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Endocrinology, Diabetes & Metabolism... 2017Herein, we present a 14-year-old patient with short stature (134 cm) referred from Paediatrics to our department for complementary evaluation since growth hormone (GH)...
UNLABELLED
Herein, we present a 14-year-old patient with short stature (134 cm) referred from Paediatrics to our department for complementary evaluation since growth hormone (GH) treatment failed to show any improvement. He was born premature and small for gestational age. Genital examination classified the patient as Tanner I-II with small penis and testicular size for his age. Biochemical analyses revealed normal GH levels with low serum insulin-like growth factor-1 (IGF-1). Molecular diagnosis confirmed several mutations in and , and so he was diagnosed with Laron Syndrome or GH insensibility and treated with IGF-1 substitutive therapy.
LEARNING POINTS
Evaluation of the GH/IGF-1 axis when short stature does not respond to conservative treatment must be included in the ordinary practice.Laron Syndrome real incidence should be calculated once undiagnosed cases arise, as treatment, due to lack of market, is unaffordable.Even when adulthood is reached, and no longitudinal growth can be achieved, still IGF-1 treatment in Laron Syndrome patients should be pursued as metabolic and protective derangements could arise.
PubMed: 29147569
DOI: 10.1530/EDM-17-0126 -
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 -
AJNR. American Journal of Neuroradiology Apr 2002Patients with Laron syndrome have an inborn growth hormone resistance. We investigated abnormalities in the upper airways and cervical spine in patients with Laron...
BACKGROUND AND PURPOSE
Patients with Laron syndrome have an inborn growth hormone resistance. We investigated abnormalities in the upper airways and cervical spine in patients with Laron syndrome.
METHODS
We prospectively examined 11 patients (one child aged 9 years and 10 adults aged 36-68 years), 10 of whom underwent MR imaging of the spine or head; nine, radiography of the cervical spine; and four, CT of C1-C2. The width of the spinal canal was evaluated visually and quantitatively and compared with reference values. The smallest diameter of the oropharynx and the thickness of the palate were measured and compared with reference values. Nine age-matched female patients referred for MR imaging for unrelated reasons served as control subjects.
RESULTS
Cervical spinal stenosis was present in seven of the adult patients, within a confidence interval of 95%. Anomaly of the dens compatible with os odontoideum was present in three patients, causing focal myelomalacia in two. The atlanto-odontoid joint showed osteoarthritic changes in six of the adult patients. The mediolateral diameter of the oropharynx was significantly smaller in the patients with Laron syndrome than in the control subjects (P <.005). There was no difference in the thickness of the soft palate.
CONCLUSION
Patients with Laron syndrome develop significant narrowing of the cervical spinal canal and early degenerative changes of the atlanto-odontoid joint. Laron syndrome is associated with os odontoideum causing myelomalacia. The dimensions of the oropharynx are small. Patients may be prone to neurologic morbidity and sleep disturbances. Routine MR imaging of the cervical spine is recommended in these patients.
Topics: Adult; Aged; Atlanto-Axial Joint; Cervical Vertebrae; Child; Dwarfism; Female; Humans; Insulin-Like Growth Factor I; Magnetic Resonance Imaging; Male; Middle Aged; Odontoid Process; Oropharynx; Osteoarthritis; Prospective Studies; Spinal Canal; Spinal Stenosis; Tomography, X-Ray Computed
PubMed: 11950656
DOI: No ID Found -
Diabetes Research and Clinical Practice Feb 2023We examined the effect of growth hormone (GH) counter-regulation on carbohydrate metabolism in individuals with life-long diminished insulin secretion (DIS).
AIMS
We examined the effect of growth hormone (GH) counter-regulation on carbohydrate metabolism in individuals with life-long diminished insulin secretion (DIS).
METHODS
Adults homozygous for the E180 splice site mutation of GHR [Laron syndrome (LS)], adults with a gain-of-function mutation in CDKN1c [Guevara-Rosenbloom syndrome (GRS)], and controls were evaluated for body composition, leptin, total and high molecular weight (HMW) adiponectin, insulin-like growth factor (IGF) axis molecules, and a 5-hour oral glucose tolerance test (OGTT), with measurements of glucose, insulin, glucagon, ghrelin, pancreatic polypeptide, gastric inhibitory peptide, glucagon-like peptide-1, peptide YY, and islet amyloid polypeptide (IAPP).
