This Article Abstract Full Text (PDF) All Versions of this Article: 91/3/1076    most recent Author Manuscript (PDF) Submit a related Letter to the Editor Purchase Article View Shopping Cart Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Jorge, A. A. L. Articles by Arnhold, I. J. P. Search for Related Content PubMed PubMed Citation Articles by Jorge, A. A. L. Articles by Arnhold, I. J. P. Related Collections Neuroendocrinology and Pituitary Pediatric Endocrinology

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

Unidade de Endocrinologia do Desenvolvimento, Laboratorio de Hormonios e Genetica Molecular LIM/42, Disciplina de Endocrinologia, Hospital das Clinicas, 05403-900, São Paulo, Brazil

Address all correspondence and requests for reprints to: Alexander A. L. Jorge, M.D., Hospital das Clinicas, Laboratorio de Hormonios, Avenida Dr Eneas de Carvalho Aguiar 155 PAMB, 2 andar Bloco 6, 05403-900, São Paulo, Brazil. E-mail: alexj{at}usp.br.

	Abstract

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Context: A polymorphism in GHR gene, the presence or absence of exon 3, has been shown to influence the 1- and 2-yr growth responses to human recombinant GH (hGH) therapy in children without GH deficiency (GHD).

Objective: The objective of this study was to assess the influence of GHR-exon-3 genotype on the short and long-term response to hGH therapy in children with GHD.

Setting: The study was conducted in the university hospital.

Design and Patients: Genotype and retrospective analysis was performed on data of 75 children with GHD.

Intervention: Intervention consisted of hGH treatment at a mean dose of 33 µg/kg·d and GHR-exon-3 genotype by multiplex PCR.

Main Outcome Measures: The main outcome measures were GHR genotype: full-length (fl) and exon 3-deleted (d3) alleles, growth velocity in 58 children who remained prepubertal during the first year, and adult height in 44 patients with GHD after 7.5 ± 3.0 yr of treatment.

Results: Clinical and laboratory data at the start of treatment and hGH doses were indistinguishable among patients with different GHR-exon-3 genotypes (fl/fl vs. fl/d3 or d3/d3). Patients carrying at least one GHRd3 allele had a significantly better growth velocity in the first year of hGH replacement (12.3 ± 2.6 vs. 10.6 ± 2.3 cm/yr; P < 0.05) and achieved a taller adult height (final height SD score, –0.8 ± 1.1 vs. –1.7 ± 1.2; P < 0.05) when compared with patients homozygous for GHRfl alleles.

Conclusions: Patients with GHD who are homozygous for GHR exon 3 fl were less responsive to short- and long-term hGH therapy. Approximately half of the population is homozygous for GHRfl, and future studies adjusting hGH therapy to genotype may improve outcome.

	Introduction

Top Abstract Introduction Subjects and Methods Results Discussion References

 
GH REPLACEMENT IS standard therapy for children with short stature due to GH deficiency (GHD). The usual treatment is carried out with fixed doses of human recombinant GH (hGH) adjusted for body weight or surface (1). Several studies assessed the different variables, which can influence final height after hGH therapy in children with GHD: duration of treatment (2, 3), height SD score (SDS) at the start of treatment (2, 4), bone age delay (3), height at puberty onset (4, 5), midparental height (2), and first year of treatment growth velocity (GV) (2) were positively correlated, whereas age at the beginning of treatment (2) and maximum GH peak in stimulation tests (3) had a negative correlation. These factors explain only partially the interindividual variability in response to hGH treatment in children with GHD, implying that further parameters may be missing from current models. Study of genes encoding factors involved in GH action have not been investigated in patients with GHD.

