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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

Department of Pediatrics, Institut de Recerca, Hospital Vall d’Hebron, Centre for Biomedical Research on Rare Diseases (Centro de Investigación Biomédica en Red de Enfermedades Raras), Autonomous University, 08035, Barcelona, Spain

Address all correspondence and requests for reprints to: Antonio Carrascosa, Servicio de Pediatría, Unidad de Endocrinología, Hospital Maternoinfantil Vall d’Hebron, Paseo Vall d’Hebron 119, 08035, Barcelona, Spain. E-mail: ancarrascosa{at}vhebron.net.

	Abstract

Top Abstract Introduction Patients and Methods Results Discussion References

 
Context: In short small-for-gestational-age (SGA) patients, the exon 3-deleted(d3)/full-length (fl)-GHR polymorphism was associated with responsiveness to GH therapy (30–48 µg/kg·d); however, these results were not confirmed for higher GH doses (56–66 µg/kg·d). We hypothesized that higher doses would mask the lower dose differences.

Objective: Our objective was to evaluate, in short SGA patients, 2-yr growth response to GH therapy (32.1 ± 3.8 µg/kg·d) according to exon d3/fl-GHR genotypes.

Setting: This was a 2-yr follow-up study.

Patients: There was a total of 60 short SGA children (d3/d3 n = 8, d3/fl n = 23, and fl/fl n = 29). There were 11 children that entered puberty during the second follow-up year. Results were evaluated for all patients (group A1, n = 60, 7.7 ± 2.7 yr) and for patients who remained prepubertal (group A2, n = 49, 6.9 ± 2.2 yr).

Main Outcome Measures: Patients were followed by a single clinical team, and exon d3/fl-GHR genotypes were determined and analyzed in the same hospital.

Results: In groups A1 and A2, growth velocity significantly (P < 0.0001) increased during the first and second years of therapy, as did height SD score (SDS). These increases were similar in each exon d3/fl-GHR genotype. Total 2-yr height gain (cm, SDS) did not differ statistically among genotypes: group A1, 15.0 ± 2.0 cm and 1.15 ± 0.45 SDS in d3/d3, 16.0 ± 2.4 cm and 1.17 ± 0.51 SDS in d3/fl, 16.1 ± 2.4 cm and 1.15 ± 0.53 SDS in fl/fl; and group A2, 15.4 ± 2.0 cm and 1.03 ± 0.42 SDS in d3/d3, 15.6 ± 2.1 cm and 1.22 ± 0.51 in d3/fl, and 16.2 ± 2.6 cm and 1.21 ± 0.56 SDS in fl/fl.

Conclusions: These results did not confirm our hypothesis and show that, in short SGA children, 2-yr growth response to GH therapy 32.1 ± 3.8 µg/kg·d was similar for each exon d3/fl-GHR genotype carried, as occurred in our previous study using 66 µg/kg·d.

	Introduction

Top Abstract Introduction Patients and Methods Results Discussion References

 
In short small-for-gestational-age (SGA) children, exon 3-deleted (d3) and full-length (fl) GH receptor polymorphism was associated with growth responsiveness to 2-yr GH therapy in a study of 60 SGA patients: children with d3/d3 and d3/fl genotypes grew more than those with the fl/fl genotype (1). However, in another study including 60 SGA patients treated for 1 yr (2) and in our 2-yr controlled prospective study including 86 SGA patients (3), such differences were not confirmed. Because GH dose differed among these studies [first study 30 µg/kg·d in 35 SGA patients and 44–48 µg/kg·d in 25 SGA patients (1); second study 56 µg/kg·d (2); and our study 66 µg/kg·d (3)], we hypothesize that the higher doses used in the second and our studies would mask the exon d3/fl-GHR genotype differences observed when lower doses were used, as in the first study.

Here, we report growth response, according to the exon d3/fl-GHR polymorphism genotypes, to 2-yr GH therapy in 60 Spanish short SGA children treated with GH at a dose of 32.1 ± 3.8 µg/kg·d and followed by a single clinical team. In addition, these results were compared with those previously reported in a 2-yr controlled prospective study including 86 short SGA patients treated with 66 µg/kg·d and 84 short SGA non-GH-treated patients (3).

