Growth Hormone Insensitivity Syndrome Research Articles

Long-Term Treatment of Growth Hormone Insensitivity Syndrome with IGF-I

A total of 33 patients (17 female, 16 male) with Laron syndrome (n = 31) or hGH-1 gene (n = 2, type IA deletion) from 22 centres in 12 countries were enrolled in a study conducted by Pharmacia & Upjohn, Stockholm, which was designed to test the efficacy, in terms of growth promotion and safety, of IGF-I (Igef^TM). The patients were treated with 40–120 μg/kg IGF-I s.c. twice daily after meals. After the study ended, the patients continued to be treated on an individual basis. The results of 17 patients, who were treated for 48 months or longer were available for the present analysis. Six patients were treated for up to 72 months. When treatment started, the mean age of these patients (8 female, 9 male) was 9.1 (3.7–13.5) years and mean height was –6.5 ± 1.3 SDS. At the end of the observation period, the mean age of the 17 patients was 14.2 (9.1–17.7) years and mean height was –4.9 ± 1.9 SDS. All patients showed a significant increase in growth during the final year on IGF-I, with two of them reaching the age-corresponding 3rd centile. The total gain in height (ΔHT) was 1.7 ± 1.2 SDS. ΔHT SDS correlated negatively with age at onset of treatment (R² = –0.78, p < 0.02). BMI was 0.6 ± 1.8 SDS at start of treatment and 1.8 ± 1.5 SDS at the end of observation. Total ΔHT SDS correlated positively with total ΔBMI SDS (R² = 0.59, p < 0.01). Long-term treatment of patients with GHIS thus proved to be effective in promoting growth. If treatment is started at an early age, there is considerable potential for achieving height normalisation. The treatment modalities need to be optimized with respect to the growth-promoting and metabolic effects of IFG-I.

Functional characterization of truncated growth hormone (GH) receptor-(1-277) causing partial GH insensitivity syndrome with high GH-binding protein.

We have previously reported a novel heterozygous donor splice site mutation in intron 9 of the GH receptor (GHR) gene in Japanese siblings who showed partial GH insensitivity and high serum GH-binding protein (GHBP) levels. This mutation caused the splicing abnormality and produced the truncated GHR consisting of 277 amino acids (GHR-277), which lacked most of the intracellular domain of GHR, including both boxes 1 and 2. In this study, we have characterized the function of GHR-277 expression in COS-7 and CHO cells in vitro. Scatchard analysis revealed that GHR-277 possessed approximately 1.5 times higher affinity to GH and twice the number of binding sites compared to wild-type full-length GHR (GHR-fl). The GHBP level in culture medium of GHR-277-expressing cells was approximately 3 times higher than that in GHR-fl-expressing cells. Interestingly, the ligand-induced internalization of GHR-277 was significantly reduced compared with that of GHR-fl. Moreover, in GH-induced tyrosine phosphorylation of signal transducer and activator of transcription-5 (STAT5), GHR-277 exerted a dominant negative effect when GHR-277 and GHR-fl were cotransfected. These in vitro data would well explain the clinical characteristics in our patients showing high serum GHBP levels and development of short stature despite a heterozygous mutation of the GHR gene.

Functional Characterization of Truncated Growth Hormone (GH) Receptor-(1-277) Causing Partial GH Insensitivity Syndrome with High GH-Binding Protein

Functional Characterization of Truncated Growth Hormone (GH) Receptor-(1-277) Causing Partial GH Insensitivity Syndrome with High GH-Binding Protein

Relationship between phenotype and genotype in growth hormone insensitivity syndrome.

Growth hormone insensitivity syndrome (GHIS) of genetic origin is associated with many different mutations of the growth hormone receptor (GHR) gene and a recently described genetic defect of the insulin-like growth factor I (IGF-I) gene. Phenotypic and biochemical features were examined in a cohort of 82 patients with GHIS from 23 countries. The mean age of these patients was 8.3 years, their mean height SDS was -6.09 and their median IGF-binding protein-3 (IGFBP-3) SDS was -8.5. In total, 19 of the 82 patients (23%) were growth hormone-binding protein (GHBP)-positive (> 10%). The mean heights in GHBP-negative and GHBP-positive patients were -6.45 SDS and -4.89 SDS, respectively (p < 0.001). Sixteen different GHR gene mutations were identified in 27 patients with GHIS. All of these patients had homozygous mutations, except one who had a compound heterozygous mutation. There was no relationship between the type or site within the GHR gene of the mutation and the height SDS or IGFBP-3 SDS of the patients. GHIS is associated with a wide variation in the severity of clinical and biochemical phenotypes. This variation cannot clearly be accounted for by defects in the GHR gene alone. Other genes or environmental factors must contribute to the control of growth in patients with GHIS.

