-
Journal of Pediatric Nursing 2019
Review
Topics: Chromosome Disorders; Clinical Competence; Endocrinology; Genetic Testing; Humans; Infant; Insulin-Like Growth Factor I; Laron Syndrome; Male; Medical History Taking; Mutation; Pediatric Nursing; Practice Patterns, Nurses'; Receptors, Somatotropin
PubMed: 31409498
DOI: 10.1016/j.pedn.2019.06.006 -
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 -
Journal of Pediatric Endocrinology &... Oct 2021Laron syndrome (LS) is a disease caused by growth hormone receptor (GHR) defects. It is characterized by severe postnatal growth retardation and distinctive facial...
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.
Topics: Adolescent; Carrier Proteins; Child; Female; Humans; Laron Syndrome; Male; Mutation, Missense; Patient Acuity; Phenotype; Polymorphism, Single Nucleotide; Receptors, Somatotropin; Siblings; Turkey
PubMed: 34218547
DOI: 10.1515/jpem-2021-0044 -
Stem Cell Reviews and Reports Feb 2023Pathway involving insulin-like growth factor 1 (IGF-1) plays significant role in growth and development. Crucial role of IGF-1 was discovered inter alia through studies...
Pathway involving insulin-like growth factor 1 (IGF-1) plays significant role in growth and development. Crucial role of IGF-1 was discovered inter alia through studies involving deficient patients with short stature, including Laron syndrome individuals. Noteworthy, despite disturbances in proper growth, elevated values for selected stem cell populations were found in IGF-1 deficient patients. Therefore, here we focused on investigating role of these cells-very small embryonic-like (VSEL) and hematopoietic stem cells (HSC), in the pathology. For the first time we performed long-term observation of these populations in response to rhIGF-1 (mecasermin) therapy. Enrolled pediatric subjects with IGF-1 deficiency syndrome were monitored for 4-5 years of rhIGF-1 treatment. Selected stem cells were analyzed in peripheral blood flow cytometrically, together with chemoattractant SDF-1 using immunoenzymatic method. Patients' data were collected for correlation of experimental results with clinical outcome. IGF-1 deficient patients were found to demonstrate initially higher levels of VSEL and HSC compared to healthy controls, with their gradual decrease in response to therapy. These changes were significantly associated with SDF-1 plasma levels. Correlations of VSEL and HSC were also reported in reference to growth-related parameters, and IGF-1 and IGFBP3 values. Noteworthy, rhIGF-1 was shown to efficiently induce development of Laron patients achieving at least proper rate of growth (compared to healthy group) in 80% of subjects. In conclusion, here we provided novel insight into stem cells participation in IGF-1 deficiency in patients. Thus, we demonstrated basis for future studies in context of stem cells and IGF-1 role in growth disturbances.
Topics: Humans; Child; Insulin-Like Growth Factor I; Laron Syndrome; Stem Cells
PubMed: 36269524
DOI: 10.1007/s12015-022-10457-2 -
Oncotarget Jul 2019The insulin-like growth factors (IGF) have a key role in the development of gynecological cancers, including endometrial tumors. Uterine serous carcinoma (USC)...
The insulin-like growth factors (IGF) have a key role in the development of gynecological cancers, including endometrial tumors. Uterine serous carcinoma (USC) constitutes a defined histological category among endometrial cancers. Laron syndrome (LS) is a genetic type of dwarfism that results from mutation of the growth hormone receptor () gene, and is the best characterized entity under the spectrum of the congenital IGF1 deficiencies. Epidemiological studies have shown that LS patients are protected from cancer development. Recent genome-wide association studies conducted on LS-derived lymphoblastoid cells led to the identification of a series of metabolic genes whose over-representation in this condition might be linked to cancer protection. Our analyses led to the identification of , a potential cell cycle regulator, as a new downstream target for IGF1 action. The aim of the present paper was to investigate the regulation of gene expression by IGF1 and insulin in endometrial cancer cell lines and to assess the impact of tumor suppressor p53 on expression and biological action. Using USC-derived cell lines expressing a wild type or a mutant p53 gene, we demonstrate that IGF1 inhibited mRNA and protein levels in cells containing a wild type . On the other hand, IGF1 potently stimulated ZYG11A expression in mutant p53-expressing cells. Data presented here links the IGF1 and p53 signaling pathways with ZYG11A action. The clinical implications of the present study in endometrial and other types of cancer must be further investigated.
PubMed: 31320996
DOI: 10.18632/oncotarget.27055 -
Diabetic Medicine : a Journal of the... Oct 2019To determine the long-term risk of diabetes in a cohort of children treated with recombinant human growth hormone in Israel, using data from the Israeli National...
AIMS
To determine the long-term risk of diabetes in a cohort of children treated with recombinant human growth hormone in Israel, using data from the Israeli National Diabetes Register.
