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Zavattari P.,Servizio di Endocrinologia Pediatrica | Zavattari P.,University of Cagliari | Loche A.,Servizio di Endocrinologia Pediatrica | Loche A.,Friedrich Miescher Institute for Biomedical Research | And 6 more authors.
Annals of Human Genetics | Year: 2011

Several studies have reported an association of the intronic single nucleotide polymorphism (SNP) rs9939609 of the fat mass and obesity-associated (FTO) gene with obesity and with a number of obesity-related features. We studied the association of rs9939609 with obesity in 912 obese children and adolescents (426 males and 486 females, mean ± SD age 10.5 ± 3.3 years) and in 543 normal weight subjects. A number of biochemical and clinical parameters was also evaluated in 700 of these patients. In the obese group, mean body mass index standard deviation score (BMI-SDS) was similar between the three genotypes. The A allele was present in 55% of the patients' and in 43% of controls' chromosomes. The distribution of heterozygotes was similar between patients and controls (47%), while the distribution of AA homozygotes was significantly higher in patients (31% vs. 20%). Logistic regression analysis on the genotypes yielded a χ 2 of 35.5 with an odds ratio of 1.6 (CI = 1.3-1.8), P < 1 × 10 -5. None of the clinical and metabolic parameters tested was associated with the genotype. In conclusion, we have confirmed the strong association between FTO and obesity, and shown that only AA homozygotes are predisposed to develop obesity while TT homozygotes might be protected. Finally, we found no association between rs9939609 and a number of obesity-related abnormalities. © 2011 The Authors, Annals of Human Genetics © 2011 Blackwell Publishing Ltd/University College London.


Ghizzoni L.,University of Turin | Cappa M.,Ospedale Pediatrico Bambino Gesu | Vottero A.,University of Parma | Ubertini G.,Ospedale Pediatrico Bambino Gesu | And 11 more authors.
European Journal of Endocrinology | Year: 2011

Objective: Premature pubarche (PP) is the most frequent sign of nonclassic congenital adrenal hyperplasia (NCCAH) due to 21-hydroxylase deficiency in childhood. The aim of this study was to assess the relationship between the CYP21A2 genotype and baseline and ACTH-stimulated 17-hydroxyprogesterone (17-OHP) and cortisol serum levels in patients presenting with PP. Patients and methods: A total of 152 Italian children with PP were studied. Baseline and ACTH-stimulated 17-OHP and cortisol serum levels were measured and CYP21A2 gene was genotyped in all subjects. Results: Baseline and ACTH-stimulated serum 17-OHP levels were significantly higher in NCCAH patients than in both heterozygotes and children with idiopathic PP (IPP). Of the patient population, four NCCAH patients (7.3%) exhibited baseline 17-OHP values < 2 ng/ml (6 nmol/l). An ACTH-stimulated 17-OHP cutoff level of 14 ng/ml (42 nmol/l) identified by the receiver-operating characteristics curves showed the best sensitivity (90.9%) and specificity (100%) in distinguishing NCCAH patients. This value, while correctly identifying all unaffected children, missed 9% of affected individuals. Cortisol response to ACTH stimulation was < 18.2 μg/dl (500 nmol/l) in 14 NCCAH patients (28%) and none of the heterozygotes or IPP children. Among the 55 NCCAH patients, 54.5% were homozygous for mild CYP21A2 mutations, 41.8% were compound heterozygotes for one mild and one severe CYP21A2 gene mutations, and 3.6% had two severe CYP21A2 gene mutations. Conclusion: In children with PP, baseline 17-OHP levels are not useful to rule out the diagnosis of NCCAH, which is accomplished by means of ACTH testing only. The different percentages of severe and mild CYP21A2 gene mutations found in PP children compared with adult NCCAH patients is an indirect evidence that the enzyme defect is under-diagnosed in childhood, and it might not lead to the development of hyperandrogenic symptoms in adulthood. Stress-dose glucocorticoids should be considered in patients with suboptimal cortisol response to ACTH stimulation. © 2011 European Society of Endocrinology.


Di Iorgi N.,University of Genoa | Napoli F.,University of Genoa | Allegri A.,University of Genoa | Secco A.,University of Genoa | And 9 more authors.
Journal of Clinical Endocrinology and Metabolism | Year: 2010

