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Endokrynologia Polska 2017Short stature is the main problem that paediatric endocrinologists have to grapple with. Endocrine disorders account for only 5% of patients with short stature, but this... (Review)
Review
Short stature is the main problem that paediatric endocrinologists have to grapple with. Endocrine disorders account for only 5% of patients with short stature, but this is still one of the most common causes of reports to the endocrine clinic and hospitalisation in the endocrine department. A properly functioning growth hormone/insulin-like growth factor (GH/IGF) axis is one of the most important factors in proper growth. A lot of genetic defects in this axis lead to syndromes marked by impaired growth, like Laron syndrome, muta-tions in the STAT5B, insulin-like growth factor 1 (IGF1), and insulin-like growth factor 1 receptor (IGF1R) and mutations in the acid labile subunit (ALS). Two proteases important for the proper functioning of the GH/IGF axis: pregnancy-associated plasma protein-A (PAPP-A) and pregnancy-associated plasma protein-A2 (PAPP-A2), have been described. The first description of the new syndrome of growth failure associated with mutation in the PAPP-A2 gene was given by Andrew Dauber et al. This review evaluates the current data concerning PAPP-A2 function, and particularly the effect of PAPP-A2 mutation on growth.
Topics: Animals; Female; Growth; Growth Hormone; Humans; Insulin-Like Growth Factor I; Male; Mice; Mutation; Pregnancy-Associated Plasma Protein-A
PubMed: 29238946
DOI: 10.5603/EP.a2017.0060 -
Hormone Research in Paediatrics 2022The aim of the study was to describe focal epilepsy in patients with Laron syndrome (LS).
OBJECTIVE
The aim of the study was to describe focal epilepsy in patients with Laron syndrome (LS).
METHODS
Data were retrieved from medical records of a single-center cohort of 75 patients with LS.
RESULTS
We describe for the first time 4 patients with concomitant focal epilepsy and LS. Two of them experienced episodes of status epilepticus. Electroencephalogram examination in all 4 patients showed interictal epileptiform discharges in the temporal regions. Three achieved long-term seizure freedom on antiseizure medications.
CONCLUSION
Patients with LS may be at risk of developing focal epilepsy, which seems to be unrelated to hypoglycemic episodes in childhood.
Topics: Electroencephalography; Epilepsies, Partial; Humans; Laron Syndrome; Retrospective Studies; Seizures
PubMed: 35358968
DOI: 10.1159/000524350 -
Frontiers in Endocrinology 2023Linear growth during childhood is the result of the synergic contribution of different factors. The best growth determinant system during each period of life is... (Review)
Review
Linear growth during childhood is the result of the synergic contribution of different factors. The best growth determinant system during each period of life is represented by the growth hormone-insulin-like growth factor axis (GH-IGF), even if several other factors are involved in normal growth. Within the broad spectrum of growth disorders, an increased importance has been placed on growth hormone insensitivity (GHI). GHI was reported for the first time by Laron as a syndrome characterized by short stature due to GH receptor (GHR) mutation. To date, it is recognized that GHI represents a wide diagnostic category, including a broad spectrum of defects. The peculiar characteristic of GHI is the low IGF-1 levels associated with normal or elevated GH levels and the lack of IGF-1 response after GH administration. Recombinant IGF-1 preparations may be used in the treatment of these patients.
Topics: Dwarfism; Human Growth Hormone; Insulin-Like Growth Factor I; Humans; Growth Disorders
PubMed: 37008935
DOI: 10.3389/fendo.2023.1141039 -
Gene Therapy Jun 2022
Topics: Genetic Therapy; Humans; Insulin-Like Growth Factor I; Laron Syndrome; Mutation
PubMed: 35283485
DOI: 10.1038/s41434-022-00329-2 -
Journal of Medical Case Reports Jul 2011Primary growth hormone resistance or growth hormone insensitivity syndrome, also known as Laron syndrome, is a hereditary disease caused by deletions or different types...
INTRODUCTION
Primary growth hormone resistance or growth hormone insensitivity syndrome, also known as Laron syndrome, is a hereditary disease caused by deletions or different types of mutations in the growth hormone receptor gene or by post-receptor defects. This disorder is characterized by a clinical appearance of severe growth hormone deficiency with high levels of circulating growth hormone in contrast to low serum insulin-like growth factor 1 values.
