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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 -
Molecular and Cellular Endocrinology Dec 2020Emerging evidence links the growth hormone (GH)-insulin-like growth factor-1 (IGF1) endocrine axis to cancer development. While this putative correlation is of major... (Review)
Review
Emerging evidence links the growth hormone (GH)-insulin-like growth factor-1 (IGF1) endocrine axis to cancer development. While this putative correlation is of major translational relevance, most clinical and epidemiological reports to date found no causal linkage between GH therapy and enhanced cancer risk. Thus, it is generally agreed that GH therapy constitutes a safe pharmacological intervention. The present review focuses on a number of issues in the area of GH-IGF1 action in cancer development. Emphasis is given to the idea that GH and IGF1 do not conform to the definition of oncogenic factors. Specifically, these hormones, even at high pharmacological doses, are unable to induce malignant transformation. However, the GH-IGF1 axis is capable of 'pushing' already transformed cells through the various phases of the cell cycle. Viral and cellular oncogenes require an intact IGF1 signaling pathway in order to elicit transformation; in other words, oncogenic agents adopt the IGF1 pathway. This universal mechanism of action of oncogenes has broad implications in oncology. Our review provides an in-depth analysis of the interplay between the GH-IGF1 axis and cancer genes, including tumor suppressors p53 and BRCA1. Finally, the safety of GH therapy in both children and adults needs further long-term follow-up studies.
Topics: Adult; Cell Cycle; Child; Disease Progression; Human Growth Hormone; Humans; Insulin-Like Growth Factor I; Neoplasms; Oncogenes; Signal Transduction
PubMed: 32919021
DOI: 10.1016/j.mce.2020.111003 -
Pediatric Endocrinology Reviews : PER Aug 2020
Topics: Body Height; Child; Humans; Klinefelter Syndrome; Phenotype
PubMed: 32780959
DOI: 10.17458/per.vol17.2020.lte.kml.klinefeltersyndrometall -
Growth Hormone & IGF Research :... 2020Individuals affected with two genetic syndromes identified in Ecuador have severe short stature and diminished insulin secretion, along with essentially different GH...
UNLABELLED
Individuals affected with two genetic syndromes identified in Ecuador have severe short stature and diminished insulin secretion, along with essentially different GH counterregulatory effects on insulin action, which leads to the appearance of opposing metabolic phenotypes. In the case of Laron syndrome, subjects have enhanced insulin sensitivity and diminished incidence of type 2 diabetes mellitus. In the other clinical entity, individuals have innate insulin resistance, a varying degree of carbohydrate metabolism disturbances, glucose intolerance, and eventually insulin-resistant diabetes mellitus. Since both groups have diminished insulin secretion, the standard homeostatic minimal models for assessment of insulin sensitivity and resistance were used to see if they could properly identify the metabolic status, especially considering that these methodologies are simple and non-invasive procedures.
METHODS
Fasting insulin concentrations, fasting glucose/fasting insulin ratio and various minimal models were determined in individuals from the two syndromic cohorts, as well as in a control group made of first-degree normal relatives of the insulin-resistant phenotype subjects.
RESULTS
The metabolic characteristics of enhanced insulin sensitivity in one of the syndromes and innate insulin resistance in the other could not be properly ascertained by the selected methodology. Furthermore, results were confusing and even discrepant with the clinical findings.
CONCLUSIONS
The standard homeostatic minimal models could not properly identify or discriminate insulin sensitivity and resistance in subjects with inherently diminished secretion. It is thereby suggested that these models should be used with caution in clinical situations where reduced secretion of the metabolic peptide is found or suspected.
Topics: Case-Control Studies; Dwarfism; Glucose Intolerance; Growth Disorders; Human Growth Hormone; Humans; Insulin Resistance; Laron Syndrome; Prognosis; Syndrome
PubMed: 32763832
DOI: 10.1016/j.ghir.2020.101339 -
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 -
Growth Hormone & IGF Research :... Jun 2020Laron Syndrome (LS), (OMIM# 262500), a rare recessively inherited disease caused by deletions or mutations of the GH receptor, gene characterized by dwarfism with low or...