GHR (growth hormone receptor gene, MIM*600946) is an obvious candidate gene to influence the response to hGH therapy. GH is a major determinant of postnatal growth, and GHR is responsible for the mediation of all GH actions (6). The GHR gene is located in the short arm of chromosome 5 (p13.1-p12) and includes nine coding exons and several alternatively spliced noncoding exons in the 5'-untranslated region (7). Two of the most common isoforms of GHR in humans are generated by retention (full-length GHR, GHRfl; NM_000163) or exclusion of exon 3 (exon 3-deleted GHR, GHRd3; AF210633) (8). These isoforms present a widespread distribution in humans, with the frequency of each allele ranging from 68–75% for GHRfl and 25–32% for GHRd3 (8, 9). Recently, Dos Santos et al. (9) reported that, among children with idiopathic short stature or who were born small for gestational age, patients with at least one GHRd3 allele presented better first- and second-year response to hGH therapy than patients homozygous for GHRfl.

There are no data on the effect of GHR-exon-3 genotype on final height or on the response to hGH therapy in patients with GHD. The aim of our study was to evaluate the influence of GHR-exon-3 polymorphism on the first-year growth response and final height of children with severe GHD treated with hGH.

	Subjects and Methods

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Subjects

Informed parental consent, patient assent, and approval by the Hospital Ethics Committee were obtained before initiating the studies. Seventy-five patients from a single center were diagnosed with GHD after failure of GH stimulation by both clonidine and insulin-induced hypoglycemia tests. Fifty-eight patients who remained prepubertal throughout the first year of GH therapy were chosen for the evaluation of the influence of GHR exon 3 genotype on the first year of hGH therapy. Forty-four patients with GHD who reached final height after 7.5 ± 3 yr of hGH treatment (including 27 patients analyzed for the first-year response) were selected for the assessment of the effect of genotype on final height.

Magnetic resonance imaging (MRI) of the hypothalamic-pituitary region was performed in all patients in a 1.5 Tesla unit (Signa, GE, Milwaukee, WI) (10). Patients with central nervous system tumors, meningoencephalocele, and previous radiation therapy were not included. According to the hormonal response to the combined test (insulin + TRH + GnRH), patients were classified as isolated GHD (IGHD) or combined pituitary hormone deficiency (CPHD) (10). Patients with IGHD and CPHD presented similar growth responses during hGH treatment and, therefore, were analyzed together. Patients with CPHD were on regular replacement therapy for other hormonal deficiencies.

All children were evaluated at baseline and every 3 months during hGH treatment. Evaluations were performed at the same period of day and included measurements of weight (measured with a digital scale), standing height (mean of three measurements on a stadiometer) expressed in centimeters and SDS according to British standards (11), and pubertal status graded according to Marshall and Tanner (12, 13). Body mass index (BMI) was calculated (weight/height²) and expressed as SDS. GV was determined after an observation period of at least 6 months. Target height was calculated [(father’s height + mother’s height and +13 cm for boys or –13 cm for girls)/2] and expressed as SDS. Left hand and wrist x-rays for bone age determination were assessed by two observers based on the method of Greulich and Pyle (14). Pretreatment GV is not available due to the severity of short stature in the majority of patients and the prompt GHD diagnosis; treatment was usually initiated before the minimum observation period necessary to calculate a reliable GV. hGH was administered sc at a mean dose of 33 µg/kg·d (0.1 U/kg·d) by their parents or tutors, 7 d/wk. The dose was adjusted according to changes in weight at each visit. Criteria for discontinuation of hGH treatment were GV less than 2 cm/yr observed during a minimum 6 months of follow-up. The adult height was measured an average of 2 yr after hGH withdrawal.

