MicroRNA 132-3p Is Upregulated in Laron Syndrome Patients and Controls Longevity Gene Expression

The growth hormone (GH)–insulin-like growth factor-1 (IGF1) endocrine axis is a central player in normal growth and metabolism as well as in a number of pathologies, including cancer. The GH–IGF1 hormonal system, in addition, has emerged as a major determinant of lifespan and healthspan. Laron syndrome (LS), the best characterized entity under the spectrum of the congenital IGF1 deficiencies, results from mutation of the GH receptor (GHR) gene, leading to dwarfism, obesity and other defects. Consistent with the key role of IGF1 in cellular proliferation, epidemiological studies have shown that LS patients are protected from cancer development. While reduced expression of components of the GH-IGF1 axis is associated with enhanced longevity in animal models, it is still unknown whether LS is associated with an increased lifespan. MicroRNAs (miRs) are endogenous short non-coding RNAs that regulate the expression of complementary mRNAs. While a number of miRs involved in the regulation of IGF components have been identified, no previous studies have investigated the differential expression of miRs in congenital IGF1 deficiencies. The present study was aimed at identifying miRs that are differentially expressed in LS and that might account for the phenotypic features of LS patients, including longevity. Our genomic analyses provide evidence that miR-132-3p was highly expressed in LS. In addition, we identified SIRT1, a member of the sirtuin family of histone deacetylases, as a target for negative regulation by miR-132-3p. The data was consistent with the notion that low concentrations of IGF1 in LS lead to elevated miR-132-3p levels, with ensuing reduction in SIRT1 gene expression. The impact of the IGF1-miR-132-3p-SIRT1 loop on aging merits further investigation.

Laron syndrome in three female siblings with the development of subclinical hypothyroidism and dyslipidemia in one case: first report of a Syrian family

ABSTRACT Laron syndrome (LS) is a rare autosomal recessive disorder characterized by dwarfism and typical facial phenotype. This report is the first to present three cases of Laron syndrome affecting three female siblings from Syria. The index case presented at age of 8.5 years with severe short stature: low level of Insulin-like growth factor 1 (IGF-1), elevated levels of fasting and post-stimulation growth hormone (GH), consistent with the diagnosis of Laron syndrome. At the age of 9.5 years, she developed non-autoimmune subclinical hypothyroidism treated with Levothyroxine, then she developed dyslipidemia at the age of 11.3 years. Later, we identified two female siblings of the patient with Laron syndrome. Laron syndrome is a rare genetic disease, reporting of new cases of this rare syndrome must encourage pediatricians to develop high clinical suspicion if faced with patients with very short stature and typical facial features.

Role of the GH-IGF1 axis on the hypothalamus-pituitary-testicular axis function: lessons from Laron syndrome

BACKGROUND. Animal studies suggest that insulin-like growth factor 1 (IGF1) may influence the function of the hypothalamus-pituitary-testicular axis, especially in childhood, but the evidence in humans is scanty. Laron syndrome, a human model of IGF1 deficiency, may help to solve this issue. PURPOSE. This systematic review aims to analyze puberty onset and progression, testicular volume, gonadotropin, and total testosterone serum levels, sperm parameters and fertility, and penile length in patients with Laron syndrome. METHODS. Specific key-words were used. All data on male patients with Laron syndrome were included. RESULTS. Seventeen articles matched the inclusion criteria and entered in the analysis, for a total of 125 male patients. Puberty was absent in 8.9% and delayed in 35.6% of untreated patients of pubertal age. After onset, the duration of the pubertal process was prolonged in 76.9% of untreated patients. The growth spurt was absent in 52.6% and delayed in 31.6% of untreated patients. The testicular volume was small in the two patients who did not receive any treatment. Treatment with IGF1 increased gonadotropin and testosterone serum levels in 5 out of 5 patients of pubertal age. No effect was found in 4 out of 4 patients younger than 5 years. No study reported data on sperm parameters and fertility. Micropenis occurred in 67.2% of patients. CONCLUSION AND FUTURE PERSPECTIVES. Delayed puberty is common in patients with Laron syndrome. The growth hormone-IGF1 axis may influence the time of puberty onset. Serum levels of IGF1 should be investigated in children with delayed puberty, scarce progression of testicular growth, and/or micropenis.IGF1 levels might be measured in children with delayed puberty, poor testicular growth, and/or micropenis.

