BackgroundAlthough diabetic kidney disease demonstrates both familial clustering and single nucleotide polymorphism heritability, the specific genetic factors influencing risk remain largely unknown.MethodsTo identify genetic variants predisposing to diabetic kidney disease, we performed genome-wide association study (GWAS) analyses. Through collaboration with the Diabetes Nephropathy Collaborative Research Initiative, we assembled a large collection of type 1 diabetes cohorts with harmonized diabetic kidney disease phenotypes. We used a spectrum of ten diabetic kidney disease definitions based on albuminuria and renal function.ResultsOur GWAS meta-analysis included association results for up to 19,406 individuals of European descent with type 1 diabetes. We identified 16 genome-wide significant risk loci. The variant with the strongest association (rs55703767) is a common missense mutation in the collagen type IV alpha 3 chain (COL4A3) gene, which encodes a major structural component of the glomerular basement membrane (GBM). Mutations in COL4A3 are implicated in heritable nephropathies, including the progressive inherited nephropathy Alport syndrome. The rs55703767 minor allele (Asp326Tyr) is protective against several definitions of diabetic kidney disease, including albuminuria and ESKD, and demonstrated a significant association with GBM width; protective allele carriers had thinner GBM before any signs of kidney disease, and its effect was dependent on glycemia. Three other loci are in or near genes with known or suggestive involvement in this condition (BMP7) or renal biology (COLEC11 and DDR1).ConclusionsThe 16 diabetic kidney disease–associated loci may provide novel insights into the pathogenesis of this condition and help identify potential biologic targets for prevention and treatment.

BackgroundUntil recently increasing prevalence of overweight and obesity among pediatric population in Europe and worldwide contributes to major well-known risks for metabolic consequences in later life. The aim of this study was to determine the prevalence of overweight/obesity among children and adolescents in Lithuania and assess its association with energy balance related behaviors as well as familial demographic and socioeconomic factors.MethodsCross-sectional study included 3990 7–17 years old schoolchildren from 40 schools of Kaunas region, Lithuania. Study participants underwent anthropometric measurements. Body mass index (BMI) was evaluated according to International Obesity Task Force (IOTF) criteria for children and adolescents. Children and adolescents and their parents filled in the questionnaires on parental sociodemographic characteristics, dietary habits, TV watching time, and family socioeconomic status.ResultsThe prevalence of underweight, overweight, and obesity among boys and girls was 6.9 and 11.7 % (P < 0.05), 12.6 and 12.6 % (P > 0.05), and 4.9 and 3.4 % (P < 0.05), respectively. Obesity was significantly more prevalent in the 7–9 years old group (6.7 and 4.8 % in boys and girls, respectively, P < 0.05). Lower meals frequency and breakfast skipping were directly associated with overweight/obesity (P < 0.05); however, physical inactivity was not associated with higher BMI. Children‘s overweight/obesity was directly associated with lower paternal education and unemployment (OR 1.30, P = 0.013 and OR 1.56, P = 0.003, respectively).ConclusionsThe prevalence of overweight and obesity among 7–17 years old Lithuanian children and adolescents was more prevalent in younger age, still being one of the lowest across the European countries. Meals frequency, breakfast skipping, paternal education and unemployment as well as a family history of arterial hypertension were found to be associated with children’s and adolescents’ overweight/obesity.

Background: Fetal growth restriction (FGR) has been related to several health risks, which have been generally identified in small-for-gestational age (SGA) individuals. Objective: To evaluate the impact of FGR on body composition and hormonal status in infants born either small-or appropriate-for-gestational age (AGA). Methods: Fetal growth was assessed by ultrasound every 4 weeks from mid-gestation to birth in 248 high-risk pregnancies for SGA. Fetal growth velocity was calculated as change in the estimated fetal weight percentiles and FGR defined as its reduction by more than 20 percentiles from 22 gestational weeks to birth. Impact of FGR on body composition, cord insulin, IGF-I, IGF binding protein-3 (IGFBP-3), and cortisol concentrations was assessed in SGA and AGA newborns. Results: Growth-retarded AGA infants showed significantly reduced birth weight, ponderal index, percentage of fat mass, and bone mineral density when compared with AGA newborns with stable intrauterine growth. Cord IGF-I and IGFBP-3 concentrations were significantly decreased in growthretarded infants in both SGA and AGA groups. Cord insulin concentration was significantly lower and cord cortisol significantly higher in AGA infants with FGR versus AGA newborns with stable intrauterine growth.After adjustment for gestational age and gender, birth weight was directly related to fetal growth velocity and cord IGF-I concentration. The variation in infant's adiposity was best explained by fetal growth velocity and cord insulin concentration. Conclusions: FGR affects body composition and hormonal parameters in newborns with birth weight within the normal range, suggesting these individuals could be at similar metabolic risks as SGA.