Hormone assays

GH was measured before and 60, 90, and 120 min after clonidine stimulation (0.1 mg/m², by mouth). Glucose and GH were measured in basal state and 15, 30, 45, 60, and 90 min after insulin injection (0.1 U/kg). GH was initially measured by an immunoradiometric (IRMA) assay and subsequently by an immunofluorometric (IFMA) method with monoclonal antibodies (AutoDELFIA; Wallac, Turku, Finland). The assays were standardized with the international standard 80/505 of the World Health Organization and levels from 0.1–38 ng/ml presented an interassay coefficient of variation less than 10%. GHD was considered when GH peaks after both clonidine and hypoglycemia stimulation tests were less than 7 µg/liter measured by IRMA or less than 3.3 µg/liter measured by IFMA (15). Basal IGF-I levels were determined by RIA after ethanol extraction (DSL, Webster, TX), and basal IGFBP-3 levels were measured by IRMA (DSL). The interassay coefficient of variation was less than 10% for IGF-I from 18–500 µg/liter and for IGFBP-3 from 0.14–12 mg/liter.

Molecular studies

Genomic DNA was isolated from peripheral blood leukocytes by standard methods from all patients. The frequency of GHR transcript variants regarding the retention (GHRfl) or exclusion (GHRd3) of exon 3 was tested in all patients and in the control group using a simple multiplex PCR assay described by Pantel et al. (8). Amplification products were analyzed by electrophoresis on a 1% agarose gel stained with ethidium bromide. The fl allele (GHRfl) is represented by a 935-bp fragment and the d3 allele (GHRd3) by a 532-bp fragment.

Statistical analysis

Qualitative variables are listed as frequencies and percentages, whereas quantitative variables are shown as mean ± SD, or median and range. GHR-d3/d3 and d3/fl patients were grouped to compare them with patients with GHR-fl/fl genotype (9).

The short-term response to hGH was evaluated by GV and gain in height SDS in the first year of treatment. The long-term response to hGH was assessed by adult height SDS and adult height SDS minus midparental height SDS. Patients were compared by genotype relative to the short- and long-term response to hGH treatment endpoints by ² or Fisher exact test, as appropriate. Patients were also divided by genotype and compared with regard to continuous parameters (e.g. age, bone age, midparental height SDS, height at start of treatment, BMI SDS, and hGH dose), as well as changes in these parameters. Comparisons were made by unpaired t test or Kruskal-Wallis test, as appropriate. To assess whether genetic variants had independent prognostic significance for outcome, we performed multiple regression analyses adjusting for the established influential factors. A P value of <0.05 was considered statistically significant. All statistical analyses were performed with SigmaStat for Windows (version 2.03; SPSS, Inc., San Rafael, CA).

	Results

Top Abstract Introduction Subjects and Methods Results Discussion References

 
First-year GV

We analyzed the growth response to hGH during the first year of treatment in 58 prepubertal children (36 boys and 22 girls) who, at the start of treatment, had a chronological age of 8.9 ± 3.8 yr, bone age of 4.6 ± 2.9 yr, and severe short stature (height SDS = –4.2 ± 1.5) with marked GHD, as shown by the median of highest GH level obtained in two different stimulation tests being 0.7 ng/ml (range, 0.1–3.8 ng/ml) and the presence of extremely low IGF-I (29 ± 30 µg/liter corresponding to –4.4 ± 1.9 SD) and IGFBP-3 (0.9 ± 0.5 mg/liter corresponding to –4.2 ± 1.8 SD). Nineteen patients presented IGHD and 39 had CPHD. Among the latter, central hypothyroidism was found in 65%; ACTH deficiency in 75%, diabetes insipidus in 13%, and in 75%, central hypogonadism was diagnosed during follow-up. Eighty-four percent of the patients had either a defined genetic molecular cause of GHD (four patients with PROP-1, three with GHRH-R, and two with GH-1 mutations) or an anatomic abnormality of the pituitary gland on MRI (interrupted stalk in 16 and ectopic posterior lobe in 24 patients) (10).

The distribution of patients among the different GHR genotypes was 47% fl/fl, 41% fl/d3, and 12% d3/d3. Children with GHR-exon-3 genotypes fl/d3 and d3/d3 were similar in relation to basal characteristics.