Laron Syndrome (LS), (OMIM# 262500), a rare recessively inherited disease caused by deletions or mutations of the GH receptor, gene characterized by dwarfism with low or undetectable serum IGF-I in the presence of high serum GH. In addition to dwarfism, the IGF-I deficiency leads to metabolic abnormalities including aberrations in protein biosynthesis and homeostasis. The only available treatment for LS patients is (r)IGF-I administration. The present study was aimed to determine the plasma concentrations of specific amino acids and their metabolites in the blood of untreated and IGF-I-treated LS patients. The study involved a total of 10 LS patients (3 untreated and 7 treated), 2 heterozygote mothers and 3aged subjects. Forty healthy boys and girls served as controls. The analysis of amino acids and their metabolites was performed using the LC-MS/MS analysis and Waters Acc-Q Tag ultra-derivatization kit. Serum IGF-I levels were measured by a one-step sandwich chemiluminescence immunoassay. The results revealed that long-term IGF-I deficiency in LS patients led to abnormal changes in the plasma amino acids metabolism, such as low levels of plasma citrulline, sarcosine and taurine that increased upon IGF-I replacement. The plasma amino acid levels of the heterozygous family members resembled those of the untreated LS patients, whereas the pattern in the 2 double heterozygote sisters previously treated with IGF-I resembled that of the presently IGF-I-treated patients. In addition, plasma ɑ-amino adipic acid levels were elevated in both untreated and IGF-I-treated patients. In summary our data revealed that LS patients, a condition associated with congenital IGF-I deficiency, have an abnormal plasma amino acid metabolism that is partially restored by IGF-I treatment.
Topics: Adolescent; Adult; Aged; Aged, 80 and over; Amino Acids; Biomarkers; Case-Control Studies; Child; Child, Preschool; Female; Follow-Up Studies; Growth Disorders; Hearing Loss, Sensorineural; Humans; Infant; Insulin-Like Growth Factor I; Laron Syndrome; Male; Middle Aged; Pilot Projects; Prognosis; Young Adult
PubMed: 32200226
DOI: 10.1016/j.ghir.2020.02.001 -
Growth Hormone & IGF Research :... Apr 2020We have shown that subjects with Laron syndrome (LS) due to growth hormone receptor deficiency (GHRD) and their relatives have comparable brain structure and function;...
BACKGROUND
We have shown that subjects with Laron syndrome (LS) due to growth hormone receptor deficiency (GHRD) and their relatives have comparable brain structure and function; moreover, the brain of individuals affected with GHRD appears like those of younger people. While the functionally absent growth hormone receptor and the diminished concentrations of the insulin-like growth factor-I have been associated to these findings, the role of the insulin-glucose axis is emerging as an unavoidable consideration when determining the aetiology of these observations. In consequence, we decided to search for the potential and discrete associations between the neurological findings and several parameters of carbohydrate metabolism that might exist in the subjects affected with GHRD.
SUBJECTS AND METHODS
Individuals affected with GHRD were compared to relative controls. Besides standard measures of anthropometry, body composition and brain characteristics, the elements of the carbohydrate metabolism (CHO), including glucose, insulin, triacylglycerol and the free insulin growth factor binding protein 1 (IGFBP1) concentrations were determined. In addition, the correlations existing between the parameters of CHO and brain characteristics were established.
RESULTS
Besides the phenotypical characteristics of GHRD subjects, including those of brain structure and function, enhanced insulin sensitivity, and other minor, we observed that the insulin-regulated IGFBP1 had a consistent negative correlation with the main elements of the carbohydrate metabolism only in the individuals affected with the disease, and not in their relatives.
CONCLUSIONS
When compared to their relatives, subjects with GHRD who lack the counter-regulatory effects of GH on the insulin axis, despite their increased risk factor profile due to obesity and increased body fat percentage, have a healthy and younger looking brain associated to an enhanced and coordinated insulin sensitivity. Furthermore, it was observed that in the GHRD subjects IGFBP1 negatively correlates, in a constant and systematic manner, with the main elements of the CHO metabolism. These observations suggest a direct relationship between an efficient insulin sensitivity and a healthy brain.
Topics: Adipose Tissue; Adult; Blood Glucose; Body Composition; Brain; Carbohydrate Metabolism; Case-Control Studies; Family; Fasting; Female; Functional Neuroimaging; Humans; Insulin; Insulin Resistance; Insulin-Like Growth Factor Binding Protein 1; Laron Syndrome; Magnetic Resonance Imaging; Male; Middle Aged; Obesity; Postprandial Period; Receptors, Somatotropin; Triglycerides
PubMed: 32145513
DOI: 10.1016/j.ghir.2020.02.004 -
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