Pregnancies are rare in women with pituitary adenomas, which may relate to hormone excess from secretory subtypes such as prolactinomas or corticotroph adenomas. Decreased fertility may also result from pituitary hormone deficiencies due to compression of the gland by large tumours and/or surgical or radiation treatment of the lesion. Counselling premenopausal women with pituitary adenomas about their chance of conceiving spontaneously or with assisted reproductive technology, and the optimal pre-conception treatment, should start at the time of initial diagnosis. The normal physiological changes during pregnancy need to be considered when interpreting endocrine tests in women with pituitary adenomas. Dose adjustments in hormone substitution therapies may be needed across the trimesters. When medical therapy is used for pituitary hormone excess, consideration should be given to the known efficacy and safety data specific to pregnant women for each therapeutic option. In healthy women, pituitary gland size increases during pregnancy. Since some pituitary adenomas also enlarge during pregnancy, there is a risk of visual impairment, especially in women with macroadenomas or tumours near the optic chiasm. Pituitary apoplexy represents a rare acute complication of adenomas requiring surveillance, with surgical intervention needed in some cases. This guideline describes the choice and timing of diagnostic tests and treatments from the pre-conception stage until after delivery, taking into account adenoma size, location and endocrine activity. In most cases, pregnant women with pituitary adenomas should be managed by a multidisciplinary team in a centre specialised in the treatment of such tumours.

Summary. The aim of this study was to evaluate leptin concentration at birth and in early

Small for gestational age (SGA) children are more prone to have precocious pubarche and exaggerated precocious adrenarche, an earlier onset of pubertal development and menarche, and faster progression of puberty than children born of appropriate for gestational age (AGA) size. The majority of studies investigating the onset of puberty in children born SGA and AGA established that, although puberty begins at an appropriate time (based on chronological age and actual height) in SGA children, onset is earlier relative to AGA children. Evaluating pubertal growth in SGA children, a more modest bone age delay from chronological age at the onset of puberty and more rapid bone maturation during puberty compared to AGA children were reported. Peak height velocity in adolescence is reached at an earlier pubertal stage and lasts for a shorter period in children born SGA than in those born AGA. These differences lead to an earlier fusion of the growth plates and a shorter adult height. The pathophysiological mechanism underlying the unique pubertal growth pattern of children born SGA remains unclear. However, it seems that this is not only related to birth weight, gestational age, adiposity or obesity, but that there may also be an influence of rapid weight gain in early childhood on pubertal onset: excess weight gain in childhood may be related to central adiposity, decreased insulin sensitivity, and increased IGF-I levels and might thus predispose to precocious pubarche.

Context Germline mutations in the aryl hydrocarbon receptor-interacting protein (AIP) gene are responsible for a subset of familial isolated pituitary adenoma (FIPA) cases and sporadic pituitary neuroendocrine tumors (PitNETs). Objective To compare prospectively diagnosed AIP mutation-positive (AIPmut) PitNET patients with clinically presenting patients and to compare the clinical characteristics of AIPmut and AIPneg PitNET patients. Design 12-year prospective, observational study. Participants & Setting We studied probands and family members of FIPA kindreds and sporadic patients with disease onset ≤18 years or macroadenomas with onset ≤30 years (n = 1477). This was a collaborative study conducted at referral centers for pituitary diseases. Interventions & Outcome AIP testing and clinical screening for pituitary disease. Comparison of characteristics of prospectively diagnosed (n = 22) vs clinically presenting AIPmut PitNET patients (n = 145), and AIPmut (n = 167) vs AIPneg PitNET patients (n = 1310). Results Prospectively diagnosed AIPmut PitNET patients had smaller lesions with less suprasellar extension or cavernous sinus invasion and required fewer treatments with fewer operations and no radiotherapy compared with clinically presenting cases; there were fewer cases with active disease and hypopituitarism at last follow-up. When comparing AIPmut and AIPneg cases, AIPmut patients were more often males, younger, more often had GH excess, pituitary apoplexy, suprasellar extension, and more patients required multimodal therapy, including radiotherapy. AIPmut patients (n = 136) with GH excess were taller than AIPneg counterparts (n = 650). Conclusions Prospectively diagnosed AIPmut patients show better outcomes than clinically presenting cases, demonstrating the benefits of genetic and clinical screening. AIP-related pituitary disease has a wide spectrum ranging from aggressively growing lesions to stable or indolent disease course.

BackgroundFetal growth restriction (FGR) followed by rapid weight gain during early life has been suggested to be the initial sequence promoting central adiposity and insulin resistance. However, the link between fetal and early postnatal growth and the associated anthropometric and metabolic changes have been poorly studied.Methodology/Principal FindingsOver the first year of post-natal life, changes in body mass index, skinfold thickness and hormonal concentrations were prospectively monitored in 94 infants in whom the fetal growth velocity had previously been measured using a repeated standardized procedure of ultrasound fetal measurements. 45 infants, thinner at birth, had experienced previous FGR (FGR+) regardless of birth weight. Growth pattern in the first four months of life was characterized by greater change in BMI z-score in FGR+ (+1.26+/−1.2 vs +0.58 +/−1.17 SD in FGR−) resulting in the restoration of BMI and of fat mass to values similar to FGR−, independently of caloric intakes. Growth velocity after 4 months was similar and BMI z-score and fat mass remained similar at 12 months of age. At both time-points, fetal growth velocity was an independent predictor of fat mass in FGR+. At one year, fasting insulin levels were not different but leptin was significantly higher in the FGR+ (4.43+/−1.41 vs 2.63+/−1 ng/ml in FGR−).ConclusionEarly catch-up growth is related to the fetal growth pattern itself, irrespective of birth weight, and is associated with higher insulin sensitivity and lower leptin levels after birth. Catch-up growth promotes the restoration of body size and fat stores without detrimental consequences at one year of age on body composition or metabolic profile. The higher leptin concentration at one year may reflect a positive energy balance in children who previously faced fetal growth restriction.