Purpose The study aimed to define the clinical, biochemical and genetic features of adult patient... more Purpose The study aimed to define the clinical, biochemical and genetic features of adult patients with osteopenia/osteoporosis and/or bone fragility and low serum alkaline phosphatase (sALP). Methods Twenty-two patients with at least two sALP values below the reference range were retrospectively enrolled after exclusion of secondary causes. Data about clinical features, mineral and bone markers, serum pyridoxal-5’-phosphate (PLP), urine phosphoethanolamine (PEA), lumbar and femur bone densitometry, and column X-ray were collected. Peripheral blood DNA of each participant was analyzed to detect ALPL gene anomalies. Results Pathogenic ALPL variants (pALPL) occurred in 23% and benign variants in 36% of patients (bALPL), while nine patients harbored wild-type alleles (wtALPL). Fragility fractures and dental anomalies were more frequent in patients harboring pALPL and bALPL than in wtALPL patients. Of note, wtALPL patients comprised women treated with tamoxifen for hormone-sensitive bre...
Journal of biological regulators and homeostatic agents, 2015
Parathormone (PTH) has been suggested to affect the cardiovascular system. Teriparatide (TPT), th... more Parathormone (PTH) has been suggested to affect the cardiovascular system. Teriparatide (TPT), the hormonally active 1-34 fragment of PTH, provides an anabolic treatment for osteoporosis. The aim of the present study was to evaluate the cardiometabolic effects of 18-month treatment with 20 μg/ die teriparatide subcutaneosly. Fourteen women with postmenopausal severe osteoporosis treated with once-daily sc 20 μg TPT (67.6 ± 2.5 years; BMI 27.7 ± 1.0 kg/m²) and 24 age- and BMI-matched severe osteoporotic women treated with iv yearly 5 mg zoledronate (ZLN) were evaluated at baseline and at 12-18 months of treatment for anthropometric measures, calcium, glucose and lipid metabolic parameters, and assessment of cardiac geometry by conventional echocardiography. TPT was effective in increasing mean lumbar spine bone mineral density with no clinically relevant changes in calcium metabolism parameters. TPT patients experienced an increase of BMI (27.7 ± 1.0 at baseline vs 29.0 ± 1.0 kg/m² a...
Primary hyperparathyroidism (PHPT) is the third most common endocrine disease. Kidney is a target... more Primary hyperparathyroidism (PHPT) is the third most common endocrine disease. Kidney is a target of both chronic elevated PTH and calcium in PHPT. The classic PHPT complications of symptomatic kidney stones and nephrocalcinosis have become rare and the PHPT current presentation is asymptomatic with uncertain and long-lasting progression. Nonetheless, the routine use of imaging and of biochemical determinations have revealed the frequent occurrence of asymptomatic kidney stones, hypercalciuria and reduced kidney function in asymptomatic PHPT patients. Though the pathogenesis is far from being elucidated, PHPT is associated with reduced renal function, in terms of estimated glomerular filtration rate, and related increased morbidity and mortality. In the last decade, the effort of the Kidney Disease: Improving Global Outcomes (KDIGO) panel of experts highlighted that even mild reduction of kidney function is associated with increased risk of cardiovascular disease. These consideratio...
Context. Hypovitaminosis D frequently occurs in early life and increases with age. Vitamin D has ... more Context. Hypovitaminosis D frequently occurs in early life and increases with age. Vitamin D has been suggested to influence cardiac performance and N-terminal-pro-type B natriuretic peptide (NT-proBNP) release in adults with heart failure.Objectives. To assess the vitamin D status and the impact of hypovitaminosis D on circulating NT-proBNP levels in young patients with congenital heart defects (CHD).Design and Patients. This cross-sectional study included the assessment of serum 25-hydroxyvitamin D (25OHD), parathyroid function markers, and NT-proBNP levels in a series of 230 young in-patients (117 females, 113 males; 6.4 (4.0–9.1) years (median, interquartile range)) with CHD.Results. Serum 25OHD levels <20 ng/mL were detected in 55.3% of patients. Optimal 25OHD levels (>30 ng/mL) occurred in 25% of patients. Serum 25OHD levels inversely correlated with age (r=-0.169,P=0.013) and height standard deviation score (r=-0.269,P=0.001). After correction for age, 25OHD negatively ...
