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Massa O Iafusco D D'Amato E Gloyn AL Hattersley AT Pasquino B Tonini G Dammacco F Zanette G Meschi F Porzio O Bottazzo G Crinó A Lorini R Cerutti F Vanelli M Barbetti F;Early Onset Diabetes Study Group of the Italian Society of Pediatric Endocrinology Diabetology 《Human mutation》2005,25(1):22-27
Permanent neonatal diabetes mellitus (PNDM) is a rare condition characterized by severe hyperglycemia constantly requiring insulin treatment from its onset. Complete deficiency of glucokinase (GCK) can cause PNDM; however, the genetic etiology is unknown in most PNDM patients. Recently, heterozygous activating mutations of KCNJ11, encoding Kir6.2, the pore forming subunit of the ATP-dependent potassium (K(ATP)) channel of the pancreatic beta-cell, were found in patients with PNDM. Closure of the K(ATP) channel exerts a pivotal role in insulin secretion by modifying the resting membrane potential that leads to insulin exocytosis. We screened the KCNJ11 gene in 12 Italian patients with PNDM (onset within 3 months from birth) and in six patients with non-autoimmune, insulin-requiring diabetes diagnosed during the first year of life. Five different heterozygous mutations were identified: c.149G>C (p.R50P), c.175G>A (p.V59M), c.509A>G (p.K170R), c.510G>C (p.K170N), and c.601C>T (p.R201C) in eight patients with diabetes diagnosed between day 3 and 182. Mutations at Arg50 and Lys170 residues are novel. Four patients also presented with motor and/or developmental delay as previously reported. We conclude that KCNJ11 mutations are a common cause of PNDM either in isolation or associated with developmental delay. Permanent diabetes of non autoimmune origin can present up to 6 months from birth in individuals with KCNJ11 and EIF2AK3 mutations. Therefore, we suggest that the acronym PNDM be replaced with the more comprehensive permanent diabetes mellitus of infancy (PDMI), linking it to the gene product (e.g., GCK-PDMI, KCNJ11-PDMI) to avoid confusion between patients with early-onset, autoimmune type 1 diabetes. 相似文献
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Permanent diabetes mellitus in the first year of life 总被引:5,自引:0,他引:5
Iafusco D Stazi MA Cotichini R Cotellessa M Martinucci ME Mazzella M Cherubini V Barbetti F Martinetti M Cerutti F Prisco F;Early Onset Diabetes Study Group of the Italian Society of Paediatric Endocrinology Diabetology 《Diabetologia》2002,45(6):798-804
AIMS/HYPOTHESIS: The pathogenesis of permanent diabetes mellitus diagnosed early in life is heterogeneous and, in most cases, not known. We aimed at identifying markers differentiating between non-autoimmune and autoimmune diabetes. METHODS: The clinical, genetic and epidemiological features of 111 diabetic patients (62 males) who received insulin within 12 months of life were studied. RESULTS: The epidemic curve by age of diabetes onset revealed two subsets of patients at a cutoff of 180 days. In the group with diabetes onset before 180 days ("early onset" permanent diabetes) the analysis of HLA susceptibility heterodimers (available for 21 individuals) showed that 76% had a "protective" HLA genotype for Type I (insulin-dependent) diabetes mellitus as compared to 11.9% (5/42) of the later onset group. Accordingly, "early onset" children were less likely to have autoimmunity markers (4 out of 26 tested) than children with onset after 180 days (13 out 20 tested) (15.4% vs. 65.0%, p<0.01). Of note, 19 out of 20 (or the 95%) patients who were born on the island of Sardinia, an Italian region where the incidence of Type I diabetes is six times higher than continental Italy (33/100,000/year vs 5/100,000/year), were included in the later onset group (>180 days). Small-for-date birthweight, a possible sign of reduced foetal insulin secretion, was more common in the "early onset" group (OR=9.9, 95%-CI 2.6-38.6). CONCLUSION/INTERPRETATION: These results, obtained in the largest population-based cohort of diabetic infants hitherto reported, suggest that "early onset" permanent diabetes cases differ from later onset cases and that most of them do not have an autoimmune pathogenesis. 相似文献
