Anna Maria Barbieri

Fondazione IRCCS Ca' Granda - Ospedale Maggiore Policlinico, Milano, Lombardy, Italy

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Publications (15)88.36 Total impact

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    ABSTRACT: Objective A polymorphism in the promoter region of the IGF-I gene has been linked to serum IGF-I levels, risk of diabetes and cardiovascular diseases with conflicting results. Aim of this study was to investigate the impact of this polymorphism on the short- (1 yr, n=98) and long- (5 yrs, n=50) term metabolic response to rhGH in GHD adults.Design and Methods Prospective study on GHD adults. Different genotypes were studied by microsatellite method. According to the most frequent 192 bp allele (19 CA-repeats) subjects were divided in homozygous (19/19), heterozygous (19/X) and non-carriers (X/X).Results Basal characteristics of patients as well as their response to rhGH in terms of decrease in BF% and increase in IGF-I levels were not different in the three genotypes groups. Conversely, after 1-year rhGH, a significant worsening of insulin sensitivity (i.e. increase in fasting glucose levels and HOMA-IR) and a significant improvement in lipid profile (i.e. reduction in total- and LDL-cholesterol) was recorded only in homozygous subjects. In the long-term, insulin sensitivity was restored in all the patients, while a significant improvement in lipid profile was observed in homozygous and heterozygous, but not in non-carriers. No difference in rhGH dose among groups was recorded throughout study.Conclusions In GHD adults, the presence of the wild type allele in the IGF-I gene promoter may enhance sensitivity to either negative or positive metabolic changes induced by rhGH.
    European Journal of Endocrinology 11/2013; · 3.14 Impact Factor
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    ABSTRACT: Hepatotoxicity is one of the most serious adverse effect in acromegalic patients treated with pegvisomant (PEG-V). Recent studies found an association between this adverse event and the UGT1A1 allele 28 polymorphism associated with Gilbert's syndrome. To determine whether UGT1A1*28 and alcohol dehydrogenase (ADH) polymorphisms influence liver toxicity during PEG-V treatment. Multicenter observational retrospective study conducted in 13 tertiary care endocrinology Units in Italy. 112 patients with active disease resistant to somatostatin analogs and 108 controls were enrolled . Clinical and biochemical data were recorded by electronic clinical reporting forms. Blood or DNA samples were sent to the coordinating center for genotyping. No differences in genotypes between patients and controls were found. During PEG-V therapy liver function tests (LFT) abnormalities and overt hepatotoxicity developed in 17% and 4.5% of patients, respectively. Logistic and linear regression analyses showed an association between LFT abnormalities during follow up visit and prior events of LFT abnormalities in medical history (OR = 1.25; P = 0.04) and the number of concomitant medications, other than somatostatin analogs (B = 3.9; P = 0.03). No correlation between LFT alterations and UGT1A1 allele 28 as well as ADH1C and B polymorphisms was found. UGT1A1 allele 28 and ADH1C and B polymorphisms do not predict increased risk of hepatotoxicity during PEG-V therapy. Conversely, patients with multi-therapies and with previous episodes of liver disease should be carefully managed, due to the observed association between these conditions and LFT abnormalities during PEG-V therapy.
    European Journal of Endocrinology 11/2013; · 3.14 Impact Factor
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    ABSTRACT: Progressive osseous heteroplasia (POH) is a rare autosomal dominant disorder of mesenchymal differentiation characterized by progressive heterotopic ossification (HO) of dermis, deep connective tissues and skeletal muscle. Usually, initial bone formation occurs during infancy as primary osteoma cutis (OC) then progressively extending into deep connective tissues and skeletal muscle over childhood. Most cases of POH are caused by paternally inherited inactivating mutations of GNAS gene. Maternally inherited mutations as well as epigentic defects of the same gene lead to pseudohypoparathyroidism (PHP) and Albright's hereditary osteodystrophy (AHO). During the last decade, some reports documented the existence of patients with POH showing additional features characteristics of AHO such as short stature and brachydactyly, previously thought to occur only in other GNAS-associated disorders. Thus, POH can now be considered as part of a wide spectrum of ectopic bone formation disorders caused by inactivating GNAS mutations. Here, we report genetic and epigenetic analysis of GNAS locus in 10 patients affected with POH or primary OC, further expanding the spectrum of mutations associated with this rare disease and indicating that, unlike PHP, methylation alterations at the same locus are absent or uncommon in this disorder.
