This Article Abstract Full Text (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 Sanchez, J. E. Articles by Cleveland, W. W. Search for Related Content PubMed PubMed Citation Articles by Sanchez, J. E. Articles by Cleveland, W. W.

Growth Hormone Receptor Mutations in Children with Idiopathic Short Stature¹

Department of Pediatrics, University of Miami School of Medicine, Miami, Florida 33136

Address all correspondence and requests for reprints to: Janine E. Sanchez, M.D., Mailman Center for Child Development, 1601 NW 12th Avenue, Suite 3044A, Miami, Florida 33136. E-mail: jsanche2{at}mednet.med.miami.edu

	Abstract

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Homozygous or compound heterozygous mutations in the GH receptor (GHR) gene result in GH insensitivity syndrome. Previous reports have shown that some heterozygous mutations may induce a partial insensitivity to GH, but others appear to have limited effect on growth. To investigate further these observations, we analyzed the GHR gene in 17 subjects with idiopathic short stature (ISS). All subjects had a height 2 SD or more below the mean and/or abnormal growth velocity. In addition, serum GH levels were 10 ng/mL or more and insulin-like growth factor I levels were normal or low. A novel heterozygous mutation resulting in a valine to isoleucine change (V144I) in exon 6 in the extracellular domain was found in one subject. His mother and one brother had significant short stature and also had the identical mutation. Affected family members also had a polymorphism in exon 6 of the GHR gene, which has been present in other subjects who had short stature and heterozygous mutations of the GHR gene. The other subjects with ISS had normal GHR genes. However, eight subjects had neutral polymorphisms distributed throughout the GHR locus. Accumulating evidence suggests that GHR gene mutations account for up to 5% of all ISS patients. These mutations should be considered when other causes of short stature have been eliminated.

	Introduction

Top Abstract Introduction Subjects and Methods Results Discussion References

 
The GH receptor (GHR) mediates the action of GH. Homozygous and compound heterozygous mutations of the GHR result in complete GH insensitivity syndrome (GHIS; Laron syndrome). This condition is characterized by severe short stature and a subnormal growth rate. By contrast, simple heterozygous mutations in the GHR do not have a consistent effect on linear growth. Laron et al. (1) and Woods et al. (2) reported short stature in several subjects with heterozygous mutations. However, Rosenbloom et al. found minimal or no effect on stature of heterozygous mutations of the GHR (3). Goddard and co-workers found eight patients with heterozygous mutations in the GHR gene in a group of 100 subjects with short stature (4, 5). Six unique mutations were identified in this group. Diminished GHR function due to decreased ligand binding or reduced availability of cell surface receptors was demonstrated in four of these patients (4).

Idiopathic short stature (ISS) is defined by a subnormal rate of growth and no explanation for short stature after an exhaustive evaluation. In this study, we sought to determine whether children with ISS have defects in the GHR gene that may cause partial insensitivity to GH. We detected a novel mutation (amino acid V144I) in one patient and in two members of his family who also have significant short stature. The same amino acid that is altered in this family was previously reported by Amselem et al. (6) to have a mutation in a patient with GHIS who is a compound heterozygote.

	Subjects and Methods

Top Abstract Introduction Subjects and Methods Results Discussion References

 
Subject

Candidates for study were selected from patients seen in the pediatric endocrine clinic based on the following criteria: 1) short stature (height 2 SD or more below the mean using the National Center for Health Statistics Percentiles) and/or growth velocity less than 2 SD for age, 2) normal plasma GH level (GH 10 µg/L) after provocative testing with insulin or clonidine, and 3) normal or low insulin-like growth factor I (IGF-I) levels for age. Patients with known causes of short stature (e.g. chromosomal abnormality, inflammatory bowel disease, hypopituitarism, or tumor) were excluded from the study. In a group of 100 patients, 17 patients met the criteria and were available for study (see Table 1). Informed consent was obtained from the subjects, and the investigations were approved by the university’s human research subjects committee.

