scholarly journals Growth Hormone (GH) Deficiency Type II: A Novel GH-1 Gene Mutation (GH-R178H) Affecting Secretion and Action

2010 ◽  
Vol 24 (1) ◽  
pp. 276-276
Author(s):  
Vibor Petkovic ◽  
Michela Godi ◽  
Amit V. Pandey ◽  
Didier Lochmatter ◽  
Charles R. Buchanan ◽  
...  
Keyword(s):  
Short Stature ◽  
Gh Deficiency ◽  
Functional Characterization ◽  
Provocation Test ◽  
Bone Age ◽  
Janus Kinase ◽  
Dominant Form ◽  
Gh Secretion ◽  
Gh Receptor ◽  
Igf I

ABSTRACT Context and Objective Main features of the autosomal dominant form of GH deficiency (IGHD II) include markedly reduced secretion of GH combined with low concentrations of IGF-I leading to short stature. Design, Setting, and Patients A female patient presented with short stature (height −6.0 sd score) and a delayed bone age of 2 yr at the chronological age of 5 yr. Later, at the age of 9 yr, GHD was confirmed by standard GH provocation test, which revealed subnormal concentrations of GH and a very low IGF-I. Genetic analysis of the GH-1 gene revealed the presence of a heterozygous R178H mutation. Interventions and Results AtT-20 cells coexpressing both wt-GH and GH-R178H showed a reduced GH secretion after forskolin stimulation compared with the cells expressing only wt-GH, supporting the diagnosis of IGHD II. Because reduced GH concentrations found in the circulation of our untreated patient could not totally explain her severe short stature, functional characterization of the GH-R178H performed by studies of GH receptor binding and activation of the Janus kinase-2/signal transducer and activator of transcription-5 pathway revealed a reduced binding affinity of GH-R178H for GH receptor and signaling compared with the wt-GH. Conclusion This is the first report of a patient suffering from short stature caused by a GH-1 gene alteration affecting not only GH secretion (IGHD II) but also GH binding and signaling, highlighting the necessity of functional analysis of any GH variant, even in the alleged situation of IGHD II.

scholarly journals Ghrelin test for the assessment of GH status in successfully treated patients with acromegaly

2006 ◽  
Vol 154 (5) ◽  
pp. 659-666 ◽  
Author(s):  
S Pekic ◽  
M Doknic ◽  
D Miljic ◽  
M Joksimovic ◽  
J Glodic ◽  
...  
Keyword(s):  
Gh Deficiency ◽  
Provocation Test ◽  
Tolerance Test ◽  
Oral Glucose ◽  
Provocative Test ◽  
Gh Secretion ◽  
Control Subjects ◽  
Igf I ◽  
Secretory Capacity ◽  
Igfbp 3

Objective: Posttreatment assessment of disease activity and definition of cure of acromegaly, using measurement of GH secretion, remains problematic. Furthermore, with our efforts to achieve tight biochemical control of the disease it is foreseeable that a proportion of patients may be rendered GH deficient, thus requiring testing for GH deficiency. The aim of our study was to evaluate residual GH secretion in cured patients with acromegaly. Design and methods: At baseline, circulating GH, IGF-I, IGFBP-3, leptin and lipid (cholesterol and tri-glycerides) levels were measured in 33 acromegalic patients nine years after treatment with surgery of whom 6 were additionally irradiated. Two tests were performed: the GH suppression test - oral glucose tolerance test (OGTT) and the GH provocation test - ghrelin test (1 μg/kg i.v. bolus) and the results were compared with 11 age- and sex-matched control subjects. Results: According to the consensus criteria (normal IGF-I levels and post-OGTT GH nadir <1 μg/l), 21 treated acromegalic patients were cured, 6 had discordant IGF-I and GH nadir values during OGTT, while 6 had persistent acromegaly. After the GH provocative test with ghrelin (cut-off for severe GH deficiency is GH <3 μg/l), we detected 9 severely GH deficient patients (GHD) among 21 cured acromegalic patients. Mean GH peak (±s.e.m.) response to the ghrelin test in GHD acromegalics was significantly lower compared with acromegalics with sufficient GH secretory capacity and control subjects (1.2 ± 0.2 μg/l vs 20.1 ± 2.4 μg/l vs 31.1 ± 2.5 μg/l respectively, P<0.0001). Mean IGF-I and IGFBP-3 levels were not different between GHD and GH-sufficient cured acromegalics. Leptin levels and body mass index (BMI) were significantly higher in GHD male acromegalics compared with GH-sufficient male acromegalics. GHD female acromegalics tended to have higher BMIs while leptin levels were not different. Conclusions: The assessment of residual GH secretory capacity by the GH provocation test is necessary in the long-term follow-up of successfully treated acromegalics since a large proportion of these patients are rendered GH deficient.

