Download PDF
Horm Metab Res 2010; 42(3): 194-197
DOI: 10.1055/s-0029-1242744
Humans, Clinical

© Georg Thieme Verlag KG Stuttgart · New York

The Growth Hormone Receptor (GHR) Polymorphism in Growth-retarded Children with Cushing Disease: Lack of Association with Growth and Measures of the Somatotropic Axis

L. Drori-Herishanu1 , M. Lodish1 , 2 , S. Verma1 , 2 , E. Bimpaki1 , M. F. Keil2 , A. Horvath1 , C. A. Stratakis1 , 2
  • 1Section on Endocrinology & Genetics, Program on Developmental Endocrinology & Genetics (PDEGEN), National Institutes of Health (NIH), Bethesda, USA
  • 2Pediatric Endocrinology Inter-Institute Training Program (PEITP), National Institutes of Health (NIH), Bethesda, USA
Further Information

Publication History

received 02.05.2009

accepted 18.10.2009

Publication Date:
09 December 2009 (online)

Also available at
    Permissions and Reprints

Abstract

Pediatric Cushing disease (CD) often presents with short stature, but we have observed significant inter-individual variability in the growth delay caused by endogenous hypercortisolism. Glucocorticoids cause growth retardation by affecting the growth hormone (GH) – insulin-like growth factor-1 (IGF 1) somatotropic axis, but also other, GH-independent sites. Recently, the GH receptor (GHR) gene was found to have a common polymorphism (P) that leads to a deletion (d3) or retention of exon 3. In this study, we tested the hypothesis that the GH receptor polymorphism (GHR-P) maybe one of the significant variants that determines the degree of growth delay among patients with CD. GHR genotyping was performed on 56 children with newly diagnosed CD (24 females, 32 males, mean age of 12.9±3.3 years) who were followed at our institution between the years 1997–2007. Correlation analysis included genotype, measures of growth and the somatotropic axis, and anthropometrics. Within the group, 31 (12 girls, 19 boys) expressed the full length GHR allele, 10 (4 girls, 6 boys) were d3-GHR homozygotes and 15 (7 girls, 8 boys) were d3-GHR heterozygotes. No significant differences were found between the GHR genotypes and patient's height and/or growth velocity, or any other measures that we evaluated. The presence of a well-studied and common GHR polymorphism does not appear to be responsible for the variability of growth delay observed in patients with Cushing disease.

Key words

Cushing syndrome - cortisol - pituitary gland - growth hormone receptor - genetics