Context: The accuracy of the glucagon test in the diagnosis of central adrenal insufficiency in young children has not yet been definitively established. Objective: The aim of this study was to investigate the diagnostic accuracy of the glucagon test as an alternative to the insulin tolerance test (ITT) in children with GH deficiency under 6 yr of age. Design and Setting: This was a prospective study conducted in two Pediatric Endocrinology Centers. Patients and Methods: Forty-eight children (median age, 4.2 yr) with GH deficiency confirmed by a peak GH to ITT and arginine less than 10 μg/liter were enrolled: 24 with normal hypothalamicpituitary anatomy, seven with isolated anterior pituitary hypoplasia, and 17 with structural hypothalamic-pituitary abnormalities at magnetic resonance imaging. Twelve subjects had central adrenal insufficiency defined by a peak cortisol response of less than 20 μg/dl to ITT. All children underwent a glucagon stimulation test with blood sampling for cortisol and glucose (time 0 to 180 min) after the im administration of 30 μg/kg of glucagon. Results: Themeanpeakcortisol after glucagonwasnot significantly differentfromthat obtained after ITT in the whole cohort (25.9 vs. 26.0 μg/dl; P=0.908), and it was significantly reduced in patients with structural hypothalamic-pituitary abnormalities (P < 0.001). Receiver operating characteristic curve analysis showed that the best diagnostic accuracy was obtained with a peak cortisol cutoff to glucagon of 14.6 μg/dl (sensitivity, 66.67%; specificity, 100%; area under the curve = 0.91; 95% confidence interval, 0.82-0.99). Using this cutoff, 91.67% of the patients were correctly classified. Conclusions: This study shows that glucagon is an accurate and safe diagnostic test for adrenal function in young children who are at risk for adrenal insufficiency. Copyright © 2010 by The Endocrine Society.


Loche S.,Servizio di Endocrinologia Pediatrica
Hormone Research in Paediatrics | Year: 2011

Children with idiopathic short stature (ISS) may not reach an adult height within their genetic target. In 2003, the United States Food and Drug Administration approved biosynthetic growth hormone (GH) for the treatment of children with ISS whose heights exceeded 2.25 standard deviation scores below the mean and who were considered unlikely to reach a normal adult height. Results of controlled studies have shown that, although GH treatment leads to a substantial increase in adult height, the individual response to therapy is difficult to predict. A number of auxological variables (i.e., age and height at start of treatment, bone age delay, mean predicted height, height velocity and first-year responsiveness) are used in multivariate analyses to predict outcomes. Estimation of target height, predicted adult height and pattern of growth should guide the decision to treat a child with ISS. Copyright © 2011 S. Karger AG, Basel.


Vottero A.,University of Parma | Guzzetti C.,Servizio di Endocrinologia Pediatrica | Loche S.,Servizio di Endocrinologia Pediatrica
Endocrine Development | Year: 2013

Growth hormone (GH) secretion from the pituitary is regulated by a complex network of CNS and peripheral inputs. Circulating GH binds to its receptor and initiates a cascade of signaling events which involve the JAK2-STAT pathway, the PI3K/Akt pathway and the RAS/MAPK pathway, leading to the transcription of several genes, including insulin-like growth factor 1 (IGF-1), IGFBP3, ALS, and others. Recent findings indicate that nutrition plays an important role in GH secretion and action. Furthermore, data are emerging which suggest that the RAS-MAPK pathway as well as epigenetic regulation of transcription may be important in determining both circulating and locally produced IGF-1. Copyright © 2013 S. Karger AG, Basel.


Loche S.,Servizio di Endocrinologia Pediatrica | Guzzetti C.,Servizio di Endocrinologia Pediatrica | Pilia S.,Servizio di Endocrinologia Pediatrica | Ibba A.,Servizio di Endocrinologia Pediatrica | And 4 more authors.
Clinical Endocrinology | Year: 2011

Objectives An inverse relationship has been shown between body mass index (BMI) and the peak growth hormone (GH) response to stimulation in adults and in children with short stature. This relation is observed even within a normal range of BMI. The aim of this study was to investigate the effect of BMI on the GH response to clonidine in a large number of children with short stature. Design We conducted a retrospective study on the GH response to clonidine in a single centre. Methods We studied 202 children with short stature (135 M and 67 F) who underwent clonidine testing from 2007 to 2009. Results One hundred and twenty-eight patients had a GH peak >10 Îg/l. In univariate regression analysis, the peak GH after clonidine was negatively correlated with BMI-standard deviation score (BMI-SDS) and positively correlated with height velocity-SDS and IGF-I-SDS. Only the relationship between peak GH and BMI-SDS remained significant in children with a BMI-SDS from -2 to +2. In the multivariate stepwise regression analysis, BMI-SDS and IGF-I-SDS were the only significant variables in the entire cohort, explaining 19·5% of the variance in peak GH. When only subjects with BMI-SDS between -2·0 and +2·0 were included in the analysis (n = 173), BMI-SDS alone explained 21·4% of the variability in peak GH. The number of patients who failed the clonidine test increased with increasing BMI-SDS. Conclusions BMI affects the GH response to clonidine in children with short stature and should be considered when interpreting the results to the stimulation test. © 2011 Blackwell Publishing Ltd.


