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RAPID COMUNICATION |
Department of Pediatrics (A.C., C.E., M.F.-C., P.A., M.C., L.A.), Hospital Vall d’Hebron, Autonomous University, 08035 Barcelona, Spain; Medical Unit (R.E.), Pfizer Spain, 28108 Madrid, Spain; WW Medical Endocrine Care (H.W.), Pfizer GmbH, 76139 Karlsruhe, Germany; WW Endocrine Care Team (L.F.), Pfizer Health AB, 191 90 Sollentuna, Sweden; and Clinical Polyomics (L.P.), Pfizer Inc., New York, New York 10017
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.
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Abstract |
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 Top Abstract IntroductionPatients and MethodsResultsDiscussionReferences |
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Objective: The objective of the study was to evaluate whether the d3/fl-GHR genotypes influence the intensity of spontaneous and/or GH therapy-stimulated growth in small-for-gestational-age (SGA) patients.
Design: This was a 2-yr prospective, controlled, randomized trial.
Setting: Thirty Spanish hospitals participated. Auxologic and GH secretion evaluation was hospital based, whereas molecular analyses and auxologic data computation were centralized.
Patients: Patients included 170 short SGA children: 140 remained prepubertal and 30 entered puberty during the second follow-up year.
Intervention: Eighty-six were treated with GH (66 µg/kg·d) for 2 yr and 84 were not treated.
Main Outcome Measures: Previous and 2-yr follow-up auxologic data were recorded at each hospital, d3/fl-GHR genotypes determined, and data analyzed for patients who remained prepubertal (group 1, 68 GH treated and 72 non-GH treated) and for all the patients (group 2).
Results: In group 1 GH-treated patients, growth velocity, and height-SD score during the first and second years, total 2-yr height gain (18.5 ± 2.4 cm in d3/d3; 18.4 ± 2.6 in d3/fl; 19.5 ± 2.3 in fl/fl), 
2-yr height increase (9.1 ± 2.4 cm in d3/d3; 9.4 ± 3.0 in d3/fl; 10.4 ± 2.1 in fl/fl), first-year growth prediction and studentized residual values (0.08 ± 1.26 in d3/d3; 0.28 ± 1.21 in d3/fl; 0.67 ± 0.95 in fl/fl) did not differ among the d3/fl-GHR genotypes. In group 1 non-GH-treated patients, neither growth velocity nor height-SD score changed significantly, and values were similar in each d3/fl-GHR genotype. Results in all patients (group 2) were similar to those in group 1.
Conclusions: In short non-GH-deficient SGA children, both spontaneous growth rate and responsiveness to 66 µg/k·d GH therapy were similar for each d3/fl-GHR genotype carried.
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Introduction |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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Recently the d3/fl-GH receptor polymorphism (d3/fl-GHR) has been associated with responsiveness to GH therapy in short SGA and idiopathic short stature (ISS) French children (15), German patients with Turner syndrome (16), and GH-deficient Brazilian children (17). However, other studies failed to find similar results in SGA German children (16) and GH-deficient Italian patients (18).
We report the results of a Spanish 2-yr controlled, prospective trial in 170 (86 GH treated and 84 non-GH treated) short SGA children analyzed according to their d3/fl-GHR genotypes.
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Patients and Methods |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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One hundred seventy Spanish prepubertal short SGA Caucasian patients (84 boys aged 8.0 ± 2.7 yr and 86 girls aged 7.4 ± 2.5 yr) were included in a 2-yr prospective and controlled trial. Thirty hospitals participated and patients were recruited from September 2001 to December 2002. Patients were assigned to treatment or not in a randomized and double-blind form at each hospital. Inclusion criteria were: gestational age greater than 35 wk; birth weight and/or birth length less than –2 SD (19); age over 3 yr; prepubertal stage; height less than – 2 SD (20); never having been treated with GH or other anabolic agents; normal thyroid, kidney, gastrointestinal, pulmonary, and liver functions; GH response peak more than 10 ng/ml; and normal karyotype in girls. Exclusion criteria were neonatal brain injury, chromosomopathies, malformation syndromes, chronic diseases, and steroid therapy.