At the beginning of treatment, there were no significant differences between genotype groups concerning gender, isolated or combined GHD, parental height, highest GH peak, chronological age, bone age, basal height SDS, and BMI SDS (Table 1). The mean hGH dose during the first year was 31 ± 5 µg/kg·d (0.09 ± 0.01 U/kg·d) and did not differ significantly between the two groups. However, patients who carry one or two copies of GHRd3 allele presented a statistically significant better GV in the first year when compared with patients homozygous for GHRfl allele (12.3 ± 2.6 vs. 10.6 ± 2.3 cm/yr, respectively; P = 0.014) (Table 1 and Fig. 1). A 1.7 cm/yr difference in GV between the two groups was observed (95 percent confidence interval for difference of means, 0.4–2.9 cm/yr). These translated into greater gains in height SDS after the first year of treatment in relation to baseline in patients with fl/d3 and d3/d3 genotype compared with patients with fl/fl genotype (Table 1). A multiple linear regression model taking into account genotype, chronological age, bone age, midparental height SDS, and hGH dose was performed. A relationship between GV in the first year of treatment with GHR genotype (P < 0.001) was demonstrated. GHR-exon-3 genotype explained 21% of the variability in GV during the first year of hGH treatment. Other variables were not significantly related to first-year GV.

View larger version (15K): [in this window] [in a new window]   FIG. 1. Individual growth velocity of children with GHD during the first year of hGH treatment, according to GHR-exon-3 genotype. Solid and dashed lines indicate mean and ±1 SD, respectively.

Forty-four patients (25 boys and 19 girls) reached final height after 7.5 ± 3 yr of hGH treatment. At the start of treatment, the age of the patients was 11 ± 3.5 yr with markedly delayed bone age (6.1 ± 3.2 yr), severe short stature (height SDS = –4.4 ± 1.5), and 91% of them were prepubertal. Complete GHD was demonstrated by the median of the highest GH level obtained in two different stimulation tests of 0.7 ng/ml (range, 0.1–2.2 ng/ml). Ten patients presented IGHD and 34 had CPHD. Among the latter, central hypothyroidism was found in 68%; ACTH deficiency was found in 61%, central hypogonadism was found in 57%, and diabetes insipidus was found in 9%. Puberty was induced in 66% of the patients at the age of 17.8 ± 5.6 yr. Among the patients who started puberty spontaneously, the mean age was 13.9 ± 1.4 yr. Sixty-six percent of the patients had either a defined genetic molecular cause of GHD or an anatomic abnormality of the pituitary gland on MRI. After treatment was terminated, the patients were retested for GH secretion by insulin-induced hypoglycemia, at least 1 month after withdrawal of hGH treatment, and 90% of patients had their GHD status confirmed.

Among the patients with adult height, 50% presented fl/fl GHR-exon-3 genotype, 41% presented fl/d3 genotype, and 9% presented d3/d3 genotype. Patients with GHR-d3/d3 and d3/fl genotypes were combined and compared with patients with GHR-fl/fl genotype. These two groups are similar concerning gender distribution, isolated or combined GHD, spontaneous or induced puberty, age at puberty onset, parental height, highest GH peak, chronological age and bone age at the start of treatment, basal height SDS, and BMI SDS (Table 2). The weighted mean hGH dose during treatment was 35 ± 7 µg/kg·d (0.106 ± 0.02 U/kg·d) and did not differ significantly between the two groups.

View larger version (14K): [in this window] [in a new window]   FIG. 2. Individual adult height SDS in patients with GHD after long-term treatment with hGH, according to GHR-exon-3 genotype. Solid and dashed lines indicate mean and ±1 SD, respectively.

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Despite the striking development of genetic studies in the last decades, genetic factors that influence the response to hGH therapy remain mostly unknown. Recently, Dos Santos et al. (9) demonstrated that individual differences in GHR-exon-3 genotype have medically relevant effects on the growth rate in the first and second year during hGH treatment in heterogeneous groups of children with idiopathic short stature or children who were born small for gestational age.