	Patients and Methods

Top Abstract Introduction Patients and Methods Results Discussion References

 
Patients

A total of 60 Spanish Caucasian short SGA patients (17 girls, 43 boys, mean age 7.7 ± 2.7 yr) treated with GH (32.1 ± 3.8 µg/kg·d) was included in a retrospective study to evaluate 2-yr growth response according to exon d3/fl-GHR genotypes. Patients were followed by a single clinical team at the Pediatric Endocrine Unit of the Children’s Hospital Vall d’Hebron, Barcelona, and GH therapy was started between January 2000 and March 2005. Inclusion criteria were: gestational age older than 35 wk; birth weight and/or birth length less than –2 SD (4); age older than 3 yr; prepubertal stage; height at inclusion less than –2 SD; never having been treated with GH or other anabolic agents; normal thyroid, kidney, gastrointestinal, lung, and liver functions; and normal karyotype in girls. Exclusion criteria were: neonatal brain injury, chromosomopathies, malformation syndromes, chronic diseases and steroid therapy, and height SD score (SDS) increase lower than 0.5 during the 2-yr GH therapy.

Paternal, maternal, and target heights of patients were similar and not statistically significantly different for all the patients (group A1, n = 60: –1.35 ± 1.08 SDS, –1.06 ± 0.98 SDS, and –1.20 ± 0.83 SDS, respectively; group A2, n = 49: –1.27 ± 1.12 SDS, –1.01 ± 0.99 SDS, and –1.13 ± 0.87 SDS, respectively) and for each exon d3/fl-GHR genotype in groups A1 and A2 (data not shown). GH response peaks to two provocative stimuli (insulin-induced hypoglycemia and exercise-propranolol or L-dopa) were under 10 ng/ml in 34 patients (56.66%), one under 10 ng/ml and the other over in 17 patients (28.33%), and both over 10 ng/ml in nine patients (15.00%).

Height and weight were measured 12 and 6 months before the start of GH therapy, at the start, and every 4 months thereafter. Growth velocities before the start of GH therapy (PGV) and for the two following 1-yr periods were calculated. Height and weight were transformed into SDS according to age, sex, and pubertal stage-matched control values recently reported in Spanish cross-sectional and longitudinal studies (5, 6, 7). Total height gain (first year height gain + second year height gain in SDS and in cm), body mass index (BMI), and BMI SDS were calculated. Serum IGF-I was measured, and the results are expressed as SDS according to age- and sex-matched control values (8).

Of the 60 patients, 11 entered puberty during the 6th and 12th months of the second follow-up year (testicular volume > 4 ml in boys and appearance of breast buds in girls); thus, only 49 (13 girls and 36 boys, 6.9 ± 2.2 yr) remained strictly prepubertal during the 2 follow-up years. For this reason, the results were evaluated for all patients (group A1) and for patients who remained prepubertal during the 2 follow-up years (group A2).

GH response according to GH dose and exon d3/fl-GHR genotypes

Clinical and anthropometric data of group A1 patients were compared with those previously reported by us in a 2-yr controlled prospective study including 86 patients treated with GH at 66 µg/kg·d (group B1) and 84 non-GH-treated patients (group C1) (3). Similarly, data of group A2 patients were compared with those of patients who in the previous study (3) remained prepubertal during follow-up: 68 GH treated (group B2) and 72 non-GH treated (group B2).

Exon d3/fl-GHR genotyping

The exon d3/fl-GHR genotypes were evaluated according to Pantel et al. (9) with modifications as previously reported (3, 10). When a homozygous d3/d3 genotype was detected (a single band corresponding to 532 bp) and/or when a band potentially corresponding to the 935-bp product was mildly amplified, a second PCR using only G1 and G3 primers was performed, followed by electrophoresis.

Hormone measurements

Serum GH and IGF-I were measured by commercial assays (IMMULITE; Diagnostic Products Corp., Los Angeles, CA). Reference values for IGF-I SDS calculations were those previously reported (8).

Ethics

Because this work formed part of the usual care of these patients, the study was not submitted to the Ethics Committee of Hospital Vall d’Hebron. However, written informed consent was obtained for each subject older than 12 yr, and informed parental consent was also obtained for all patients regardless of age.