Height and weight were measured 6–12 months before study inclusion, at inclusion, and every 4 months thereafter. Growth velocities before inclusion (PGV) and for the two consecutive 1-yr periods were calculated. Parental heights were measured in 166 patients (81 boys and 85 girls). Height and weight were transformed into SD scores (SDS) according to age-, sex-, and pubertal stage-matched control values recently reported in Spanish cross-sectional and longitudinal studies (19, 20, 21). Total height gain (first year height gain + second year height gain), increment in SDS (second year height-SDS minus inclusion height-SDS) and in centimeters (first year height gain minus PGV + second year height gain minus PGV), body mass index (BMI), BMI-SDS, and target height-SDS were calculated. Serum IGF-I and IGF binding protein (IGFBP)-3 were measured and expressed as SDS according to age- and sex-matched control values, and the IGF-I to IGFBP-3 (nanograms per milligram) ratio was calculated.
Of the 170 patients, 86 (48 boys aged 8.5 ± 2.6 yr, 38 girls aged 7.4 ± 2.9 yr) were treated with GH (66 µg/kg body weight per day) for 2 yr, and the other 84 (36 boys aged 7.5 ± 2.8 yr, 48 girls aged 7.4 ± 2.1 yr) were not treated. Eighteen GH-treated and 12 non-GH-treated patients entered puberty during the second follow-up year (testicular volume > 4 ml in boys and appearance of breast buds in girls); thus, only 68 GH-treated (39 boys aged 7.8 ± 2.3 yr, 29 girls aged 6.2 ± 2.3 yr) and 72 non-GH-treated (32 boys aged 7.0 ± 2.6 yr, 40 girls aged 6.8 ± 1.7 yr) patients remained strictly prepubertal during the 2 follow-up years. For this reason the results were evaluated in two different arms: for patients who patients remained prepubertal during the 2 follow-up years (group 1) and for all the patients (group 2).
Growth prediction
Growth prediction for the first year of therapy was calculated according to Ranke et al. (22) for the 166 patients with target height data. Residual growth and studentized residuals were calculated in only 85 GH-treated patients.
Genotyping
The d3/fl-GHR genotypes were evaluated according to Pantel et al. (23) with modifications. 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 carried out, followed by electrophoresis.
Hormone measurements
Serum GH was measured in each hospital laboratory by commercial assays. Serum IGF-I and IGFBP-3 were measured in a central laboratory by commercial RIA assays (Nichols Institute, San Juan Capistrano, CA). Reference values for IGF-I and IGFBP-3 SDS calculations were generated in the central laboratory (24).
Ethics
This work was approved by the ethics committee of each participating hospital. Written informed consent was obtained for each subject over 12 yr of age, 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 between GH-treated and non-GH-treated groups and among the d3/fl-GHR genotypes were calculated using nonparametric tests (Mann-Whitney U tests and Kruskal-Wallis test) with the Statview 4.5 program (SAS Institute, Cary, NC).
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Results |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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Similar d3/fl-GHR genotype frequencies were found in GH-treated (n = 68) and non-GH-treated (n = 72) patients. At study inclusion, chronological age, birth length, birth weight, parental heights, target height, height-SDS, PGV (centimeters per year, SDS) were not statistically different between GH-treated and non-GH-treated patients or among d3/fl-GHR genotypes (Table 1
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2-yr height increase values did not differ statistically among the d3/fl-GHR genotypes. In non-GH-treated patients, PGV did not change significantly during the first and second years of follow-up nor did height-SDS, and these values were similar in each d3/fl-GHR genotype. Total 2-yr height gain and 2-yr height increase values did not differ statistically among the d3/fl-GHR genotypes (Table 1
and Fig. 1). BMI-SDS values at inclusion and during the 2 yr of follow-up were similar and not statistically different among d3/fl-GHR genotypes (GH treated and non-GH treated) (data not shown).
