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The Journal of Clinical Endocrinology... Dec 1999Fifty patients with primary GH resistance (Laron syndrome) due to molecular defects of the GH receptor or post-receptor pathways were followed from infancy through... (Review)
Review
Fifty patients with primary GH resistance (Laron syndrome) due to molecular defects of the GH receptor or post-receptor pathways were followed from infancy through adulthood. This condition leading to long-term insulin-like growth factor-I (IGF-I) deprivation caused marked growth retardation (-4 to 8 height SD), acromicia, organomicria, retarded development of the skeletal and muscular systems, a small cranium, slow motor development, and impairment of intellectual development in some of the patients. In addition, there was progressive obesity, insulin resistance, a tendency for hypoglycemia, followed later in life by hypercholesterolemia and by glucose intolerance and even diabetes. IGF-I treatment of children with Laron syndrome, by our and other groups (150-240 microg/day sc), stimulated growth (8 cm in the first year and 4-5 cm in the following years) and normalized the biochemical abnormalities. Overdosage led to adverse effects such as hypoglycemia, edema, swelling of soft tissues, and hyperandrogenism. It is concluded that primary IGF-I deprivation induces severe auxological, biochemical, and hormonal changes, the only treatment being biosynthetic IGF-I administration.
Topics: Adolescent; Adult; Child; Child, Preschool; Drug Resistance; Female; Human Growth Hormone; Humans; Insulin-Like Growth Factor I; Male; Mutation; Receptors, Somatotropin; Recombinant Proteins
PubMed: 10599694
DOI: 10.1210/jcem.84.12.6255 -
Genetics and Molecular Biology 2020Laron's syndrome (LS) is a rare genetic disorder characterized by insensitivity to growth hormone (GH). Up to the present time, over 70 mutations of GH receptor (GHR)...
Laron's syndrome (LS) is a rare genetic disorder characterized by insensitivity to growth hormone (GH). Up to the present time, over 70 mutations of GH receptor (GHR) gene have been identified leading to GH/insulin-like growth factor type 1 (IGF1) signaling pathway defect. The number of LS patients worldwide is unknown, as many are probably undiagnosed. We report two sibs from a consanguineous family from Minas Gerais, southeastern Brazil. The parents have three children. The older, a 4-years-old girl was 80.2 cm tall (-5.7 SDS height/age), and the youngest sister, aged 3 years, was 73.2 cm tall (-5.82 SDS height/age). Their clinical and biochemical features are typical of LS patients, such as high serum level of GH and low IGF1 concentrations. A homozygous c.1A>T nucleotide substitution in GHR exon 2 in the probands' samples was identified. Their parents and healthy sister are heterozygous for the same variant that abolishes the translation initiation codon of GHR. This mutation has not been reported in Brazilian patients and was previously associated with an LS phenotype in a single 29-year-old Spanish man. In addition to this case report, we summarize the main characteristics and molecular data of the 21 LS Brazilian patients who have been published to date.
PubMed: 31429861
DOI: 10.1590/1678-4685-GMB-2018-0197 -
Endocrine Connections Aug 2021Animal studies suggest that insulin-like growth factor 1 (IGF1) may influence the function of the hypothalamus-pituitary-testicular axis, especially in childhood, but...
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 keywords were used. All data on male patients with Laron syndrome were included.
RESULTS
Seventeen articles matched the inclusion criteria and were 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 five out of five patients of pubertal age. No effect was found in four out of four 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.
PubMed: 34319907
DOI: 10.1530/EC-21-0252 -
Acta Endocrinologica (Bucharest,... 2016Levels of insulin-like growth factor-I are characteristically low in Laron syndrome which is a factor that has important roles on vascular health and development....
BACKGROUND AND OBJECTIVES
Levels of insulin-like growth factor-I are characteristically low in Laron syndrome which is a factor that has important roles on vascular health and development. Congenital insulin-like growth factor-I deficiency was reported to be associated with some vascular disorders. However, vasculitis diseases and Laron Syndrome association has not been reported in English literature up to date.
PATIENT
We report the case of a two and a half years old Turkish girl, who was diagnosed as Laron syndrome when she was 12 months old. She presented with acute vasculitis lesions. Her physical examination and laboratory studies did not reveal a specific infectious agent or also an autoimmune disease was not detected. Her lesions disappeared during hospitalization without a complication.
CONCLUSION
Since insulin-like growth factor-I reduces endothelial cell oxidative stress and maintains the structural integrity of vessels, some common mechanisms might be responsible for the occurrence of vasculitis in this patient with Laron syndome. The role of insulin-like growth factor-I and recombinant human insulin-like growth factor-I treatment choice in vasculitis diseases is a matter of investigation.
PubMed: 31149133
DOI: 10.4183/aeb.2016.465 -
European Journal of Endocrinology Feb 2021The European Increlex® Growth Forum Database Registry monitors the effectiveness and safety of recombinant human insulin-like growth factor-1 (rhIGF1; mecasermin,... (Observational Study)
Observational Study
OBJECTIVE
The European Increlex® Growth Forum Database Registry monitors the effectiveness and safety of recombinant human insulin-like growth factor-1 (rhIGF1; mecasermin, Increlex®) therapy in patients with severe primary IGF1 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 rhIGF1 therapy from 10 European countries were enrolled in 2008-2017 (n = 242). The treatment-naïve/prepubertal (NPP) cohort (n = 138) was divided into subgroups based on reported genetic diagnosis of 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). In 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 years vs 7.00 years) at baseline and height SDS gain in year 1 (0.64 vs 0.70), although NPP-non-LS-responders were taller (P < 0.001) at baseline. BMI 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, rhIGF1 therapy promotes linear growth. The safety profile was consistent with previous studies.