    Bone 06/2013; · 3.82 Impact Factor
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    ABSTRACT: Abstract Pseudohypoparathyroidism type Ia (PHP Ia) is a rare disease characterized by an elevated parathyroid hormone due to the resistance to its action in target tissues. We report a new GNAS mutation causing PHP Ia and an atypical early-onset primary hypothyroidism. A 3-year-old boy was diagnosed with obesity, delayed pyschomotor development, and round face. The laboratory evaluation at the age of 1 year showed primary hypothyroidism, hypocalcemia, hyperphosphatemia, elevated alkaline phosphatase, and parathyroid hormone. These data led to the diagnosis of PHP Ia. Molecular analysis revealed a novel missense mutation in GNAS exon 1 (TCG→CGC, Cys3→Arg) in both the child and his mother. Although previously reported cases described delayed subclinical hypothyroidism as the more common thyroid abnormality, we report a not previously described GNAS mutation associated with an atypical early-onset primary hypothyroidism. These observations broaden the clinical spectrum of PHP Ia and its associated mutations.
    Journal of pediatric endocrinology & metabolism: JPEM 02/2013; · 0.75 Impact Factor
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    ABSTRACT: Context: Pseudohypoparathyroidism type I (PHP-I) includes two main subtypes, PHP-Ia and -Ib. About 70% of PHP-Ia patients, who show Albright hereditary osteodystrophy (AHO) associated with resistance toward multiple hormones (PTH/TSH/GHRH/gonadotropins), carry heterozygous mutations in GNAS Gsα-coding exons 1-13, whereas the majority of PHP-Ib patients, who classically display hormone resistance limited to PTH and TSH with no AHO sign, have methylation defects in the imprinted GNAS cluster. Recently, methylation defects have been detected also in patients with PHP and different degrees of AHO, indicating a molecular overlap between the two forms. Objectives: To collect patients with the following characteristics: clinical PHP-I (with or without AHO), no mutation in Gsα-coding sequence but presence of GNAS methylation alterations; to investigate the existence of correlations between the degree of the epigenetic defect and the severity of the disease. Patients and methods: We quantified GNAS methylation alterations by both PCR-pyro-sequencing and MS-MLPA in genomic DNA from 63 patients with PHP-I and correlated these findings with clinical parameters (age at diagnosis, calcium, phosphorus, PTH, TSH levels, presence or absence of each AHO sign). Results: By both approaches, the degree of the imprinting defect did not correlate with the onset of the disease, the severity of endocrine resistances, nor with the presence/absence of specific AHO signs. Conclusions: Similar molecular alterations may lead to a broad spectrum of diseases, from isolated PTH resistance to complete PHP-Ia, and the degree of methylation alterations does not reflect or anticipate the severity and the type of different PHP/AHO manifestations.
    The Journal of clinical endocrinology and metabolism 01/2013; · 6.50 Impact Factor
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    ABSTRACT: 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 yet. Few both in vitro and in vivo studies showed an association between Arg990Gly-CASR polymorphism and cinacalcet sensitivity, though in patients with severe CASR inactivating mutations the drug substantially retained its positive clinical effects. Recently, a new class of allosteric antagonists of CASR, i.e. calcilytics, has been synthesized. Calcilytics are structurally similar to calcimimetics, but exert their effects acting on a different allosteric site. Infusion of calcilytics was followed by transient rise in PTH and calcium. One of these compounds, ronacaleret, was able to increase femur BMD in post menopausal women, but with induction of mild hyperparathyroidism. In the future, calcilytics may contribute to the osteoporosis treatment choice.
    Clinical Cases in Mineral and Bone Metabolism 01/2013; 10(3):162-165.
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    ABSTRACT: ABSTRACT Pseudohypoparathyroidism (PHP) is a rare heterogeneous genetic disorder characterized by end-organ resistance to parathyroid hormone (PTH) due to partial deficiency of the α subunit of the stimulatory G protein (Gsα), encoded by the GNAS gene. Heterozygous inactivating GNAS mutations lead to either PHP type Ia (PHP-Ia), when maternally inherited, or pseudo-pseudohypoparathroidism (PPHP), if paternally derived. Both diseases feature typical physical traits identified as Albright's hereditary osteodystrophy (AHO) in the presence or absence of multihormone resistance, respectively. GNAS mutations are detected in 60-70% of affected subjects, most patients/families harbor private mutations and no genotype-phenotype correlation has been found to date. We investigated Gsα-coding GNAS exons in a large panel of PHP-Ia/PPHP patients collected over the past decade in the two Italian referring centers for PHP. Of 49 patients carrying GNAS mutations, in 19 patients we identified 15 novel mutations. No apparent correlation was found between clinical/biochemical data and results of molecular analysis. Furthermore, we summarized the current knowledge of GNAS molecular pathology and updated the GNAS locus specific database. These results further expand the spectrum of GNAS mutations associated with PHP/PPHP and underline the importance of identifying such genetic alterations to supplement clinical evaluation and genetic counseling.