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). IGF-I-SDS, IGFBP-3-SDS, and IGF-I to IGFBP-3 ratio did not differ statistically between GH-treated and non-GH-treated patients at inclusion. In the GH-treated, a significant increase (P < 0.0001) in IGF-I-SDS was observed at the first and second years (–0.68 ± 1.45, +1.16 ± 0.91, and +0.93 ± 1.12, respectively, n = 27). The same occurred for IGFBP-3-SDS (0.57 ± 1.14, 1.77 ± 0.86, and 1.71 ± 0.85, respectively, n = 27) and IGF-I to IGFBP-3 ratio (48.3 ± 24.6, 77.5 ± 22.0, and 88.3 ± 30.6, respectively). In the non-GH-treated, IGF-I-SDS, IGFBP-3-SDS, and IGF-I to IGFBP-3 ratio values at inclusion (–0.93 ± 1.21, 0.61 ± 1.03, and 45.5 ± 18.6, respectively) remained similar and did not differ statistically at the first and second follow-up years (data not shown).
Group 2: all patients
At study inclusion, no significant differences were found between GH-treated (n = 86) and non-GH-treated (n = 84) patients for chronological age (see Patients and Methods), d3/fl-GHR genotype frequencies (d3/d3: 8.9 and 10.7%; d3/fl: 43.8 and 46.4%; fl/fl: 47.2 and 42.8%, respectively) for height-SDS, PGV, birth length, birth weight, parental heights, target height, IGF-I-SDS, IGFBP-3-SDS, and IGF-I to IGFBP-3 ratio, as also occurred when data were analyzed according to d3/fl-GHR genotypes. When these data were compared with the corresponding data of group 1 patients (68 GH treated and 72 non-GH treated), no statistically significant differences were observed (Figs. 1 and 2 and data not shown).
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2-yr height increase was 9.9 ± 2.8 cm and 1.61 ± 0.84 SDS. These values did not differ among the d3/fl-GHR genotypes. The same occurred when these data were compared with the corresponding data of the 68 GH-treated patients of group 1 (Figs. 1 and 2 and data not shown).
In non-GH-treated patients, PGV (4.7 ± 0.9 cm/yr, –1.47 ± 0.94 SDS) did not change significantly during the first (5.2 ± 1.3 cm/yr, –0.59 ± 1.21 SDS) and second (5.2 ± 1.4 cm/yr, –0.64 ± 1.27 SDS) years of follow-up nor did height-SDS (–3.16 ± 0.81 at inclusion, –3.06 ± 0.75 at 1 yr and –3.11 ± 0.87 at 2 yr), and these values were similar in each d3/fl-GHR genotype. Total 2-yr height gain was 10.5 ± 2.1 cm, and 2-yr height increases were 0.9 ± 2.6 cm and 0.06 ± 0.76 SDS. These values did not differ among the d3/fl-GHR genotypes. The same occurred when these data were compared with the corresponding data of the 72 non-GH-treated patients of group 1 (Figs. 1 and 2 and data not shown).
In GH-treated patients, first-year growth prediction was similar and did not differ statistically in each d3/fl-GHR genotype. The same occurred in the non-GH-treated group when the prediction was calculated as if they were treated with the same GH dose (66 µg/kg·d). When these data were compared with the corresponding data of the 68 GH-treated and 72 non-GH-treated patients of group 1, no statistically significant differences were found (data not shown). In GH-treated patients, studentized residuals showed no statistically significant differences among the d3/fl-GHR genotypes (0.4 ± 1.2 in d3/d3, 0.2 ± 1.2 in d3/fl, and 0.6 ± 0.9 in fl/fl), and these values were similar and did not differ from those found in the 68 GH-treated patients of group 1.
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Discussion |
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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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 (6, 7, 8, 9, 22, 25). Recently in two cohorts of prepubertal short children, Dos Santos et al. (15) reported significant differences in 2-yr GH therapy responsiveness according to the d3/fl-GHR genotype borne. The first cohort (25 SGA and 51 ISS children) was treated with 44–48 µg/kg·d and the second (35 SGA and 61 ISS children) with 30 µg/kg·d. Children bearing d3/d3 and d3/fl genotypes grew more than those bearing the fl/fl genotype. In addition, those authors (15) showed in vitro that HEK293 cells transfected with the d3-GHR isoform had an increased response to GH therapy, compared with those with the full-length isoform.
Our study in 84 short SGA patients treated for 2 yr with GH at 66 µg/k·d and a previous German study in 60 short SGA treated for 1 yr with GH at 52–57 µg/k·d (16) did not confirm the results obtained by Dos Santos et al. (15), who did not evaluate the short SGA patients as a group but mixed with ISS children, with SGA children representing 32.8 and 36.4% in the cohorts treated with 45–48 and 30 µg/k·d, respectively. Whether this could explain the different clinical results obtained should be considered, and further studies on GH therapy effects in SGA and ISS children studied separately are required.