Treatment of growth hormone insensitivity syndrome with insulin‐like growth factor I: relationship between growth response and severity of phenotype

Treatment of growth hormone insensitivity syndrome with insulin‐like growth factor I: relationship between growth response and severity of phenotype

Treatment of growth hormone insensitivity syndrome with insulin‐like growth factor I: long‐term results of the European multicentre study

Treatment of growth hormone insensitivity syndrome with insulin‐like growth factor I: long‐term results of the European multicentre study

An aetiological profile of short stature in the Indian subcontinent.

To determine the aetiological causes of short stature in a developing region of the world. A retrospective analysis was made of data from 193 subjects who were primarily evaluated for short stature in the Endocrinology Department, Institute of Medical Sciences, Kashmir, India. These subjects had a height of more than 3 standard deviations (SD) below the mean for their age and sex, and were seen over a decade (January 1987 to December 1996). A logical and comprehensive clinical and investigative protocol was followed to identify the aetiology of short stature. Growth hormone deficiency was the commonest identifiable cause of short stature and accounted for 22.8% of cases. Thirty-six subjects (18.7%) had a normal variant short stature. Renal tubular acidosis was diagnosed in 10.4%, primary hypothyroidism, malnutrition and hypothalamic syndrome in 7.8% each, and growth hormone insensitivity syndrome in 4.1% cases. We conclude that, in addition to growth hormone deficiency and normal variant short stature, distal renal tubular acidosis and growth hormone insensitivity syndrome are significant causes of short stature in India.

Can we escape our genetic destiny?

During 1998, progress has been made in the identification of specific genes that are responsible for, or predispose to, endocrine disorders. Several genetic abnormalities of the thyroid have been described, such as two new mutations in exon 10 of the thyrotropin-receptor gene, resulting in a clinical picture of thyroid hypoplasia and congenital hypothyroidism as well as germ-line neo-mutations in the extracellular portion of the thyrotropin receptor, leading to an opposite clinical picture of severe congenital hyperthyroidism. In addition to previously disovered mutations, new mutations in the PIT-I and the PROP-I gene, responsible for combined pituitary hormone deficiency, have been reported. In patients with septo-optic dysplasia a mutation in the homeobox gene HESXI/Hesxl was found, indicating that the gene plays an important role in the development of Will the forebrain, midline, and pituitary. Growth hormone insensitivity syndrome (GHIS) is now associated with'a broad spectrum of mutations of the GH receptor gene. Woods and colleagues showed that GHIS is, a highly variable condition--from severely affected patients with classical GH insensitivity to a larger group of with idiopathic short stature. Other genetic and/or environmental factors must, therefore, contribute to the phenotype. Intriguing results were found when families with LeriWeill dyschondrosteosis (LWD), a dominant inherited skeletal dysplasia characterised by disproportionate short stature with mesomelic limb shortening, were studied. Various mutations of the short stature homeoboxcontaining gene (SHOX) were found in patients with LWD. These S H O X mutations, however, have also been found in idiopathic growth retardation and Turner (XO) short stature, conditions without bone dysplasia. One explanation is that loss of other genes from the nonpseudoautosomal region of the X chromosome in Turner 's syndrome may mask the full phenotype of S H O X haploinsufficiency. The variable expression in families segretating for a S H O X deletion or mutation suggests that there may be a modifying gene, or genes, on an autosome or on the X chromosome itself, and background genetic effects and environmental factors may also play a role. The mentioned genetic disorders are just examples. Reports about various mutations have appeared in 1998, indicating that in the coming, years many endocrine disorders will be found to be genetically determined. Research in the field of obesity and leptin has progressed. In a large population of massively obese people, however, no mutations of the leptin receptor were found. Feeding behaviour and caloric balance are also modified by neuronal effectors such as neuropeptide Y,

Clinical significance and molecular mechanisms of bioinactive growth hormone (review).