Several studies reported somatic mutations of many genes (MEN1, CTNNB1, CDKIs and others) in para... more Several studies reported somatic mutations of many genes (MEN1, CTNNB1, CDKIs and others) in parathyroid adenoma, although with different prevalence. Recently, activating mutations of the EZH2 and ZFX oncogenes were identified in benign parathyroid adenoma by whole exome sequencing. The same mutations had been found in blood and ovary malignant tumours. On one hand, this result raised the hypothesis that these oncogenes may play a role in the onset of parathyroid tumour, but it would also suggest they may be involved in malignant, rather benign, parathyroid neoplasm. Our aim was to verify the occurrence of selected mutations of the EZH2 and ZFX genes in an Italian cohort of 23 sporadic parathyroid carcinomas, 12 atypical and 45 typical adenomas. DNA was extracted from paraffin-embedded tissues, PCR amplified and directly sequenced. No mutations were detected in the coding sequence and boundaries of both genes in any of the samples. Two polymorphisms of the EZH2 gene were identified ...
Clinical cases in mineral and bone metabolism : the official journal of the Italian Society of Osteoporosis, Mineral Metabolism, and Skeletal Diseases, 2013
Calcium sensing receptor (CASR) is a G-protein couple receptor which plays a key role in calcium ... more Calcium sensing receptor (CASR) is a G-protein couple receptor which plays a key role in calcium homeostasis in vertebrates. Its extracellular domain is sensitive to divalent cations, aminoacids and polyamines. In parathyroid glands, CASR activation causes parathyroid hormone (PTH) reduction and subsequently a decrease in blood calcium concentration. In PTH-dependent disorders, e.g. primary and secondary hyperparathyroidism (HPT), the need for therapeutic options other than surgery led to the synthesis of various allosteric CASR agonists (calcimimetics), such as cinacalcet. Cinacalcet is the only calcimimetic approved for HPT secondary to chronic kidney disease (CDK), parathyroid carcinoma, and, in some countries, primary HPT. Clinical trials showed that cinacalcet reduced PTH and calcemia both in CDK and primary HPT, lowering the risk of bone fractures, surgery, and cardiovascular complications in the former patients. Long-term safety and pharmacoeconomics have to be fully tested y...
DM1 and DM2 are progressive multisystem genetic disorders that share a similar pathogenetic mecha... more DM1 and DM2 are progressive multisystem genetic disorders that share a similar pathogenetic mechanism and clinical manifestations. The endocrine features include insulin resistance and testicular failure. Some clinical studies showed how hypogonadism do not correlate to muscle weakness in DM1 but there are no studies that evaluate directly the contribution of endocrine disorders (as hypogonadism and insulin resistance) on atrophy on muscle fibers. Atrogin1 and MuRF1 belong to the ubiquitin proteasome pathway (UPP) and their gene expression have been observed in a wide range of in vivo models of skeletal muscle atrophy including diabetes, cancer, renal failure and denervation. The aim of the study is to evaluate the influence of gonadic function, insulin resistance to muscle fiber atrophy in myotonic dystrophies. The study has been carried out on 18 male patients, 10 DM1 (age 49+/-8,1years) and 8 DM2 (age 55*/-7,9years). Patients under 18 and over 65 years were excluded. Other exclusion criteria were testosterone and statin therapy, cardiac failure (stage 3 and 4 NYHA). Muscle strength was measured by manual muscle testing (MRC score) and QMA (Gainesville, Giorgia). Gonadic function was evaluated by measurement of total testosterone, free testosterone, and gonadotropin (LH,FSH) levels. HOMA-IR as index of insulin resistance was calculated from fasting glucose and insulin level. Body composition was measured by bioelectric impedance analysis and DEXA. Biceps brachii biopsy has been performed in all patients. Atrophy and hypertrophy factors of muscle fibres have been calculated on fast or slow myosin immunostained muscle sections. The correlations between metabolic alteration and muscle fibre atrophy/hypertrophy and the expression of atrogin1 evaluated by western blot on frozen muscle will be presented
Components of the tumour microenvironment initiate and promote cancer development. In this study,... more Components of the tumour microenvironment initiate and promote cancer development. In this study, we investigated the stromal component of parathyroid neoplasia. Immunohistochemistry for alpha-smooth muscle actin (α-SMA) showed an abundant periacinar distribution of α-SMA+ cells in normal parathyroid glands (n=3). This pattern was progressively lost in parathyroid adenomas (PAds; n=6) where α-SMA+cells were found to surround new microvessels, as observed in foetal parathyroid glands (n=2). Moreover, in atypical adenomas (n=5) and carcinomas (n=4), α-SMA+ cells disappeared from the parenchyma and accumulated in the capsula and fibrous bands. At variance with normal glands, parathyroid tumours (n=37) expressed high levels of fibroblast-activation protein (FAP) transcripts, a marker of tumour-associated fibroblasts. We analysed the ability of PAd-derived cells to activate fibroblasts using human bone-marrow mesenchymal stem cells (hBM-MSCs). PAd-derived cells induced a significant incr...