Statistical analysis

Results are expressed as percentages and mean ± SD. Differences for the variables evaluated among the exon d3/fl-GHR genotypes, and between GH-treated and non-GH-treated groups were calculated using ANOVA parametric tests (Bonferroni/Dunn). Differences for exon d3/fl-GHR genotype frequencies were analyzed by the ² test. The StatView 4.5 program (Abacus Concepts, Inc., Berkeley, CA) was used.

	Results

Top Abstract Introduction Patients and Methods Results Discussion References

 
GH therapy response according to exon d3/fl-GHR genotypes

Clinical and anthropometric parameters for groups A1 (all patients, n = 60) and A2 (patients who remained prepubertal during the 2-yr study, n = 49) are shown in Table 1. In both groups, birth length and birth weight (data not shown), height SDS, PGV (cm/yr, SDS), and chronological age at the start of GH therapy did not differ statistically or when the data were analyzed according to the three different exon d3/fl-GHR genotypes. The genotype frequencies were not statistically different between groups A1 and A2.

GH therapy response according to GH dose and exon d3/fl-GHR genotypes

Mean values of birth length, birth weight, parental heights and target height (data not shown), and height SDS and PGV (cm/yr, SDS) at the start of GH therapy were not statistically different among GH patients treated with either 32.1 ± 3.8 µg/kg·d (groups A1 and A2; Table 1) or 66 µg/kg·d (groups B1 and B2) and non-GH-treated patients (groups C1 and C2) (data of groups B and C in Ref. 3 , and in Figs. 1 and 2). In addition, similar results were found when these data were analyzed according to the three different exon d3/fl-GHR genotypes (data of groups A1 and A2 in Table 1, Figs. 1 and 2, and data of groups B1, B2, C1, and C2 in Ref. 3 , and in Figs. 1 and 2). Chronological ages at the start of GH therapy were similar in groups A1, B1, and C1, and in groups A2, B2, and C2.

View larger version (23K): [in this window] [in a new window]   FIG. 1. Height SDS at the start of GH therapy and height-SDS increment at end of 2 follow-up years according to the respective exon d3/fl-GHR genotypes (d3/d3, d3/fl, and fl/fl) in short pubertal SGA children not GH treated (group C2), treated with 32.1 ± 3.8 µg/kg·d (Group A2), or with 66 µg/kg·d (Group B2). Results are expressed as mean and SD. No significant differences were observed among groups, or among exon d3/fl-GHR genotypes for height SDS at the start of GH therapy. Height-SDS increment showed significant differences (P < 0.0001) among groups C2, A2, and B2, whereas no significant differences were observed among the exon d3/fl-GHR genotypes in each group.

View larger version (24K): [in this window] [in a new window]   FIG. 2. Previous growth velocity (cm/yr) (A) and 2-yr total height gain in cm (B) according to the respective exon d3/fl-GHR genotypes (d3/d3, d3/fl, and fl/fl) in short prepubertal SGA children not GH treated (group C2), treated with 32.1 ± 3.8 µg/kg·d (Group A2), or with 66 µg/kg·d (group B2). Results are expressed as mean and SD. No significant differences were observed among groups, or exon d3/fl-GHR genotypes for previous growth velocity (cm/yr). Two-year total height gain (cm) showed significant differences (P < 0.0001) among groups C2, A2, and B2, whereas no significant differences were observed among the exon d3/fl-GHR genotypes in each group.

In patients who remained prepubertal during the 2-yr follow-up (non-GH-treated: group C2, GH treated with 32.1 ± 3.8 µg/kg·d: group A2 and GH treated with 66 µg/kg·d: group B2), Fig. 1 shows height SDS at inclusion and total height SDS increase at the end of the 2-yr follow-up according to exon d3/fl-GHR genotypes. Figure 2A shows PGV (cm/yr) and Fig. 2B total height gain (cm) according to exon d3/fl-GHR genotypes. Despite statistically significant differences among groups A2, B2, and C2 (P < 0.0001), these differences were not statistically significant among exon d3/fl-GHR genotypes in each group. Similar results were found when these data were analyzed for groups A1, B1, and C1, which include all patients (data not shown).