IGF-I was measured by RIA [Quest Diagnostics Nichols Institute Diagnostics (San Juan Capistrano, CA)], and GH-binding protein (GHBP) was measured by ligand mediated immunofunctional assays [Genentech, Inc. (South San Francisco, CA), and Quest Diagnostics Nichols Institute Diagnostics] (7). GHBP corresponds to the extracellular domain of the GHR.

Molecular methodology

The GHR consists of an extracellular domain (exons 2–7), a single transmembrane domain (exon 8), and an intracellular domain (exons 9 and 10). PCR amplification of exons 2–10 of the GHR gene was performed (8). PCR fragments cover only the coding regions of the exons. New primers were designed for exons 8, 9, and 10 (9, 10). Exon 10 was studied in three sections (a, b, and c) due to its large size. Exon 8 primers were: forward, 5'-CCCGGGATCCACTAGTCGTAATTCTGAAAGCG-3'; and reverse, 5'-GGCCCTCGAGCTAACACAACTGGTACAGA-AGG-3'. Exon 9 primers were: forward, 5'-CCCGGGATCCTAAGCTTTTAAGATGTCAAAACC-3'; and reverse, 5'-GGCCCTCGAGTCAGGT-GTTAATTAGTACTAGC-3'. Exon 10a primers were: forward, 5'-CCCGGGATCCGCTAATTCATTTAATTATTATG-3'; and reverse, 5'-GGCTGAGCAACCTCTGAGGTACCCT-3'. Exon 10b primers were: forward, 5'-GAGACTGATTTCAATGCCAATGACA-3'; and reverse, 5'-TGGGAC-ATCCCTGCCTTATTCTTTT-3'. Exon 10c primers were: forward, 5'-ACCAGCAGGTAGTGTGGTCCTTTCC-3'; and reverse, 5'-GGCCCTCGAGTATTAAATACGTAGCTCTTGGG-3'. Exon 10a forward and 10c reverse were designed by Genentech. PCR parameters were 30-s denaturation (94 C), 30-s annealing (47 C for exon 8, 57 C for exon 9, 60 C for exon 10a, 55 C for exon 10b, and 65 C for exon 10c), and 30-s polymerization (72 C). After amplification, 5–10 µL PCR product were analyzed by electrophoresis on a 2% agarose gel with an appropriate mol wt marker to exclude large deletions or insertions. Both single chain conformational polymorphism (SSCP) and heteroduplex analysis (HdA) were used to scan for base pair mutations and small insertions or deletions.

For SSCP analysis, 1–3 µL PCR product were mixed with loading buffer, denatured at 92 C for 3 min, and placed on ice. Samples were electrophoresed at 15 C on a 1.0-mm MDE gel over a range of watt-hours depending on exon size. Bands were visualized using silver staining. HdA was performed using 5–10 µL PCR product, which were then denatured at 95 C for 3 min followed by slow cooling to 37 C for 25 min. Samples were electrophoresed at room temperature on a 0.8-mm gel at 20 V/cm using a Life Technologies MS2 sequencing apparatus (Gaithersburg, MD) and were then visualized by staining with ethidium bromide. DNA sequencing of an exon was performed if there was an abnormality on either SSCP or HdA. For sequencing, PCR fragments were purified from agarose gels with Qiaquick Gel Extraction kit (Qiagen, Chatsworth, CA). Sequencing was performed with the Exo^- Pfu Cyclist cycle sequencing kit (Stratagene, La Jolla, CA) and [³²P]deoxy-ATP incorporation. Sequencing primers were the same as those used to amplify the template. Electrophoresis was carried out on denaturing 6% Long Ranger gels (FMC Bioproducts, Rockland, ME) in 1 x TBE at 55 watts constant power. Gels were dried and subjected to autoradiography for 16–24 h.