    Human Mutation 12/2012; · 5.21 Impact Factor
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    ABSTRACT: Previous studies have demonstrated a gain-of-function of the calcium-sensing receptor (CASR) gene R990G polymorphism. In this study, activation of the R990G CASR stably transfected in HEK-293 (HEK-990G) cells compared with that of the common variant (HEK-wild-type (WT)) by increasing concentrations of CaCl(2) or calcimimetic R-568 caused significantly higher intracellular free calcium concentration ([Ca(2+)](i)) and lower Ca-EC(50). Moreover, the [Ca(2+)](i) oscillation percentage was higher with a larger sinusoidal pattern in HEK-990G. R-568 induced a shift of the oscillatory events from 4 to 2  mmol/l extracellular calcium concentration in HEK-990G cells and increased the sinusoidal oscillation percentage in comparison with HEK-WT. Preincubation with thapsigargin or phospholipase C inhibitors completely prevented oscillations in both cell lines, consistent with the involvement of the inositol trisphosphate pathway, while protein kinase C inhibitor prevented oscillations in HEK-WT cells only. Finally, CaCl(2) and R-568 caused a significant increase in p44/42 extracellular signaling-regulated kinase phosphorylation, with the mean Ca-EC(50) values being significantly lower in HEK-990G. Our findings demonstrated that the 990G allele is associated with high sensitivity to R-568, which provided new evidence for differences in CASR signaling.
    Journal of Molecular Endocrinology 10/2010; 45(4):245-56. · 3.58 Impact Factor
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    ABSTRACT: Context: The two main subtypes of pseudohypoparathyroidism (PHP), PHP-Ia and -Ib, are caused by mutations in GNAS exons 1-13 and methylation defects in the imprinted GNAS cluster, respectively. PHP-Ia patients show Albright hereditary osteodystrophy (AHO) and resistance toward PTH and additional hormones, whereas PHP-Ib patients do not have AHO, and hormone resistance appears to be limited to PTH and TSH. Recently, methylation defects have been detected in few patients with PHP and mild AHO, indicating a molecular overlap between the two forms. Objectives: The aim of the study was to screen patients with clinically diagnosed PHP-Ia for methylation defects and to investigate the presence of correlations between the molecular findings and AHO severity. Patients and Methods: We investigated differential methylation of GNAS regions and STX16 microdeletions in genomic DNA from 40 patients with sporadic AHO and multihormone resistance, with no mutations in Gsalpha-coding GNAS exons. Results: Molecular analysis showed GNAS cluster imprinting defects in 24 of the 40 patients analyzed. No STX16 deletion was detected. The presence of imprinting defects was not associated with the severity of AHO or with specific AHO signs. Conclusions: We report the largest series of the literature of patients with clinical AHO and multihormone resistance and no mutation in the Gsalpha gene. Our findings of frequent GNAS imprinting defects further confirm the existence of an overlap between molecular and clinical features of PHP-Ia and PHP-Ib and highlight the necessity of a new clinical classification of the disease that takes into account the recent knowledge on the molecular basis underlying these defects.
    The Journal of clinical endocrinology and metabolism 02/2010; 95(2):651-8. · 6.50 Impact Factor
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    ABSTRACT: Hypogonadism frequently occurs in men with type 2 diabetes mellitus (T2DM), while the role of glycemic control and visceral obesity is still unclear. This study aimed to assess the Leydig cell function, including the new sensitive marker insulin-like factor 3 (INSL3), in T2DM patients without overt hypogonadism and the influence of either glycemic control or visceral adiposity. Thirty T2DM patients (age 57.1+/-6.2 years, body mass index (BMI) 28.0+/-4.3) without overt hypogonadism and 30 age- and BMI-matched controls were studied. Anthropometric, glycometabolic parameters and testosterone, SHBG, LH, INSL3 levels, bioavailable and free testosterone (BT and cFT) were evaluated. The human chorionic gonadotrophin (hCG) test was also performed. Patients had lower total testosterone (452.6+/-130.0 vs 512.6+/-117.3 ng/dl, P=0.06), BT (189.7+/-36.4 vs 237.1+/-94.1 ng/dl, P=0.002), cFT (8.1+/-1.6 vs 10.1+/-4.0 ng/dl, P=0.002), and higher LH levels (3.5+/-1.6 vs 2.6+/-1.2 mU/ml, P=0.01) versus controls. Serum INSL3 concentrations were also lower in patients (1.1+/-0.3 vs 1.5+/-0.7 ng/ml, P=0.01). These hormonal parameters, including INSL3, did not differ between T2DM patients with poor or good glycemic control (HbA1c>9 or <7% respectively). In patients, waist circumferences (97.9+/-12.4 cm) negatively correlated with INSL3 (P=0.03) and basal, as well as hCG-stimulated testosterone levels (P=0.04 and 0.004 respectively). Basal or stimulated hormonal levels and INSL3 concentrations were not different between patients with (40%) or without erectile dysfunction. An early impairment of the overall Leydig cell function is present in men with T2DM, mainly related to visceral adiposity rather than to glycemic control.