RESULTS
Both syndromic cohorts displayed DIS during OGTT. LS subjects had higher serum concentrations of total and HMW adiponectin, and lower levels of IGF-I, IGF-II, and IGF-Binding Protein-3 than individuals in other study groups. Furthermore, they displayed normal glycemic responses during OGTT with the lowest IAPP secretion. In contrast, individuals with GRS had higher levels of protein glycation, deficient glucose control during OGTT, and increased secretion of IAPP.
CONCLUSIONS
A distinct metabolic phenotype depending on GH counter-regulatory status, associates with diabetes development and excess glucose-induced IAPP secretion.
Topics: Humans; Insulin Secretion; Adiponectin; Syndrome; Insulin; Human Growth Hormone; Glucose; Islet Amyloid Polypeptide; Phenotype; Insulin-Like Growth Factor I
PubMed: 36549505
DOI: 10.1016/j.diabres.2022.110228 -
Cureus Dec 2022Laron syndrome is a rare, genetic, growth hormone insensitivity disorder caused by mutations in the growth hormone receptor gene. Affected patients have severe postnatal...
Laron syndrome is a rare, genetic, growth hormone insensitivity disorder caused by mutations in the growth hormone receptor gene. Affected patients have severe postnatal growth failure, characteristic facial features, and metabolic abnormalities, including severe obesity and metabolic syndrome. Women with Laron syndrome are usually subfertile, mainly due to obesity and metabolic dysregulation, and require treatment for their chronic reproductive dysfunction. To date, infertility in Laron syndrome patients is a rarely addressed problem and, as a result, adequate data regarding its treatment are lacking. Here we present, for the first time in the literature, a rare case of successful treatment of a young woman with Laron syndrome who suffered from infertility due to hyperprolactinemia.
PubMed: 36721555
DOI: 10.7759/cureus.33090 -
Molecular Metabolism May 2018Laron syndrome (LS) is a rare, autosomal recessive disorder in humans caused by loss-of-function mutations of the growth hormone receptor (GHR) gene. To establish a...
OBJECTIVE
Laron syndrome (LS) is a rare, autosomal recessive disorder in humans caused by loss-of-function mutations of the growth hormone receptor (GHR) gene. To establish a large animal model for LS, pigs with GHR knockout (KO) mutations were generated and characterized.
METHODS
CRISPR/Cas9 technology was applied to mutate exon 3 of the GHR gene in porcine zygotes. Two heterozygous founder sows with a 1-bp or 7-bp insertion in GHR exon 3 were obtained, and their heterozygous F1 offspring were intercrossed to produce GHR-KO, heterozygous GHR mutant, and wild-type pigs. Since the latter two groups were not significantly different in any parameter investigated, they were pooled as the GHR expressing control group. The characterization program included body and organ growth, body composition, endocrine and clinical-chemical parameters, as well as signaling studies in liver tissue.
RESULTS
GHR-KO pigs lacked GHR and had markedly reduced serum insulin-like growth factor 1 (IGF1) levels and reduced IGF-binding protein 3 (IGFBP3) activity but increased IGFBP2 levels. Serum GH concentrations were significantly elevated compared with control pigs. GHR-KO pigs had a normal birth weight. Growth retardation became significant at the age of five weeks. At the age of six months, the body weight of GHR-KO pigs was reduced by 60% compared with controls. Most organ weights of GHR-KO pigs were reduced proportionally to body weight. However, the weights of liver, kidneys, and heart were disproportionately reduced, while the relative brain weight was almost doubled. GHR-KO pigs had a markedly increased percentage of total body fat relative to body weight and displayed transient juvenile hypoglycemia along with decreased serum triglyceride and cholesterol levels. Analysis of insulin receptor related signaling in the liver of adult fasted pigs revealed increased phosphorylation of IRS1 and PI3K. In agreement with the loss of GHR, phosphorylation of STAT5 was significantly reduced. In contrast, phosphorylation of JAK2 was significantly increased, possibly due to the increased serum leptin levels and increased hepatic leptin receptor expression and activation in GHR-KO pigs. In addition, increased mTOR phosphorylation was observed in GHR-KO liver samples, and phosphorylation studies of downstream substrates suggested the activation of mainly mTOR complex 2.
