Şükran Darcan

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.

Stiffness of the abdominal aorta in obese children.

Obesity is pathogenically related to clinical and subclinical disorders that contribute to the development of atherosclerotic plaques and their complications leading to onset of cardiovascular events. Arterial stiffness may be an indicator of early vascular changes signaling the development of vascular disease. The purpose of this study was to assess the stiffness of the abdominal aorta using transthoracic echocardiography in normotensive obese and hypertensive obese pediatric patients and a control group. The study group consisted of 25 healthy children (M/F: 13/12) as a control group (Group I), 25 normotensive obese children (M/F: 13/12) (Group II) and 25 hypertensive obese children (M/F: 14/11) (Group III). The mean ages were 12.1 +/- 1.8, 11.9 +/- 1.5 and 12.4 +/- 1.4 years, respectively. Aortic strain (S), pressure strain elastic modulus (Ep) and normalized Ep (Ep*) measurements were significantly different in the hypertensive obese group, and cholesterol levels and body mass index were higher in this group. These findings may be important in determining the relationship between obesity and cardiovascular risk factors at pediatric age.

The relation of arterial stiffness with intrauterine growth retardation.

Background:  Much epidemiological evidence has linked low birthweight with late cardiovascular risk. Intrauterine growth retardation (IUGR) is associated with the increased risk of cardiovascular disease in adult life; it is unclear whether the relationship is present at younger ages. We evaluated whether abdominal aortic stiffness was altered in patients with IUGR (born at term with birthweight small for gestational age) in younger ages.

Serum IGF-1 and IGFBP-3 Levels in Healthy Children Between 0 and 6 Years of Age

Objective: Along with growth hormone (GH) levels, measurements of serum insulin-like growth factor-1 (IGF-1) and IGF-binding protein-3 (IGFBP-3) are used in the diagnosis of GH deficiency and in monitoring the efficacy and safety of long-term GH treatment. The purpose of the present study was to establish reference values for serum IGF-1 and IGFBP-3 in healthy Turkish children less than 6 years of age. Methods: This study was designed as a multicenter project. Five hundred sixty-seven healthy children younger than 6 years of age from different geographical regions of Turkey, with weight and height values between the 10th and 90th percentiles according to the national standards were included in the study. In addition to anthropometric parameters, serum IGF-1 and IGFBP-3 levels were measured in all subjects. Results: Although not statistically significant, the serum IGF-1 levels in infants at age 6 months were lower than those in infants at age 3 months. The IGF-1 levels showed a slow increase with age. Serum IGF-1 levels were lower in girls as compared to boys only at age 6 months. No correlation was found between either serum IGFBP-3 levels and body mass index (BMI) or serum IGFBP-3 and weight and height standard deviation scores (SDS). A weak correlation was observed between serum IGF-1 and IGFBP-3 concentrations. Conclusions: The age- and gender-specific reference values for serum IGF-1 and IGFBP-3 reported in this study will aid in the diagnosis of GH deficiency and in the monitoring of children receiving GH treatment. 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.

Bone mineral density in pediatric and adolescent renal transplant patients: How to evaluate

Abstract:  Reduced bone mass is a common complication of renal transplantation in adults but only few data are present for pediatric transplant patients. Bone mineral status of pediatric renal transplant patients ages ranging from 7.5 to 17.6 years (mean age 14.9 ± 2.3) who were at least 6 months postrenal transplantation was examined. Bone mineral density (BMD) of lumbar vertebrea and femoral neck was determined by dual energy X‐ray absorptiometry (DEXA) and z‐scores according to age, puberty, height and bone age were compared to sex and ethnic specific reference data. z‐scores were calculated for both areal and volumetric bone density. BMD L1‐4 z‐scores were more than 2 SD below the mean according to chronological age in 12 patients (63%), pubertal status in six patients (31.5%), bone age in five patients (26.3%) and height in five patients (26.3%). The BMD femoral neck z‐scores were more than 2 SD below the mean according to age in 10 patients (55.5%), puberty in five patients (27.7%), bone age in three (16.6%) patients and height in five (26.3%) patients. Correction of the vertebrae and femoral neck for bone size yielded osteoporotic values for seven patients (36.8%) for lumbar BMD and for four patients (22%) for femoral neck BMD. The use of aBMD in growth‐retarded children has some restrictions in determining z‐scores. Deficits in spinal bone density still persisted after correcting for height, puberty, bone age and volume. In renal transplant patients who have short stature it is reasonable to give values corrected for height, puberty, bone age and bone size and interpret each of these values for each patient.

The exon 3-deleted/full-length growth hormone receptor polymorphism and response to growth hormone therapy in growth hormone deficiency and Turner syndrome: a multicenter study.