Growth Hormone Deficiency in 2 Siblings Associated with Combined GH1 Gene Polymorphisms

2012 ◽  
Vol 120 (05) ◽  
pp. 308-310 ◽  
Author(s):  
M. Yamamoto ◽  
G. Iguchi ◽  
H. Fukuoka ◽  
K. Miyako ◽  
Y. Takahashi
Keyword(s):  
Short Stature ◽  
Gene Polymorphisms ◽  
Gh Deficiency ◽  
Pedigree Analysis ◽  
Hormone Deficiency ◽  
Sequencing Analysis ◽  
Gh Secretion ◽  
Igf I ◽  
History Of

AbstractThis study was performed to clarify the pathophysiology of familial short stature with moderate GH deficiency.The siblings showed moderate GH deficiency with short stature. Pedigree analysis revealed an accumulation of the history of short stature in father’s relatives, although there was no consanguinity.We performed sequencing analysis of GH1 and GHSR gene in the siblings.We detected SNPs in the GH1 gene in the combination of the  − 278G,  − 57T, +1169T, and +2103C in one allele from the father and the  − 278T,  − 57G, +1169 A, and +2103T in the other allele from the mother in the siblings. In the previous report, the −278G and  − 57T allele are associated with low serum IGF-I levels in patients with isolated GH deficiency and the haplotype of the  − 278T,  − 57G, +1169 A, and +2103T allele exhibited an impaired GH secretion in vitro.It is suggested that these haplotypes were responsible at least in part for the GH deficiency and short stature in these siblings.

Final height of patients treated for isolated GH deficiency: examination of 83 patients

1997 ◽  
pp. 53-60 ◽  
Author(s):  
E Cacciari ◽  
A Cicognani ◽  
P Pirazzoli ◽  
S Zucchini ◽  
S Salardi ◽  
...  
Keyword(s):  
Short Stature ◽  
Gh Deficiency ◽  
Final Height ◽  
Bone Age ◽  
Untreated Group ◽  
Age At Diagnosis ◽  
Chronological Age ◽  
Target Height ◽  
Gh Secretion ◽  
Height Gain

The aim of the present study was to evaluate retrospectively the influence of various auxological and laboratory parameters on final height in a group of GH-deficient children after replacement therapy and to compare their final height with that of a group of short children with normal GH secretion and hence not treated. The final height was evaluated of 83 patients (51 males and 32 females) affected by idiopathic isolated GH deficiency and treated with recombinant human GH (hGH) for 2-7 years. Inclusion criteria at the start of treatment were short stature (mean height for chronological age in standard deviation score (SDS) -2.21) due to idiopathic isolated GH deficiency (GH peak < 8 micrograms/l after two pharmacological tests and/or mean GH concentration < 3.3 micrograms/l during the night) and treatment with recombinant hGH for at least 2 years at a dose of 15-20 U/m2 per week by s.c. injection for 6 or 7 days/ week. Mean chronological age at diagnosis was 12.2 +/- 1.7 years; 35 were prepubertal and 48 pubertal. The final height of 51 untreated short stature (mean height for chronological age in SDS -2.13 at diagnosis) subjects (42 males and 9 females: 29 prepubertal and 22 pubertal at diagnosis with mean chronological age 11.6 +/- 2.4 years) with normal GH secretion was also evaluated. In the treated subjects final height SDS was higher than that of the untreated group (-1.3 vs -1.7 SDS; P = 0.01). Both treated and untreated subjects showed a final height lower than target height, but 39% of the treated subjects vs only 20% of the untreated group (P = 0.035) had a final height greater than target height. In the treated subjects this percentage was higher in the patients improving their height for bone age in the first years of therapy. While treated females showed a positive correlation only between target and final height (P = 0.0001), in treated males final height correlated with the Bayley-Pinneau prediction at diagnosis, height for chronological age and bone age at diagnosis and target height. Patients who started therapy before puberty also showed these correlations with data calculated at the onset of puberty, together with a correlation with chronological age at the onset of puberty. When considering the influence of GH response at tests on final height, the percentage of subjects exceeding target height increased progressively according to the severity of the GH deficiency. There was no difference in height gain between the patients starting therapy before or during puberty. The height gain, however modest, obtained by our treated patients, the number of patients with final height greater than target height and the favourable comparison with the untreated short-stature subjects represent a promising result, which could be improved by personalizing treatment.