CONCLUSION
GHR-KO pigs resemble the pathophysiology of LS and are an interesting model for mechanistic studies and treatment trials.
Topics: Adiposity; Animals; Body Weight; Growth Hormone; Insulin-Like Growth Factor Binding Protein 2; Insulin-Like Growth Factor Binding Protein 3; Insulin-Like Growth Factor I; Janus Kinase 2; Laron Syndrome; Liver; Mechanistic Target of Rapamycin Complex 2; Receptors, Somatotropin; STAT5 Transcription Factor; Signal Transduction; Swine
PubMed: 29678421
DOI: 10.1016/j.molmet.2018.03.006 -
Journal of Translational Medicine Nov 2012Insulin-like growth factor I (IGF-I) is a polypeptide hormone produced mainly by the liver in response to the endocrine GH stimulus, but it is also secreted by multiple... (Review)
Review
Insulin-like growth factor I (IGF-I) is a polypeptide hormone produced mainly by the liver in response to the endocrine GH stimulus, but it is also secreted by multiple tissues for autocrine/paracrine purposes. IGF-I is partly responsible for systemic GH activities although it possesses a wide number of own properties (anabolic, antioxidant, anti-inflammatory and cytoprotective actions). IGF-I is a closely regulated hormone. Consequently, its logical therapeutical applications seems to be limited to restore physiological circulating levels in order to recover the clinical consequences of IGF-I deficiency, conditions where, despite continuous discrepancies, IGF-I treatment has never been related to oncogenesis. Currently the best characterized conditions of IGF-I deficiency are Laron Syndrome, in children; liver cirrhosis, in adults; aging including age-related-cardiovascular and neurological diseases; and more recently, intrauterine growth restriction. The aim of this review is to summarize the increasing list of roles of IGF-I, both in physiological and pathological conditions, underlying that its potential therapeutical options seem to be limited to those proven states of local or systemic IGF-I deficiency as a replacement treatment, rather than increasing its level upper the normal range.
Topics: Animals; Disease; Growth and Development; Humans; Insulin-Like Growth Factor I; Organ Specificity
PubMed: 23148873
DOI: 10.1186/1479-5876-10-224 -
AJNR. American Journal of Neuroradiology Sep 2011Patients with LS have an inborn growth hormone resistance, resulting in failure to generate IGF-1. The purpose of this study was to evaluate the size of the eye and...
BACKGROUND AND PURPOSE
Patients with LS have an inborn growth hormone resistance, resulting in failure to generate IGF-1. The purpose of this study was to evaluate the size of the eye and orbit in LS.
MATERIALS AND METHODS
We retrospectively reviewed the MR imaging of the brain in 9 patients with LS for the following parameters: axial diameter of the globe, interzygomatic distance, perpendicular distance from the interzygomatic line to margins of the globe, medial-to-lateral diameter of the orbit at the anterior orbital rim, distance from the anterior orbital rim to the anterior globe, maximal distance between the medial walls of the orbits, lateral orbital wall angle, lateral orbital wall length, and mediolateral thickness of the intraorbital fat in the most cranial image of the orbit. All measurements were made bilaterally. Twenty patients referred for MR imaging for unrelated reasons served as control subjects.
RESULTS
Compared with the control group, the patients with LS had a significantly smaller maximal globe diameter and shallower but wider orbits due to a shorter lateral wall, a smaller medial distance between the orbits, and a larger angle of the orbit. The ratio between the most anterior orbital diameter and the globe was greater than that in controls. The position of the globe was more anterior in relation to the interzygomatic line.
CONCLUSIONS
Shallow and wide orbits and small globes relative to orbital size are seen in LS and may be secondary to IGF-1 deficiency.