Mild phenotype in two siblings with a missense GHR variant

Objectives Laron syndrome (LS) is a disease caused by growth hormone receptor (GHR) defects. It is characterized by severe postnatal growth retardation and distinctive facial features. Case presentation In this case report, we describe the clinical and biochemical characteristics of two siblings with LS, a sister and a brother, and identify a homozygous c.344A> C (p.Asn115Thr) variant in GHR. The sister was 11 years 9 months old with a height of 127.5 cm (-3.86 SDS), and the brother was 14 years 10 months old with a height of 139 cm (-4.27 SDS). Their phenotype did not have features suggesting classical LS. Conclusion In the current literature, there are three cases with the same missense variant. Our cases differ from them in clinical (higher height SDS, mild dysmorphism including a broad forehead, malar hypoplasia, prominent columella and chin, thick lips) and biochemical characteristics. Here, we present the variable expressivity in the two siblings.

Laron syndrome: a case report

Laron syndrome (LS) is a rare, genetic disorder inherited in an autosomal recessive manner. The disease is caused by mutations of the growth hormone (GH) gene, leading to GH/insulin-like growth factor type 1 (IGF1) signalling pathway defect. A 13-month-old, male child, born of second-degree consanguineous marriage presented with short stature (57 cm, below- 3 SD) with normal head size, mild motor developmental delay, micropenis and bone age of 9 months. Basal GH was 28.7 ng/ml (normal 1-13.6 ng/ml). IGF-1 was less than 20 ng/ml (normal up to 170 ng/ml). GH stimulation test done using clonidine revealed increased levels. Post stimulation levels at 30 min, 60 min, 90 min (ng/ml) were 29.3, 37.9, 29.3 respectively, which was suggestive of resistance to GH that is laron dwarfism. Treatment is focused on improving growth and generally includes injections of insulin-like growth factor 1 (IGF-1). This case is being reported for its rarity and early detection.

Transient juvenile hypoglycemia in growth hormone receptor deficiency – mechanistic insights from Laron syndrome and tailored animal models

Aim of the study is to find possible explanations for vanishing juvenile hypoglycemia in growth hormone receptor deficiency (GHRD) in human patients and animal models. We reviewed parameters of glucose metabolism in distinct age groups in two human cohorts (Israeli and Ecuadorian) of Laron syndrome (LS) patients, a mouse model (Ghr-KO mouse) and provide additional data for a porcine model (GHR-KO pig). Juvenile hypoglycemia is a common symptom of GHRD and vanishes in adulthood. In the Israeli cohort, developing metabolic syndrome is associated with decreasing insulin sensitivity, insulinopenia and glucose intolerance, increasing glucose levels with age. In Ecuadorian patients and both animal models, insulin sensitivity is preserved or even enhanced. Alterations in food intake and energy consumption do not explain the differences in glucose levels, neither is the accumulation of body fat associated with negative effects in the Ecuadorian cohort or the animal models. A reduced beta cell mass and resulting insulin secretory capacity is common and leads to glucose intolerance in Ghr-KO mice, while glucose tolerance is preserved in Ecuadorian patients and the GHR-KO pig. In human patients and the GHR-KO pig, a simultaneous occurrence of normoglycemia with the onset of puberty is reported. Reduced gluconeogenesis in GHRD is discussed to cause the juvenile hypoglycemia and a counter regulatory stimulation of gluconeogenesis can be hypothesized. A coherent study assessing endogenous glucose production and beta-cell capacity in the hypoglycemic and normoglycemic age group is needed. This can be performed in GHR-KO pigs, including castrated animals.