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Corrias A Grugni G Crinò A Di Candia S Chiabotto P Cogliardi A Chiumello G De Medici C Spera S Gargantini L Iughetti L Luce A Mariani B Ragusa L Salvatoni A Andrulli S Mussa A Beccaria L;Study Group for Genetic Obesity of Italian Society of Pediatric Endocrinology Diabetology 《Clinical endocrinology》2012,76(6):843-850
Objective A recent study evidenced by metyrapone test a central adrenal insufficiency (CAI) in 60% of Prader–Willi syndrome (PWS) children. These results were not confirmed in investigations with low [Low‐Dose Tetracosactrin Stimulation Test (LDTST), 1 μg] or standard‐dose tetracosactrin stimulation tests. We extended the research by LDTST in paediatric patients with PWS. Design Cross‐sectional evaluation of adrenal stress response to LDTST in a PWS cohort of a tertiary care referral centre. Patients Eighty‐four children with PWS. Measurements Assessment of adrenal response by morning cortisol and ACTH dosage, and 1‐μg tetracosactrin test. Response was considered appropriate when cortisol reached 500 nm ; below this threshold, patients were submitted to a second test. Responses were correlated with the patients’ clinical and molecular characteristics to assess genotype–phenotype correlation. Results Pathological cortisol peak responses to the LDTST were registered in 12 patients (14·3%) who had reduced basal (169·4 ± 83·3 nm ) and stimulated (428·1 ± 69·6 nm ) cortisol levels compared to patients with normal responses (367·1 ± 170·6 and 775·9 ± 191·3 nm , P < 0·001). Body mass index standard deviation score was negatively correlated with basal and peak cortisol levels (both P < 0·001), and the patients’ ages (P < 0·001). In patients with deletion on chromosome 15, the cortisol peak was significantly lower than that in uniparental disomy (UPD) cases (P = 0·030). At multiple regression analysis, the predictors of peak response were basal cortisol, age, and UPD subclass (r2 = 0·353, P < 0·001). Standard‐dose (250 μg) tetracosactrin test confirmed CAI in 4/12 patients (4·8% of the cohort). Conclusions Our results support the hypothesis that, albeit rare, CAI may be part of the PWS in childhood. 相似文献
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Icks A Rosenbauer J Holl RW Grabert M Rathmann W Giani G;German Working Group for Pediatric Diabetology 《Diabetes care》2001,24(3):435-440
OBJECTIVE: To compare hospitalization in a multicenter-based cohort of diabetic children and adolescents (aged 1-19 years) in Germany with that of the general population. RESEARCH DESIGN AND METHODS: Based on standardized documentation, hospital stays after manifestation were ascertained in diabetic subjects 1-19 years of age in 1997. Hospitalization data in the general German population were derived from official statistics. Incidence rates and numbers of hospital days were estimated. Ratios of hospitalization incidences and numbers of hospital days between the diabetic and the general population were calculated. Costs for hospital care in the German diabetic population in 1997 were determined. RESULTS: A total of 5,874 patients came from 61 pediatric centers (52% male, age [mean +/- SD] 12.2 +/- 4.3 years, diabetes duration 4.6 +/- 4.4 years). Hospitalization incidence rates and hospital days per person-year (95% CI) were 0.27 (0.25-0.29) and 1.80 (1.75-1.84) in the diabetic population and 0.0948 (0.0946-0.0949) and 0.6416 (0.6412-0.6420) in the general population. The standardized ratio of hospital incidences was 3.1 (2.9-3.2), and the ratio of numbers of hospital days was 2.8 (2.7-2.9). Costs for hospital care after manifestation were estimated to be $506 (U.S. dollars) per person-year and $12.4 million in the whole German diabetic population aged 1-19 years in 1997; including hospital stays at diabetes onset, total annual costs were $24 million ($970 per person-year). CONCLUSIONS: Diabetic children and adolescents in Germany had an approximately three times higher hospitalization risk and three times more hospital days than the age-matched general population. Including hospitalization at diabetes onset, the annual costs of hospital care for the German diabetic population aged 1-19 years amounted to approximately 1% of all costs for hospital care in this age-group. Thus, costs were largely overproportional (diabetes prevalence 0.1%). 相似文献