scholarly journals Evaluation of the Biological Activity of a Growth Hormone (GH) Mutant (R77C) and Its Impact on GH Responsiveness and Stature

2007 ◽  
Vol 92 (8) ◽  
pp. 2893-2901 ◽  
Author(s):  
Vibor Petkovic ◽  
Amélie Besson ◽  
Mario Thevis ◽  
Didier Lochmatter ◽  
Andrée Eblé ◽  
...  
Keyword(s):  
Short Stature ◽  
Pubertal Development ◽  
Functional Characterization ◽  
Index Patient ◽  
Janus Kinase ◽  
Gh Receptor ◽  
Significant Difference ◽  
Microscopy Analysis ◽  
Possible Cause

Abstract Context and Objective: A single missense mutation in the GH-1 gene converting codon 77 from arginine (R) to cysteine (C) yields a mutant GH-R77C peptide, which was described as natural GH antagonist. Design, Setting, and Patients: Heterozygosity for GH-R77C/wt-GH was identified in a Syrian family. The index patient, a boy, was referred for assessment of his short stature (−2.5 sd score) and partial GH insensitivity was diagnosed. His mother and grandfather were also carrying the same mutation and showed partial GH insensitivity with modest short stature. Interventions and Results: Functional characterization of the GH-R77C was performed through studies of GH receptor binding and activation of Janus kinase 2/Stat5 pathway. No differences in the binding affinity and bioactivity between wt-GH and GH-R77C were found. Similarly, cell viability and proliferation after expression of both GH peptides in AtT-20 cells were identical. Quantitative confocal microscopy analysis revealed no significant difference in the extent of subcellular colocalization between wt-GH and GH-R77C with endoplasmic reticulum, Golgi, or secretory vesicles. Furthermore studies demonstrated a reduced capability of GH-R77C to induce GHR/GHBP gene transcription rate when compared with wt-GH. Conclusion: Reduced GH receptor/GH-binding protein expression might be a possible cause for the partial GH insensitivity with delay in growth and pubertal development found in our patients. In addition, this group of patients deserves further attention because they could represent a distinct clinical entity underlining that an altered GH peptide may also have a direct impact on GHR/GHBP gene expression causing partial GH insensitivity.

scholarly journals Can exaggerated response to a GH provocative test identify patients with partial GH insensitivity syndrome?

2002 ◽  
pp. 319-323 ◽  
Author(s):  
Y Rakover ◽  
A Silbergeld ◽  
I Lavi ◽  
R Masalha ◽  
IB Shlomo
Keyword(s):  
Short Stature ◽  
Binding Protein ◽  
Standard Deviation Score ◽  
Bone Age ◽  
The Other ◽  
Provocative Test ◽  
Igf I ◽  
Parental Height ◽  
The Difference ◽  
Igfbp 3