METHODS
Between 1988 and 2009, 2513 children were approved for growth hormone treatment. They were assigned to one of two groups. The first group included children treated for isolated growth hormone deficiency and who were small for gestational age and the second included those treated for multiple pituitary hormone deficiency, chronic renal failure, Turner syndrome or Prader-Willi syndrome. The cohort was cross-linked with the Israeli National Diabetes Register for 2014 (mean follow-up duration 12.1±5.3 years), and prevalent cases of diabetes were identified. Standardized prevalence ratios for diabetes were calculated for people aged 10-29 years.
RESULTS
In 2014, a total of 23 individuals were identified with diabetes (four with pre-existing diabetes, seven developed diabetes before age 17 years and 12 developed it at a later age). In the isolated growth hormone deficiency and small-for-gestational-age group there was no difference in the prevalence of diabetes compared with the general population (standardized prevalence ratio 2.05, 95% CI 0.94-3.89). In the group that included people with multiple pituitary hormone deficiency, chronic renal failure, Turner syndrome and Prader-Willi syndrome there was a significantly higher diabetes prevalence (standardized prevalence ratio 11.94, 95% CI 6.53-20.00) compared with the general population.
CONCLUSIONS
No difference in diabetes prevalence was found in the isolated growth hormone deficiency and small-for-gestational-age group, compared with the general population. Children treated with growth hormone with pre-existing risk factors had an increased prevalence of diabetes. It is advisable to monitor blood glucose levels closely during and after growth hormone treatment, especially in such children.
Topics: Adolescent; Child; Child, Preschool; Diabetes Mellitus; Female; Follow-Up Studies; Human Growth Hormone; Humans; Infant, Small for Gestational Age; Israel; Kidney Failure, Chronic; Male; Pituitary Hormones; Prader-Willi Syndrome; Prevalence; Recombinant Proteins; Risk Factors; Turner Syndrome
PubMed: 30690790
DOI: 10.1111/dme.13910 -
Journal of Neuroendocrinology Apr 2023Growth hormone receptor deficiency (GHRD) results in low serum insulin-like growth factor 1 (IGF1) and high, but non-functional serum growth hormone (GH) levels in human...
Growth hormone receptor deficiency (GHRD) results in low serum insulin-like growth factor 1 (IGF1) and high, but non-functional serum growth hormone (GH) levels in human Laron syndrome (LS) patients and animal models. This study investigated the quantitative histomorphological and molecular alterations associated with GHRD. Pituitary glands from 6 months old growth hormone receptor deficient (GHR-KO) and control pigs were analyzed using a quantitative histomorphological approach in paraffin (9 GHR-KO [5 males, 4 females] vs. 11 controls [5 males, 6 females]), ultrathin sections tissue sections (3 male GHR-KO vs. 3 male controls) and label-free proteomics (4 GHR-KO vs. 4 control pigs [2 per sex]). GHR-KO pigs displayed reduced body weights (60% reduction in comparison to controls; p < .0001) and decreased pituitary volumes (54% reduction in comparison to controls; p < .0001). The volume proportion of the adenohypophysis did not differ in GHR-KO and control pituitaries (65% vs. 71%; p = .0506) and GHR-KO adenohypophyses displayed a reduced absolute volume but an unaltered volume density of somatotrophs in comparison to controls (21% vs. 18%; p = .3164). In GHR-KO pigs, somatotroph cells displayed a significantly reduced volume density of granules (23.5%) as compared to controls (67.7%; p < .0001). Holistic proteome analysis of adenohypophysis samples identified 4660 proteins, of which 592 were differentially abundant between the GHR-KO and control groups. In GHR-KO samples, the abundance of somatotropin precursor was decreased, whereas increased abundances of proteins involved in protein production, transport and endoplasmic reticulum (ER) stress were revealed. Increased protein production and secretion as well as significantly reduced proportion of GH-storing granules in somatotroph cells of the adenohypophysis without an increase in volume density of somatotroph cells in the adenohypophysis could explain elevated serum GH levels in GHR-KO pigs.
PubMed: 37160285
DOI: 10.1111/jne.13277 -
The Journal of Clinical Endocrinology... Jul 2021Severe forms of growth hormone insensitivity (GHI) are characterized by extreme short stature, dysmorphism, and metabolic anomalies.
CONTEXT
Severe forms of growth hormone insensitivity (GHI) are characterized by extreme short stature, dysmorphism, and metabolic anomalies.
OBJECTIVE
This work aims to identify the genetic cause of growth failure in 3 "classical" GHI individuals.
METHODS
A novel intronic growth hormone receptor gene (GHR) variant was identified, and in vitro splicing assays confirmed aberrant splicing. A 6Ω pseudoexon GHR vector and patient fibroblast analysis assessed the consequences of the novel pseudoexon inclusion and the impact on GHR function.
RESULTS
We identified a novel homozygous intronic GHR variant (g.5:42700940T > G, c.618+836T > G), 44 bp downstream of the previously recognized intronic 6Ψ GHR pseudoexon mutation in the index patient. Two siblings also harbored the novel intronic 6Ω pseudoexon GHR variant in compound heterozygosity with the known GHR c.181C > T (R43X) mutation. In vitro splicing analysis confirmed inclusion of a 151-bp mutant 6Ω pseudoexon not identified in wild-type constructs. Inclusion of the 6Ω pseudoexon causes a frameshift resulting in a nonfunctional truncated GHR lacking the transmembrane and intracellular domains. The truncated 6Ω pseudoexon protein demonstrated extracellular accumulation and diminished activation of STAT5B signaling following GH stimulation.