Screening assay for V144I mutation

A screening assay for the novel GHR mutation, V144I, was designed based on the normal sequence around the mutation. A mismatched primer pair was designed to create a restriction site for enzyme Hsp92II, which recognized the mutant DNA sequence exclusively and digested the fragment at the mutation site (see Fig. 1). The PCR product was digested overnight with Hsp92II and analyzed on a 3% NuSieve 3:1 agarose gel (FMC Bioproducts). Those samples containing the mutation demonstrate two bands (102 and 124 bp), and those without the mutation show only one band (124 bp), corresponding to undigested product. This screening assay was validated using DNA from subjects who were documented to be normal or abnormal by DNA sequencing. This assay was applied to the molecular analysis of the GHR gene for the novel mutation in three adults with short stature and controls of normal height.

View larger version (22K): [in this window] [in a new window]   Figure 1. Mismatch primer formation. A mismatch primer pair creates a restriction site for enzyme Hsp92II, which recognizes the mutated DNA sequence and cuts the fragment at that site. Those samples containing the mutation demonstrate two bands, and those without the mutation (wild-type) show only one band.

	Results

Top Abstract Introduction Subjects and Methods Results Discussion References

We studied 17 children (13 males and 4 females) with ISS (see Table 1). The mean age at time of evaluation was 10.5 yr (range, 5.9–15.2 yr). The bone age, on the average, showed a delay of 2.3 yr, with a range of +0.3 to -4.9 yr. Heights ranged from 0.8–3.2 SD below the mean, with an average of 2.4 SD below the mean.

The GHR gene was normal in 16 subjects. Conformational changes were detected by SSCP and HdA in 8 of these children (see Table 2), but proved to be secondary to known polymorphisms (noncoding changes) in exons 6 and 10 (4) (Goddard, A, personal communication). One of these 8 children had a known polymorphism in both exons 6 and 10.

View larger version (58K): [in this window] [in a new window]   Figure 2. DNA sequencing of exon 6 in subject 018 and family members. Note the heterozygous base pair change (G to A) in codon 144 in the mother and brother B2, as opposed to the normal homozygous G in the father and brother B1.

View larger version (11K): [in this window] [in a new window]   Figure 3. Pedigree of subject ISS018, indicating current heights (given in SD) of the proband and family members.

The index patient is a Caucasian of Cuban origin. None of the 28 Caucasian Cuban controls evaluated using the V144I screening assay demonstrated this mutation (results not shown), nor did 3 Caucasian Cuban adults with heights less than 2 SD who were also screened for this mutation.

The GHBP levels in the two affected brothers were dissimilar, with the older brother having a level in the high normal range (653 pmol/L), and the younger brother having a level in the low normal range (105 pmol/L). Their unaffected brother had an intermediate level (222 pmol/L).

Evaluation of a GHR exon 6 polymorphism in subject 018 and his family

The patient, his mother, and his affected brother (B2) were also determined to be heterozygous (A/G) for the previously reported polymorphism in exon 6 at position G168 (3). This polymorphism is not predicted to cause an amino acid change. His father and unaffected brother (B1) were homozygous (G/G) at this locus. We screened 21 subjects from our Cuban control population with normal height (same control population screened for V144I mutation) for this polymorphism and found a range consisting of 45% A/A, 40% A/G, and 15% G/G. There was no association between the polymorphism and final height or failure to achieve target height in the controls. In addition, this polymorphism (either A/G or G/G) was more common in the controls we studied than in the 17 ISS patients we evaluated (50% of controls and 30% of ISS patients).

	Discussion

Top Abstract Introduction Subjects and Methods Results Discussion References

 
The cause of most cases of short stature remains undetermined at the genetic level. We have detected a possible cause of ISS that confirms the previous results of Goddard et al. (4), who first suggested that heterozygous GHR mutations affect receptor function and result in partial insensitivity to GH. Results from this study and from those of Goddard’s study (4, 5) suggest that these mutations may account for approximately 5% of selected ISS patients.