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Scaramuzza A Iafusco D Lombardo F Rabbone I Toni S;Italian Society of Endocrinology Diabetology 《Pediatrics》2008,122(2):473-4; author reply 474
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Comorbidity of attention deficit hyperactivity disorder and type 1 diabetes in children and adolescents: Analysis based on the multicentre DPV registry
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Doerte Hilgard Katja Konrad Michael Meusers Bela Bartus Klaus‐Peter Otto Rudolf Lepler Edith Schober Esther Bollow Reinhard W. Holl for the German/Austrian DPV Study Group the Working Group on Psychiatric Psychotherapeutic Psychological Aspects of Paediatric Diabetology the BMBF Competence Network Diabetes Germany 《Pediatric diabetes》2017,18(8):706-713
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Grugni G Marzullo P Ragusa L Sartorio A Trifirò G Liuzzi A Crinò A;Genetic Obesity Study Group of the Italian Society of Pediatric Endocrinology Diabetology 《Clinical endocrinology》2006,65(4):492-499
OBJECTIVE: It is unclear if poor health outcomes of adult patients with Prader-Willi syndrome (PWS) are influenced by GH deficiency (GHD). Few studies have been focused on PWS adults, but further information on the concomitant role of obesity on GH/IGF-I axis function is needed. The aim of our study was to investigate the prevalence of GHD in a large group of adult subjects with genetically confirmed PWS. DESIGN AND SUBJECTS: We studied the GH response to a combined administration of GHRH (1 microg/kg i.v. at 0 minutes) and arginine (ARG) (30 g i.v., infused from 0 to 30 minutes) as well as the baseline IGF-I levels, in a group of 44 PWS adults (18 males, 26 females) aged 18-41.1 years. The same protocol was carried out in a control group of 17 obese subjects (7 males, 10 females) aged 21.8-45.8 years. MEASUREMENTS: Blood samples were taken at -15 and 0 minutes and then 30, 45, 60, 90 and 120 minutes after GHRH administration. Serum GH and total IGF-I concentrations were measured by chemioluminescence. Statistical analysis was performed by Student's t-test for unpaired data, and using analysis of variance for parametric and nonparametric (Mann-Whitney test) data, where appropriate. The relationship between pairs of variables was assessed by Pearson's correlation. Independent variables influencing GH secretion were tested by multiple linear regression analysis. RESULTS: The GH response to GHRH + ARG was significantly lower in PWS patients (GH peak (mean +/- SE) 8.4 +/- 1.2 microg/l; AUC: 471.4 +/- 77.8 microg/l/h) than obese subjects (GH peak 15.7 +/- 2.9 microg/l, P < 0.02; AUC 956 +/- 182.9 microg/l/h, P < 0.005). When considered individually, 17 of 44 PWS individuals (38.6%) were severely GHD, according to the cut-off limit of 4.1 microg/l for obese individuals, and low IGF-I-values were present in 33 PWS patients. Moreover, impaired GH response was combined with subnormal IGF-I levels in all PWS patients with GHD. CONCLUSIONS: Adult subjects with PWS had a reduced responsiveness to GHRH + ARG administration associated with reduced IGF-I levels. In addition, a severe GHD for age was demonstrated in a significant percentage of PWS subjects. These findings are in agreement with the hypothesis that a complex derangement of hypothalamus-pituitary axis occurred in PWS, and suggested that impaired GH secretion is not an artefact of obesity. 相似文献