    European Journal of Endocrinology 09/2009; 161(6):853-9. · 3.14 Impact Factor
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    ABSTRACT: Cell growth and proliferation require coordinated ribosomal biogenesis and translation. Eukaryotic initiation factors (eIFs) control translation at the rate-limiting step of initiation. So far, only two eIFs connect extracellular stimuli to global translation rates: eIF4E acts in the eIF4F complex and regulates binding of capped messenger RNA to 40S subunits, downstream of growth factors, and eIF2 controls loading of the ternary complex on the 40S subunit and is inhibited on stress stimuli. No eIFs have been found to link extracellular stimuli to the activity of the large 60S ribosomal subunit. eIF6 binds 60S ribosomes precluding ribosome joining in vitro. However, studies in yeasts showed that eIF6 is required for ribosome biogenesis rather than translation. Here we show that mammalian eIF6 is required for efficient initiation of translation, in vivo. eIF6 null embryos are lethal at preimplantation. Heterozygous mice have 50% reduction of eIF6 levels in all tissues, and show reduced mass of hepatic and adipose tissues due to a lower number of cells and to impaired G1/S cell cycle progression. eIF6(+/-) cells retain sufficient nucleolar eIF6 and normal ribosome biogenesis. The liver of eIF6(+/-) mice displays an increase of 80S in polysomal profiles, indicating a defect in initiation of translation. Consistently, isolated hepatocytes have impaired insulin-stimulated translation. Heterozygous mouse embryonic fibroblasts recapitulate the organism phenotype and have normal ribosome biogenesis, reduced insulin-stimulated translation, and delayed G1/S phase progression. Furthermore, eIF6(+/-) cells are resistant to oncogene-induced transformation. Thus, eIF6 is the first eIF associated with the large 60S subunit that regulates translation in response to extracellular signals.
    Nature 10/2008; 455(7213):684-8. · 38.60 Impact Factor
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    ABSTRACT: The criteria for defining subclinical hypercortisolism (SH) are debated and a real gold standard test or combination of tests is lacking. Recently, late-night salivary cortisol (MSC) has been described as a sensitive and easy-to-perform marker for diagnosing overt hypercortisolism. No data are available on the role of MSC in the diagnosis of SH. The aim of this study was to evaluate the sensitivity and specificity of MSC levels in the diagnosis of SH in patients with adrenal incidentalomas (AI). In 103 (females/males, 69/34) patients with AI, MSC levels were studied. One milligram overnight dexamethasone suppression test (DST), urinary-free cortisol (UFC), and ACTH plasma levels were also evaluated. Patients were defined as affected by SH if they showed two of the following criteria: DST>83 nmol/l, ACTH <2.2 pmol/l, and UFC >193 nmol/24 h. No difference in MSC levels in patients with SH (3.1+/-3.1 nmol/l) compared with patients without SH (2.2+/-2.8 nmol/l) was observed. In patients with SH, MSC levels were significantly correlated with DST (r=0.4, P<0.05). Using the cut-off of 5.1 nmol/l, the sensitivity and specificity of MSC levels for diagnosis of SH is 22.7 and 87.7% respectively. In patients with AI, normal levels of MSC do not exclude SH, whereas high levels may suggest the presence of SH identified by conventional tests. Thus, MSC is not suitable as a screening test, although it may be used in conjunction with other tests as the confirming test in selected patients.