The significance of the V144I mutation detected in this study remains to be determined. It seems likely that this mutation affected the stature of the subjects involved. However, studies of receptor function are needed to confirm this hypothesis. Nonetheless, the potential importance of this base pair change to GH binding is suggested by findings in a previous report by Amselem et al. (6). In that study, a patient with GHIS (a compound heterozygote) had a mutant allele at the same amino acid (144) as the patient in this study. That mutation was in a different base pair (second base position of the codon as opposed to the first in our patient) and was predicted to cause a valine to aspartic acid substitution. As this change was associated with GHIS, the amino acid V144 is likely to be important for receptor function. The valine is close to the dimerization domain of the GHR. Although site-directed mutagenesis of specific residues of the GHR has been conducted, amino acid 144 has not been mutagenized to our knowledge. The closest substitution has been at amino acid 132, which resulted in an 8-fold decrease in GH binding (11). The patient described by Amselem was a compound heterozygote and also had a mutation in exon 4 of the GHR (6). It is not known whether the mutations in exons 6 and 4 were equally deleterious in this patient. The father of the patient with GHIS had significant short stature (-2.2 SD) and was heterozygous for the mutation in exon 6 and normal in exon 4 (S. Amselem, personal communication). The mother of the patient with GHIS was heterozygous for the mutation in exon 4 and normal in exon 6 and had a height of -1.3 SD (personal communication).

These data suggest that some mutations in the heterozygous state have a greater effect on stature than others. Indeed, whereas many obligate carriers of GHIS have obtained a normal height, others have not (1, 2, 3). Many other factors may influence the biological effect of a mutation on linear growth and adult height. This is underscored by a recent report of a heterozygous dominant negative mutation in the GHR gene in a family with GHIS (12). In this family, the mother’s height was not as severely affected as her children’s despite the fact that they had the identical heterozygous mutation.

Our index patient had minor bone age delay (6 months) compared to his unaffected brother B1, who had a significant delay (2.5 yr). Although they are both currently at the same SD score for height, the unaffected brother has a much better prognosis for adult height due to his delay. The unaffected father reported a history consistent with pubertal and growth delay as well and has a normal adult height (-0.5 SD). The affected mother had normal pubertal development (menses at age 11 yr), and the affected brother B2 also had only minor bone age delay (1 yr). Thus, in this family there are two different etiologies of short stature in childhood. The mother, index patient, and brother B2 have a mutation in the GHR gene, and the father and brother B1 have classic pubertal and constitutional growth delay.

Differences in the levels of GHBP in family members may also provide an explanation for differences in the effect of their genotypes. Whereas the older of the two affected brothers had levels in the high normal range, the younger affected brother’s levels were low normal. Their unaffected brother had intermediate levels. We cannot explain why there is such a wide discrepancy between the affected brothers in this study, but there was a fluctuation of more than 100 pmol/L in the GHBP level in the older affected brother on two occasions. Moreover, GHBP levels do not always correlate with GH levels or GHR function in patients with GHIS (13, 14, 15).

The polymorphism in exon 6 (G168) was present in all affected family members with the novel mutation, a finding similar to that observed in all patients with GHR mutations that were reported by Goddard et al. The polymorphism was not present in the unaffected family members in this study. The combined effect of this polymorphism and any mutation in the GHR gene is hard to assess, as there have been no reports of subjects with short stature, heterozygous GHR mutations, and no G168 polymorphism. We found the frequency of the polymorphism to be lower in the population of ISS patients than in the control subjects, in contrast to the findings of Goddard et al. (5). Hence, from our study, this particular polymorphism is not associated with short stature.

With respect to the other 16 patients with ISS in the study group without mutations in the GHR gene, the use of both SSCP and HdA increased the likelihood of detecting any exon mutations that might be present. However, neither system has complete sensitivity, and even the combination might not detect all mutations. It is possible, albeit unlikely, that one of these 16 patients has a GHR exon mutation that was not discovered by our investigations. In addition, undetected defects may be in noncoding regions of this gene or in downstream proteins.

Some investigators have treated patients with GHR defects with standard or high dose GH with variable outcomes in growth (4). With the recent successful advent of IGF-I therapy for patients with GHIS (16, 17, 18, 19, 20, 21), a logical extension of this study is IGF-I treatment for our index patient and his brother as well as others with similar GHR defects. IGF-I treatment at this time is more difficult than GH treatment and is only available on a research basis. Hence, it may be appropriate at this time to attempt GH therapy initially and only advance to IGF-I therapy if GH therapy shows poor results. Obviously, the final clinical results will depend on the degree of diminished GHR function.

