-
Clinical Case Reports Feb 2018We report a case of short stature irresponsive to growth hormone (GH) replacement therapy. Low GH response to provocative tests and undetectable IGF-1 levels had...
We report a case of short stature irresponsive to growth hormone (GH) replacement therapy. Low GH response to provocative tests and undetectable IGF-1 levels had suggested GH deficiency, while response to therapy indicated GH insensitivity. Molecular evaluation of the GH/IGF-1 axis should be performed in these cases to improve diagnosis and therapy.
PubMed: 29445490
DOI: 10.1002/ccr3.1349 -
Italian Journal of Pediatrics Oct 2017Mutations localized in the Growth Hormone Receptor (GHR) gene are often associated with the pathogenesis of Laron Syndrome, an autosomal recessive hereditary disorder... (Review)
Review
BACKGROUND
Mutations localized in the Growth Hormone Receptor (GHR) gene are often associated with the pathogenesis of Laron Syndrome, an autosomal recessive hereditary disorder characterized by severe growth retardation. Biochemically, patients present normal to high circulating GH levels, in presence of very low or undetectable IGF-I levels, which do not rise after rhGH treatment.
CASE PRESENTATION
We describe the case of a 3.8 years old girl with symmetrical short stature (-3.76 SDS), low IGF-1 and IGFBP-3, in presence of normal GH levels. Parents were not relatives and there was no family history of short stature. During the second day of birth, she developed severe hypoglycaemia that required glucose infusion. She presented frontal bossing and depressed nasal bridge. IGF-1 generation test showed no response, suggesting a GH resistance evidence. In the hypothesis of Laron Syndrome, we decided to perform a molecular analysis of Growth Hormone Receptor (GHR) gene. This analysis demonstrated that the patient was compound heterozygote for two missense mutations.
CONCLUSIONS
GHR gene mutations are a well demonstrated cause of GH insensitivity. In heterozygous patients, probably the normal stature may be achieved by a compensatory mechanism of GH secretion or signalling. On the contrary, in homozygous or compound heterozygous patients these compensatory mechanisms are inadequate, and short stature may be the consequence.
Topics: Child; Child, Preschool; Female; Genetic Predisposition to Disease; Heterozygote; Humans; Italy; Laron Syndrome; Mutation, Missense; Prognosis; Receptors, Somatotropin; Severity of Illness Index
PubMed: 29025428
DOI: 10.1186/s13052-017-0411-7 -
Cellular and Molecular Life Sciences :... Mar 2023Signal transducer and activator of transcription (STAT) proteins act downstream of cytokine receptors to facilitate changes in gene expression that impact a range of...
Signal transducer and activator of transcription (STAT) proteins act downstream of cytokine receptors to facilitate changes in gene expression that impact a range of developmental and homeostatic processes. Patients harbouring loss-of-function (LOF) STAT5B mutations exhibit postnatal growth failure due to lack of responsiveness to growth hormone as well as immune perturbation, a disorder called growth hormone insensitivity syndrome with immune dysregulation 1 (GHISID1). This study aimed to generate a zebrafish model of this disease by targeting the stat5.1 gene using CRISPR/Cas9 and characterising the effects on growth and immunity. The zebrafish Stat5.1 mutants were smaller, but exhibited increased adiposity, with concomitant dysregulation of growth and lipid metabolism genes. The mutants also displayed impaired lymphopoiesis with reduced T cells throughout the lifespan, along with broader disruption of the lymphoid compartment in adulthood, including evidence of T cell activation. Collectively, these findings confirm that zebrafish Stat5.1 mutants mimic the clinical impacts of human STAT5B LOF mutations, establishing them as a model of GHISID1.
Topics: Animals; Humans; Zebrafish; STAT5 Transcription Factor; Laron Syndrome; Mutation; Growth Hormone
PubMed: 36995466
DOI: 10.1007/s00018-023-04759-y -
International Journal of Molecular... Feb 2021Anti-Müllerian hormone (AMH) is secreted by Sertoli or granulosa cells. Recent evidence suggests that AMH may play a role in the pathogenesis of hypogonadotropic...