About 80% of short children are not deficient in endogenous growth hormone (GH) and termed idiopathic short stature (ISS). The causes of impaired growth in children with ISS are various. Short stature and low insulin-like growth factor-I (IGF-I) concentration despite normal to high GH concentration suggest impaired GH effect. The prototypical GH insensitivity syndrome was described and characterized by the absent or defective GH receptors. Growth retardation resulting from biologically inactive GH was also described, but the molecular basis of biologically inactive GH has remained unclear. Recently, two unique point mutations in the GH-1 gene in the children with short stature whose GH were supposed as bioinactive were reported. Mutant GH R77C not only failed to stimulate tyrosine phosphorylation by itself, but it also inhibited the activity of wild-type GH. This mutant GH exerted an antagonistic effect. Another mutant D112G was only bio-inactive. This case was a typical Kowarski syndrome. The molecular heterogeneity of mutant GH reflected clinical phenotype of bioinactive GH syndrome.

The D152H mutation found in growth hormone insensitivity syndrome impairs expression and function of human growth hormone receptor but is silent in rat receptor

In two patients with growth hormone (GH) insensitivity syndrome (Laron syndrome), in whom the GH receptor is able to bind the hormone, the D152H mutation was identified, and lack of dimerization was proposed to explain GH resistance in these patients. To examine further the consequences of the substitution of conserved aspartate 152 on the function of the GH receptor (GHR), we reproduced the mutation in vitro on the full length GH receptor cDNA from man and rat. Effects of the mutation on expression and activity of the GHR were analyzed in 293 cells transfected with wild-type and mutant GHR cDNAs. Mutant human receptor protein was expressed at a lower level than wild-type receptor and its activity was reduced: GH-dependent signal transducer and activator of transcription 5 (Stat5)-mediated transactivation of a reporter gene was lower in 293 cells transfected with mutant GHR cDNA than in transfected cells expressing a comparable level of wild-type GHR. The membrane-bound form of the mutant and of the wild-type human GHR were able to homodimerize, as suggested by the size of the complexes detected in cross-linking experiments with 125I-human (h) GH, and also by the activity in the functional test. With the soluble GHR resulting from proteolysis of the wild-type membrane form, no dimeric complexes could be detected. However, when a soluble receptor lacking the transmembrane and cytoplasmic domains of the receptor was expressed, wild-type and not mutant GH binding protein (GHBP) was able to form dimers in the presence of hGH. The amino acid substitution has no effect on either expression or function of the rat receptor. Structural modeling of D152H soluble human and rat GHR (GHBP) supports the species-specific functional consequences of the mutation. Evaluation of the functional importance of the mutation strongly suggests that impairment in expression and activity of the mutant receptor, rather than complete lack of dimerization, explains the GH resistance of the patients.

Heterozygous mutation in the WSXWS equivalent motif of the growth hormone receptor in a child with poor response to growth hormone therapy

Besides complete GH insensitivity syndrome (GHIS) described by Laron, clinical and molecular evidences have accumulated concerning partial GHIS. We studied GH receptor (GHR) gene in children who show poor response to GH treatment and detected a patient with a heterozygous mutation in exon 7 leading to the Y222H substitution. This missense mutation, located in the YGEFS motif of the GHR equivalent to the WSXWS motif highly conserved throughout all members of the cytokine receptor family, has not been described so far. Although we cannot conclude on the deleterious effect of this mutation, there are several lines of evidence suggesting that it could account for the partial GH insensitivity: (i) hormonal data including IGF-I generation test; (ii) molecular data - no other mutation was identified in the coding sequence, the father who has the same mutation is short, the brother did not inherit the mutated allele and was of normal height.

Changes in serum IGF-I and IGFBP-3 concentrations during the IGF-I generation test performed prospectively in children with short stature.

