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Endocrine-related Cancer May 2016The growth hormone (GH)-insulin-like growth factor-1 (IGF1) pathway emerged in recent years as a critical player in cancer biology. Enhanced expression or activation of...
The growth hormone (GH)-insulin-like growth factor-1 (IGF1) pathway emerged in recent years as a critical player in cancer biology. Enhanced expression or activation of specific components of the GH-IGF1 axis, including the IGF1 receptor (IGF1R), is consistently associated with a transformed phenotype. Recent epidemiological studies have shown that patients with Laron syndrome (LS), the best-characterized entity among the congenital IGF1 deficiencies, seem to be protected from cancer development. To identify IGF1-dependent genes and signaling pathways associated with cancer protection in LS, we conducted a genome-wide analysis using immortalized lymphoblastoid cells derived from LS patients and healthy controls of the same gender, age range, and ethnic origin. Our analyses identified a collection of genes that are either over- or under-represented in LS-derived lymphoblastoids. Gene differential expression occurs in several gene families, including cell cycle, metabolic control, cytokine-cytokine receptor interaction, Jak-STAT signaling, and PI3K-AKT signaling. Major differences between LS and healthy controls were also noticed in pathways associated with cell cycle distribution, apoptosis, and autophagy. Our results highlight the key role of the GH-IGF1 axis in the initiation and progression of cancer. Furthermore, data are consistent with the concept that homozygous congenital IGF1 deficiency may confer protection against future tumor development.
Topics: Adult; Apoptosis; Autophagy; Cell Cycle; Cell Line; Cell Proliferation; Extracellular Signal-Regulated MAP Kinases; Female; Humans; Insulin-Like Growth Factor I; Laron Syndrome; Middle Aged; Neoplasms; PTEN Phosphohydrolase; Proto-Oncogene Proteins c-akt; Receptor, IGF Type 1; Receptors, Somatomedin; Signal Transduction; Sp1 Transcription Factor; Transcriptome
PubMed: 27090428
DOI: 10.1530/ERC-16-0054 -
Growth Hormone & IGF Research :... Jun 2016Growth hormone (GH) promotes postnatal human growth primarily by regulating insulin-like growth factor (IGF)-I production through activation of the GH receptor... (Review)
Review
Growth hormone (GH) promotes postnatal human growth primarily by regulating insulin-like growth factor (IGF)-I production through activation of the GH receptor (GHR)-signal transducer and activator of transcription (STAT)-5B signaling cascade. The critical importance of STAT5B in human IGF-I production was confirmed with the identification of the first homozygous, autosomal recessive, STAT5B mutation in a young female patient who phenotypically resembled patients with classical growth hormone insensitivity (GHI) syndrome (Laron syndrome) due to mutations in the GHR gene, presenting with severe postnatal growth failure and marked IGF-I deficiency. Of note, the closely related STAT5A, which shares >95% amino acid identity with STAT5B, could not compensate for loss of functional STAT5B. To date, 7 homozygous, inactivating, STAT5B mutations in 10 patients have been reported. STAT5B deficient patients, unlike patients deficient in GHR, can also present with a novel, potentially fatal, primary immunodeficiency, which can manifest as chronic pulmonary disease. STAT5B deficiency may be underestimated in endocrine, immunology and pulmonary clinics.
Topics: Animals; Growth Disorders; Hearing Loss, Sensorineural; Humans; Immunologic Deficiency Syndromes; Insulin-Like Growth Factor I; Laron Syndrome; Mice; Mutation; STAT5 Transcription Factor; T-Lymphocytes, Regulatory
PubMed: 26703237
DOI: 10.1016/j.ghir.2015.12.006 -
Journal of Pediatric Endocrinology &... Jun 2018Laron syndrome (LS), which can be defined as primary growth hormone resistance or insensitivity, is a rare genetic disease inherited by an autosomal recessive trait....
