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The Indian Journal of Medical Research Nov 2020
Topics: Anemia, Aplastic; Fanconi Anemia; Humans; Laron Syndrome
PubMed: 35345205
DOI: 10.4103/ijmr.IJMR_2317_19 -
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 -
Reviews in Endocrine & Metabolic... Mar 2021Growth hormone insensitivity (GHI) syndrome, first described in 1966, is classically associated with monogenic defects in the GH receptor (GHR) gene which result in... (Review)
Review
Growth hormone insensitivity (GHI) syndrome, first described in 1966, is classically associated with monogenic defects in the GH receptor (GHR) gene which result in severe post-natal growth failure as consequences of insulin-like growth factor I (IGF-I) deficiency. Over the years, recognition of other monogenic defects downstream of GHR has greatly expanded understanding of primary causes of GHI and growth retardation, with either IGF-I deficiency or IGF-I insensitivity as clinical outcomes. Mutations in IGF1 and signaling component STAT5B disrupt IGF-I production, while defects in IGFALS and PAPPA2, disrupt transport and release of circulating IGF-I, respectively, affecting bioavailability of the growth-promoting IGF-I. Defects in IGF1R, cognate cell-surface receptor for IGF-I, disrupt not only IGF-I actions, but actions of the related IGF-II peptides. The importance of IGF-II for normal developmental growth is emphasized with recent identification of defects in the maternally imprinted IGF2 gene. Current application of next-generation genomic sequencing has expedited the pace of identifying new molecular defects in known genes or in new genes, thereby expanding the spectrum of GH and IGF insensitivity. This review discusses insights gained and future directions from patient-based molecular and functional studies.
Topics: Abnormalities, Multiple; Growth Disorders; Growth Hormone; Human Growth Hormone; Humans; Insulin-Like Growth Factor I; Laron Syndrome; Mutation
PubMed: 33029712
DOI: 10.1007/s11154-020-09603-3 -
Molecular and Cellular Pediatrics Sep 2020Linear bone growth is achieved by the division of chondrocytes at the growth plate and is regulated by endocrine and paracrine factors such as growth hormone. Mutations...
BACKGROUND
Linear bone growth is achieved by the division of chondrocytes at the growth plate and is regulated by endocrine and paracrine factors such as growth hormone. Mutations that negatively affect chondrogenesis can be a contributor to short stature. One such mutation can occur in the ACAN gene, causing short stature and advanced bone age. Similarly, mutations in growth hormone receptors (GHR) can lead to Laron syndrome (LS), one of the several disorders that are collectively called growth hormone insensitivity syndrome (GHI). Another example is Floating-Harbor syndrome (FHS), a rare autosomal dominant due to mutations in the SRCAP gene that can also result in short stature.
CASE PRESENTATION
We report the case of a 6-year-old female with concomitant mutations in the three genes mentioned above. The mutations reported here were found on genetic studies and are usually benign, causing a variant of undetermined significance. However, our patient's phenotype could only be explained by the compounded effects of pathogenic mutations of these genes. Some of the same mutations were also found in the patient's father and her paternal grandfather. Both also presented with short stature, though not to the same degree as our patient. While these mutations are often reported to be insignificant, they gave rise to severe short stature and a specific phenotype in the patient when presented together. We think that even though the GHI spectrum is inherited through an autosomal recessive pattern, the sum of these heterozygous mutations resulted in severe short stature despite the limited GHI seen in our patient, the father, and the grandfather, through a rare ACAN and SRCAP mutation that, to our knowledge, has not been previously reported as a pathogenic mutation in the literature.
CONCLUSION
We investigated the possible synergistic effects of these variations on exacerbation or masking of the signs and symptoms of GHI with the hope of providing a better understanding of these genes and their function through our rare case.
PubMed: 32935225
DOI: 10.1186/s40348-020-00104-6 -
Malaysian Orthopaedic Journal Mar 2020Marjolin's ulcer is an atypical malignancy that develops from deep scars of chronically traumatised skin. Laron syndrome (LS) is a rare autosomal recessive growth...