	Discussion

Top Abstract Introduction Patients and Methods Results Discussion References

 
In short SGA patients, responsiveness to GH therapy varies from patient to patient, and genetic differences in the GH-IGF-I axis cascade, which leads to biological effects, have been suggested (11, 12, 13, 14, 15, 16, 17, 18, 19, 20). In two cohorts of short SGA patients, Dos Santos et al. (1) recently reported significant differences in 2-yr GH therapy response according to the exon d3/fl-GHR genotype carried. The first cohort (n = 25) was treated with 44–48 µg/kg·d and the second (n = 35) with 30 µg/kg·d. Children with d3/d3 and d3/fl genotypes grew more than those with the fl/fl genotype, although results were not given only for SGA children but mixed with those of children with idiopathic short stature (51 in the first and 61 in the second cohorts). In addition, those authors showed that HEK293 cells transfected with one or two d3-GHR isoforms had an increased response to GH compared with those with two fl-GHR isoforms (1).

In our previous 2-yr controlled prospective study including 86 short SGA patients treated for 2 yr with GH at 66 µg/kg·d (3) and in the Binder et al. (2) study in 60 short SGA treated for 1 yr with GH at 52–57 µg/kg·d, the results obtained by Dos Santos et al. (1) were not confirmed, and we hypothesized (3) that, among other unknown factors, the higher doses used in the Binder et al. (2) and our studies would mask the exon d3/fl-GHR genotype differences observed when lower doses were used, as was the case in the Dos Santos et al. study (1).

The results of our present study using similar doses to those of Dos Santos et al. (1) did not confirm our hypothesis (3), suggesting that other unidentified factors may be responsible for such differences. Dos Santos et al. (1) did not evaluate the short SGA patients as a group but mixed with idiopathic short stature children, with SGA children representing 32.8 and 36.4% in the cohorts treated with 44–48 and 30 µg/kg·d, respectively. Whether this could explain the different clinical results obtained should be considered. In addition to the Dos Santos et al. study (1), two other publications also showed that after 1-yr GH therapy at 38 µg/kg·d in 53 Turner syndrome patients (2) and 33 µg/kg·d in 58 GH-deficient patients (21), the increase in height velocity was significantly greater in patients with the d3/d3-GHR genotype than in those with the fl/fl-GHR genotype. By contrast, two recent studies failed to find similar results in 54 (22) and 107 (23) GH-deficient children treated for 1 yr with 28 µg/kg·d and at replacement doses, respectively, although in the first study exon d3/fl-GHR genotypes were not described in detail (22).

Since we (3, 10) and others (24) found a certain percentage of inaccuracy in amplifying the fl-GHR allele and consequently in genotype assignment with the multiplex competitive PCR technique described by Pantel et al. (9), when a homozygous d3/d3-GHR was detected, in our study we performed a second PCR using only G1 and G3 primers; this led to a genotype reassignment to d3/fl-GHR in approximately 20% of previously d3/d3-GHR results. Because this methodology was not applied in the previous studies including short SGA patients (1, 2), we cannot exclude the fact that the different technique used in genotype assignment would contribute to the different results obtained in studies in which the number of patients carrying the d3/d3-GHR genotype is low. Moreover, the same considerations would be made for previous studies including GH-deficient, idiopathic short stature, and Turner patients (1, 2, 21, 22), and further studies in these patients are required. Additional studies evaluating the effect of long-term GH therapy on adult height, according to the exon d3/fl-GHR genotypes and the GH dose used, are also required.

In addition, other genotype differences related to growth regulation and responsiveness to GH therapy in short SGA children, including the GHR-IGF-I axis cascade (15, 16, 17, 18, 19), not evaluated in our previous (3) and present studies or in the others (1, 2, 21, 22) should also be considered in the interpretation of discordant results. In our present and previous (3) studies, only patients with height SDS increase over 0.5 were included, which suggests that main genotype anomalies of GHR-IGF-I axis could be excluded. According to this criterion, in the present study, seven patients were excluded from the initial sample of 67 patients. Of these seven patients with poor growth response to 2-yr GH therapy, two carried the d3/d3-GHR genotype, two the d3/fl-GHR genotype, and three the fl/fl- GHR genotype; these data show that poor GH responders were distributed similarly in all d3/fl-GHR genotypes. The inclusion of these seven patients in the sample did not change the results obtained for the analyzed sample of 60 patients (data not shown). Moreover, the scant number of patients carrying the d3/d3-GHR genotype included in the present and in the previously reported studies (1, 2, 3, 21, 22) should also be considered.