GH ligand binding to GHR represents the first step in GHR activation. GH binding to preformed dimers of GHRs located on the cell membrane surface (16) induces a relative rotation of intracytoplasmatic subunits of the dimerized receptors, resulting in activation of Janus kinase 2 and downstream signaling pathways (17). The 22 residues codified by exon 3 are located in the extracellular domain of the GHR, but not in the GH binding interface (18). Initial experimental studies demonstrated that GHRd3 and GHRfl present similar binding capacity to GH (19). Recently, Dos Santos et al. (9) reported that cells transiently transfected with GHRd3 induce higher transcription activity in luciferase reporter assays after treatment with 22-kDa hGH than cells transfected with GHRfl. No difference in transcriptional activity between cells transfected with GHRd3 alone or together with GHRfl was observed (9), suggesting a dominant effect of GHRd3 allele. The mechanism by which the deletion of the region encoded by GHR exon 3 could increase receptor activity has not been elucidated.

It is clear that different patients, even with the same diagnosis, can present different degrees of sensitivity to GH, and this diversity can influence the outcome of hGH therapy. These interindividual differences in GH sensitivity can probably be more clearly observed in patients with severe GHD, in whom replacement with hGH completely resolves the cause of their growth impairment. It is well recognized that patients with severe GHD can benefit the most from hGH therapy (20) and that this benefit has a negative correlation with the maximum GH level during stimulation tests (21, 22). It is noteworthy that all our patients had severe GHD due to the stringent diagnostic criteria adopted in our unit (peak GH < 3.3 µg/liter by IFMA on stimulation tests). Hence, our patients comprise a homogenous severe GHD cohort, ideal to evaluate the effect of GHR-exon-3 genotype on the growth response. The severity of GHD is supported by extremely low levels of GH peak in stimulation tests (mean of 0.7 µg/liter), high percentage of patients with CPHD (72%), and high frequency of confirmation of GHD at the retest performed in adult life (90%). When patients are classified as GHD using higher arbitrary GH cut-off levels at stimulation tests, a subset of patients might have other causes for their growth impairment rather than GHD. The frequency of each GHR-exon-3 genotype in this cohort of patients with GHD was similar to those observed in other studies (8, 9).

In this study, GV during the first year of hGH treatment in 58 children with GHD who remained prepubertal were analyzed in relation to GHR-exon-3 genotype. During the first year of hGH therapy patients who carried full-length GHR in homozygous state presented lower GV than patients that were heterozygous or homozygous for d3 allele (Fig. 1), which could not be explained by pretreatment characteristics or differences in hGH dose. The same positive effect of the presence of GHRd3 allele was observed in the group of 44 patients with GHD followed until adult height. Multiple linear regression analysis, adjusting for other established influential factors, confirmed that genotype was related to adult height SDS after long-term hGH treatment. Patients homozygous for GHRfl allele reached an adult height in average 0.9 SD lower than patients who carry at least one GHRd3 allele. All these data together strongly suggests that GHR-exon-3 genotype influences the short and long-term response to hGH treatment in patients with GHD.

In conclusion, for the first time, a direct relation between genetic variability and adult height after long-term treatment with hGH was demonstrated. Patients with GHD who carry at least one GHRd3 allele had a small but statistically significant higher first-year growth response and taller final height after hGH treatment than patients who are homozygous for the GHRfl allele, treated under the same conditions. These data consolidate the influence of GHR-exon-3 genotype on response to hGH treatment and its importance in hGH pharmacogenomics. Approximately half of the population is homozygous for GHR-exon-3 full-length status and consequently have slightly lower hGH sensitivity. Further prospective studies are needed to confirm the importance of GHR-exon-3 genotype in the response to hGH therapy in children with GHD and verify whether personalization and adjustment of hGH therapy according to this genotype will improve outcome.