Other children with ISS who have a similar clinical picture to our patient may also have GHR mutations. This etiology should be considered when other causes of short stature have been excluded.

	Acknowledgments

 
We thank Dr. Gary Berkovitz for his critical review and insightful comments, and Dr. Audrey Goddard for her helpful discussions.

	Footnotes

 
¹ This work was supported in part by Grant 96-28R from Genentech, Inc. Foundation for Growth and Development.

Received April 10, 1998.

Revised July 20, 1998.

Accepted July 28, 1998.

	References

Top Abstract Introduction Subjects and Methods Results Discussion References

 

1. Laron Z, Klinger B, Erster B, Silbergeld A. 1989 Serum GH binding protein activities identifies the heterozygous carriers for Laron type dwarfism. Endocrinologica. 121:603–608.
2. Woods KA, Dastot F, Preece MA, et al. 1997 Phenotype: genotype relationships in growth hormone insensitivity syndrome. J Clin Endocrinol Metab. 82:3529–3535.[Abstract/Free Full Text]
3. Rosenbloom AL, Guevara-Aguirre J, Rosenfeld RG, Fielder PJ. 1994 Is there heterozygote expression of growth hormone receptor deficiency? Acta Paediatr. 399(Suppl):125–127.
4. Goddard AD, Covello R, Luoh S, et al. 1995 Mutations of the growth hormone receptor in children with idiopathic short stature. N Engl J Med. 333:1093–1098.[Abstract/Free Full Text]
5. Goddard AD, Dowd P, Chernausek S, et al. 1997 Partial growth-hormone insensitivity: the role of growth-hormone receptor mutations in idiopathic short stature. J Pediatr. 131:S51–S55.
6. Amselem S, Duquesnoy P, Duriez B, et al. 1993 Spectrum of growth hormone receptor mutations and associated haplotypes in Laron syndrome. Hum Mol Genet. 2:355–359.[Abstract/Free Full Text]
7. Carlsson LMS, Rowland AM, Clark RG, Gesundheit N, Wong WLT. 1991 Ligand-mediated immunofunctional assay (LIFA) for quantification of growth hormone binding protein in human blood. J Clin Endocrinol Metab. 73:1216–1223.[Abstract]
8. Baumbach L, Schiavi A, Barlett R, et al. 1997 Clinical, biochemical and molecular investigations of a genetic isolate of growth hormone insensitivity (Laron’s syndrome). J Clin Endocrinol Metab. 82:444–451.[Abstract/Free Full Text]
9. Leung DW, Spencer SA, Cachianes G, et al. 1987 Growth hormone receptor and serum binding protein: purification, cloning, and expression. Nature. 330:537–543.[CrossRef][Medline]
10. Godowski PJ, Leung DW, Meacham LR, et al. 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]
11. Bass J, Mulkerrin M, Wells J. 1991 A systemic mutational analysis of hormone-binding determinants in the human growth hormone receptor. Proc Natl Acad Sci USA. 88:4498–4502.[Abstract/Free Full Text]
12. Iida K, Takahashi Y, Kaji H, et al. 1997 A deletion in the intracellular domain of the growth hormone (GH) receptor caused by a mutation of the splice donor site in GH insensitivity syndrome [Abstract P1–93]. Proc of the 79th Annual Meet of The Endocrine Soc. 1997; 158.
13. Rosenbloom AL, Guevara-Aguirre J, Rosenfeld RG, Fielder PJ. 1990 The little women of Loja: growth hormone receptor deficiency in an inbred population of southern Ecuador. N Engl J Med. 323:1367–1374.[Abstract]
14. Buchanan CR, Maheshwari HG, Norman MR, Morrell DJ, Preece MA. 1991 Laron-type dwarfism with apparently normal high affinity serum growth hormone-binding protein. Clin Endocrinol (Oxf). 35:179–185.[Medline]
15. Woods KA, Savage MO. 1996 Laron syndrome: typical and atypical forms. In: Ross RJM, Savage MO, eds. Growth hormone resistance. London: Balliere-Tindall; 371–388.
16. Laron Z, Anin S, Klipper-Aurbach Y, Klinger B. 1992 Effects of insulin-like growth factor on linear growth, head circumference, and body fat in patients with Laron-type dwarfism. Lancet. 339:1258–1261.[CrossRef][Medline]
17. Walker JL, Van Wyk JJ, Underwood LE. 1992 Stimulation of statural growth by recombinant insulin-like growth factor I in a child with growth hormone insensitivity syndrome. J Pediatr. 121:641–646.[CrossRef][Medline]
18. Guevara-Aguirre J, Vasconez O, Martinez V, et al. 1995 A randomized, double-bind, placebo-controlled trial on safety and efficacy of recombinant human insulin-like growth factor I in children with growth hormone receptor deficiency. J Clin Endocrinol Metab. 77:1465–1471.[Abstract]
19. Klinger B, Laron Z. 1995 Three year IGF-I treatment of children with Laron syndrome. J Pediatr Endocrinol Metab. 8:149–158.[Medline]
20. Ranke MB, Savage MO, Chatelain PG, et al. 1995 Insulin-like growth factor I improves height in growth hormone insensitivity: two year’s results. Horm Res. 44:253–264.[Medline]
21. Backeljauw PF, Underwood LE, GHIS Collaborative Group. 1996 Prolonged treatment with recombinant insulin-like growth factor I in children with growth hormone insensitivity syndrome–a clinical research center study. J Clin Endocrinol Metab. 81:3312–3317.[Abstract]