CONCLUSION
Novel GHR 6Ω pseudoexon inclusion results in loss of GHR function consistent with a severe GHI phenotype. This represents a novel mechanism of Laron syndrome and is the first deep intronic variant identified causing severe postnatal growth failure. The 2 kindreds originate from the same town in Campania, Southern Italy, implying common ancestry. Our findings highlight the importance of studying variation in deep intronic regions as a cause of monogenic disorders.
PubMed: 34453441
DOI: 10.1210/clinem/dgab550 -
Cells Jun 2021Endometrial cancer is the most common gynecologic malignancy in Western countries. The insulin-like growth factor-1 (IGF1) axis has an important role in endometrial...
Endometrial cancer is the most common gynecologic malignancy in Western countries. The insulin-like growth factor-1 (IGF1) axis has an important role in endometrial cancer biology and emerged as a promising therapeutic target in oncology. However, there is an urgent need to identify biomarkers that may help in patient stratification and prognosis. Laron syndrome (LS) is a type of dwarfism that results from the mutation of the growth hormone receptor (GHR) gene, leading to congenital IGF1 deficiency. While high circulating IGF1 is regarded as a risk factor in cancer, epidemiological studies have shown that LS patients are protected from cancer development. Recent genome-wide profilings conducted on LS-derived lymphoblastoid cells led to the identification of a series of genes whose over- or under-representation in this condition might be mechanistically linked to cancer protection. The olfactory receptor 5 subfamily H member 2 () was the top downregulated gene in LS, its expression level being 5.8-fold lower than in the control cells. In addition to their typical role in the olfactory epithelium, olfactory receptors (ORs) are expressed in multiple tissues and play non-classical roles in various pathologies, including cancer. The aim of our study was to investigate the regulation of gene expression by IGF1 in endometrial cancer. Data showed that IGF1 and insulin stimulate OR5H2 mRNA and the protein levels in uterine cancer cell lines expressing either a wild-type or a mutant p53. OR5H2 silencing led to IGF1R downregulation, with ensuing reductions in the downstream cytoplasmic mediators. In addition, OR5H2 knockdown reduced the proliferation rate and cell cycle progression. Analyses of olfr196 (the mouse orthologue of OR5H2) mRNA expression in animal models of GHR deficiency or GH overexpression corroborated the human data. In summary, OR5H2 emerged as a novel target for positive regulation by IGF1, with potential relevance in endometrial cancer.
Topics: Animals; Cell Line, Tumor; Cell Proliferation; Cystadenocarcinoma, Serous; Endometrial Neoplasms; Female; Gene Expression Regulation, Neoplastic; Humans; Insulin-Like Growth Factor I; Laron Syndrome; Mice; Mice, Transgenic; Receptor, IGF Type 1; Receptors, Odorant; Signal Transduction
PubMed: 34204736
DOI: 10.3390/cells10061483 -
The Journal of Clinical Endocrinology... Jul 2021Severe forms of Growth Hormone Insensitivity (GHI) are characterized by extreme short stature, dysmorphism and metabolic anomalies.
CONTEXT
Severe forms of Growth Hormone Insensitivity (GHI) are characterized by extreme short stature, dysmorphism and metabolic anomalies.
OBJECTIVE
Identification of the genetic cause of growth failure in 3 'classical' GHI subjects.
DESIGN
A novel intronic GHR variant was identified, and in vitro splicing assays confirmed aberrant splicing. A 6Ω pseudoexon GHR vector and patient fibroblast analysis assessed the consequences of the novel pseudoexon inclusion and the impact on GHR function.
RESULTS
We identified a novel homozygous intronic GHR variant (g.5:42700940T>G, c.618 + 836T> G), 44bp downstream of the previously recognized intronic 6Ψ GHR pseudoexon mutation in the index patient. Two siblings also harbored the novel intronic 6Ω pseudoexon GHR variant in compound heterozygosity with the known GHR c.181C>T (R43X) mutation. In vitro splicing analysis confirmed inclusion of a 151bp mutant 6Ω pseudoexon not identified in wild-type constructs. Inclusion of the 6Ω pseudoexon causes a frameshift resulting in a non-functional truncated GHR lacking the transmembrane and intracellular domains. The truncated 6Ω pseudoexon protein demonstrated extracellular accumulation and diminished activation of STAT5B signaling following growth hormone stimulation.
CONCLUSION
Novel GHR 6Ω pseudoexon inclusion results in loss of GHR function consistent with a severe GHI phenotype. This represents a novel mechanism of Laron syndrome and is the first deep intronic variant identified causing severe postnatal growth failure. The 2 kindreds originate from the same town in Campania, Southern Italy, implying common ancestry. Our findings highlight the importance of studying variation in deep intronic regions as a cause of monogenic disorders.
PubMed: 34318893
DOI: 10.1210/clinem/dgab550