    European Journal of Endocrinology 10/2008; 160(1):87-92. · 3.14 Impact Factor
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    ABSTRACT: Dopamine-agonist cabergoline (CB) reduces prolactin (PRL) secretion and tumor size in 80% of patients with prolactin-secreting adenomas (PRL-omas) by binding type 2 dopamine receptor (DRD2). The mechanisms responsible for resistance to CB remain largely unknown. To assess the association of DRD2 with sensitivity to CB, TaqI-A1/A2, TaqI-B1/B2, HphI-G/T and NcoI-C/T genotypes were determined in a cross-sectional retrospective study, including 203 patients with PRL-oma. DRD2 alleles frequencies did not differ between patients and 212 healthy subjects. Conversely, NcoI-T allele frequency was higher in resistant rather than responsive patients, considering both PRL normalization (56.6 vs 45.3%, P=0.038) and tumor shrinkage (70.4 vs 41.4%, P=0.006). Finally, [TaqI A1-/TaqI B1-/HphI T-/NcoI T-] haplotype was found in 34.5% of patients normalizing PRL with < or =3 mg/week of CB vs 11.3% of resistants (P=0.021). In conclusion, resistance to CB was associated with DRD2 NcoI-T+ allele, consistent with evidence suggesting that this variant may lead to reduction and instability of DRD2 mRNA or protein.
    The Pharmacogenomics Journal 04/2008; 8(5):357-63. · 5.13 Impact Factor
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    ABSTRACT: Macroprolactinaemia may represent a relevant cause of misdiagnosis, unnecessary investigation and inappropriate treatment. The aim of this study was to investigate the clinical and neuroradiological characteristics of patients with and without macroprolactinaemia and to evaluate the impact of macroprolactin determination on the diagnostic work-up of hyperprolactinaemic patients. Retrospective analysis in 135 consecutive hyperprolactinaemic patients (111 women and 24 men; mean age 37 +/- 11.6 years) whose archived sera were subsequently tested for macroprolactin. Recoveries </= 40% after polyethylene glycol precipitation were indicative of macroprolactinaemia. Macroprolactin, entirely explaining biochemical hyperprolactinaemia, was found in 42.2% of patients, a third of whom presented with signs and symptoms of hyperprolactinaemia. Determination of macroprolactin changed the initial diagnosis in a consistent proportion of patients. In particular, idiopathic hyperprolactinaemia, initially diagnosed in 41 patients, was then excluded in 28 of them. Diagnosis of prolactin-secreting pituitary microadenoma shifted to non-secreting pituitary microadenoma in 10 of 49 patients, while in all patients with prolactin-secreting pituitary macroadenoma or hyperprolactinaemia due to stalk deafferentation the presence of macroprolactin was excluded and the initial diagnosis confirmed. Finally, macroprolactin was present in the majority of patients with magnetic resonance imaging (MRI) scans suggestive for primary empty sella (4 of 5 women) or pituitary hyperplasia (12 of 17 women, 3 of 3 men). Collectively, about half of subjects with macroprolactinaemia showed variable MRI abnormalities. The presence of macroprolactin was a relevant cause of misdiagnosis in patients with hyperprolactinaemia. However, due to the unexpected high frequency of pituitary abnormalities observed in the present series, we suggest that the diagnostic algorithm of hyperprolactinaemic states should include both polyethylene glycol precipitation test and MRI imaging.
    European Journal of Clinical Investigation 08/2007; 37(7):552-7. · 3.37 Impact Factor
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    ABSTRACT: Ectopic periarticular calcifications associated with elevated levels of serum phosphate represent the principal clinical features of hyperphosphatemic familial tumoral calcinosis (HFTC), a rare autosomal recessive metabolic disorder. The disease can be caused by recessive mutations in at least two different genes: GalNAc transferase 3 (GALNT3), encoding a glycosyltransferase that initiates mucin-type O-glycosylation, and fibroblast growth factor 23 (FGF23), which encodes a regulator of phosphate circulating levels. In the current study, we performed mutation analyses of the GALNT3 gene in a subject with HFTC and in his relatives. Sequence analyses revealed that the proband was a compound heterozygote for two novel nonsense mutations in exon 4 (Y322X) and in exon 7 (Q481X). Cosegregation of the mutations with the disease within the family was confirmed by polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) analysis. This is the first report describing the simultaneous presence of two different stop codons in the coding sequence of the GALNT3 gene.
    Journal of Human Genetics 02/2007; 52(5):464-8. · 2.37 Impact Factor

Publication Stats

181 Citations
88.36 Total Impact Points

Institutions

  • 2013
    • Fondazione IRCCS Ca' Granda - Ospedale Maggiore Policlinico
      • Endocrinology and Diabetology
      Milano, Lombardy, Italy
  • 2012
    • University of Milan
      • Department of Clinical Sciences and Community Health
      Milano, Lombardy, Italy
  • 2010
    • Ospedale di San Raffaele Istituto di Ricovero e Cura a Carattere Scientifico
      Milano, Lombardy, Italy