Genotype and phenotype heterogeneity in patients with GH insensitivity syndrome suggests that partial defects exist in the GH receptor. Children with partial GH resistance would be expected to have short stature, elevated GH levels and relatively low levels of IGF-I and IGFBP-3. Provocation tests of the GH-IGF-I axis may help to identify such children. The IGF-I generation test in particular may demonstrate impaired secretion of IGF-I and IGFBP-3. This prospective study assesses the usefulness of the IGF-I generation test in the identification of short children with possible GH insensitivity. Prepubertal children referred for assessment of short stature underwent a standard GH provocation test followed by an IGF-I generation test. Thirty-seven prepubertal children (14 girls, 23 boys) with short stature (height < 2nd centile UK standards 1990) aged 4.5-12.6 years were investigated prospectively. Assessment included history, physical examination, auxological observations (height, weight, bone age). GH provocation tests (glucagon 15 micrograms/kg i.m. or insulin 0.15 U/kg/i.v.) was followed by an IGF-I generation test (hGH 0.1 iu/kg/s.c. daily for 4 days). GH was assayed during the provocation test. IGF-I and IGFBP-3 were measured at 0900 h on day 0 and 4 of the IGF-I generation test. GH and IGF-I were measured by radioimmunoassay, IGFBP-3 by IRMA and basal GHBP by HPLC. Height SDS was calculated according to the UK Height Standards 1990. The absolute and percentage changes of IGF-I and IGFBP-3 during the IGF-I generation test were calculated. The 37 children were divided into three groups according to the peak GH level (mean +/- SEM) during the provocation test: Group 1 (peak GH < 20 mU/l) n = 11, five girls, six boys age 7.1 +/- 0.7 years, height SDS -2.5 +/- 0.1, peak GH 14.5 +/- 1.6 mU/l, IGF-I 92.0 +/- 10.4 micrograms/l, IGFBP-3 2.6 +/- 0.4 mg/l. Group 2 (peak GH 20-40 mU/l) n = 12, six girls, six boys age 8.6 +/- 0.7 years, height SDS -2.6 +/- 0.1, peak GH 28.4 +/- 1.6 mU/l, IGF-I 121-5 +/- 13.4 micrograms/l, IGFBP-3 2.9 +/- 0.2 mg/l. Group 3 (peak GH > 40 mU/l) n = 14, three girls, 11 boys, aged 8.5 +/- 0.6 years, height SDS -2.3 +/- 0.1, peak GH 60.7 +/- 4.1 mU/l, IGF-I 112.4 +/- 10.9 micrograms/l, IGFBP-3 3.1 +/- 0.3 mg/l. There were no significant differences in the absolute increases of IGF-I or IGFBP-3 (mean +/- SEM) during the IGF-I generation test, IGF-I; Group 1, 48.8 +/- 9.5 micrograms/l, Group 2, 42.7 +/- 4.8 micrograms/l. Group 3, 45.5 +/- 5.1 micrograms/l, IGFBP-3; Group 1, 1.1 +/- 1.2 mg/l. Group 2, 1.2 +/- 0.2 mg/l, Group 3, 0.85 +/- 0.1 mg/l. There were no significant differences in the percentage increases (mean +/- SEM) of IGF-I; Group 1, 55 +/- 9%, Group 2, 35 +/- 5%, Group 3, 42 +/- 8%, or IGFBP-3; Group 1, 64 +/- 17%, Group 2, 44 +/- 8%, Group 3.32 +/- 6%. GHBP values were normal in all three groups. In Group 3 (peak GH > 40 mU/l) four individual patients had either low basal IGF-I levels (n = 2) (< 5th centile of normal range for age) or low basal IGFBP-3 levels (n = 1) (< 5th centile of normal range for age) or low IGF-I responses in the IGF-I generation test (2 x CV of IGF-I assay) (n = 1). No single subject had all the characteristics of GH insensitivity syndrome. The responses during an IGF-I generation test did not identify a clear group of children with GH insensitivity. Individual patients had low basal IGF-I or IGFBP-3 values and a poor response in the generation test, features which, in the presence of high GH levels on provocation, are consistent with partial GH insensitivity.

Growth Hormone (GH) Insensitivity Syndrome with High Serum GH-Binding Protein Levels Caused by a Heterozygous Splice Site Mutation of the GH Receptor Gene Producing a Lack of Intracellular Domain

Growth Hormone (GH) Insensitivity Syndrome with High Serum GH-Binding Protein Levels Caused by a Heterozygous Splice Site Mutation of the GH Receptor Gene Producing a Lack of Intracellular Domain

A mammalian model for Laron syndrome produced by targeted disruption of the mouse growth hormone receptor/binding protein gene (the Laron mouse).