	Acknowledgments

 
We are indebted to Manuela G. M. Rocha for review of patient charts.

	Footnotes

 
First Published Online November 15, 2005

Abbreviations: BMI, Body mass index; CPHD, combined pituitary hormone deficiency; d3, exon 3-deleted; fl, full-length; GHD, GH deficiency; GV, growth velocity; hGH, human recombinant GH; IFMA, immunofluorometric; IGHD, isolated GHD; IRMA, immunoradiometric; MRI, magnetic resonance imaging; SDS, SD score.

This work was supported by grants from Fundacao de Amparo a Pesquisa do Estado de São Paulo (00/14092-4 and 02/09687-4 to A.A.L.J.) and from Conselho Nacional de Desenvolvimento Científico e Tecnologico (301246/1995-5 to B.B.M. and 303444/2002-9 to I.J.P.A.).

Received September 7, 2005.

Accepted November 9, 2005.

	References

Top Abstract Introduction Subjects and Methods Results Discussion References

 

1. GH Research Society 2000 Consensus guidelines for the diagnosis and treatment of growth hormone (GH) deficiency in childhood and adolescence: summary statement of the GH Research Society. J Clin Endocrinol Metab 85:3990–3993[Free Full Text]
2. Blethen SL, Baptista J, Kuntze J, Foley T, LaFranchi S, Johanson A 1997 Adult height in growth hormone (GH)-deficient children treated with biosynthetic GH. The Genentech Growth Study Group. J Clin Endocrinol Metab 82:418–420[Abstract/Free Full Text]
3. Carel JC, Ecosse E, Nicolino M, Tauber M, Leger J, Cabrol S, Bastie-Sigeac I, Chaussain JL, Coste J 2002 Adult height after long term treatment with recombinant growth hormone for idiopathic isolated growth hormone deficiency: observational follow up study of the French population based registry. BMJ 325:70
4. Hibi I, Tanaka T 1989 Final height of patients with idiopathic growth hormone deficiency after long-term growth hormone treatment. Committee for Treatment of Growth Hormone Deficient Children, Growth Science Foundation, Japan. Acta Endocrinol (Copenh) 120:409–415[Medline]
5. Bourguignon JP, Vandeweghe M, Vanderschueren-Lodeweyckx M, Malvaux P, Wolter R, Du Caju M, Ernould C 1986 Pubertal growth and final height in hypopituitary boys: a minor role of bone age at onset of puberty. J Clin Endocrinol Metab 63:376–382[Abstract]
6. Laron Z 1999 Natural history of the classical form of primary growth hormone (GH) resistance (Laron syndrome). J Pediatr Endocrinol Metab 12(Suppl 1):231–249
7. Godowski PJ, Leung DW, Meacham LR, Galgani JP, Hellmiss R, Keret R, Rotwein PS, Parks JS, Laron Z, Wood WI 1989 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 USA 86:8083–8087[Abstract/Free Full Text]
8. 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]
9. 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]
