Samim Ozen

Effects of Environmental Endocrine Disruptors on Pubertal Development

The onset and course of puberty are under the control of the neuroendocrine system. Factors affecting the timing and regulation of the functions of this system may alter the onset and course of puberty. Several environmental endocrine disruptors (EDs) with significant influences on the normal course of puberty have been identified. Numerous animal and human studies concerning EDs have been conducted showing that these substances may extensively affect human health; nevertheless, there are still several issues that remain to be clarified. In this paper, the available evidence from animal and human studies on the effects of environmental EDs with the potential to cause precocious or delayed puberty was reviewed. Conflict of interest:None declared.

Rare Causes of Primary Adrenal Insufficiency: Genetic and Clinical Characterization of a Large Nationwide Cohort

Context: Primary adrenal insufficiency (PAI) is a life-threatening condition that is often due to monogenic causes in children. Although congenital adrenal hyperplasia occurs commonly, several other important molecular causes have been reported, often with overlapping clinical and biochemical features. The relative prevalence of these conditions is not known, but making a specific diagnosis can have important implications for management. Objective: The objective of the study was to investigate the clinical and molecular genetic characteristics of a nationwide cohort of children with PAI of unknown etiology. Design: A structured questionnaire was used to evaluate clinical, biochemical, and imaging data. Genetic analysis was performed using Haloplex capture and next-generation sequencing. Patients with congenital adrenal hyperplasia, adrenoleukodystrophy, autoimmune adrenal insufficiency, or obvious syndromic PAI were excluded. Setting: The study was conducted in 19 tertiary pediatric endocrinology clinics. Patients: Ninety-five children (48 females, aged 0–18 y, eight familial) with PAI of unknown etiology participated in the study. Results: A genetic diagnosis was obtained in 77 patients (81%). The range of etiologies was as follows: MC2R (n = 25), NR0B1 (n = 12), STAR (n = 11), CYP11A1 (n = 9), MRAP (n = 9), NNT (n = 7), ABCD1 (n = 2), NR5A1 (n = 1), and AAAS (n = 1). Recurrent mutations occurred in several genes, such as c.560delT in MC2R, p.R451W in CYP11A1, and c.IVS3ds+1delG in MRAP. Several important clinical and molecular insights emerged. Conclusion: This is the largest nationwide study of the molecular genetics of childhood PAI undertaken. Achieving a molecular diagnosis in more than 80% of children has important translational impact for counseling families, presymptomatic diagnosis, personalized treatment (eg, mineralocorticoid replacement), predicting comorbidities (eg, neurological, puberty/fertility), and targeting clinical genetic testing in the future.

The relation of vitamin D deficiency with puberty and insulin resistance in obese children and adolescents.

Abstract The prevalence of obesity among children and adolescents has been rapidly increasing in recent years. Obese individuals are at risk for vitamin D deficiency. The aim of this study was to investigate the relation of vitamin D deficiency with puberty and insulin resistance in obese children and adolescents. A total of 106 children and adolescents (48 prepubertal and 58 pubertal) between 8 and 16 years of age were included in the study. Fasting blood glucose, insulin, lipid profile, calcium, phosphorus, alkaline phosphatase, parathyroid hormone, 25-hydroxyvitamin D [25(OH)D] levels, as well as blood glucose and insulin concentrations at 120 min of oral glucose tolerance test were measured. Insulin resistance was calculated using the homeostasis model assessment. Daily vitamin D intake was questioned. Serum 25(OH)D level was normal in only 3.8%, insufficient in 34.0%, and deficient in 62.2% of the subjects. There was a statistically significant rate of 25(OH)D deficiency in the pubertal group compared with that in the prepubertal group. Those subjects with 25(OH)D deficiency were found to have greater insulin resistance. Vitamin D deficiency is common among obese children and adolescents. Low vitamin D levels in obese individuals may accelerate the development of metabolic syndrome, type 2 diabetes mellitus, and cardiovascular disease by further increasing insulin resistance.

Clinical course of Hashimoto's thyroiditis and effects of levothyroxine therapy on the clinical course of the disease in children and adolescents.

Objective: The aim of this study was to evaluate the clinical course of Hashimoto’s thyroiditis (HT) in children and adolescents and the effects of levothyroxine therapy on the clinical course and laboratory findings. Methods: The clinical and laboratory data of 101 patients with HT at presentation and during a three-year follow-up period were retrospectively evaluated using patient records. Results: The mean age of the patients at the time of diagnosis was 12.3±2.90 years and female/male ratio was 5.7/1. The complaint at the time of hospital presentation was goiter in 57.8% of the patients. At baseline, 36.7% of the patients were euthyroid, whereas 32.7% had subclinical hypothyroidism, 16.6 % of subjects were evaluated as hypothyroid. Twelve of the 28 patients who were initially euthyroid and not receiving therapy developed subclinical or overt hypothyroidism during the first 18 months of the follow-up period and were started on thyroid medication. At presentation, the mean anti-thyroglobulin (anti-Tg) and anti-thyroperoxidase antibody levels were 450±725 IU/mL and 392±428 IU/mL, respectively and at the end of the follow-up period, a significant decrease was observed in the anti-Tg levels of patients receiving levothyroxine from the beginning. Conclusions: Thyroid functions of the patients with HT should be monitored periodically for hypothyroidism. Levothyroxine therapy may positively affect the clinical course of the disease and the antibody titers. Conflict of interest:None declared.