Topics: Adolescent; Body Height; Body Weight; Child; Female; Growth; Growth Disorders; Hearing Loss, Sensorineural; Humans; Hypoglycemia; Insulin-Like Growth Factor I; Laron Syndrome; Longitudinal Studies; Male; Patient Safety; Puberty; Recombinant Proteins; Treatment Outcome; Young Adult
PubMed: 33434161
DOI: 10.1530/EJE-20-0325 -
International Journal of Molecular... Nov 2021The 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,...
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.
Topics: 3' Untranslated Regions; Adult; Case-Control Studies; Cell Line; Cell Proliferation; Female; Humans; Insulin-Like Growth Factor I; Laron Syndrome; Longevity; MicroRNAs; Middle Aged; Sirtuin 1; Up-Regulation
PubMed: 34769292
DOI: 10.3390/ijms222111861 -
Reviews in Endocrine & Metabolic... Mar 2021Growth hormone (GH) induces pleiotropic effects on growth and metabolism via binding and subsequent activation of the growth hormone receptor (GHR) and its downstream... (Review)
Review
Growth hormone (GH) induces pleiotropic effects on growth and metabolism via binding and subsequent activation of the growth hormone receptor (GHR) and its downstream signaling pathways. Growth hormone insensitivity (GHI) describes a group of disorders in which there is resistance to the action of GH and resultant insulin-like growth factor I (IGF-I) deficiency. GHI is commonly due to genetic disorders of the GH receptor causing GH receptor deficiency (e.g. Laron Syndrome (LS)), decreased activation of GHR, or defects in post-receptor signaling molecules. Genetically altered mouse lines have been invaluable to better understand the physiological impact of GHI due to the ability to do invasive and longitudinal measures of metabolism, growth, and health on a whole animal or in individual tissues/cells. In the current review, the phenotype of mouse lines with GHI will be reviewed. Mouse lines to be discussed include: 1) GHR-/- mice with a gene disruption in the GHR that results in no functional GHR throughout life, also referred to as the Laron mouse, 2) mice with temporal loss of GHR (aGHRKO) starting at 6 weeks of age, 3) mice transgenic for a GHR antagonist (GHA mice), 4) mice with GHI in select tissues or cells generated via Cre-lox or related technology, and 5) assorted mice with defects in post-receptor signaling molecules. Collectively, these mouse lines have revealed an intriguing role of GH action in health, disease, and aging.
Topics: Animals; Growth Disorders; Growth Hormone; Human Growth Hormone; Humans; Insulin-Like Growth Factor I; Laron Syndrome; Mice; Receptors, Somatotropin
PubMed: 33037595
DOI: 10.1007/s11154-020-09600-6 -
Pediatric Endocrinology Reviews : PER Mar 2008Laron syndrome (LS, congenital primary GH insensitivity) is caused by deletions or mutations in the GH receptor gene, resulting in an inability to generate insulin-like... (Review)
Review
Laron syndrome (LS, congenital primary GH insensitivity) is caused by deletions or mutations in the GH receptor gene, resulting in an inability to generate insulin-like growth factor-I (IGF-I). If untreated, the deficiency of IGF-I results in severe dwarfism, as well as skeletal and muscular underdevelopment. The only treatment is the daily administration of recombinant IGF-I. This review summarizes the present experience by several groups worldwide. The main conclusions are: A. The one or two injections regimen result in the same growth velocity; B. The growth velocity obtained with IGF-I administration is smaller than that observed with hGH in children with congenital isolated GH deficiency; C. Overdosage of IGF-I causes a series of adverse effects which can be avoided by carefully monitoring the serum IGF-I and GH levels.
Topics: Child; Humans; Insulin-Like Growth Factor I; Laron Syndrome
PubMed: 18367997
DOI: No ID Found -
Endocrine Jun 2024
Topics: Humans; Brain; Female; Magnetic Resonance Imaging; Adult; Male
PubMed: 38580893
DOI: 10.1007/s12020-024-03762-y -
Journal of Controlled Release :... Jan 2013Recombinant human IGF-1 currently represents the only available treatment option for the Laron Syndrome, a rare human disorder caused by defects in the gene encoding...
Recombinant human IGF-1 currently represents the only available treatment option for the Laron Syndrome, a rare human disorder caused by defects in the gene encoding growth hormone receptor, resulting in irreversibly retarded growth. Unfortunately, this treatment therapy, poorly impacts longitudinal growth (13% in females and 19% in males), while burdening the patients with severe side effects, including hypoglycemia, in association with the unfair chore of taking multiple daily injections that cause local intense pain. In this study, we have demonstrated that a single intraperitoneal graft of microencapsulated pig Sertoli cells, producing pig insulin-like growth factor-1, successfully promoted significant proportional growth in the Laron mouse, a unique animal model of the human Laron Syndrome. These findings indicate a novel, simply, safe and successful method for the cell therapy-based cure of the Laron Syndrome, potentially applicable to humans.
Topics: Alginates; Animals; Body Weight; Bone Development; Disease Models, Animal; Drug Compounding; Female; Glucuronic Acid; Hexuronic Acids; Insulin-Like Growth Factor I; Laron Syndrome; Male; Mice; Mice, Transgenic; Receptors, Somatotropin; Sertoli Cells; Swine; Transplantation, Heterologous
PubMed: 22964394
DOI: 10.1016/j.jconrel.2012.08.028