Anti-Müllerian hormone (AMH) is secreted by Sertoli or granulosa cells. Recent evidence suggests that AMH may play a role in the pathogenesis of hypogonadotropic hypogonadism (HH) and that its serum levels could help to discriminate HH from delayed puberty. Moreover, the growth hormone (GH)/insulin-like growth factor 1 (IGF1) system may be involved in the function of gonadotropin-releasing hormone (GnRH) neurons, as delayed puberty is commonly found in patients with GH deficiency (GHD) or with Laron syndrome, a genetic form of GH resistance. The comprehension of the stimuli enhancing the migration and secretory activity of GnRH neurons might shed light on the causes of delay of puberty or HH. With these premises, we aimed to better clarify the role of the AMH, GH, and IGF1 on GnRH neuron migration and GnRH secretion, by taking advantage of previously established models of immature (GN11 cell line) and mature (GT1-7 cell line) GnRH neurons. Expression of Amhr, Ghr, and Igf1r genes was confirmed in both cell lines. Cells were then incubated with increasing concentrations of AMH (1.5-150 ng/mL), GH (3-1000 ng/mL), or IGF1 (1.5-150 ng/mL). All hormones were able to support GN11 cell chemomigration. AMH, GH, and IGF1 significantly stimulated GnRH secretion by GT1-7 cells after a 90-min incubation. To the best of our knowledge, this is the first study investigating the direct effects of GH and IGF1 in GnRH neuron migration and of GH in the GnRH secreting pattern. Taken together with previous basic and clinical studies, these findings may provide explanatory mechanisms for data, suggesting that AMH and the GH-IGF1 system play a role in HH or the onset of puberty.
Topics: Animals; Anti-Mullerian Hormone; Cell Movement; Cells, Cultured; Gonadotropin-Releasing Hormone; Human Growth Hormone; Insulin-Like Growth Factor I; Mice; Neurons
PubMed: 33671044
DOI: 10.3390/ijms22052445 -
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 -
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 -
Journal of Bone and Mineral Research :... Jan 2019Despite increased longevity and resistance to multiple stressors, growth hormone receptor null (GHRKO) mice exhibit severe skeletal impairment. The role of GHR in...
Despite increased longevity and resistance to multiple stressors, growth hormone receptor null (GHRKO) mice exhibit severe skeletal impairment. The role of GHR in maintaining osteocyte mitochondrial function is unknown. We found that GHR ablation was detrimental to osteocyte mitochondrial function. In vivo multiphoton microscopy revealed significant reductions of >10% in mitochondrial membrane potential (MMP) in GHRKO osteocytes and reduced mitochondrial volumetric density. Reductions in MMP were accompanied by reductions in glucose transporter-1 levels, steady state ATP, NADH redox index, oxygen consumption rate, and mitochondrial reserve capacity in GHRKO osteocytes. Glycolytic capacity did not differ between control and GHRKO males' osteocytes. However, osteocytes from aged female GHRKO mice exhibited reductions in glycolytic parameters, indicating impairments in glucose metabolism, which may be sex dependent. GHRKO osteocytes exhibited increased levels of cytoplasmic reactive oxygen species (ROS) (both basal and in response to high glucose), insulin-like growth factor-1 (IGF-1), and insulin. Mitochondrial ROS levels were increased and correlated with reduced glutathione in GHRKO osteocytes. Overall, the compromised osteocyte mitochondrial function and responses to metabolic insults strongly correlated with skeletal impairments, suggesting that despite increased life span of the GHRKO mice, skeletal health span is decreased. © 2018 American Society for Bone and Mineral Research.
Topics: Animals; Cortical Bone; Insulin-Like Growth Factor I; Laron Syndrome; Mice; Mice, Mutant Strains; Mitochondria; Osteocytes; Reactive Oxygen Species
PubMed: 30216544
DOI: 10.1002/jbmr.3573 -
GeroScience Apr 2017Experimental, clinical, and epidemiological findings support the concept of developmental origins of health and disease (DOHAD), suggesting that early-life hormonal...
The GH/IGF-1 axis in a critical period early in life determines cellular DNA repair capacity by altering transcriptional regulation of DNA repair-related genes: implications for the developmental origins of cancer.
Experimental, clinical, and epidemiological findings support the concept of developmental origins of health and disease (DOHAD), suggesting that early-life hormonal influences during a sensitive period around adolescence have a powerful impact on cancer morbidity later in life. The endocrine changes that occur during puberty are highly conserved across mammalian species and include dramatic increases in circulating GH and IGF-1 levels. Importantly, patients with developmental IGF-1 deficiency due to GH insensitivity (Laron syndrome) do not develop cancer during aging. Rodents with developmental GH/IGF-1 deficiency also exhibit significantly decreased cancer incidence at old age, marked resistance to chemically induced carcinogenesis, and cellular resistance to genotoxic stressors. Early-life treatment of GH/IGF-1-deficient mice and rats with GH reverses the cancer resistance phenotype; however, the underlying molecular mechanisms remain elusive. The present study was designed to test the hypothesis that developmental GH/IGF-1 status impacts cellular DNA repair mechanisms. To achieve that goal, we assessed repair of γ-irradiation-induced DNA damage (single-cell gel electrophoresis/comet assay) and basal and post-irradiation expression of DNA repair-related genes (qPCR) in primary fibroblasts derived from control rats, Lewis dwarf rats (a model of developmental GH/IGF-1 deficiency), and GH-replete dwarf rats (GH administered beginning at 5 weeks of age, for 30 days). We found that developmental GH/IGF-1 deficiency resulted in persisting increases in cellular DNA repair capacity and upregulation of several DNA repair-related genes (e.g., Gadd45a, Bbc3). Peripubertal GH treatment reversed the radiation resistance phenotype. Fibroblasts of GH/IGF-1-deficient Snell dwarf mice also exhibited improved DNA repair capacity, showing that the persisting influence of peripubertal GH/IGF-1 status is not species-dependent. Collectively, GH/IGF-1 levels during a critical period during early life determine cellular DNA repair capacity in rodents, presumably by transcriptional control of genes involved in DNA repair. Because lifestyle factors (e.g., nutrition and childhood obesity) cause huge variation in peripubertal GH/IGF-1 levels in children, further studies are warranted to determine their persisting influence on cellular cancer resistance pathways.