A further interesting difference between the study by Dos Santos et al. (15) and ours is the GH dose used. Whereas they used doses of 44–48 and 30 µg/kg·d, we used a higher dose (66 µg/kg·d) as did Binder et al. (16) in the German study (56 µg/kg·d). In addition to the study by Dos Santos et al., two other publications showed that after 1 yr of GH therapy at 38 µg/kg·d in 53 German Turner syndrome patients (16) and 33 µg/kg·d in 58 Brazilian GH-deficient patients (17), the increase in height velocity was significantly higher in patients bearing the d3/d3-GHR genotype than in those bearing the fl/fl-GHR genotype. By contrast, a recent Italian study failed to find similar results in 54 GH-deficient children treated with 28 µg/kg·d for 1 yr, although in that study d3/fl-GHR genotypes were not described in detail (18).
Results among d3/fl-GHR genotypes differed only in the SGA patients studied by Binder et al. (16) for the studentized residuals after combining the homozygous d3/d3 with the heterozygous d3/fl to be compared with the homozygous fl/fl. In our study, the application of a similar mathematic strategy would have yielded the opposite result, with the fl/fl patients showing a tendency toward an increased response to GH therapy, compared with the combined d3/d3 and d3/fl patients, although no statistically significant differences were found (data not shown). The possibility of the high GH doses used by Binder et al. and us in short SGA children masking the d3/fl-GHR genotype differences observed when lower GH doses are used in short SGA, ISS, Turner, and GH-deficient patients should be considered.
The increment in growth rate associated with GH administration during the 2 yr of GH therapy was 9.1 ± 2.4, 9.4 ± 3.0, and 10.4 ± 2.1 cm in d3/d3, d3/fl, and fl/fl, respectively, in our work; in the study by Dos Santos et al. (15), increases were 9.4, 9.9, and 5.2 cm in cohort 1 and 8.57, 7.58, and 4.13 in cohort 2 for the d3/d3, d3/fl, and fl/fl genotypes, respectively. It seems clear that the maximum height increase during the 2 yr of GH therapy reached by the d3/d3 genotype in the study by Dos Santos et al. (15) cohort 1 was similar to the one reached by our patients, independently of genotypes. This suggests that the maximum 2-yr height increase under GH therapy was reached by all genotypes in our work, whereas it was reached only by the best responder genotypes in the work by Dos Santos et al. (15) (the d3/d3 and/or d3/fl), and this could be related to the GH doses. Further studies in short SGA children treated with these low GH doses are required to confirm or rule out this hypothesis. Additional studies evaluating the effect on adult height of long-term GH therapy, according to the d3/fl-GHR genotype carried and the GH dose used, are also required.
In the short SGA children studied by us, PGV and height-SDS at inclusion values were similar for each d3/fl-GHR genotype in GH-treated and non-GH-treated patients. In addition, in the latter, growth velocity and total height-SDS gain during the 2 yr of follow-up were also similar for each d3/fl-GH genotype. These results show that spontaneous skeletal growth in our short SGA patients did not differ among d3/fl-GH genotypes and concur with those published previously (15, 16).
In summary, the results of our 2-yr controlled clinical trial show that in prepubertal short, non-GH-deficient, SGA children, both the spontaneous growth rate and responsiveness to 66 µg/kg·d GH therapy were similar for each d3/fl-GHR genotype carried. However, due to the low d3/d3 GHR genotype frequency, a bias in our results cannot be completely excluded.
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Acknowledgments |
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Christine O’Hara is acknowledged for useful help with the English version of the manuscript.
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Footnotes |
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First Published Online June 27, 2006
1 See Acknowledgments for members of the Spanish SGA Study Group. 
Abbreviations: BMI, Body mass index; d3/fl-GHR, exon 3-deleted full-length GH receptor; IGFBP, IGF binding protein; ISS, idiopathic short stature; PGV, previous growth velocity; SDS, SD score(s); SGA, small for gestational age.
Received March 29, 2006.
Accepted June 20, 2006.
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TopAbstractIntroductionPatients and MethodsResultsDiscussionReferences |
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