Marjolin's ulcer is an atypical malignancy that develops from deep scars of chronically traumatised skin. Laron syndrome (LS) is a rare autosomal recessive growth retardation from a mutation in the growth hormone receptor (GHR) gene leading to defective GHR, growth hormone insensitivity and eventual low levels of insulin-like growth factor type 1 (IGF-1). Affected individuals present with proportionate dwarfism and other characteristic physical defects, but at the same time are conferred protection against cancer due to low serum levels of IGF-1. We report an exceptional case of Marjolin's ulcer in the foot of a female LS patient 30 years after she sustained flame burns as a 6-month-old baby. Three months before coming to us, she had a 2x3cm ulcer that turned into a rapidly enlarging fungating mass involving the leg, ankle, and foot. Histopathologic analysis of an incision biopsy showed well-differentiated squamous cell carcinoma. The extent of her lesion precluded wide excision. Below knee amputation was done. A second biopsy confirmed the histopathologic diagnosis. This is the first reported case in the literature of Marjolin's ulcer in LS which raises the possibility that IGF-1 deficiency does not completely protect against squamous cell cancer.
PubMed: 32296486
DOI: 10.5704/MOJ.2003.012 -
Molecular Metabolism Jun 2020The liver is a central target organ of growth hormone (GH), which stimulates the synthesis of insulin-like growth factor 1 (IGF1) and affects multiple biochemical...
OBJECTIVE
The liver is a central target organ of growth hormone (GH), which stimulates the synthesis of insulin-like growth factor 1 (IGF1) and affects multiple biochemical pathways. A systematic multi-omics analysis of GH effects in the liver has not been performed. GH receptor (GHR) deficiency is a unique model for studying the consequences of lacking GH action. In this study, we used molecular profiling techniques to capture a broad spectrum of these effects in the liver of a clinically relevant large animal model for Laron syndrome.
METHODS
We performed holistic proteome and targeted metabolome analyses of liver samples from 6-month-old GHR-deficient (GHR-KO) pigs and GHR-expressing controls (four males, four females per group).
RESULTS
GHR deficiency resulted in an increased abundance of enzymes involved in amino acid degradation, in the urea cycle, and in the tricarboxylic acid cycle. A decreased ratio of long-chain acylcarnitines to free carnitine suggested reduced activity of carnitine palmitoyltransferase 1A and thus reduced mitochondrial import of fatty acids for beta-oxidation. Increased levels of short-chain acylcarnitines in the liver and in the circulation of GHR-KO pigs may result from impaired beta-oxidation of short-chain fatty acids or from increased degradation of specific amino acids. The concentration of mono-unsaturated glycerophosphocholines was significantly increased in the liver of GHR-KO pigs without morphological signs of steatosis, although the abundances of several proteins functionally linked to non-alcoholic fatty liver disease (fetuin B, retinol binding protein 4, several mitochondrial proteins) were increased. Moreover, GHR-deficient liver samples revealed distinct changes in the methionine and glutathione metabolic pathways, in particular, a significantly increased level of glycine N-methyltransferase and increased levels of total and free glutathione. Several proteins revealed a sex-related abundance difference in the control group but not in the GHR-KO group.
CONCLUSIONS
Our integrated proteomics/targeted metabolomics study of GHR-deficient and control liver samples from a clinically relevant large animal model identified a spectrum of biological pathways that are significantly altered in the absence of GH action. Moreover, new insights into the role of GH in the sex-related specification of liver functions were provided.
Topics: Animals; Female; Gene Knockout Techniques; Growth Hormone; Laron Syndrome; Liver; Male; Metabolomics; Models, Animal; Non-alcoholic Fatty Liver Disease; Protein Binding; Protein Transport; Proteomics; Receptors, Somatotropin; Signal Transduction; Swine
PubMed: 32277923
DOI: 10.1016/j.molmet.2020.100978 -
Journal of Postgraduate Medicine 2020[This corrects the article DOI: 10.4103/0022-3859.138816].
