes and Endocrinology, University of San Francisco, Quito Ecuador; Founder and General Director, The Institute of Endocrinology, Metabolism and Reproduction (IEMYR), Ecuador

Jaime Guevara-Aguirre, MD is a member of the following medical societies: Endocrine Society, Pediatric Endocrine Society

Disclosure: Nothing to disclose.

Specialty Editor Board

Mary L Windle, PharmD Adjunct Associate Professor, University of Nebraska Medical Center College of Pharmacy; Editor-in-Chief, Medscape Drug Reference

Disclosure: Nothing to disclose.

George P Chrousos, MD, FAAP, MACP, MACE, FRCP(London) Professor and Chair, First Department of Pediatrics, Athens University Medical School, Aghia Sophia Children's Hospital, Greece; UNESCO Chair on Adolescent Health Care, University of Athens, Greece

George P Chrousos, MD, FAAP, MACP, MACE, FRCP(London) is a member of the following medical societies: American Academy of Pediatrics, American College of Physicians, American Pediatric Society, American Society for Clinical Investigation, Association of American Physicians, Endocrine Society, Pediatric Endocrine Society, Society for Pediatric Research, American College of Endocrinology

Disclosure: Nothing to disclose.

Chief Editor

Robert P Hoffman, MD Professor and Program Director, Department of Pediatrics, Ohio State University College of Medicine; Pediatric Endocrinologist, Division of Pediatric, Endocrinology, Diabetes, and Metabolism, Nationwide Children's Hospital

Robert P Hoffman, MD is a member of the following medical societies: American College of Pediatricians, American Diabetes Association, American Pediatric Society, Christian Medical and Dental Associations, Endocrine Society, Midwest Society for Pediatric Research, Pediatric Endocrine Society, Society for Pediatric Research

Disclosure: Nothing to disclose.

Growth Hormone Resistance Questions & Answers

References

Tables

Contributor Information and Disclosures

What would you like to print?