The effects of Pilates on metabolic control and physical performance in adolescents with type 1 diabetes mellitus

UNLABELLED Physical activity is a substantial method in the management of children and adolescents with Type 1 diabetes mellitus but it is not considered as a treatment for diabetes. The aim of this study was to investigate the effects of Pilates exercises on metabolic control and physical performance in patients with type 1 diabetes mellitus. Thirty one sedentary patients with type 1 diabetes mellitus, ranging in age from 12 to 17 (experimental group, n=17 and control group, n=14) were submitted to 12 weeks of Pilates training. Participants underwent tests to determine the physical performance and metabolic control before and after 12 weeks of Pilates session. At the end of study, there were significant alterations in physical performance of the study group. Peak power, mean power, vertical jump and flexibility of study group increased. There were no alterations for this parameters in the control group. There was no significant difference for glycated hemoglobin (HbA1c) in both groups. CONCLUSIONS Physical performance increased via Pilates exercises in the patients with type 1 DM. However there were no changes in metabolic control. In the present study, the positive effects of exercise on metabolic control could not be shown in patients with Type 1 DM.

Effects of pesticides used in agriculture on the development of precocious puberty

The present study aims to evaluate the effects of pesticides on premature breast development. Forty-five girls (group 1) with premature breast development living in the Menderes region, where greenhouse cultivation is the main income, 16 girls (group 2) living in Izmir city with early puberty, and 33 girls (group 3) who had no signs of puberty were included in the study. Endosulphan 1, endosulphan 2, endosulphan sulphate, methoxychlor, vinclozolin, 4,4-dichlorodiphenyldichlorethylene (DDE), 4,-dichlorodiphenyltrichloroethane (DDT), and 2,4-DDT were evaluated in the serum and adipose tissues of the groups by using a gas chromatography–mass spectrometry method. With the exception of 4,4′-DDE, the pesticides studied were undetectable in the serum and adipose tissue samples. The levels of basal luteinizing hormone (LH), stimulated LH, follicle-stimulating hormone, and the long axis of the uterus and both ovaries were significantly different in the girls who had premature thelarche and detectable 4,4′-DDE levels compared to the girls who had premature thelarche and undetectable 4,4′-DDE levels in serum and adipose tissues. The presence and levels of pesticides in serum and adipose tissues were not related to precocious puberty (PP). The mechanisms that lead to PP may also result in obesity, and obesity may be the underlying cause for PP in this group.

Natural History of Congenital Generalized Lipodystrophy: A Nationwide Study From Turkey

CONTEXT Congenital generalized lipodystrophy (CGL) is a rare autosomal recessive disorder characterized by near-total lack of body fat. OBJECTIVE We aimed to study natural history and disease burden of various subtypes of CGL. DESIGN We attempted to ascertain nearly all patients with CGL in Turkey. SETTING This was a nationwide study. PATIENTS OR OTHER PARTICIPANTS Participants included 33 patients (22 families) with CGL and 30 healthy controls. MAIN OUTCOME MEASURE(S) We wanted to ascertain genotypes by sequencing of the known genes. Whole-body magnetic resonance imaging was used to investigate the extent of fat loss. Metabolic abnormalities and end-organ complications were measured on prospective follow-up. RESULTS Analysis of the AGPAT2 gene revealed four previously reported and four novel mutations (CGL1; c.144C>A, c.667_705delinsCTGCG, c.268delC, and c.316+1G>T). Analysis of the BSCL2 gene revealed four different homozygous and one compound heterozygous possible disease-causing mutations (CGL2), including four novel mutations (c.280C>T, c.631delG, c.62A>T, and c.465-468delGACT). Two homozygous PTRF mutations (c.481-482insGTGA and c.259C>T) were identified (CGL4). Patients with CGL1 had preservation of adipose tissue in the palms, soles, scalp, and orbital region, and had relatively lower serum adiponectin levels as compared to CGL2 patients. CGL4 patients had myopathy and other distinct clinical features. All patients developed various metabolic abnormalities associated with insulin resistance. Hepatic involvement was more severe in CGL2. End-organ complications were observed at young ages. Two patients died at age 62 years from cardiovascular events. CONCLUSIONS CGL patients from Turkey had both previously reported and novel mutations of the AGPAT2, BSCL2, and PTRF genes. Our study highlights the early onset of severe metabolic abnormalities and increased risk of end-organ complications in patients with CGL.