In the present study, patients were followed by a single clinical team, and the anthropometric data were compared with those of age, sex, and pubertal stage-matched Spanish controls obtained in recent cross-sectional and longitudinal studies (19, 20, 21). Because 11 patients entered puberty during the 6th and 12th months of the second year of follow-up, results were analyzed in two different ways: for the whole group and for those who remained prepubertal during the 2-yr follow-up. Regardless of the number of patients in each analysis, exon d3/fl-GHR genotype frequencies, anthropometric and hormonal data at inclusion and during follow-up were similar in both groups. In patients entering puberty, pubertal growth was evaluated at the start of puberty and never during the pubertal growth peak. Our comparison of anthropometric data with age, sex, and pubertal stage-matched controls allows us to express results in SDS with similar accuracy for prepubertal and pubertal patients. Moreover, when we analyzed data for the 18-month follow-up in which the 60 patients remained prepubertal, results were similar to those found for the 2-yr analysis of groups A1 and A2 (data not shown).

Prospective studies including a similar and statistically significant number of patients with each of the three exon d3/fl-GHR genotypes evaluated with the same laboratory and anthropometric methods, with similar inclusion and exclusion criteria, treated with similar GH dosage (30 and 60 µg/kg·d) and followed from infancy to adulthood, are required to ascertain whether exon d3/fl-GHR genotypes could contribute to significant clinical differences in growth response to GH therapy during prepubertal and pubertal growth and, consequently, in adult height in SGA patients.

We found that growth response to GH therapy in groups A1 and A2, and in their respective exon d3/fl-GHR genotypes, was not related to previous GH peak response to two acute stimuli (data not shown). However, this must be confirmed with a greater number of patients. We also found that growth response to GH therapy was similar in both sexes and their respective exon d3/fl-GHR genotypes (data not shown), although this has also to be confirmed with a higher number of patients.

Growth response to GH therapy according to exon d3/fl-GHR genotypes in the present study was compared with the results previously obtained by us in short SGA patients treated with a double GH dose (66 µg/k·d; n = 86) and in control short SGA non-GH-treated patients (n = 84) (3). Regardless of the number of patients in each analysis, exon d3/fl-GHR genotype frequencies, chronological age, anthropometric and hormonal data at inclusion were similar and did not differ statistically among these groups. However, growth response was higher in the GH-treated groups that received a double dose, as previously reported (11, 12, 13, 14, 20). Despite these differences in growth response according to GH dose, we found no statistically significant differences at each GH dose among the exon d3/fl-GHR genotypes, as also occurred in the spontaneous growth rate in non-GH-treated patients.

In summary, the results of the present and previous (3) 2-yr GH therapy studies show that, in short SGA children, the exon d3/fl genotype carried did not influence the spontaneous growth rate or the growth response to GH therapy, either with 32.1 ± 3.8 or 66 µg/kg·d. However, owing to the low number of patients carrying the d3/d3-GHR genotype, a bias in our results cannot be completely excluded.

	Acknowledgments

 
We thank Christine O’Hara for useful help with the English version of the manuscript.

	Footnotes

 
First Published Online October 9, 2007

This work was supported by grants from Institute of Health Carlos III, RCMN (C03/08) and FIS PI-020803 from Ministerio de Sanidad y Consumo, Madrid, Spain, and from Pfizer Spain.

Disclosure Statement: The authors have nothing to disclose.

¹ A.C., L.A. and C.E. have contributed equally to this work.

Abbreviations: BMI, Body mass index; d3, 3-deleted; fl, full-length; SDS, SD score; SGA, small-for-gestational-age.

Received May 31, 2007.

Accepted October 1, 2007.