BACKGROUND
Laron syndrome (LS), which can be defined as primary growth hormone resistance or insensitivity, is a rare genetic disease inherited by an autosomal recessive trait. Although it is undistinguishable from growth hormone deficiency, LS has high levels of growth hormone, but insulin-like growth factor (IGF-1) cannot be synthesized. Mecasermin treatment is the only option for the patients who suffer from LS. This study aims to research cardiac findings of children with LS, who receive treatment with mecasermin.
METHODS
The study enrolled five children four males and one female, 4 M/1 F with LS, two of whom were siblings with a mean age of 6.3±2.1 years, a body weight of 13.36±4.74 kg, a height of 88±8.7 cm, and a body mass index (BMI) of 16.47±3.35. Their demographic data were obtained from their family and files. The children received mecasermin via subcutaneous injection at 0.04-0.12 μg/kg doses twice per day. The duration of mecasermin treatment was 8-53 months. All of them were examined clinically by electrocardiogram and echocardiogram.
RESULTS
Their cardiac examinations were normal, except for one case, who had systolic murmur at cardiac auscultation. Arrhythmia was not observed on their electrocardiograms. The echocardiograms did not show a significant congenital cardiac anomaly. Their cardiac measure and functions were within normal ranges. The echocardiogram of the child with the murmur showed mitral and tricuspid insufficiency. The Doppler images showed pulmonary hypertension findings. These findings were proven by angiography. The vasoreactivity test results of that patient were negative. No reason could be found for the observed pulmonary hypertension. We diagnosed this finding as a primary pulmonary hypertension and Bosentan therapy was started.
CONCLUSIONS
In this study, we showed that cardiac findings were consistent with previous studies. To the best of our knowledge, the observed pulmonary hypertension in children with LS, who received treatment with or without mecasermin, is reported for first time in the literature.
Topics: Child; Child, Preschool; Echocardiography; Female; Heart; Humans; Infant; Insulin-Like Growth Factor I; Laron Syndrome; Male; Mitral Valve Insufficiency; Recombinant Proteins
PubMed: 29750649
DOI: 10.1515/jpem-2017-0473 -
Journal of Pediatric Endocrinology &... Apr 1999Partial growth hormone (GH) insensitivity can be defined as the clinical and biochemical features of IGF-I deficiency without GH deficiency and in the absence of the... (Review)
Review
Partial growth hormone (GH) insensitivity can be defined as the clinical and biochemical features of IGF-I deficiency without GH deficiency and in the absence of the dysmorphic features of Laron syndrome. There is good evidence that this form of GH insensitivity exists, both in the context of severe GH resistance, and also in some patients with idiopathic short stature. The series of GH insensitivity patients in the European study shows a spectrum of clinical and biological defects, with several patients at the milder end of the spectrum having normal facies. The report of the presence of heterozygous mutations of the GH receptor in patients with idiopathic short stature has been confirmed by documentation of dominantly inherited mutations in familial short stature. Molecular screening in our unit of a group of 31 children with idiopathic short stature and normal GHBP, failed to identify mutations of the intracellular domain of the GH receptor. Consequently, although partial GH insensitivity is a proven entity, the clinical and biochemical identification of patients with GH resistance should precede molecular analysis. The analysis of individual patients and their families is more likely to reveal mutations, rather than a strategy of blanket molecular screening.
Topics: Abnormalities, Multiple; Child; Drug Resistance; Europe; Growth Disorders; Human Growth Hormone; Humans; Insulin-Like Growth Factor I; Receptors, Somatotropin; Syndrome
PubMed: 10698589
DOI: No ID Found -
Israel Journal of Medical Sciences Dec 1993Three siblings with Laron syndrome (LS) and normal serum growth hormone binding protein (GHBP) are described. Basal serum levels of hGH were high and IGF-1 low, and in...
Three siblings with Laron syndrome (LS) and normal serum growth hormone binding protein (GHBP) are described. Basal serum levels of hGH were high and IGF-1 low, and in contradistinction to the classical form of the disease serum GHBP and IGFBP-3 were normal in these patients. After 7 days of human growth hormone administration serum IGFBP-3 levels as well as the number of red blood cell IGF receptor sites increased. After short- and long-term IGF-1 administration the IGF-1 receptor binding capacity as well as the number of IGF receptor sites decreased to levels found in control subjects. One year treatment with IGF-1 increased the growth velocity by 47-96% in the two older children. It is concluded that the findings described are compatible with a normal GH receptor and normal signal transmission for IGFBP-3 synthesis but a defect exists in the post-GH receptor mechanism for the generation of IGF-1. This is the first description of this type of defect leading to a variant of Laron syndrome.