Background/Aim: The exon 3-deleted/full-length (d3/fl) growth hormone (GH) receptor (GHR) polymorphism has been associated with responsiveness to GH therapy in some diagnostic groups. However, there are still controversies on this issue. To evaluate the effect of the GHR exon 3 polymorphism on growth after 1 and 2 years of GH therapy in Turkish patients with GH deficiency (GHD) and Turner’s syndrome (TS) and the distribution of GHR exon 3 isoforms. Materials and Methods: 218 patients with GHD (125 males/93 females) and 43 patients with TS were included in the study. The control group included 477 healthy adults aged from 18 to 57 years (54 females/423 males). Anthropometric parameters and insulin-like growth factor (IGF)-1 and IGF binding protein (IGFBP)-3 were evaluated annually. GHR isoforms were studied using simple multiplex PCR. Height and body mass index were expressed as standard deviation score (SDS). Results: There were no differences among TS, GHD and healthy adults regarding the distribution of GHR exon 3 isoforms (fl/fl, fl/d3 and d3/d3). There was a significant increase in height SDS in both diagnostic groups on GH therapy; however, there were neither differences in height SDS and Δheight velocity between fl/fl, fl/d3 and d3/d3 groups nor a correlation between the distribution of GHR exon 3 isoforms and change in IGF-1 SDS and IGFBP-3 SDS levels on GH therapy in either of the diagnostic groups. There was also no gender difference in GHR isoforms in healthy adults. Conclusion: The results suggest that responsiveness to GH therapy does not depend on the exon 3 GHR genotypes in GHD and TS patients.

Unexpected clinical features in a female patient with proopiomelanocortin (POMC) deficiency.

Abstract Background/aims: Loss of function mutations of proopiomelanocortin (POMC) gene results in adrenal insufficiency, early-onset hyperphagic obesity, and red hair. However, neuromotor retardation with POMC deficiency has not been reported before. Case report: We report a female patient whose initial diagnosis was neurometabolic disease because of motor mental retardation, ataxia, and bilateral hyperintense lesions in the basal ganglia in cranial magnetic resonance imaging, increased lactate-lipid peak in proton magnetic resonance spectroscopy. She was consulted due to rapid weight gain, obesity, and episodes of hypoglycemia and homozygous mutation (c.64delA) in POMC gene was found. Conclusion: Severe motor mental retardation and cranial magnetic resonance imagingpathology in patients with POMC deficiency have not been reported previously in the literature. Bilateral hyperintense lesions in the basal ganglia and the increased lactate-lipid peak was thought to be the result of recurrent hypoglycemia.

Idiopathic Hypogonadotropic Hypogonadism Caused by Inactivating Mutations in SRA1.

Objective: What initiates the pubertal process in humans and other mammals is still unknown. We hypothesized that gene(s) taking roles in triggering human puberty may be identified by studying a cohort of idiopathic hypogonadotropic hypogonadism (IHH). Methods: A cohort of IHH cases was studied based on autozygosity mapping coupled with whole exome sequencing. Results: Our studies revealed three independent families in which IHH/delayed puberty is associated with inactivating SRA1 variants. SRA1 was the first gene to be identified to function through its protein as well as noncoding functional ribonucleic acid products. These products act as co-regulators of nuclear receptors including sex steroid receptors as well as SF-1 and LRH-1, the master regulators of steroidogenesis. Functional studies with a mutant SRA1 construct showed a reduced co-activation of ligand-dependent activity of the estrogen receptor alpha, as assessed by luciferase reporter assay in HeLa cells. Conclusion: Our findings strongly suggest that SRA1 gene function is required for initiation of puberty in humans. Furthermore, SRA1 with its alternative products and functionality may provide a potential explanation for the versatility and complexity of the pubertal process.

Turner syndrome and associated problems in turkish children: A multicenter study

Objective: Turner syndrome (TS) is a chromosomal disorder caused by complete or partial X chromosome monosomy that manifests various clinical features depending on the karyotype and on the genetic background of affected girls. This study aimed to systematically investigate the key clinical features of TS in relationship to karyotype in a large pediatric Turkish patient population. Methods: Our retrospective study included 842 karyotype-proven TS patients aged 0-18 years who were evaluated in 35 different centers in Turkey in the years 2013-2014. Results: The most common karyotype was 45,X (50.7%), followed by 45,X/46,XX (10.8%), 46,X,i(Xq) (10.1%) and 45,X/46,X,i(Xq) (9.5%). Mean age at diagnosis was 10.2±4.4 years. The most common presenting complaints were short stature and delayed puberty. Among patients diagnosed before age one year, the ratio of karyotype 45,X was significantly higher than that of other karyotype groups. Cardiac defects (bicuspid aortic valve, coarctation of the aorta and aortic stenosis) were the most common congenital anomalies, occurring in 25% of the TS cases. This was followed by urinary system anomalies (horseshoe kidney, double collector duct system and renal rotation) detected in 16.3%. Hashimoto’s thyroiditis was found in 11.1% of patients, gastrointestinal abnormalities in 8.9%, ear nose and throat problems in 22.6%, dermatologic problems in 21.8% and osteoporosis in 15.3%. Learning difficulties and/or psychosocial problems were encountered in 39.1%. Insulin resistance and impaired fasting glucose were detected in 3.4% and 2.2%, respectively. Dyslipidemia prevalence was 11.4%. Conclusion: This comprehensive study systematically evaluated the largest group of karyotype-proven TS girls to date. The karyotype distribution, congenital anomaly and comorbidity profile closely parallel that from other countries and support the need for close medical surveillance of these complex patients throughout their lifespan.