Search

OBJECTIVE: To investigate in a large sample of overweight/obese (OW/OB) children and adolescents the prevalence of prediabetic phenotypes such as impaired fasting glucose (IFG) and impaired glucose tolerance (IGT), and to assess their association with cardiometabolic risk (CMR) factors including hepatic steatosis (HS). METHODS: Population data were obtained from the CARdiometabolic risk factors in children and adolescents in ITALY study. Between 2003 and 2013, 3088 youths (972 children and 2116 adolescents) received oral glucose tolerance test (OGTT) and were included in the study. In 798 individuals, abdominal ultrasound for identification of HS was available. RESULTS: The prevalence of IFG (3.2 vs. 3.3%) and IGT (4.6 vs. 5.0%) was similar between children and adolescents. Children with isolated IGT had a 2-11 fold increased risk of high LDL-C, non-HDL-C, Tg/HDL-C ratio, and low insulin sensitivity, when compared to those with normal glucose tolerance (NGT). No significant association of IFG with any CMR factor was found in children. Among adolescents, IGT subjects, and to a lesser extent those with IFG, showed a worse CMR profile compared to NGT subgroup. In the overall sample, IGT phenotype showed a twofold increased risk of HS compared to NGT subgroup. CONCLUSIONS: Our study shows an unexpected similar prevalence of IFG and IGT between children and adolescents with overweight/obesity. The IGT phenotype was associated with a worse CMR profile in both children and adolescents. Phenotyping prediabetes conditions by OGTT should be done as part of prediction and prevention of cardiometabolic diseases in OW/OB youth since early childhood.

Purpose: We aimed to investigate a cohort of female and male patients with idiopathic central precocious puberty (CPP), negative for Makorin Ring Finger Protein 3 (MKRN3) defect, by molecular screening for Delta-like 1 homolog (DLK1) defects. DLK1 is an imprinted gene, whose mutations have been described as a rare cause of CPP in girls and adult women with precocious menarche, obesity and metabolic derangement. Methods: We enrolled 14 girls with familial CPP and 13 boys with familial or sporadic CPP from multiple academic hospital centers. Gene sequencing of DLK1 gene was performed. Circulating levels of DLK1 were measured and clinical and biochemical characteristics were described in those with DLK1 defects. Results: A novel heterozygous mutation in DLK1, c.288_289insC (p.Cys97Leufs*16), was identified in a male proband, his sister and their father. Age at onset of puberty was in line with previous reports in the girl and 8years in the boy. The father with untreated CPP showed short stature. No metabolic derangement was present in the father except hypercholesterolemia. Undetectable Dlk1 serum levels indicated the complete lack of protein production in the three affected patients. Conclusion: A DLK1 defect has been identified for the first time in a boy, underscoring the importance of genetic testing in males with idiopathic or sporadic CPP. The short stature reported by his untreated father suggests the need for timely diagnosis and treatment of subjects with DLK1 defects.

Context Hypogonadism in Prader-Willi syndrome (PWS) is generally attributed to hypothalamic dysfunction or to primary gonadal defect. MKRN3, a maternal imprinted gene located on 15q11.2-q13 region, encodes makorin ring finger protein 3, whose deficiency causes precocious puberty, an extremely rare symptom in PWS. Objective This study aimed to evaluate MKRN3 levels in patients with PWS and to analyze its correlation with sexual hormone levels, insulin resistance and Body Mass Index (BMI). Methods We performed an observational cross-sectional study and enrolled 80 patients with genetically confirmed diagnosis of PWS with median age of 9.6 years. Results MKRN3 levels were measurable in 49 PWS patients with a geometric mean of 34.9 +/- 22 pg/ml (median: 28.4). Unmeasurable levels of MKRN3 were found in 31 patients. No statistically significant differences were found between patients with and without measurable MKRN3 levels for any clinical, biochemical, or genetic characteristics. However, MKRN3 levels were inversely correlated with HOMA-IR index (p: 0.005) and HbA1c (p: 0.046) values. No statistically significant correlations were found between MKRN3 and LH, estradiol and testosterone concentrations, pubertal development and genetic defect, whereas a direct correlation with FSH was found (p: 0.007). Conclusions The typical genetic defect of PWS should lead to unmeasurable levels of the MKRN3 protein due to the inactivation of the paternal allele. Measurable circulating MKRN3 could suggest the possible involvement of tissue-specific imprinting mechanisms and other regulatory factors in gene expression. Correlations with HOMA-IR index, HbA1c, and FSH suggest peripheral actions of MKRN3, but future studies are warranted to investigate this topic.

Aim of our study is to verify the association between the genetic predisposition to hyperinsulinism due to the presence of the insulin gene (INS) I/I genotype and the development of sleep-related breathing disorders (SRBD) in obese children and adolescents. Two hundred and fifty-six obese children and adolescents (125 girls) have been investigated. As initial screening all subjects’ mothers filled out the Sleep Disturbances Scale for Children (SDSC). The Sleep- Disordered Breathing (SDB) scale has been taken into account. Successively, a subgroup of 34 patients belonging to the first (14 children) and the last (20 children) SDB score quintiles underwent an overnight polysomnography and the apnea-hypopnea index (AHI) was evaluated. All subjects were genotyped for the INS VNTR and fasting insulin levels were evaluated. The population was divided into two groups according to the genotype: the first group was comprehensive of patients homozygotes for class I allele and the second group was composed by class III allele heterozygotes and homozygotes patients. Subjects I/I showed statistically significant higher insulin levels (p