Topics: Adult; Carrier Proteins; Child; Child, Preschool; Dwarfism, Pituitary; Female; Humans; Infant; Insulin-Like Growth Factor I; Male; Receptors, Somatotropin; Recombinant Proteins; Syndrome
PubMed: 8300382
DOI: No ID Found -
World Journal of Clinical Cases Dec 2019Laron syndrome (LS) is an autosomal recessive hereditary condition affecting only 1/1000000 births. The cause is associated with mutations in the growth hormone (GH)...
BACKGROUND
Laron syndrome (LS) is an autosomal recessive hereditary condition affecting only 1/1000000 births. The cause is associated with mutations in the growth hormone (GH) receptor (GHR), leading to GH insensitivity. LS patients typically present with severe growth retardation, obesity, and abnormal sexual maturation. Currently, LS diagnosis is performed post-delivery. Therefore, we assessed the efficiency of Pre-implantation Genetic Testing (PGT) coupled with monoplex-polymerase chain reaction (PCR) technology for detecting this monogenic disease in embryos from a couple confirmed as LS heterozygous carriers.
CASE SUMMARY
The couple LS-carriers were confirmed by the presence of a first child born with LS. The couple underwent a standard fertilization (IVF) protocol. DNA was collected from trophectoderm cells from day 5 embryos. Whole genome amplification (WGA) was performed using a Sureplex DNA Amplification System and analyzed by PCR, targeting the deletion of the exons 5 and 6 in the gene as well as PGT by Next-generation Sequencing (Illumina). Eleven embryos were collected and analyzed. 27.3% were the wild type for GHR, 45.5% were heterozygotes, and 18.2% homozygous mutants. One embryo yielded no results. Three 2-embryos transfers were performed; 2 normal homozygous and four heterozygous carriers were selected for transfer. The first two transfers were unsuccessful, whereas the final transfer with two heterozygous embryos resulted in clinical pregnancy. The genomic composition of the fetus was verified, applying the same techniques using amniocytes, extracted after 21 wk of the ongoing pregnancy. The fetus was confirmed as GHR deletion in exon 5-6, carrier. A non-affected baby was born.
CONCLUSION
Here, we present a case demonstrating that using WGA as a template in addition to PCR targeting specific gene regions, exons 5 and 6 on the gene, could identify LS carrier embryos. This provides evidence that WGA and PCR serve as an excellent tool to detect this specific monogenic disease in IVF embryos, thus allowing selection of candidate embryos for transfer successfully when a specific inherited genetic mutation/disease is suspected.
PubMed: 31832405
DOI: 10.12998/wjcc.v7.i23.4029 -
Israel Journal of Medical Sciences May 1995
Topics: Abnormalities, Multiple; Growth Disorders; Humans; Hypoparathyroidism; Infant, Newborn; Microcephaly; Syndrome
PubMed: 7759229
DOI: No ID Found -
Endocrine Reviews Apr 2019Several components of the GH axis are involved in tumor progression, and GH-induced intracellular signaling has been strongly associated with breast cancer... (Review)
Review
Several components of the GH axis are involved in tumor progression, and GH-induced intracellular signaling has been strongly associated with breast cancer susceptibility in genome-wide association studies. In the general population, high IGF-I levels and low IGF-binding protein-3 levels within the normal range are associated with the development of common malignancies, and components of the GH-IGF signaling system exhibit correlations with clinical, histopathological, and therapeutic parameters in cancer patients. Despite promising findings in preclinical studies, anticancer therapies targeting the GH-IGF signaling system have led to disappointing results in clinical trials. There is substantial evidence for some degree of protection against tumor development in several animal models and in patients with genetic defects associated with GH deficiency or resistance. In contrast, the link between GH excess and cancer risk in acromegaly patients is much less clear, and cancer screening in acromegaly has been a highly controversial issue. Recent studies have shown that increased life expectancy in acromegaly patients who attain normal GH and IGF-I levels is associated with more deaths due to age-related cancers. Replacement GH therapy in GH deficiency hypopituitary adults and short children has been shown to be safe when no other risk factors for malignancy are present. Nevertheless, the use of GH in cancer survivors and in short children with RASopathies, chromosomal breakage syndromes, or DNA-repair disorders should be carefully evaluated owing to an increased risk of recurrence, primary cancer, or second neoplasia in these individuals.