This article has been cited by other articles:

				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]

				M. O Savage, C. Camacho-Hubner, A. David, L. A Metherell, V. Hwa, R. G Rosenfeld, and A. J L Clark Idiopathic short stature: will genetics influence the choice between GH and IGF-I therapy? Eur. J. Endocrinol., August 1, 2007; 157(suppl_1): S33 - S37. [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]

				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]

				A. Pilotta, P. Mella, M. Filisetti, B. Felappi, E. Prandi, G. Parrinello, L. D. Notarangelo, and F. Buzi 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., March 1, 2006; 91(3): 1178 - 1180. [Abstract] [Full Text] [PDF]

				P. E Mullis Genetic control of growth Eur. J. Endocrinol., January 1, 2005; 152(1): 11 - 31. [Abstract] [Full Text] [PDF]

				A. A. Jorge, S. C. Souza, I. J. Arnhold, and B. B. Mendonca Poor Reproducibility of IGF-I and IGF Binding Protein-3 Generation Test in Children with Short Stature and Normal Coding Region of the GH Receptor Gene J. Clin. Endocrinol. Metab., February 1, 2002; 87(2): 469 - 472. [Abstract] [Full Text] [PDF]

				M. Sjoberg, T. Salazar, C. Espinosa, A. Dagnino, A. Avila, M. Eggers, F. Cassorla, P. Carvallo, and M. V. Mericq Study of GH Sensitivity in Chilean Patients with Idiopathic Short Stature J. Clin. Endocrinol. Metab., September 1, 2001; 86(9): 4375 - 4381. [Abstract] [Full Text] [PDF]

				M. Salerno, B. Balestrieri, E. Matrecano, A. Officioso, R. G. Rosenfeld, S. Di Maio, G. Fimiani, M. V. Ursini, and C. Pignata Abnormal GH Receptor Signaling in Children with Idiopathic Short Stature J. Clin. Endocrinol. Metab., August 1, 2001; 86(8): 3882 - 3888. [Abstract] [Full Text] [PDF]

This Article Abstract Full Text (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 Sanchez, J. E. Articles by Cleveland, W. W. Search for Related Content PubMed PubMed Citation Articles by Sanchez, J. E. Articles by Cleveland, W. W.