References

  • 1 Savage MO, Storr HL, Grossman AB, Krassas GE. Growth and growth hormone secretion in paediatric Cushing's disease.  Hormones (Athens, Greece). 2003;  2 93-97
    Google Scholar
  • 2 Voutilainen R, Leisti S, Perheentupa J. Growth in Cushing syndrome.  Eur J Pediatr. 1985;  144 141-145
    Google Scholar
  • 3 Storr HL, Chan LF, Grossman AB, Savage MO. Paediatric Cushing's syndrome: epidemiology, investigation and therapeutic advances.  Trends Endocrinol Metab. 2007;  18 167-174
    Google Scholar
  • 4 Hochberg Z. Mechanisms of steroid impairment of growth.  Horm Res. 2002;  58 ((Suppl 1)) 33-38
    Google Scholar
  • 5 Magiakou MA, Mastorakos G, Gomez MT, Rose SR, Chrousos GP. Suppressed spontaneous and stimulated growth hormone secretion in patients with Cushing's disease before and after surgical cure.  J Clin Endocrinol Metab. 1994;  78 131-137
    Google Scholar
  • 6 Lichanska AM, Waters MJ. New insights into growth hormone receptor function and clinical implications.  Horm Res. 2008;  69 138-145
    Google Scholar
  • 7 Buzi F, Mella P, Pilotta A, Prandi E, Lanfranchi F, Carapella T. Growth hormone receptor polymorphisms.  Endocr Dev. 2007;  11 28-35
    Google Scholar
  • 8 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 Gen. 2004;  36 720-724
    Google Scholar
  • 9 Binder G, Baur F, Schweizer R, Ranke MB. The d3-growth hormone (GH) receptor polymorphism is associated with increased responsiveness to GH in Turner syndrome and short small-for-gestational-age children.  J Clin Endocrinol Metab. 2006;  91 659-664
    Google Scholar
  • 10 Binder G, Trebar B, Baur F, Schweizer R, Ranke MB. Homozygosity of the d3-growth hormone receptor polymorphism is associated with a high total effect of GH on growth and a low BMI in girls with Turner syndrome.  Clin Endocrinol. 2008;  68 567-572
    Google Scholar
  • 11 Jorge AA, Marchisotti FG, Montenegro LR, Carvalho LR, Mendonca BB, Arnhold IJ. Growth hormone (GH) pharmacogenetics: influence of GH receptor exon 3 retention or deletion on first-year growth response and final height in patients with severe GH deficiency.  J Clin Endocrinol Metab. 2006;  91 1076-1080
    Google Scholar
  • 12 Pilotta A, Mella P, Filisetti M, Felappi B, Prandi E, Parrinello G, Notarangelo LD, Buzi F. Common polymorphisms of the growth hormone (GH) receptor do not correlate with the growth response to exogenous recombinant human GH in GH-deficient children.  J Clin Endocrinol Metab. 2006;  91 1178-1180
    Google Scholar
  • 13 Carrascosa A, Audi L, Esteban C, Fernandez-Cancio M, Andaluz P, Gussinye M, Clemente M, Yeste D, Albisu MA. Growth hormone (GH) dose, but not exon 3-deleted/full-length GH receptor polymorphism genotypes, influences growth response to two-year GH Therapy in Short Small-for-Gestational-Age Children.  J Clin Endocrinol Metab. 2008;  93 147-153
    Google Scholar
  • 14 Carrascosa A, Audi L, Fernandez-Cancio M, Esteban C, Andaluz P, Vilaro E, Clemente M, Yeste D, Albisu MA, Gussinye M. The exon 3-deleted/full-length growth hormone receptor polymorphism did not influence growth response to growth hormone therapy over two years in prepubertal short children born at term with adequate weight and length for gestational age.  J Clin Endocrinol Metab. 2008;  93 764-770
    Google Scholar
  • 15 Blum WF, Machinis K, Shavrikova EP, Keller A, Stobbe H, Pfaeffle RW, Amselem S. The growth response to growth hormone (GH) treatment in children with isolated GH deficiency is independent of the presence of the exon 3-minus isoform of the GH receptor.  J Clin Endocrinol Metab. 2006;  91 4171-4174
    Google Scholar
  • 16 de Graaff LC, Meyer S, Els C, Hokken-Koelega AC. GH receptor d3 polymorphism in Dutch patients with MPHD and IGHD born small or appropriate for gestational age.  Clin Endocrinol. 2008;  68 930-934
    Google Scholar
  • 17 Carrascosa A, Esteban C, Espadero R, Fernandez-Cancio M, Andaluz P, Clemente M, Audi L, Wollmann H, Fryklund L, Parodi L. The d3/fl-growth hormone (GH) receptor polymorphism does not influence the effect of GH treatment (66 microg/kg per day) or the spontaneous growth in short non-GH-deficient small-for-gestational-age children: results from a two-year controlled prospective study in 170 Spanish patients.  J Clin Endocrinol Metab. 2006;  91 3281-3286
    Google Scholar