OBJECTIVES: In the majority of children with short stature, the etiology is unknown. Mutations of the GH receptor (GHR) have been reported in a few children with apparent idiopathic short stature (ISS). These patients had low IGF-I, IGF-binding protein-3 (IGFBP-3) and GH-binding protein (GHBP), but a normal or exaggerated GH response to provocative stimuli, suggestive of partial GH insensitivity (GHI). We attempted to identify children with partial GHI syndrome, based on their response to GH provocative stimuli and other parameters of the GH-IGF-I axis. SUBJECTS AND METHODS: One hundred and sixty-four pre-pubertal children (97 boys, 67 girls) aged 7.2 (0.5-16.75) years were studied. All had short stature with height <3rd centile. The weight, bone age (BA) and body mass index (BMI) of the subjects, as well as the parents' heights and mid parental height (MPH) were assessed. Basal blood samples were taken for IGF-I, IGFBP-3 and GHBP. All subjects underwent a GH provocative test with either clonidine, arginine or insulin. The subjects were divided into three groups: (A) patients with peak GH concentration <18 mIU/l in two different provocative tests (GH deficiency - GHD, n=33); (B) patients with peak GH between 18.2 and 39.8 mIU/l (normal response, n=78); (C) patients with peak GH >40 mIU/l (exaggerated GH response, n=53). RESULTS: No significant differences were found in age, height (standard deviation score (SDS)), parental height (SDS) and the difference between chronological age and bone age (DeltaBA) between the groups. Patients with GHD were heavier (P=0.039) and had significantly higher BMI (SDS) (P=0.001) than the other groups. MPH (SDS) was lower in the group of exaggerated responders (P=0.04) compared with the other groups. No significant differences were found between the groups for the biochemical parameters when expressed nominally or in SDS, except for IGFBP-3 (SDS), which was lower in the GHD group (P=0.005). The GHBP levels were not lower in the group of exaggerated GH response to provocative stimuli. Height (SDS) correlated negatively with basal GH values in pooled data of all the subjects (r=-0.358, P<0.0001), in normal responders (r=-0.45, P<0.0001) and in the exaggerated responders (r=-0.341, P<0.0001), but not in the GHD group. CONCLUSION: Exaggerated GH response to provocative tests alone does not appear to be useful in identifying children with GHI.

scholarly journals Phenotype and Genetic Analysis of a Syndrome Caused by an Inactivating Mutation in the Growth Hormone-Releasing Hormone Receptor: Dwarfism of Sindh1

1998 ◽  
Vol 83 (11) ◽  
pp. 4065-4074
Author(s):  
Hiralal G. Maheshwari ◽  
Bernard L. Silverman ◽  
Josée Dupuis ◽  
Gerhard Baumann
Keyword(s):  
Gh Deficiency ◽  
Postnatal Growth ◽  
N Gene ◽  
Molecular Characteristics ◽  
Clinical Genetic ◽  
Gh Treatment ◽  
Gh Secretion ◽  
Absolute Requirement ◽  
Igf I ◽  
Igf Binding

We report, in detail, a new form of familial dwarfism, including its phenotypic features, hormonal profile, and molecular basis. Following a newspaper report of severe dwarfism in two villages in the province of Sindh, Pakistan, we organized an expedition to study its clinical, genetic, and molecular characteristics. We identified 18 dwarfs (15 male, 3 female), all members of a consanguineous kindred, ranging in age from newborn to 28 yr. Mean height was 7.2 sd below the norm, with mean adult heights of 130 cm for males and 113.5 cm for females. Body proportions and habitus were normal; but head circumference was 4.1 sd, and blood pressure approximately 3 sd below the norm. There was no dysmorphism, no microphallus, and no history of hypoglycemia. Serum GH did not respond to provocative stimuli (GHRH, l-dopa, or clonidine). Insulin-like growth factor I (IGF-I) and IGF-binding protein 3 were low (5.2 ± 2.0 ng/mL and 0.42 ± 0.13 μg/mL, respectively; mean ± sd) but rose normally with GH treatment. One affected, dwarfed couple had a son, demonstrating fertility in both sexes. Clinical and endocrinological evidence suggested isolated GH deficiency with a recessive inheritance pattern. The GH-N gene was found to be intact. Linkage analysis of microsatellite chromosomal markers near other candidate genes yielded a high LOD score (6.26) for the GHRH receptor (GHRH-R) locus. DNA sequencing revealed a nonsense mutation (Glu50→Stop) in the extracellular domain of the GHRH-R. This mutation predicts a severely truncated GHRH-R; it is identical to that recently reported in four patients from two other families. Inheritance is autosomal recessive (chromosome 7p) with a high degree of penetrance. Relatives heterozygous for the mutation had moderately decreased IGF-I levels and slightly blunted GH responses to GHRH and l-dopa, but they showed only minimal or no height deficit. This syndrome represents the human homologue of the little (lit/lit) mouse and closely resembles its phenotype. It demonstrates the absolute requirement of GHRH signaling for pituitary GH secretion and postnatal growth in humans, and its relatively minor (but discernible) biological importance in extrapituitary sites. The syndrome is distinct from other forms of GH deficiency with respect to microcephaly, asymptomatic hypotension, and absence of features such as facial dysplasia, significant truncal obesity, microphallus, or hypoglycemia. Its discovery raises the possibility of milder mutations in the GHRH-R gene as potential causes for partial GH insufficiency and idiopathic short stature.