Topics: Adult; Aged; Eye; Female; Humans; Laron Syndrome; Male; Middle Aged; Orbit; Organ Size; Retrospective Studies
PubMed: 21757529
DOI: 10.3174/ajnr.A2573 -
The Journal of Clinical Endocrinology... Oct 2021Growth hormone insensitivity (GHI) in children is characterized by short stature, functional insulin-like growth factor (IGF)-I deficiency, and normal or elevated serum...
CONTEXT
Growth hormone insensitivity (GHI) in children is characterized by short stature, functional insulin-like growth factor (IGF)-I deficiency, and normal or elevated serum growth hormone (GH) concentrations. The clinical and genetic etiology of GHI is expanding.
OBJECTIVE
We undertook genetic characterization of short stature patients referred with suspected GHI and features which overlapped with known GH-IGF-I axis defects.
METHODS
Between 2008 and 2020, our center received 149 GHI referrals for genetic testing. Genetic analysis utilized a combination of candidate gene sequencing, whole exome sequencing, array comparative genomic hybridization, and a targeted whole genome short stature gene panel.
RESULTS
Genetic diagnoses were identified in 80/149 subjects (54%) with 45/80 (56%) having known GH-IGF-I axis defects (GHR n = 40, IGFALS n = 4, IGFIR n = 1). The remaining 35/80 (44%) had diagnoses of 3M syndrome (n = 10) (OBSL1 n = 7, CUL7 n = 2, and CCDC8 n = 1), Noonan syndrome (n = 4) (PTPN11 n = 2, SOS1 n = 1, and SOS2 n = 1), Silver-Russell syndrome (n = 2) (loss of methylation on chromosome 11p15 and uniparental disomy for chromosome 7), Class 3-5 copy number variations (n = 10), and disorders not previously associated with GHI (n = 9) (Barth syndrome, autoimmune lymphoproliferative syndrome, microcephalic osteodysplastic primordial dwarfism type II, achondroplasia, glycogen storage disease type IXb, lysinuric protein intolerance, multiminicore disease, macrocephaly, alopecia, cutis laxa, and scoliosis syndrome, and Bloom syndrome).
CONCLUSION
We report the wide range of diagnoses in 149 patients referred with suspected GHI, which emphasizes the need to recognize GHI as a spectrum of clinical entities in undiagnosed short stature patients. Detailed clinical and genetic assessment may identify a diagnosis and inform clinical management.
Topics: Adolescent; Adult; Biomarkers; Body Height; Child; Child, Preschool; Comparative Genomic Hybridization; DNA Copy Number Variations; Female; Follow-Up Studies; Genetic Testing; Growth Disorders; Human Growth Hormone; Humans; Infant; Insulin-Like Growth Factor I; Laron Syndrome; Male; Prognosis; Young Adult
PubMed: 34136918
DOI: 10.1210/clinem/dgab437 -
The Journals of Gerontology. Series A,... Jun 2012This review focuses on cardiovascular protective effects of insulin-like growth factor (IGF)-1, provides a landscape of molecular mechanisms involved in cardiovascular... (Review)
Review
This review focuses on cardiovascular protective effects of insulin-like growth factor (IGF)-1, provides a landscape of molecular mechanisms involved in cardiovascular alterations in patients and animal models with congenital and adult-onset IGF-1 deficiency, and explores the link between age-related IGF-1 deficiency and the molecular, cellular, and functional changes that occur in the cardiovascular system during aging. Microvascular protection conferred by endocrine and paracrine IGF-1 signaling, its implications for the pathophysiology of cardiac failure and vascular cognitive impairment, and the role of impaired cellular stress resistance in cardiovascular aging considered here are based on emerging knowledge of the effects of IGF-1 on Nrf2-driven antioxidant response.
Topics: Aging; Animals; Cardiovascular Diseases; Cognition Disorders; Disease Models, Animal; Female; Heart Failure; Humans; Insulin-Like Growth Factor I; Laron Syndrome; Male; Mice; Microvessels; NF-E2-Related Factor 2; Paracrine Communication; Rats
PubMed: 22451468
DOI: 10.1093/gerona/gls072