  • 18 Raz B, Janner M, Petkovic V, Lochmatter D, Eble A, Dattani MT, Hindmarsh PC, Fluck CE, Mullis PE. Influence of growth hormone (GH) receptor deletion of exon 3 and full-length isoforms on GH response and final height in patients with severe GH deficiency.  J Clin Endocrinol Metab. 2008;  93 974-980
    Google Scholar
  • 19 Tauber M, Ester W, Auriol F, Molinas C, Fauvel J, Caliebe J, Nugent T, Fryklund L, Ranke MB, Savage MO, Clark AJ, Johnston LB, Hokken-Koelega AC. GH responsiveness in a large multinational cohort of SGA children with short stature (NESTEGG) is related to the exon 3 GHR polymorphism.  Clin Endocrinol. 2007;  67 457-461
    Google Scholar
  • 20 Toyoshima MT, Castroneves LA, Costalonga EF, Mendonca BB, Arnhold IJ, Jorge AA. Exon 3-deleted genotype of growth hormone receptor (GHRd3) positively influences IGF-1 increase at generation test in children with idiopathic short stature.  Clin Endocrinol. 2007;  67 500-504
    Google Scholar
  • 21 Jensen RB, Vielwerth S, Larsen T, Greisen G, Leffers H, Juul A. The presence of the d3-growth hormone receptor polymorphism is negatively associated with fetal growth but positively associated with postnatal growth in healthy subjects.  J Clin Endocrinol Metab. 2007;  92 2758-2763
    Google Scholar
  • 22 Schreiner F, Stutte S, Bartmann P, Gohlke B, Woelfle J. Association of the growth hormone receptor d3-variant and catch-up growth of preterm infants with birth weight of less than 1500 grams.  J Clin Endocrinol Metab. 2007;  92 4489-4493
    Google Scholar
  • 23 Mericq V, Roman R, Iniguez G, Angel B, Salazar T, Avila A, Perez-Bravo F, Cassorla F. Relationship between nocturnal growth hormone concentrations, serum IGF-I/IGFBP-3 levels, insulin sensitivity and GH receptor allelic variant in small for gestational age children.  Horm Res. 2007;  68 132-138
    Google Scholar
  • 24 Pantel J, Machinis K, Sobrier ML, Duquesnoy P, Goossens M, Amselem S. Species-specific alternative splice mimicry at the growth hormone receptor locus revealed by the lineage of retroelements during primate evolution.  J Biol Chem. 2000;  275 18664-18669
    Google Scholar
  • 25 Adetunji O, Macfarlane I, Javadpour M, Alfirevic A, Pirmohamed M, Blair J. The d3/fl-growth hormone (GH) receptor gene polymorphism does not influence quality of life and body composition in GH-deficient adults receiving GH replacement therapy.  Eur J Endocrinol. 2009;  161 541-546
    Google Scholar
  • 26 van der Klaauw AA, van der Straaten T, Baak-Pablo R, Biermasz NR, Guchelaar HJ, Pereira AM, Smit JW, Romijn JA. Influence of the d3-growth hormone (GH) receptor isoform on short-term and long-term treatment response to GH replacement in GH-deficient adults.  J Clin Endocrinol Metab. 2008;  93 2828-2834
    Google Scholar
  • 27 Schmid C, Krayenbuehl PA, Bernays RL, Zwimpfer C, Maly FE, Wiesli P. Growth hormone (GH) receptor isoform in acromegaly: lower concentrations of GH but not insulin-like growth factor-1 in patients with a genomic deletion of exon 3 in the GH receptor gene.  Clinical chemistry. 2007;  53 1484-1488
    Google Scholar
  • 28 Mercado M, Gonzalez B, Sandoval C, Esquenazi Y, Mier F, Vargas G, de los Monteros AL, Sosa E. Clinical and biochemical impact of the d3 growth hormone receptor genotype in acromegaly.  J Clin Endocrinol Metab. 2008;  93 3411-3415
    Google Scholar
  • 29 Bianchi A, Giustina A, Cimino V, Pola R, Angelini F, Pontecorvi A, De Marinis L. Influence of growth hormone receptor d3 and full-length isoforms on biochemical treatment outcomes in acromegaly.  J Clin Endocrinol Metab. 2009;  94 2015-2022
    Google Scholar
  • 30 Barbosa EJ, Palming J, Glad CA, Filipsson H, Koranyi J, Bengtsson BA, Carlsson LM, Boguszewski CL, Johannsson G. Influence of the exon 3-deleted/full-length growth hormone (GH) receptor polymorphism on the response to GH replacement therapy in adults with severe GH deficiency.  J Clin Endocrinol Metab. 2009;  94 639-644
    Google Scholar

Correspondence

C. A. StratakisMD, D(Med).Sc. 

Chief, Section on Endocrinology & Genetics (SEGEN)

Director Pediatric Endocrinology

Training Program DEB NICHD NIH

Building 10

CRC, Room 1-3330

10 Center Dr., MSC1103 Bethesda

20892 Maryland

USA

Phone: +1 301 496 4686/496 6683

Fax: +1 301 402 0574/480 0378

Email: stratakc@mail.nih.gov

      >