scholarly journals Cut-off limits of the peak GH response to stimulation tests for the diagnosis of GH deficiency in children and adolescents: study in patients with organic GHD

2016 ◽  
Vol 175 (1) ◽  
pp. 41-47 ◽  
Author(s):  
Chiara Guzzetti ◽  
Anastasia Ibba ◽  
Sabrina Pilia ◽  
Nadia Beltrami ◽  
Natascia Di Iorgi ◽  
...  
Keyword(s):  
Diagnostic Accuracy ◽  
Children And Adolescents ◽  
Roc Analysis ◽  
Operating Characteristic ◽  
Gh Deficiency ◽  
Tolerance Test ◽  
Gh Secretion ◽  
Insulin Tolerance ◽  
Igf I ◽  
Stimulation Tests

ObjectiveThe diagnosis of GH deficiency (GHD) in children and adolescents is established when GH concentrations fail to reach an arbitrary cut-off level after at least two provocative tests. The objective of the study was to define the optimal GH cut-offs to provocative tests in children and adolescents.DesignRetrospective study in 372 subjects who underwent evaluation of GH secretion. GH and IGF-I were measured by chemiluminescence assay in all samples. Receiver operating characteristic (ROC) analysis was used to evaluate the optimal GH cut-offs and the diagnostic accuracy of provocative tests.MethodsSeventy four patients with organic GHD (GH peak <10μg/L after two provocative tests) and 298 control subjects (GH response >10μg/L to at least one test) were included in the study. The provocative tests used were arginine, insulin tolerance test (ITT) and clonidine. Diagnostic criteria based on cut-offs identified by ROC analysis (best pair of values for sensitivity and specificity) were evaluated for each test individually and for each test combined with IGF-I SDS.ResultsThe optimal GH cut-off for arginine resulted 6.5μg/L, 5.1μg/L for ITT and 6.8μg/L for clonidine. IGF-I SDS has low accuracy in diagnosing GHD (AUC=0.85). The combination of the results of provocative tests with IGF-I concentrations increased the specificity.ConclusionsThe results of the ROC analysis showed that the cut-off limits which discriminate between normal and GHD are lower than those commonly employed. IGF-I is characterized by low diagnostic accuracy.

scholarly journals Liver-Derived IGF-I Contributes to GH-Dependent Increases in Lean Mass and Bone Mineral Density in Mice with Comparable Levels of Circulating GH

2011 ◽  
Vol 25 (7) ◽  
pp. 1223-1230 ◽  
Author(s):  
Sarah M. Nordstrom ◽  
Jennifer L. Tran ◽  
Brandon C. Sos ◽  
Kay-Uwe Wagner ◽  
Ethan J. Weiss
Keyword(s):  
Bone Mineral Density ◽  
Bone Mineral ◽  
Lean Mass ◽  
Janus Kinase ◽  
Mineral Density ◽  
Gh Secretion ◽  
Igf I ◽  
And Control ◽  
Spleen Mass ◽  
Feedback Pathway

Abstract The relative contributions of circulating and locally produced IGF-I in growth remain controversial. The majority of circulating IGF-I is produced by the liver, and numerous mouse models have been developed to study the endocrine actions of IGF-I. A common drawback to these models is that the elimination of circulating IGF-I disrupts a negative feedback pathway, resulting in unregulated GH secretion. We generated a mouse with near total abrogation of circulating IGF-I by disrupting the GH signaling mediator, Janus kinase (JAK)2, in hepatocytes. We then crossed these mice, termed JAK2L, to GH-deficient little mice (Lit). Compound mutant (Lit-JAK2L) and control (Lit-Con) mice were treated with equal amounts of GH such that the only difference between the two groups was hepatic GH signaling. Both groups gained weight in response to GH but there was a reduction in the final weight of GH-treated Lit-JAK2L vs. Lit-Con mice. Similarly, lean mass increased in both groups, but there was a reduction in the final lean mass of Lit-JAK2L vs. Lit-Con mice. There was an equivalent increase in skeletal length in response to GH in Lit-Con and Lit-JAK2L mice. There was an increase in bone mineral density (BMD) in both groups, but Lit-JAK2L had lower BMD than Lit-Con mice. In addition, GH-mediated increases in spleen and kidney mass were absent in Lit-JAK2L mice. Taken together, hepatic GH-dependent production of IGF-I had a significant and nonredundant role in GH-mediated acquisition of lean mass, BMD, spleen mass, and kidney mass; however, skeletal length was dependent upon or compensated for by locally produced IGF-I.