Topics: Acromegaly; Adult; Animals; Child; Growth Hormone; Humans; Hypopituitarism; Insulin-Like Growth Factor Binding Protein 3; Insulin-Like Growth Factor I; Laron Syndrome; Neoplasms; Signal Transduction
PubMed: 30500870
DOI: 10.1210/er.2018-00166 -
Journal of Pediatric Endocrinology &... May 2023Laron dwarfism is a rare genetic disorder first reported among Israeli jewish children, subsequently about 350 cases cases have been reported worldwide. We aim to...
OBJECTIVES
Laron dwarfism is a rare genetic disorder first reported among Israeli jewish children, subsequently about 350 cases cases have been reported worldwide. We aim to describe the clinical profile of nine children with Laron dwarfism from Institute of Child Health, Chennai.
METHODS
Analysis of case records from 2010 to 2018.
RESULTS
Male:female ratio is 6:3. Mean age of the children at the time of diagnosis was 3 years. All children were extremely short, and mean height Z score (SD) was -7.7(0.8). All children had characteristic facies with no hypoglycaemic episodes. Microcephaly was present in four children out of which two had developmental delay. Three out of six boys had micropenis. All children had low insulin like growth factor-1 (IGF-1) and high basal growth hormone (GH) with a mean (SD) of 39.6 (11.2) ng/mL.
CONCLUSIONS
Suspicion of Laron syndrome should be high when child presents with features of Growth Hormone Deficiency (GHD) with extreme stunting.
Topics: Child; Humans; Male; Female; Child, Preschool; Laron Syndrome; Tertiary Healthcare; India; Growth Hormone; Dwarfism, Pituitary; Insulin-Like Growth Factor I; Dwarfism
PubMed: 36957988
DOI: 10.1515/jpem-2022-0538 -
Molecular and Cellular Endocrinology Dec 2020Emerging evidence links the growth hormone (GH)-insulin-like growth factor-1 (IGF1) endocrine axis to cancer development. While this putative correlation is of major... (Review)
Review
Emerging evidence links the growth hormone (GH)-insulin-like growth factor-1 (IGF1) endocrine axis to cancer development. While this putative correlation is of major translational relevance, most clinical and epidemiological reports to date found no causal linkage between GH therapy and enhanced cancer risk. Thus, it is generally agreed that GH therapy constitutes a safe pharmacological intervention. The present review focuses on a number of issues in the area of GH-IGF1 action in cancer development. Emphasis is given to the idea that GH and IGF1 do not conform to the definition of oncogenic factors. Specifically, these hormones, even at high pharmacological doses, are unable to induce malignant transformation. However, the GH-IGF1 axis is capable of 'pushing' already transformed cells through the various phases of the cell cycle. Viral and cellular oncogenes require an intact IGF1 signaling pathway in order to elicit transformation; in other words, oncogenic agents adopt the IGF1 pathway. This universal mechanism of action of oncogenes has broad implications in oncology. Our review provides an in-depth analysis of the interplay between the GH-IGF1 axis and cancer genes, including tumor suppressors p53 and BRCA1. Finally, the safety of GH therapy in both children and adults needs further long-term follow-up studies.
Topics: Adult; Cell Cycle; Child; Disease Progression; Human Growth Hormone; Humans; Insulin-Like Growth Factor I; Neoplasms; Oncogenes; Signal Transduction
PubMed: 32919021
DOI: 10.1016/j.mce.2020.111003