Laron syndrome [growth hormone (GH) insensitivity syndrome] is a hereditary dwarfism resulting from defects in the GH receptor (GHR) gene. GHR deficiency has not been reported in mammals other than humans. Many aspects of GHR dysfunction remain unknown because of ethical and practical limitations in studying humans. To create a mammalian model for this disease, we generated mice bearing a disrupted GHR/binding protein (GHR/BP) gene through a homologous gene targeting approach. Homozygous GHR/BP knockout mice showed severe postnatal growth retardation, proportionate dwarfism, absence of the GHR and GH binding protein, greatly decreased serum insulin-like growth factor I and elevated serum GH concentrations. These characteristics represent the phenotype typical of individuals with Laron syndrome. Animals heterozygous for the GHR/BP defect show only minimal growth impairment but have an intermediate biochemical phenotype, with decreased GHR and GH binding protein expression and slightly diminished insulin-like growth factor I levels. These findings indicate that the GHR/BP-deficient mouse (Laron mouse) is a suitable model for human Laron syndrome that will prove useful for the elucidation of many aspects of GHR/BP function that cannot be obtained in humans.

Phenotype: genotype relationships in growth hormone insensitivity syndrome.

GH insensitivity syndrome (GHIS) is associated with many different mutations of the GH receptor (GHR) gene. We examined the phenotypic and biochemical features in 82 GHIS patients from 23 countries, each fulfilling diagnostic criteria of GHIS. There were 45 males and 37 females [mean age, 8.25 yr; mean height, -6.09 SD score, and mean insulin-like growth factor (IGF)-binding protein-3 (IGFBP-3), -7.99 SD score]. Sixty-three were GH-binding protein (GHBP) negative; 19 were GHBP positive (> 10% binding). The mean height in GHBP-negative subjects was -6.5 SD score, and that in GHBP-positive patients was -4.9 SD score (P = < 0.001). Clinical and biochemical heterogeneity was demonstrated by the wide range of height (-2.2 to -10.4 SD score) and IGFBP-3 (-1.4 to -14.7 SD score) values, which were positively correlated (r2 = 0.45; P = < 0.001). This contrasted with the lack of correlation between mean parental height SD score and height SD score (r2 = 0.01). Fifteen different GH receptor gene mutations were identified in 27 patients. All had homozygous defects, except 1 who had a compound heterozygous defect. The mutations were 5 nonsense, 2 frame shift, 4 splice, 4 missense, and 1 compound heterozygote. There was no relationship between mutation type or exon of the GHR gene involved and height or IGFBP-3 SD score. In conclusion, GHIS is associated with wide variation in the severity of clinical and biochemical phenotypes. This variation cannot clearly be accounted for by defects in the GHR gene. Other genetic and/or environmental factors must, therefore, contribute to phenotype in GHIS.

Novel Compound Heterozygous Mutations of Growth Hormone (GH) Receptor Gene in a Patient with GH Insensitivity Syndrome

Novel Compound Heterozygous Mutations of Growth Hormone (GH) Receptor Gene in a Patient with GH Insensitivity Syndrome

Partial growth-hormone insensitivity: The role of growth-hormone receptor mutations in idiopathic short stature

Mutations in the GHR locus may play a role in the cause of idiopathic short stature (ISS) by impairing growth-hormone (GH) receptor (GHR) function. At one extreme, mutations that nullify the function of the GH receptor are linked to complete GH insensitivity syndrome, or Laron syndrome, and we hypothesized that less-disruptive mutations could contribute to partial GH insensitivity syndrome. Low levels of GH binding protein may indicate mutations in the extracellular domain of the receptor, and by focusing on 14 children with ISS who had low GH binding protein and insulin-like growth factor I levels, we found three heterozygotes and one compound heterozygote for mutations in the extracellular domain of the receptor. We have since extended our study to a broader spectrum of patients, adding 76 patients with ISS who were treated with GH in a phase II study of the safety and efficacy of recombinant human GH in ISS and also adding 10 patients who were ascertained as having ISS by pediatric endocrinologists in private practice. The GHR gene has thus been analyzed in 100 patients with ISS, eight of whom were found to carry mutations: four in our original study and four with normal or elevated levels of GH binding protein. The latter group consists of three carriers of heterozygous extracellular domain mutations and one carrier of a heterozygous intracellular domain mutation. Family data suggest that the carriers of these mutations have a range of phenotypes, supporting our hypothesis that the expression of these heterozygous mutations as partial GH insensitivity syndrome depends on the genetic makeup of the person. (J Pediatr 1997;131:S51-5)