Identification and In Vitro Functional Verification of Two Novel Mutations of GHR Gene in the Chinese Children with Laron Syndrome

PurposeLaron syndrome (LS) is a severe growth disorder caused by GHR gene mutation or post-receptor pathways defect. The clinical features of these patients collected in our present study were summarized, GHR gene variants were investigated and further in vitro functional verification was carried out.MethodsFour patients with LS were collected, their clinical characteristics were summarized, genomic DNA was extracted, and GHR gene was amplified and sequenced. GHR wild type (GHR-WT) and mutant GHR expression plasmids were constructed, and transiently transfected into HepG2 cells and HEK293T cells to observe the subcellular distribution of the GHR protein by immunofluorescence and to determine the expression of GHR and its post-receptor signaling pathway changes by Western blotting.ResultsAll of the four patients were male, and the median height was -4.72 SDS. Four GHR gene variants including c.587A>C (p.Y196S), c.766C>T (p.Q256*), c.808A>G (p.I270V) and c.1707-1710del (p.E570Afs*30) were identified, and the latter two were novel mutations. The results of mutant GHR plasmids transfection experiments and immunofluorescence assay showed that the subcellular distribution of GHR-Q256* and GHR-E570Afs*30 mutant proteins in HepG2 and HEK293T cells presented with a unique ring-like pattern, gathering around the nucleus, while GHR-Y196S mutant protein was evenly distributed on HepG2 cell membrane similar to GHR-WT. The GHR protein levels of HepG2 cells transiently transfected with GHR-Y196S, GHR-Q256* and GHR-E570Afs*30 were all significantly lower when compared with cells transfected with GHR-WT (P<0.05). Further mutant GHR post-receptor signal transduction investigation demonstrated that GH induced phosphorylated STAT5 levels of HepG2 cells transfected with three mutant plasmids were all significantly decreased in comparison with that of GHR-WT (P<0.05).ConclusionsTwo novel GHR gene mutations (I270V and E570Afs*30) were found in our patients with LS. GHR mutations influenced the subcellular distribution and GHR protein levels, then led to the impaired post-receptor signal transduction, suggesting that the GHR mutations contributed to the pathological condition of LS patients.

Laron Syndrome Research Paves the Way for New Insights in Oncological Investigation

Laron syndrome (LS) is a rare genetic endocrinopathy that results from mutation of the growth hormone receptor (GH-R) 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 ‘mining’ genomic data from LS patients, we were able to generate clinically-relevant information in oncology and, potentially, related disciplines.

Effectiveness and safety of rhIGF-1 therapy in patients with or without Laron syndrome

Objective The European Increlex® Growth Forum Database Registry monitors effectiveness and safety of recombinant human insulin-like growth factor-1 (rhIGF-1; mecasermin, Increlex®) therapy in patients with severe primary IGF-1 deficiency (SPIGFD). We present data from patients with and without a reported genetic diagnosis of Laron syndrome (LS). Design Ongoing, open-label, observational registry (NCT00903110). Methods Children and adolescents receiving rhIGF-1 therapy from 10 European countries were enrolled 2008-2017 (N = 242). The treatment-naïve/prepubertal (NPP) cohort (N = 138) was divided into subgroups based on reported genetic diagnosis of Laron syndrome (LS, N = 21 or non-LS, N = 117). Multivariate analysis of the NPP-non-LS subgroup was conducted to identify factors predictive of growth response (first-year-height standard deviation score [SDS] gain ≥0.3). Assessments included change in height and weight over 5 years and adverse events (AEs). Results Height SDS gain from baseline was greater in the NPP-LS than the NPP-non-LS subgroup after 1 years’ treatment (P<0.05). Among the NPP-non-LS subgroup, 56% were responders; young age at baseline was a positive independent predictive factor (P<0.001). NPP-non-LS-responders and the NPP-LS subgroup had a similar mean age (6.07 versus 7.00 years) at baseline and height SDS gain in year 1 (0.64 versus 0.70), although, NPP-non-LS-responders were taller (P<0.001) at baseline. Body mass index SDS changes did not differ across subgroups. Treatment-emergent AEs were experienced by 65.3% of patients; hypoglycaemia was most common. Conclusions In most NPP children with SPIGFD, with or without LS, rhIGF-1 therapy promotes linear growth. The safety profile was consistent with previous studies.