10. Osorio MG, Marui S, Jorge AA, Latronico AC, Lo LS, Leite CC, Estefan V, Mendonca BB, Arnhold IJ 2002 Pituitary magnetic resonance imaging and function in patients with growth hormone deficiency with and without mutations in GHRH-R, GH-1, or PROP-1 genes. J Clin Endocrinol Metab 87:5076–5084[Abstract/Free Full Text]
11. Tanner JM, Whitehouse RH, Takaishi M 1966 Standards from birth to maturity for height, weight, height velocity, and weight velocity: British children, 1965. I. Arch Dis Child 41:454–471[Medline]
12. Marshall WA, Tanner JM 1970 Variations in the pattern of pubertal changes in boys. Arch Dis Child 45:13–23[Medline]
13. Marshall WA, Tanner JM 1969 Variations in pattern of pubertal changes in girls. Arch Dis Child 44:291–303[Medline]
14. Greulich WW, Pyle SI 1959 Radiographic atlas of skeletal development of the hand and wrist. 2nd ed. Stanford, CA: Stanford University Press
15. Silva EG, Slhessarenko N, Arnhold IJ, Batista MC, Estefan V, Osorio MG, Marui S, Mendonca BB 2003 GH values after clonidine stimulation measured by immunofluorometric assay in normal prepubertal children and GH-deficient patients. Horm Res 59:229–233[CrossRef][Medline]
16. Gent J, Van Den Eijnden M, Van Kerkhof P, Strous GJ 2003 Dimerization and signal transduction of the growth hormone receptor. Mol Endocrinol 17:967–975[Abstract/Free Full Text]
17. Brown RJ, Adams JJ, Pelekanos RA, Wan Y, McKinstry WJ, Palethorpe K, Seeber RM, Monks TA, Eidne KA, Parker MW, Waters MJ 2005 Model for growth hormone receptor activation based on subunit rotation within a receptor dimer. Nat Struct Mol Biol 12:814–821.[CrossRef][Medline]
18. Bass SH, Mulkerrin MG, Wells JA 1991 A systematic mutational analysis of hormone-binding determinants in the human growth hormone receptor. Proc Natl Acad Sci USA 88:4498–4502[Abstract/Free Full Text]
19. Sobrier ML, Duquesnoy P, Duriez B, Amselem S, Goossens M 1993 Expression and binding properties of two isoforms of the human growth hormone receptor. FEBS Lett 319:16–20[CrossRef][Medline]
20. Radetti G, Buzi F, Cassar W, Paganini C, Stacul E, Maghnie M 2003 Growth hormone secretory pattern and response to treatment in children with short stature followed to adult height. Clin Endocrinol (Oxf) 59:27–33[Medline]
21. Ranke MB, Lindberg A, Chatelain P, Wilton P, Cutfield W, Albertsson-Wikland K, Price DA 1999 Derivation and validation of a mathematical model for predicting the response to exogenous recombinant human growth hormone (GH) in prepubertal children with idiopathic GH deficiency. KIGS International Board. Kabi Pharmacia International Growth Study. J Clin Endocrinol Metab 84:1174–1183[Abstract/Free Full Text]
22. Hanew K, Tachibana K, Yokoya S, Fujieda K, Tanaka T, Igarashi Y, Shimatsu A, Tanaka H, Tanizawa T, Teramoto A, Nishi Y, Hasegawa Y, Hizuka N, Hirano T, Fujita K 2005 Studies of very severe short stature with severe GH deficiency: from the data registered with the foundation for growth science. Endocr J 52:37–43[Medline]