ObjectivePrimary hyperparathyroidism (PHPT) is a challenging problem in type 1 multiple endocrine... more ObjectivePrimary hyperparathyroidism (PHPT) is a challenging problem in type 1 multiple endocrine neoplasia (MEN1) due to the high postsurgery recurrence rate. The aim was to evaluate the efficacy of cinacalcet in MEN1 patients in comparison with patients with sporadic PHPT (sPHPT) and the effect of Arg990Gly calcium-sensing receptor (CASR) polymorphism on the response to treatment.DesignThis is a randomized, crossover, double-blind study carried out in the University Hospitals.MethodsFifteen MEN1 patients with PHPT were randomized to two groups, one administered with 30 mg daily cinacalcet, titrated until calcium normalization, and one with placebo. After 3 months, patients were reassessed and after washout switched to the other treatment. For comparison, 20 sPHPT patients with similar calcium levels were administered with cinacalcet for 3 months. Ionized and total calcium, phosphate, and parathyroid hormone (PTH) were evaluated. CASR Arg990Gly was genotyped on blood DNA by direct ...
Background and objectiveSingle nucleotide polymorphisms (SNPs) of the calcium-sensing receptor (C... more Background and objectiveSingle nucleotide polymorphisms (SNPs) of the calcium-sensing receptor (CASR) gene at the regulatory region were associated with idiopathic calcium nephrolithiasis. To confirm their association with nephrolithiasis, we tested patients with primary hyperparathyroidism (PHPT).DesignA genotype–phenotype association study.MethodsIn all, 332 PHPT patients and 453 healthy controls were genotyped for the rs7652589 (G>A) and rs1501899 (G>A) SNPs sited in the noncoding regulatory region of the CASR gene. Allele, haplotype, and diplotype distribution were compared between PHPT patients and controls, and in stone forming and stone-free PHPT patients.ResultsThe allele frequency at rs7652589 and rs1501899 SNPs was similar in PHPT patients and controls. The A minor alleles at these two SNPs were more frequent in stone forming (n=157) than in stone-free (n=175) PHPT patients (rs7652589: 36.9 vs 27.1%, P=0.007; rs1501899: 37.1 vs 26.4%, P=0.003). Accordingly, homozygou...
ObjectiveA common polymorphic variant of GH receptor (exon 3 deletion, d3GHR) has been linked wit... more ObjectiveA common polymorphic variant of GH receptor (exon 3 deletion, d3GHR) has been linked with increased response to recombinant human GH (rhGH) in some patients with or without GH deficiency (GHD). The aim of the study was to investigate the impact of the GHR genotype on the phenotype of GHD adults and on the metabolic effect of rhGH therapy.DesignProspective study of GHD patients evaluated before and during short- (1 year,n=100) and long-term (5 years,n=50) rhGH therapy.MethodsEffects of rhGH on IGF1 levels, body composition (body fat percentage, BF%), body mass index, lipid profile, and glucose homeostasis (fasting insulin and glucose, insulin sensitivity indexes) were evaluated according to the presence or the absence of the d3GHR variant.ResultsThe different genotype did not influence basal phenotype of GHD. Short-term rhGH determined normalization of IGF1 levels, decrease in BF%, and worsening of insulin sensitivity, independently from the presence of the d3GHR allele. A s...