CASE PRESENTATION
We report the case of a 15-year-old Caucasian girl who was diagnosed with Silver-Russell syndrome at the age of four and a half years. Recombinant growth hormone was administered for 18 months without an appropriate increase in growth velocity. At the age of seven years, her serum growth hormone levels were high, and an insulin-like growth factor 1 generation test did not increase insulin-like growth factor 1 levels (baseline insulin-like growth factor 1 levels, 52 μg/L; reference range, 75 μg/L to 365 μg/L; and peak, 76 μg/L and 50 μg/L after 12 and 84 hours, respectively, from baseline). The genetic analysis showed that the patient was homozygous for the R217X mutation in the growth hormone receptor gene, which is characteristic of Laron syndrome. On the basis of these results, the diagnosis of primary growth hormone insensitivity syndrome was made, and recombinant insulin-like growth factor 1 therapy was initiated. The patient's treatment was well tolerated, but unexplained central hypothyroidism occurred at the age of 12.9 years. At the age of 15 years, when the patient's sexual development was almost completed and her menstrual cycle occurred irregularly, her height was 129.8 cm, which is 4.71 standard deviations below the median for normal girls her age.
CONCLUSION
The most important functional tests for the diagnosis of growth hormone insensitivity are the insulin-like growth factor 1 generation test and genetic analysis. Currently, the only effective treatment is daily administration of recombinant insulin-like growth factor 1 starting from early childhood. However, these patients show a dramatically impaired final height. In our case, unexplained central hypothyroidism occurred during treatment.
PubMed: 21745362
DOI: 10.1186/1752-1947-5-301 -
Endocrine-related Cancer May 2023Interest in investigating the role of the growth hormone (GH)/insulin-like growth factor 1 (IGF-1) axis in the initiation and progression of experimentally induced... (Review)
Review
Interest in investigating the role of the growth hormone (GH)/insulin-like growth factor 1 (IGF-1) axis in the initiation and progression of experimentally induced carcinomas has arisen due to several observations in the human population. First, subjects with Laron syndrome who lack GH signaling have significantly lower rates of cancer than people who have normal GH signaling. Second, epidemiologic studies have found strong associations between elevated circulating IGF-1 and the incidence of several common cancers. Third, women who bear children early in life have a dramatically reduced risk of developing breast cancer, which may be due to differences in hormone levels including GH. These observations have motivated multiple studies that have experimentally altered activity of the GH/IGF-1 axis in the context of experimental carcinoma models in mice and rats. Most of these studies have utilized carcinoma models for four organ systems that are also frequent sites of carcinomas in humans: the mammary gland, prostate gland, liver, and colon. This review focuses on these studies and describes some of the most common genetic models used to alter the activity of the GH/IGF-1 axis in experimentally induced carcinomas. A recurring theme that emerges from these studies is that manipulations that reduce the activity of GH or mediators of GH action also inhibit carcinogenesis in multiple model systems.
Topics: Male; Female; Rats; Mice; Humans; Animals; Growth Hormone; Insulin-Like Growth Factor I; Neoplasm Recurrence, Local; Human Growth Hormone; Carcinoma
PubMed: 36826838
DOI: 10.1530/ERC-22-0403 -
Cells Nov 2020Laron syndrome (LS) is a rare genetic endocrinopathy that results from mutation of the growth hormone receptor () gene and is typically associated with dwarfism and... (Review)
Review
Laron syndrome (LS) is a rare genetic endocrinopathy that results from mutation of the growth hormone receptor () gene and is typically associated with dwarfism and obesity. LS is the best characterized entity under the spectrum of the congenital insulin-like growth factor-1 (IGF1) deficiencies. Epidemiological analyses have shown that LS patients do not develop cancer, whereas heterozygous family members have a cancer prevalence similar to the general population. To identify genes and signaling pathways differentially represented in LS that may help delineate a biochemical and molecular basis for cancer protection, we have recently conducted a genome-wide profiling of LS patients. Studies were based on our collection of Epstein-Barr virus (EBV)-immortalized lymphoblastoid cell lines derived from LS patients, relatives and healthy controls. Bioinformatic analyses identified differences in gene expression in several pathways, including apoptosis, metabolic control, cytokine biology, Jak-STAT and PI3K-AKT signaling, etc. Genes involved in the control of cell cycle, motility, growth and oncogenic transformation are, in general, down-regulated in LS. These genetic events seem to have a major impact on the biological properties of LS cells, including proliferation, apoptosis, response to oxidative stress, etc. Furthermore, genomic analyses allowed us to identify novel IGF1 downstream target genes that have not been previously linked to the IGF1 signaling pathway. In summary, by '' genomic data from LS patients, we were able to generate clinically-relevant information in oncology and, potentially, related disciplines.