This article has been cited by other articles:

				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]

				G. Kenth, J. A M. Mergelas, and C. G. Goodyer Developmental changes in the human GH receptor and its signal transduction pathways J. Endocrinol., July 1, 2008; 198(1): 71 - 82. [Abstract] [Full Text] [PDF]

				A. A. van der Klaauw, T. van der Straaten, R. Baak-Pablo, N. R. Biermasz, H.-J. Guchelaar, A. M. Pereira, J. W. A. Smit, and J. A. Romijn 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., July 1, 2008; 93(7): 2828 - 2834. [Abstract] [Full Text] [PDF]

				B. Raz, M. Janner, V. Petkovic, D. Lochmatter, A. Eble, M. T. Dattani, P. C. Hindmarsh, C. E. Fluck, and P. E. Mullis 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., March 1, 2008; 93(3): 974 - 980. [Abstract] [Full Text] [PDF]

				A. Carrascosa, L. Audi, M. Fernandez-Cancio, C. Esteban, P. Andaluz, E. Vilaro, M. Clemente, D. Yeste, M. A. Albisu, and M. Gussinye 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., March 1, 2008; 93(3): 764 - 770. [Abstract] [Full Text] [PDF]

				A. Carrascosa, L. Audi, C. Esteban, M. Fernandez-Cancio, P. Andaluz, M. Gussinye, M. Clemente, D. Yeste, and M. A. Albisu 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., January 1, 2008; 93(1): 147 - 153. [Abstract] [Full Text] [PDF]

				F. Schreiner, S. Stutte, P. Bartmann, B. Gohlke, and J. Woelfle 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., November 1, 2007; 92(11): 4489 - 4493. [Abstract] [Full Text] [PDF]

				R. G Rosenfeld Pharmacogenomics and pharmacoproteomics in the evaluation and management of short stature Eur. J. Endocrinol., August 1, 2007; 157(suppl_1): S27 - S31. [Abstract] [Full Text] [PDF]

				C. Schmid, P.-A. Krayenbuehl, R.-L. Bernays, C. Zwimpfer, F. E. Maly, and P. Wiesli 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 Clin. Chem., August 1, 2007; 53(8): 1484 - 1488. [Abstract] [Full Text] [PDF]

				R. B. Jensen, S. Vielwerth, T. Larsen, G. Greisen, H. Leffers, and A. Juul 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., July 1, 2007; 92(7): 2758 - 2763. [Abstract] [Full Text] [PDF]

				P. Saenger, P. Czernichow, I. Hughes, and E. O. Reiter Small for Gestational Age: Short Stature and Beyond Endocr. Rev., April 1, 2007; 28(2): 219 - 251. [Abstract] [Full Text] [PDF]

				G. Kenth, Z. Shao, D. E. C. Cole, and C. G. Goodyer Relationship of the Human Growth Hormone Receptor Exon 3 Genotype with Final Adult Height and Bone Mineral Density J. Clin. Endocrinol. Metab., February 1, 2007; 92(2): 725 - 728. [Abstract] [Full Text] [PDF]

				L. Audi, C. Esteban, A. Carrascosa, R. Espadero, A. Perez-Arroyo, R. Arjona, M. Clemente, H. Wollmann, L. Fryklund, L. A. Parodi, et al. 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., December 1, 2006; 91(12): 5038 - 5043. [Abstract] [Full Text] [PDF]

				R. Pfaffle Genetics of growth in the normal child Eur. J. Endocrinol., November 1, 2006; 155(suppl_1): S27 - S33. [Abstract] [Full Text] [PDF]

				W. F. Blum, K. Machinis, E. P. Shavrikova, A. Keller, H. Stobbe, R. W. Pfaeffle, and S. Amselem 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., October 1, 2006; 91(10): 4171 - 4174. [Abstract] [Full Text] [PDF]

				A. Carrascosa, C. Esteban, R. Espadero, M. Fernandez-Cancio, P. Andaluz, M. Clemente, L. Audi, H. Wollmann, L. Fryklund, L. Parodi, et al. The d3/fl-Growth Hormone (GH) Receptor Polymorphism Does Not Influence the Effect of GH Treatment (66 {micro}g/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., September 1, 2006; 91(9): 3281 - 3286. [Abstract] [Full Text] [PDF]

				D. B. Allen Growth Hormone Therapy for Short Stature: Is the Benefit Worth the Burden? Pediatrics, July 1, 2006; 118(1): 343 - 348. [Full Text] [PDF]

				R. G. Rosenfeld The Pharmacogenomics of Human Growth. J. Clin. Endocrinol. Metab., March 1, 2006; 91(3): 795 - 796. [Full Text] [PDF]

This Article Abstract Full Text (PDF) All Versions of this Article: 91/3/1076    most recent Author Manuscript (PDF) Submit a related Letter to the Editor Purchase Article View Shopping Cart Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Copyright Permission Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Jorge, A. A. L. Articles by Arnhold, I. J. P. Search for Related Content PubMed PubMed Citation Articles by Jorge, A. A. L. Articles by Arnhold, I. J. P. Related Collections Neuroendocrinology and Pituitary Pediatric Endocrinology