Purpose The study aimed to define the clinical, biochemical and genetic features of adult patient... more Purpose The study aimed to define the clinical, biochemical and genetic features of adult patients with osteopenia/osteoporosis and/or bone fragility and low serum alkaline phosphatase (sALP). Methods Twenty-two patients with at least two sALP values below the reference range were retrospectively enrolled after exclusion of secondary causes. Data about clinical features, mineral and bone markers, serum pyridoxal-5’-phosphate (PLP), urine phosphoethanolamine (PEA), lumbar and femur bone densitometry, and column X-ray were collected. Peripheral blood DNA of each participant was analyzed to detect ALPL gene anomalies. Results Pathogenic ALPL variants (pALPL) occurred in 23% and benign variants in 36% of patients (bALPL), while nine patients harbored wild-type alleles (wtALPL). Fragility fractures and dental anomalies were more frequent in patients harboring pALPL and bALPL than in wtALPL patients. Of note, wtALPL patients comprised women treated with tamoxifen for hormone-sensitive bre...
Journal of biological regulators and homeostatic agents, 2015
Parathormone (PTH) has been suggested to affect the cardiovascular system. Teriparatide (TPT), th... more Parathormone (PTH) has been suggested to affect the cardiovascular system. Teriparatide (TPT), the hormonally active 1-34 fragment of PTH, provides an anabolic treatment for osteoporosis. The aim of the present study was to evaluate the cardiometabolic effects of 18-month treatment with 20 μg/ die teriparatide subcutaneosly. Fourteen women with postmenopausal severe osteoporosis treated with once-daily sc 20 μg TPT (67.6 ± 2.5 years; BMI 27.7 ± 1.0 kg/m²) and 24 age- and BMI-matched severe osteoporotic women treated with iv yearly 5 mg zoledronate (ZLN) were evaluated at baseline and at 12-18 months of treatment for anthropometric measures, calcium, glucose and lipid metabolic parameters, and assessment of cardiac geometry by conventional echocardiography. TPT was effective in increasing mean lumbar spine bone mineral density with no clinically relevant changes in calcium metabolism parameters. TPT patients experienced an increase of BMI (27.7 ± 1.0 at baseline vs 29.0 ± 1.0 kg/m² a...
Primary hyperparathyroidism (PHPT) is the third most common endocrine disease. Kidney is a target... more Primary hyperparathyroidism (PHPT) is the third most common endocrine disease. Kidney is a target of both chronic elevated PTH and calcium in PHPT. The classic PHPT complications of symptomatic kidney stones and nephrocalcinosis have become rare and the PHPT current presentation is asymptomatic with uncertain and long-lasting progression. Nonetheless, the routine use of imaging and of biochemical determinations have revealed the frequent occurrence of asymptomatic kidney stones, hypercalciuria and reduced kidney function in asymptomatic PHPT patients. Though the pathogenesis is far from being elucidated, PHPT is associated with reduced renal function, in terms of estimated glomerular filtration rate, and related increased morbidity and mortality. In the last decade, the effort of the Kidney Disease: Improving Global Outcomes (KDIGO) panel of experts highlighted that even mild reduction of kidney function is associated with increased risk of cardiovascular disease. These consideratio...
Context. Hypovitaminosis D frequently occurs in early life and increases with age. Vitamin D has ... more Context. Hypovitaminosis D frequently occurs in early life and increases with age. Vitamin D has been suggested to influence cardiac performance and N-terminal-pro-type B natriuretic peptide (NT-proBNP) release in adults with heart failure.Objectives. To assess the vitamin D status and the impact of hypovitaminosis D on circulating NT-proBNP levels in young patients with congenital heart defects (CHD).Design and Patients. This cross-sectional study included the assessment of serum 25-hydroxyvitamin D (25OHD), parathyroid function markers, and NT-proBNP levels in a series of 230 young in-patients (117 females, 113 males; 6.4 (4.0–9.1) years (median, interquartile range)) with CHD.Results. Serum 25OHD levels <20 ng/mL were detected in 55.3% of patients. Optimal 25OHD levels (>30 ng/mL) occurred in 25% of patients. Serum 25OHD levels inversely correlated with age (r=-0.169,P=0.013) and height standard deviation score (r=-0.269,P=0.001). After correction for age, 25OHD negatively ...