	References

Top Abstract Introduction Patients and Methods Results Discussion References

 

1. Dos Santos C, Essioux L, Teinturier C, Tauber M, Goffin V, Bougneres P 2004 A common polymorphism of the growth hormone receptor is associated with increased responsiveness to growth hormone. Nat Genet 36:720–724[CrossRef][Medline]
2. Binder G, Baur F, Schweizer R, Ranke MB 2005 The d3-growth hormone receptor polymorphism is associated with increased responsiveness to GH in Turner Syndrome and in short small-for-gestational-age children. J Clin Endocrinol Metab 91:659–664[CrossRef][Medline]
3. Carrascosa A, Esteban C, Espadero R, Fernandez-Cancio M, Andaluz P, Clemente M, Audi L, Wollmann H, Fryklund L, Parodi L, Spanish SGA Study Group 2006 The d3/fl-growth hormone (GH) receptor polymorphism does not influence the effect of GH treatment (66 µg/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 91:3281–3286[Abstract/Free Full Text]
4. Lee PA, Chernausek SD, Hokken-Koelega AC, Czernichow P, International Small for Gestational Age Advisory Board International 2003 International Small for Gestational Age Advisory Board consensus development conference statement: management of short children born small for gestational age, April 24-October 1, 2001. Pediatrics 111:1253–1261[Abstract/Free Full Text]
5. Carrascosa A, Yeste D, Copil A, Gussinye M 2004 [Secular growth changes. Weight, height and body mass index values in infant, children, adolescent and young adults from Barcelona population]. Med Clin (Barc) 123:445–451 (Spanish)
6. Carrascosa A, Yeste D, Copil A, Almar J, Salcedo S, Gussinyé M 2004 [Anthropometric growth patterns of preterm and full-term newborns (24–42 weeks’ gestational age) at the Hospital Materno-Infantil Vall d’Hebron (Barcelona)(1997–2002]. An Pediatr (Barc) 60:406–416 (Spanish)
7. Ferrández-Longas A, Baguer L, Labarta JI, Labena C, Mayayo E, Puga B, Rueda C, Ruiz-Echarri M 2005 Longitudinal study of normal Spanish children from birth to adulthood (anthropometric, pubertal, radiological and intellectual data). Pediatr Endocrinol Rev 2(Suppl 4):423–559
8. Elmlinger MW, Kühnel W, Weber MM, Ranke MB 2004 Reference ranges for two automated chemiluminescent assays for serum insulin-like growth factor I (IGF-I) and IGF-binding protein 3 (IGFBP-3). Clin Chem Lab Med 42:654–664[CrossRef][Medline]
9. Pantel J, Machinis K, Sobrier ML, Duquesnoy P, Goossens M, Amselem S 2000 Species-specific alternative splice mimicry at the growth hormone receptor locus revealed by the lineage of retroelements during primate evolution. J Biol Chem 275:18664–18669[Abstract/Free Full Text]
10. Audí L, Esteban C, Carrascosa A, Espadero R, Perez-Arroyo A, Arjona R, Clemente M, Wollmann H, Fryklund L, Parodi LA, Spanish SGA Study Group 2006 Exon 3-deleted/full-length growth hormone receptor polymorphism genotype frequencies in Spanish short small-for-gestational-age (SGA) children and adolescents (n = 247) and in an adult control population (n = 289) show increased fl/fl in short SGA. J Clin Endocrinol Metab 91:5038–5043[Abstract/Free Full Text]
11. Coutant R, Carel JC, Letrait M, Chatelain P, Coste J, Chaussain JL 1998 Short stature associated with intrauterine growth retardation: final height of untreated and growth hormone-treated children. J Clin Endocrinol Metab 83:1070–1074[Abstract/Free Full Text]
12. Carel JC, Chatelain P, Rochiccioli P, Chaussain JL 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 88:1587–1593[Abstract/Free Full Text]
13. van Pareren Y, Mulder P, Houdijk M, Jansen M, Reeser M, Hokken-Koelega A 2003 Adult height after long-term continuous growth hormone (GH) treatment in short children born small for gestational age: results of a randomized, double-blind, dose-response GH trial. J Clin Endocrinol Metab 88:3584–3590[Abstract/Free Full Text]