[This corrects the article DOI: 10.4103/0022-3859.138816].
PubMed: 32270785
DOI: 10.4103/0022-3859.169761 -
BMJ Case Reports Feb 2020In Ecuador, a developing South American country, subjects affected with genetic syndromes of severe short stature are commonly referred to as dwarfs or midgets....
In Ecuador, a developing South American country, subjects affected with genetic syndromes of severe short stature are commonly referred to as dwarfs or midgets. Furthermore, and because in earlier studies some patients had evidenced mental retardation, such abnormality is assumed to exist in all affected subjects. Herein, we present two discrete instances in which this type of branding occurs. The first is that of individuals with Laron syndrome who are still called 'dwarfs' and considered as having a degree of mental retardation despite evidence showing otherwise. A similar problem, that of a girl affected with a genetic syndrome of short stature, which might include mental retardation, is also discussed. Considering that stigmatising is a form of discrimination, it concerns us all. Hence, the use of derogatory terms such as midget, dwarf or cretin, that might unintentionally occur even when delivering the best and most devoted medical care, must be eliminated.
Topics: Attitude of Health Personnel; Child, Preschool; De Lange Syndrome; Developing Countries; Ecuador; Female; Human Growth Hormone; Humans; Laron Syndrome; Male; Middle Aged; Pregnancy; Pregnancy Complications; Repressor Proteins; Stereotyping; Terminology as Topic
PubMed: 32041755
DOI: 10.1136/bcr-2019-231737 -
Clinical Endocrinology Apr 2020To report a novel mutation in GHR and to characterize a novel mechanism of nonclassical growth hormone insensitivity.
OBJECTIVE
To report a novel mutation in GHR and to characterize a novel mechanism of nonclassical growth hormone insensitivity.
CONTEXT
Laron syndrome (LS) is a well-described disorder of growth hormone insensitivity due to mutations in the growth hormone receptor (GHR) that leads to short stature. Biochemically, LS patients classically have elevated levels of growth hormone (GH), but low levels of insulin-like growth factor (IGF)-1, IGF binding protein (IGFBP)-3 and GH binding protein (GHBP).
DESIGN
Case presentation with in vitro functional studies.
PATIENTS
A young male Caucasian child with short stature was found to have growth hormone insensitivity manifested by elevated levels of GH and GHBP.
MEASUREMENTS
Growth hormone stimulation tests revealed baseline GH level of 20.9 µg/L and maximum stimulated GH level of 52.7 µg/L and GHBP level of 4868 pmol/L. GHR gene sequencing revealed a novel heterozygous nonsense mutation (c.800G > A, p.Trp267*) in the transmembrane domain of the receptor. Immunoblot analysis of transfected GHR p.Trp267* in HEK293 revealed inhibition of GH-induced STAT5 signalling that was overcome with increasing doses of recombinant human GH.
RESULTS
Using an in vitro model, we show that elevated levels of GHBP inhibit the action of GH. Furthermore, our studies demonstrate that this inhibition by GHBP can be overcome by increasing doses of recombinant human GH.
CONCLUSIONS
To our knowledge, this is the first study to demonstrate in vitro that elevated levels of GHBP attenuate the effect of GH and inhibit GH-induced signalling, thereby leading to short stature. Though this inhibition was overcome in vitro with supraphysiologic doses of GH, significantly above endogenously available GH, it remains to be seen whether such an effect can be replicated in vivo.
Topics: Carrier Proteins; Child; Codon, Nonsense; Growth Hormone; HEK293 Cells; Human Growth Hormone; Humans; Insulin-Like Growth Factor I; Male; Receptors, Somatotropin
PubMed: 31883394
DOI: 10.1111/cen.14148 -
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