Several studies reported somatic mutations of many genes (MEN1, CTNNB1, CDKIs and others) in para... more Several studies reported somatic mutations of many genes (MEN1, CTNNB1, CDKIs and others) in parathyroid adenoma, although with different prevalence. Recently, activating mutations of the EZH2 and ZFX oncogenes were identified in benign parathyroid adenoma by whole exome sequencing. The same mutations had been found in blood and ovary malignant tumours. On one hand, this result raised the hypothesis that these oncogenes may play a role in the onset of parathyroid tumour, but it would also suggest they may be involved in malignant, rather benign, parathyroid neoplasm. Our aim was to verify the occurrence of selected mutations of the EZH2 and ZFX genes in an Italian cohort of 23 sporadic parathyroid carcinomas, 12 atypical and 45 typical adenomas. DNA was extracted from paraffin-embedded tissues, PCR amplified and directly sequenced. No mutations were detected in the coding sequence and boundaries of both genes in any of the samples. Two polymorphisms of the EZH2 gene were identified ...
Clinical cases in mineral and bone metabolism : the official journal of the Italian Society of Osteoporosis, Mineral Metabolism, and Skeletal Diseases, 2013
Calcium sensing receptor (CASR) is a G-protein couple receptor which plays a key role in calcium ... more Calcium sensing receptor (CASR) is a G-protein couple receptor which plays a key role in calcium homeostasis in vertebrates. Its extracellular domain is sensitive to divalent cations, aminoacids and polyamines. In parathyroid glands, CASR activation causes parathyroid hormone (PTH) reduction and subsequently a decrease in blood calcium concentration. In PTH-dependent disorders, e.g. primary and secondary hyperparathyroidism (HPT), the need for therapeutic options other than surgery led to the synthesis of various allosteric CASR agonists (calcimimetics), such as cinacalcet. Cinacalcet is the only calcimimetic approved for HPT secondary to chronic kidney disease (CDK), parathyroid carcinoma, and, in some countries, primary HPT. Clinical trials showed that cinacalcet reduced PTH and calcemia both in CDK and primary HPT, lowering the risk of bone fractures, surgery, and cardiovascular complications in the former patients. Long-term safety and pharmacoeconomics have to be fully tested y...
DM1 and DM2 are progressive multisystem genetic disorders that share a similar pathogenetic mecha... more DM1 and DM2 are progressive multisystem genetic disorders that share a similar pathogenetic mechanism and clinical manifestations. The endocrine features include insulin resistance and testicular failure. Some clinical studies showed how hypogonadism do not correlate to muscle weakness in DM1 but there are no studies that evaluate directly the contribution of endocrine disorders (as hypogonadism and insulin resistance) on atrophy on muscle fibers. Atrogin1 and MuRF1 belong to the ubiquitin proteasome pathway (UPP) and their gene expression have been observed in a wide range of in vivo models of skeletal muscle atrophy including diabetes, cancer, renal failure and denervation. The aim of the study is to evaluate the influence of gonadic function, insulin resistance to muscle fiber atrophy in myotonic dystrophies. The study has been carried out on 18 male patients, 10 DM1 (age 49+/-8,1years) and 8 DM2 (age 55*/-7,9years). Patients under 18 and over 65 years were excluded. Other exclusion criteria were testosterone and statin therapy, cardiac failure (stage 3 and 4 NYHA). Muscle strength was measured by manual muscle testing (MRC score) and QMA (Gainesville, Giorgia). Gonadic function was evaluated by measurement of total testosterone, free testosterone, and gonadotropin (LH,FSH) levels. HOMA-IR as index of insulin resistance was calculated from fasting glucose and insulin level. Body composition was measured by bioelectric impedance analysis and DEXA. Biceps brachii biopsy has been performed in all patients. Atrophy and hypertrophy factors of muscle fibres have been calculated on fast or slow myosin immunostained muscle sections. The correlations between metabolic alteration and muscle fibre atrophy/hypertrophy and the expression of atrogin1 evaluated by western blot on frozen muscle will be presented
Components of the tumour microenvironment initiate and promote cancer development. In this study,... more Components of the tumour microenvironment initiate and promote cancer development. In this study, we investigated the stromal component of parathyroid neoplasia. Immunohistochemistry for alpha-smooth muscle actin (α-SMA) showed an abundant periacinar distribution of α-SMA+ cells in normal parathyroid glands (n=3). This pattern was progressively lost in parathyroid adenomas (PAds; n=6) where α-SMA+cells were found to surround new microvessels, as observed in foetal parathyroid glands (n=2). Moreover, in atypical adenomas (n=5) and carcinomas (n=4), α-SMA+ cells disappeared from the parenchyma and accumulated in the capsula and fibrous bands. At variance with normal glands, parathyroid tumours (n=37) expressed high levels of fibroblast-activation protein (FAP) transcripts, a marker of tumour-associated fibroblasts. We analysed the ability of PAd-derived cells to activate fibroblasts using human bone-marrow mesenchymal stem cells (hBM-MSCs). PAd-derived cells induced a significant incr...