14. Dahlgren J, Wikland KA, Swedish Study Group for Growth Hormone Treatment 2005 Final height in short children born small for gestational age treated with growth hormone. Pediatr Res 57:216–222[Medline]
15. Goddard AD, Covello R, Luoh SM, Clackson T, Attie KM, Gesundheit N, Rundle AC, Wells JA, Carlsson LM 1995 Mutations of the growth hormone receptor in children with idiopathic short stature. N Engl J Med 333:1093–1098[Abstract/Free Full Text]
16. Sanchez J, Perera E, Baumbach L, Cleveland W 1998 Growth hormone receptor gene mutations in children with idiopathic short stature. J Clin Endocrinol Metab 83:4079–4083[Abstract/Free Full Text]
17. Sjoberg M, Salazar T, Espinosa C, Dagnino A, Avila A, Eggers M, Cassorla F, Carvallo P, Mericq MV 2001 Study of GH sensitivity in Chilean patients with idiopathic short stature. J Clin Endocrinol Metab 86:4375–4381[Abstract/Free Full Text]
18. Abuzzahab MJ, Schneider A, Goddard A, Grigorescu F, Lautier C, Keller E, Kiess W, Klammt J, Kratzsch J, Osgood D, Pfaffle R, Raile K, Seidel B, Smith RJ, Chernausek SD; Intrauterine Growth Retardation (IUGR) Study Group 2003 IGF-I receptor mutations resulting in intrauterine and postnatal growth retardation. N Engl J Med 349:2211–2222[Abstract/Free Full Text]
19. Rosenfeld RG, Hwa V 2004 New molecular mechanisms of GH resistance. Eur J Endocirnol 151(Suppl 1):S11–S15
20. de Zegher F, Hokken-Koelega A 2005 Growth hormone therapy for children born small for gestational age: Height gain is less dose dependent over the long term than over the short term. Pediatrics 115:458–462[CrossRef]
21. Jorge AA, Marchisotti FG, Montenegro LR, Carvalho LR, Mendonca BB, Arnhold IJ 2006 Growth hormone (GH) pharmacogenetics: influence of GH receptor exon 3 retention or deletion on first-year growth hormone response and final height in patients with severe GH deficiency. J Clin Endocrinol Metab 91:1076–1080[Abstract/Free Full Text]
22. Pilotta A, Mella P, Filisetti M, Felappi B, Prandi E, Parrinello G, Notarangelo LD, Buzi F 2006 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 91:1178–1180[Abstract/Free Full Text]
23. Blum WF, Macchinis K, Shavrikova EP, Keller A, Stoble H, Phaeffle RW, Amselem S 2006 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 91:4171–4174[Abstract/Free Full Text]
24. Horan M, Newsway V, Lewis YMD, Easter TE, Rees DA, Mahto A, Millar DS, Procter AM, Scanlon MF, Wilkinson IB, Hall IP, Wheatley A, Blakey J, Bath PMW, Cockcroft JR, Krawczak M, Cooper DN 2006 Genetic variation at the growth hormone (GH1) and growth hormone receptor (GHR) loci as a risk factor for hypertension and stroke. Hum Genet 119:527–540[CrossRef][Medline]

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				M. Mercado, B. Gonzalez, C. Sandoval, Y. Esquenazi, F. Mier, G. Vargas, A. L. E. de los Monteros, and E. Sosa Clinical and Biochemical Impact of the d3 Growth Hormone Receptor Genotype in Acromegaly J. Clin. Endocrinol. Metab., September 1, 2008; 93(9): 3411 - 3415. [Abstract] [Full Text] [PDF]

				L. Audi, A. Carrascosa, C. Esteban, M. Fernandez-Cancio, P. Andaluz, D. Yeste, R. Espadero, M. L. Granada, H. Wollmann, L. Fryklund, et al. The exon 3-deleted/full-length Growth Hormone Receptor Polymorphism Does Not Influence the Effect of Puberty or Growth Hormone Therapy on Glucose Homeostasis in Short Non-Growth Hormone-Deficient Small-for-Gestational-Age Children: Results from a Two-Year Controlled Prospective Study J. Clin. Endocrinol. Metab., July 1, 2008; 93(7): 2709 - 2715. [Abstract] [Full Text] [PDF]

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