National Cooperative Growth Study substudy VI: The clinical utility of growth-hormone–binding protein, insulin-like growth factor I, and insulin-like growth factor–binding protein 3 measurements

Objective: To assess the clinical utility of growth-hormone–binding protein (GHBP), along with growth hormone (GH), insulin-like growth factor I (IGF-I), and insulin-like growth factor–binding protein 3 (IGFBP-3), levels in the evaluation of short stature. Study design: Prospective substudy of the National Cooperative Growth Study, a multicenter observational study. Results: A total of 6447 assessable subjects undergoing workup for short stature were enrolled at 197 sites. At baseline the cause of short stature was undefined in 77% of subjects. Mean GHBP levels were lowest in subjects with renal disease and highest in those with Turner syndrome. No cases of complete GH insensitivity syndrome (Laron syndrome) were identified. Subjects with low GHBP levels were among those tested for GH receptor mutations. IGF-I standard deviation scores (SDS) and IGFBP-3 SDS were positively correlated; both increased during GH therapy. There was a weak positive correlation between log peak GH levels and both IGF-I SDS and IGFBP-3 SDS and a weak negative correlation between log peak GH levels and GHBP SDS. Mean changes in GHBP SDS in subjects treated with GH and untreated subjects were not significant. Change in height SDS in subjects treated with GH was negatively correlated with age and IGF-I level but not correlated with baseline GHBP SDS. Conclusion: GHBP levels are GH independent and not predictive of responses to GH therapy, although low GHBP levels may indicate GH receptor abnormalities and partial GH insensitivity. (J Pediatr 1997;131:S56-60)

Prolonged treatment with recombinant insulin-like growth factor-I in children with growth hormone insensitivity syndrome--a clinical research center study. GHIS Collaborative Group

Prolonged treatment with recombinant insulin-like growth factor-I in children with growth hormone insensitivity syndrome--a clinical research center study. GHIS Collaborative Group

Prolonged treatment with recombinant insulin-like growth factor-I in children with growth hormone insensitivity syndrome--a clinical research center study. GHIS Collaborative Group.

Eight children with GH insensitivity syndrome, five with GH receptor deficiency (Laron syndrome) and three with growth-attenuating antibodies to GH, were treated with recombinant human insulin-like growth factor I (IGF-I) for 24 months (one was treated for 36 months). Their ages at the beginning of therapy ranged from 2-11 yr. The dose of IGF-I ranged between 80-120 micrograms/kg, given sc twice daily. During the first year of treatment, height velocity (HV) improved in each patient (mean pretreatment HV, 4.0 cm/yr; mean of first year, 9.3 cm/yr). HV declined by 33% during the second year (mean HV, 6.2 cm/yr). The third year HV of the one patient so treated was approximately the same as that in the second year. The mean SD score HV before therapy was -2.4 and improved to +3.8 and +0.5 after 1 and 2 yr of therapy, respectively. Increased HV was accompanied by weight gain. IGF-I-related hypoglycemia occurred infrequently and only early in treatment. No adverse changes in biochemical profile were observed. Bone age did not advance more rapidly than chronological age (mean change in bone age, 2.1 yr; mean change in chronological age, 2.2 yr). The growth of the spleen and kidneys (determined by ultrasound) was rapid in the first year of therapy. In the second year, spleen growth slowed to a normal rate in most patients. Kidney growth, however, remained relatively rapid. These results indicate that IGF-I stimulates statural growth for at least 2 yr and confirms that this peptide has the capacity to act through endocrine mechanisms. Prolonged treatment of GH insensitivity syndrome patients shows promise. The stimulation of growth by IGF-I treatment over years needs to be documented, and patients need to be monitored for side-effects.