ObjectivePrimary hyperparathyroidism (PHPT) is a challenging problem in type 1 multiple endocrine... more ObjectivePrimary hyperparathyroidism (PHPT) is a challenging problem in type 1 multiple endocrine neoplasia (MEN1) due to the high postsurgery recurrence rate. The aim was to evaluate the efficacy of cinacalcet in MEN1 patients in comparison with patients with sporadic PHPT (sPHPT) and the effect of Arg990Gly calcium-sensing receptor (CASR) polymorphism on the response to treatment.DesignThis is a randomized, crossover, double-blind study carried out in the University Hospitals.MethodsFifteen MEN1 patients with PHPT were randomized to two groups, one administered with 30 mg daily cinacalcet, titrated until calcium normalization, and one with placebo. After 3 months, patients were reassessed and after washout switched to the other treatment. For comparison, 20 sPHPT patients with similar calcium levels were administered with cinacalcet for 3 months. Ionized and total calcium, phosphate, and parathyroid hormone (PTH) were evaluated. CASR Arg990Gly was genotyped on blood DNA by direct ...
Background and objectiveSingle nucleotide polymorphisms (SNPs) of the calcium-sensing receptor (C... more Background and objectiveSingle nucleotide polymorphisms (SNPs) of the calcium-sensing receptor (CASR) gene at the regulatory region were associated with idiopathic calcium nephrolithiasis. To confirm their association with nephrolithiasis, we tested patients with primary hyperparathyroidism (PHPT).DesignA genotype–phenotype association study.MethodsIn all, 332 PHPT patients and 453 healthy controls were genotyped for the rs7652589 (G>A) and rs1501899 (G>A) SNPs sited in the noncoding regulatory region of the CASR gene. Allele, haplotype, and diplotype distribution were compared between PHPT patients and controls, and in stone forming and stone-free PHPT patients.ResultsThe allele frequency at rs7652589 and rs1501899 SNPs was similar in PHPT patients and controls. The A minor alleles at these two SNPs were more frequent in stone forming (n=157) than in stone-free (n=175) PHPT patients (rs7652589: 36.9 vs 27.1%, P=0.007; rs1501899: 37.1 vs 26.4%, P=0.003). Accordingly, homozygou...
ObjectiveA common polymorphic variant of GH receptor (exon 3 deletion, d3GHR) has been linked wit... more ObjectiveA common polymorphic variant of GH receptor (exon 3 deletion, d3GHR) has been linked with increased response to recombinant human GH (rhGH) in some patients with or without GH deficiency (GHD). The aim of the study was to investigate the impact of the GHR genotype on the phenotype of GHD adults and on the metabolic effect of rhGH therapy.DesignProspective study of GHD patients evaluated before and during short- (1 year,n=100) and long-term (5 years,n=50) rhGH therapy.MethodsEffects of rhGH on IGF1 levels, body composition (body fat percentage, BF%), body mass index, lipid profile, and glucose homeostasis (fasting insulin and glucose, insulin sensitivity indexes) were evaluated according to the presence or the absence of the d3GHR variant.ResultsThe different genotype did not influence basal phenotype of GHD. Short-term rhGH determined normalization of IGF1 levels, decrease in BF%, and worsening of insulin sensitivity, independently from the presence of the d3GHR allele. A s...
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Papers by S. Corbetta