scholarly journals Impairments to the GH-IGF-I Axis in hSOD1G93A Mice Give Insight into Possible Mechanisms of GH Dysregulation in Patients with Amyotrophic Lateral Sclerosis

Endocrinology ◽  
2012 ◽  
Vol 153 (8) ◽  
pp. 3735-3746 ◽  
Author(s):  
F. J. Steyn ◽  
S. T. Ngo ◽  
J. D. Lee ◽  
J. W. Leong ◽  
A. J. Buckley ◽  
...  
Keyword(s):  
Amyotrophic Lateral Sclerosis ◽  
Mouse Model ◽  
Transgenic Mouse ◽  
Gh Deficiency ◽  
Transgenic Mouse Model ◽  
Endocrine Function ◽  
Α Subunit ◽  
Gh Secretion ◽  
Igf I ◽  
Lateral Sclerosis

GH deficiency has been found in subjects with amyotrophic lateral sclerosis (ALS). Disrupted endocrine function could contribute to the progressive muscle loss and hypermetabolism seen in ALS. It is not possible to study all the elements of the GH-IGF-I axis in ALS patients. Consequently, it remains unclear whether dysfunctional GH secretion contributes to disease pathogenesis and why GH and IGF-I directed treatment strategies are ineffective in human ALS. The hSOD1G93A transgenic mouse model is useful for the detailed investigation of the pathogenesis of ALS. We report that symptomatic male hSOD1G93A transgenic mice exhibit a deficiency in GH secretion similar to that seen in human ALS. Further characterization of the GH-IGF-I axis in hSOD1G93A mice reveals central and peripheral abnormalities that are not found in wild-type age-matched controls. Specifically, we observe aberrant endogenous pulsatile GH secretion, reduced pituitary GH content, and decreased circulating levels of IGF-I, indicating global GH deficiency in hSOD1G93A mice. Furthermore, a reduction in the expression of the IGF-I receptor α-subunit in skeletal muscle and lumbar spinal cords of hSOD1G93A mice suggests impaired IGF-I signaling within these tissues. This is the first account of disrupted GH secretion in a transgenic mouse model of ALS. These observations are essential for the development of effective GH and IGF-I targeted therapies in ALS.

Exercise Provocation Test for Growth Hormone Secretion: Methodologic Considerations

2008 ◽  
Vol 20 (4) ◽  
pp. 370-378 ◽  
Author(s):  
Alon Eliakim ◽  
Dan Nemet
Keyword(s):  
Growth Hormone ◽  
Gh Deficiency ◽  
Current Knowledge ◽  
Hormone Secretion ◽  
Growth Hormone Secretion ◽  
Provocation Test ◽  
Pharmacological Agents ◽  
Laboratory Exercise ◽  
Gh Secretion ◽  
Artificial Nature

The diagnosis of Growth Hormone (GH) deficiency in children with short stature is complex, and in certain cases, might be very difficult. Most of the provocative tests used to evaluate GH deficiency use pharmacological agents. The artificial nature of the pharmacological tests and the possibility that these tests might not always reflect GH secretion under normal physiological conditions provides the impetus for a more physiologic test. Exercise is one of the important GH releasing physiological stimuli. This review will summarize the current knowledge on the methods for performing laboratory exercise provocation test for GH secretion in children. In addition to recommendations of more standardized exercise protocols and environmental considerations, we will also focus on GH responses to exercise in unique populations such as obese children.

Sign in / Sign up

Export Citation Format

Share Document