Topics: Animals; Biomedical Research; Humans; Insulin-Like Growth Factor I; Intercellular Signaling Peptides and Proteins; Laron Syndrome; Neoplasms; Risk Factors
PubMed: 33182502
DOI: 10.3390/cells9112446 -
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 -
Orphanet Journal of Rare Diseases Oct 2023Severe primary insulin-like growth factor-I (IGF-I) deficiency (SPIGFD) is a rare growth disorder characterized by short stature (standard deviation score... (Review)
Review
BACKGROUND
Severe primary insulin-like growth factor-I (IGF-I) deficiency (SPIGFD) is a rare growth disorder characterized by short stature (standard deviation score [SDS] ≤ 3.0), low circulating concentrations of IGF-I (SDS ≤ 3.0), and normal or elevated concentrations of growth hormone (GH). Laron syndrome is the best characterized form of SPIGFD, caused by a defect in the GH receptor (GHR) gene. However, awareness of SPIGFD remains low, and individuals living with SPIGFD continue to face challenges associated with diagnosis, treatment and care.
OBJECTIVE
To gather perspectives on the key challenges for individuals and families living with SPIGFD through a multi-stakeholder approach. By highlighting critical gaps in the awareness, diagnosis, and management of SPIGFD, this report aims to provide recommendations to improve care for people affected by SPIGFD globally.
METHODS
An international group of clinical experts, researchers, and patient and caregiver representatives from the SPIGFD community participated in a virtual, half-day meeting to discuss key unmet needs and opportunities to improve the care of people living with SPIGFD.
RESULTS
As a rare disorder, limited awareness and understanding of SPIGFD amongst healthcare professionals (HCPs) poses significant challenges in the diagnosis and treatment of those affected. Patients often face difficulties associated with receiving a formal diagnosis, delayed treatment initiation and limited access to appropriate therapy. This has a considerable impact on the physical health and quality of life for patients, highlighting a need for more education and clearer guidance for HCPs. Support from patient advocacy groups is valuable in helping patients and their families to find appropriate care. However, there remains a need to better understand the burden that SPIGFD has on individuals beyond height, including the impact on physical, emotional, and social wellbeing.
CONCLUSIONS
To address the challenges faced by individuals and families affected by SPIGFD, greater awareness of SPIGFD is needed within the healthcare community, and a consensus on best practice in the care of individuals affected by this condition. Continued efforts are also needed at a global level to challenge existing perceptions around SPIGFD, and identify solutions that promote equitable access to appropriate care. Medical writing support was industry-sponsored.
Topics: Humans; Insulin-Like Growth Factor I; Quality of Life; Laron Syndrome; Dwarfism; Growth Disorders
PubMed: 37805563
DOI: 10.1186/s13023-023-02928-7 -
Biomolecules Mar 2023Laron syndrome (LS) is a rare genetic disorder characterized by low levels of insulin-like growth factor 1 (IGF1) and high levels of growth hormone (GH) due to mutations...
Laron syndrome (LS) is a rare genetic disorder characterized by low levels of insulin-like growth factor 1 (IGF1) and high levels of growth hormone (GH) due to mutations in the growth hormone receptor gene (). A -knockout (-KO) pig was developed as a model for LS, which displays many of the same features as humans with LS-like transient juvenile hypoglycemia. This study aimed to investigate the effects of impaired GHR signaling on immune functions and immunometabolism in -KO pigs. GHR are located on various cell types of the immune system. Therefore, we investigated lymphocyte subsets, proliferative and respiratory capacity of peripheral blood mononuclear cells (PBMCs), proteome profiles of CD4 and CD4 lymphocytes and IFN-α serum levels between wild-type (WT) controls and -KO pigs, which revealed significant differences in the relative proportion of the CD4CD8α subpopulation and in IFN-α levels. We detected no significant difference in the respiratory capacity and the capacity for polyclonal stimulation in PBMCs between the two groups. But proteome analysis of CD4 and CD4 lymphocyte populations revealed multiple significant protein abundance differences between -KO and WT pigs, involving pathways related to amino acid metabolism, beta-oxidation of fatty acids, insulin secretion signaling, and oxidative phosphorylation. This study highlights the potential use of -KO pigs as a model for studying the effects of impaired GHR signaling on immune functions.
Topics: Humans; Animals; Swine; Receptors, Somatotropin; Laron Syndrome; Leukocytes, Mononuclear; Proteome; Growth Hormone
PubMed: 37189345
DOI: 10.3390/biom13040597