Diabetes care, glycemic control, complications, and concomitant autoimmune diseases in children with type 1 diabetes in Turkey: a multicenter study.

Objective: Epidemiologic and clinical features of type 1 diabetes mellitus (T1DM) may show substantial differences among countries. The primary goal in the management of T1DM is to prevent micro- and macrovascular complications by achieving good glycemic control. The present study aimed to assess metabolic control, presence of concomitant autoimmune diseases, and of acute and long-term complications in patients diagnosed with T1DM during childhood and adolescence. The study also aimed to be a first step in the development of a national registry system for T1DM, in Turkey. Methods: Based on hospital records, this cross-sectional, multicenter study included 1 032 patients with T1DM from 12 different centers in Turkey, in whom the diagnosis was established during childhood. Epidemiological and clinical characteristics of the patients were recorded. Metabolic control, diabetes care, complications, and concomitant autoimmune diseases were evaluated. Results: Mean age, diabetes duration, and hemoglobin A1c level were 12.5±4.1 years, 4.7±3.2 years, and 8.5±1.6%, respectively. Acute complications noted in the past year included ketoacidosis in 5.2% of the patients and severe hypoglycemia in 4.9%. Chronic lymphocytic thyroiditis was noted in 12%, Graves’ disease in 0.1%, and celiac disease in 4.3% of the patients. Chronic complications including neuropathy, retinopathy, and persistent microalbuminuria were present in 2.6%, 1.4%, and 5.4% of the patients, respectively. Diabetic nephropathy was not present in any of the patients. Mean diabetes duration and age of patients with neuropathy, retinopathy and microalbuminuria were significantly different from the patients without these long-term complications (p<0.01). A significant difference was found between pubertal and prepubertal children in terms of persistent microalbuminuria and neuropathy (p=0.02 and p<0.001, respectively). Of the patients, 4.4% (n:38) were obese and 5% had short stature; 17.4% of the patients had dyslipidemia, and 14% of the dyslipidemic patients were obese. Conclusions: Although the majority of the patients in the present study were using insulin analogues, poor glycemic control was common, and chronic complications were encountered. Conflict of interest:None declared.

Distribution of gene mutations associated with familial normosmic idiopathic hypogonadotropic hypogonadism.

Objective: Normosmic idiopathic hypogonadotropic hypogonadism (nIHH) is characterized by failure of initiation or maintenance of puberty due to insufficient gonadotropin release, which is not associated with anosmia/hyposmia. The objective of this study was to determine the distribution of causative mutations in a hereditary form of nIHH. Methods: In this prospective collaborative study, 22 families with more than one affected individual (i.e. multiplex families) with nIHH were recruited and screened for genes known or suspected to be strong candidates for nIHH. Results: Mutations were identified in five genes (GNRHR, TACR3, TAC3, KISS1R, and KISS1) in 77% of families with autosomal recessively inherited nIHH. GNRHR and TACR3 mutations were the most common two causative mutations occurring with about equal frequency. Conclusions: Mutations in these five genes account for about three quarters of the causative mutations in nIHH families with more than one affected individual. This frequency is significantly greater than the previously reported rates in all inclusive (familial plus sporadic) cohorts. GNRHR and TACR3 should be the first two genes to be screened for diagnostic purposes. Identification of causative mutations in the remaining families will shed light on the regulation of puberty. Conflict of interest:None declared.

Effects of Carbohydrate Counting Method on Metabolic Control in Children with Type 1 Diabetes Mellitus

Objective: Medical nutritional therapy is important for glycemic control in children and adolescents with type 1 diabetes mellitus (T1DM). Carbohydrate (carb) counting, which is a more flexible nutritional method, has become popular in recent years. This study aimed to investigate the effects of carb counting on metabolic control, body measurements and serum lipid levels in children and adolescents with T1DM. Methods: T1DM patients aged 7-18 years and receiving flexible insulin therapy were divided into carb counting (n=52) and control (n=32) groups and were followed for 2 years in this randomized, controlled study. Demographic characteristics, body measurements, insulin requirements, hemoglobin A1c (HbA1c) and serum lipid levels at baseline and at follow-up were evaluated. Results: There were no statistically significant differences between the groups in mean HbA1c values in the year preceding the study or in age, gender, duration of diabetes, puberty stage, total daily insulin dose, body mass index (BMI) standard deviation score (SDS) and serum lipid values. While there were no differences in BMI SDS, daily insulin requirement, total cholesterol, low-density lipoprotein and triglyceride values between the two groups (p>0.05) during the follow-up, annual mean HbA1c levels of the 2nd year were significantly lower in the carb counting group (p=0.010). The mean values of high-density lipoprotein were also significantly higher in the first and 2nd years in the carb counting group (p=0.02 and p=0.043, respectively). Conclusion: Carb counting may provide good metabolic control in children and adolescents with T1DM without causing any increase in weight or in insulin requirements.