Topics: Animals; DNA Repair; Fibroblasts; Growth Hormone; Insulin-Like Growth Factor I; Longevity; Male; Mice; Neoplasms; Rats, Inbred Lew
PubMed: 28233247
DOI: 10.1007/s11357-017-9966-x -
The Journal of Biological Chemistry Jan 2022SEC23B is one of two vertebrate paralogs of SEC23, a key component of the coat protein complex II vesicles. Complete deficiency of SEC23B in mice leads to perinatal...
SEC23B is one of two vertebrate paralogs of SEC23, a key component of the coat protein complex II vesicles. Complete deficiency of SEC23B in mice leads to perinatal death caused by massive degeneration of professional secretory tissues. However, functions of SEC23B in postnatal mice and outside professional secretory tissues are unclear. In this study, we generated a Sec23b KO mouse and a knockin (KI) mouse with the E109K mutation, the most common human mutation in congenital dyserythropoietic anemia type II patients. We found that E109K mutation led to decreases in SEC23B levels and protein mislocalization. However, Sec23b mice showed no obvious abnormalities. Sec23b hemizygosity (Sec23b) was partially lethal, with only half of expected hemizygous mice surviving past weaning. Surviving Sec23b mice exhibited exocrine insufficiency, increased endoplasmic reticulum stress and apoptosis in the pancreas, and phenotypes consistent with chronic pancreatitis. Sec23b mice had mild to moderate anemia without other typical congenital dyserythropoietic anemia type II features, likely resulting from exocrine insufficiency. Moreover, Sec23b mice exhibited severe growth restriction accompanied by growth hormone (GH) insensitivity, reminiscent of Laron syndrome. Growth restriction is not associated with hepatocyte-specific Sec23b deletion, suggesting a nonliver origin of this phenotype. We propose that inflammation associated with chronic pancreatic deficiency may explain GH insensitivity in Sec23b mice. Our results reveal a genotype-phenotype correlation in SEC23B deficiency and indicate that pancreatic acinar is most sensitive to SEC23B deficiency in adult mice. The Sec23b mice provide a novel model of chronic pancreatitis and growth retardation with GH insensitivity.
Topics: Anemia, Dyserythropoietic, Congenital; Animals; Mice; Mutation, Missense; Pancreatitis, Chronic; Phenotype; Vesicular Transport Proteins
PubMed: 34954140
DOI: 10.1016/j.jbc.2021.101536 -
Nature Communications May 2018Growth hormone (GH) insensitivity syndrome (GHIS) is a rare clinical condition in which production of insulin-like growth factor 1 is blunted and, consequently,...
Growth hormone (GH) insensitivity syndrome (GHIS) is a rare clinical condition in which production of insulin-like growth factor 1 is blunted and, consequently, postnatal growth impaired. Autosomal-recessive mutations in signal transducer and activator of transcription (STAT5B), the key signal transducer for GH, cause severe GHIS with additional characteristics of immune and, often fatal, pulmonary complications. Here we report dominant-negative, inactivating STAT5B germline mutations in patients with growth failure, eczema, and elevated IgE but without severe immune and pulmonary problems. These STAT5B missense mutants are robustly tyrosine phosphorylated upon stimulation, but are unable to nuclear localize, or fail to bind canonical STAT5B DNA response elements. Importantly, each variant retains the ability to dimerize with wild-type STAT5B, disrupting the normal transcriptional functions of wild-type STAT5B. We conclude that these STAT5B variants exert dominant-negative effects through distinct pathomechanisms, manifesting in milder clinical GHIS with general sparing of the immune system.
Topics: Adolescent; Cell Line; Child; Eczema; Female; Genetic Predisposition to Disease; Germ-Line Mutation; HEK293 Cells; Human Growth Hormone; Humans; Immunoglobulin E; Infant; Insulin-Like Growth Factor I; Laron Syndrome; Male; Mutation, Missense; Response Elements; STAT5 Transcription Factor
PubMed: 29844444
DOI: 10.1038/s41467-018-04521-0