PubMed | Servizio di Endocrinologia Pediatrica
Type: Journal Article | Journal: Journal of pediatric endocrinology & metabolism : JPEM | Year: 2013

We aimed to study the influence of the fat mass and obesity-associated (FTO) gene on eating behavior in 412 obese Sardinian children and adolescents. Genome-wide association studies (GWAS) have identified several susceptibility loci for obesity. Among these, the polymorphisms in the intron 1 of the FTO gene has been found associated to weight gain and obesity in various populations.All obese patients were genotyped for the FTO single nucleotide polimorphysm (SNP) rs9939609. In all subjects we evaluated eating behavior using the Child Eating Behaviour Questionnaire (CEBQ).We found no differences in eating behavior according to the genotype, either in the entire cohort, or when subjects were subdivided into four different age groups.FTO genotype is associated with body mass index but does not influence eating behavior in a selected cohort of obese children from the isolated genetic population of Sardinia.


Marras V.,Servizio di Endocrinologia Pediatrica | Casini M.R.,Servizio di Endocrinologia Pediatrica | Pilia S.,Servizio di Endocrinologia Pediatrica | Carta D.,Servizio di Endocrinologia Pediatrica | And 4 more authors.
Hormone Research in Paediatrics | Year: 2010

Objective: Obesity is frequently associated with modifications of thyroid size and function. We evaluated the prevalence of thyroid function abnormalities and the effects of puberty and weight loss in obese children and adolescents. Methods: We examined 468 obese children (255 girls and 213 boys aged 3.7-17.9 years) and 52 normal-weight age-matched children as controls. TSH, fT3, fT4, fasting serum insulin and glucose were measured at baseline. fT3, fT4 and TSH were also measured after 6 months of lifestyle intervention in a subset of 43 patients. Results: 109 obese children showed abnormal circulating thyroid hormone concentrations (84 had elevated fT3 levels, 15 elevated TSH, 6 elevated fT4, 3 elevated fT3 and TSH, and 1 elevated fT3, fT4 and TSH levels). Serum TSH and fT3 concentrations were positively correlated with BMI-SDS. The prevalence of patients with abnormal thyroid hormone concentrations was similar between sexes and between prepubertal and pubertal subjects. After 6 months of lifestyle intervention, thyroid hormone concentrations normalized in 27 of the patients with decreased BMI-SDS, and in 2 patients in whom BMI-SDS increased. Conclusions: In obese children, an increased fT3 concentration is the most frequent thyroid function abnormality. Serum fT3 and TSH correlate with BMI. Moderate weight loss frequently restores these abnormalities. Copyright © 2010 S. Karger AG, Basel.


Zavattari P.,Servizio di Endocrinologia Pediatrica | Loche A.,Servizio di Endocrinologia Pediatrica | Civolani P.,Servizio di Endocrinologia Pediatrica | Pilia S.,Servizio di Endocrinologia Pediatrica | And 4 more authors.
Annals of Human Genetics | Year: 2010

Allelic variants of a single nucleotide polymorphism (SNP), rs7566605, located approximately 10 kb upstream of the INSIG2 gene have been found in association with body weight and with other clinical features related to obesity in some populations but not in others. Our objective was to test the association of this SNP in obese children and adolescents from the genetically isolated population of Sardinia. We tested the association of rs7566605 with body mass index (BMI) and with serum glucose and insulin concentrations and a surrogate measure of insulin resistance (HOMA-IR) in a cohort of 747 Sardinian obese children and adolescents. A case control analysis was performed using 548 ethnically-matched healthy controls. Allelic frequencies of the SNP were similar between patients and controls. Mean glucose and insulin concentration and mean HOMA-IR values were significantly higher in patients carrying the CC genotype than in the CG and GG carriers. In the patients with impaired fasting glucose (IFG) and/or impaired glucose tolerance (IGT), allele C was significantly more frequent than in controls. Although INSIG2 polymorphisms do not consistently associate with BMI, the observation of an association with glucose concentration would support a role for this gene in the metabolic complications of obesity. © 2010 The Authors Annals of Human Genetics © 2010 Blackwell Publishing Ltd/University College London.


PubMed | Servizio di Endocrinologia Pediatrica
Type: | Journal: Italian journal of pediatrics | Year: 2013

Imerslund-Grsbeck syndrome is a rare autosomal recessive disorder, characterized by vitamin B12 deficiency due to selective malabsorption of the vitamin and usually results in megaloblastic anemia appearing in childhood. It is responsive to parenteral vitamin B12 therapy.The estimated prevalence (calculated based on Scandinavian data) is less than 6:1,000,000. However, many cases may be misdiagnosed.When there is reasonable evidence to suspect that a patient suffers from IGS, a new and straightforward approach to diagnosis is mutational analysis of the appropriate genes. We report for the first time the case of a girl of Italian ancestry with IGS genetically confirmed by the detection of a homozygous missense mutation in the AMN gene (c.208-2 A > G).

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