Publications by authors named "Alev Ozön"

57 Publications

Alpha-Melanocyte-Stimulating Hormone is Elevated in Hypothalamic Obesity Associated with Childhood Craniopharyngioma.

Obesity (Silver Spring) 2021 Feb;29(2):402-408

Department of Pediatric Endocrinology, Hacettepe University, Ankara, Turkey.

Objective: The purpose of this study was to investigate the peripheral concentrations of leptin and neuropeptides taking part in the melanocortin pathway in hypothalamic obesity (HO) associated with craniopharyngioma (CP) and to find a peripheral marker for diagnosis.

Methods: Thirty-one patients (52% girls; median age 16 years) with CP were enrolled in the study group. They were grouped as CP with obesity (CP , n = 17) and CP without obesity (CP , n = 14). Two control groups without CP consisted of 27 children with obesity (OC) (55% girls; median age 13.8 years) and 25 children without obesity (normal control [NC]) (72% girls; median age 14.5 years). Obesity was defined as BMI percentile ≥ 95%. Fasting serum concentrations of leptin, brain-derived neurotrophic factor (BDNF), and alpha-melanocyte-stimulating hormone (α-MSH) were measured in the groups.

Results: Leptin and BDNF concentrations were correlated with BMI SD score (SDS) in controls (OC + NC) and CP. However, there was no correlation between α-MSH and BMI-SDS in CP or control groups. After adjusting for age, sex, and BMI-SDS, α-MSH was found to be significantly higher in CP than in other groups, whereas leptin and BDNF were comparable among the four groups.

Conclusions: Serum BDNF, just like leptin, increased with BMI, regardless of hypothalamic damage. On the contrary, α-MSH concentration was significantly high in HO, designating a potential biomarker for HO in CP.
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http://dx.doi.org/10.1002/oby.23087DOI Listing
February 2021

Basal serum thyroxine level should guide initial thyroxine replacement dose in neonates with congenital hypothyroidism.

J Clin Res Pediatr Endocrinol 2020 Dec 30. Epub 2020 Dec 30.

Hacettepe University Faculty of Medicine, Department of Pediatric Endocrinology, Ankara, Turkey.

Objective: Initial high-dose Na-L thyroxine (Na-LT4) (10-15 μg/kg/day) replacement for primary congenital hypothyroidism (CH) is recommended in guidelines. However, high-dose Na-LT4 has risks. In this study, we aimed to investigate normalizing effect of varying initial doses of Na-LT4 on serum thyroid hormone levels.

Methods: Fifty-two patients were analyzed retrospectively. The patients were classified into mild (27/51.9%), moderate (11/21.1%) and severe (14/26.9%) CH with respect to initial free thyroxine (FT4) levels. Time taken to achieve target hormone levels was compared within groups.

Results: Initial mean Na-LT4 doses for mild, moderate and severe disease were 6.9±3.3, 9.4±2.2 and 10.2±2 μg/kg/day. Serum FT4 levels reached the upper half of normal range (>1.32 ng/dL) in a median of 16, 13 and 16 days in patients with mild, moderate and severe CH with the mean time from initial treatment to first control visit 14.8 ± 6 days (range 1-36). There was no significant difference in terms of time to achieve target FT4 hormone levels according to disease severity (p=0.478). Seven (25.9%), 8 (72.7%) and 8 (57.1%) patients experienced hyperthyroidism (serum FT4 >1.94 ng/dL) in mild, moderate, severe CH groups in the first visit, respectively (p=0.016).

Conclusion: Not all patients diagnosed with CH require high-dose Na-LT4, initial dose of Na-LT4 may be tailored based on pre-treatment thyroid hormone levels. Some patients with moderate and severe CH, experienced iatrogenic hyperthyroidism even though the dose was close to the lower limit of the recommended range in guidelines; suggesting lower initial doses and closer follow-up within the first week.
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http://dx.doi.org/10.4274/jcrpe.galenos.2020.2020.0194DOI Listing
December 2020

Gender-related differences in etiology of organic central precocious puberty.

Turk J Pediatr 2020 ;62(5):763-769

Division of Pediatric Endocrinology, Department of Pediatrics, Hacettepe University Faculty of Medicine, Ankara, Turkey.

Background: Central precocious puberty (CPP) is idiopathic in 90% of girls and 60% of boys, while some cases are caused by lesions of central nervous system (CNS), a condition often referred to as organic CPP. We aimed to analyze the etiology of organic CPP in a large cohort of girls and boys and determine gender-related differences.

Methods: Medical files of 256 girls and 120 boys diagnosed and treated for CPP in a single center in the last two decades were reviewed. Patients were classified into four groups with respect to previous history and MRI findings: (1) previously established CNS pathology at the time of diagnosis, (2) novel CNS pathology previously asymptomatic, (3) incidentalomas considered to be unrelated to CPP, and (4) completely normal MRI. Group 1 and 2 were considered as organic CPP whereas group 3 and 4 were considered as idiopathic CPP.

Results: Prevalence of CNS pathology was significantly higher in boys than girls (21.7% vs 6.2%). Previous CNS pathologies such as developmental anomaly of CNS, parenchymal injury, necrotic lesions and hydrocephalus were present in 3.5% of girls and 8.3% of boys. Prevalence of novel CNS pathology as determined by imaging among neurologically asymptomatic patients was 2.8% in girls and 14.5% in boys. The most common novel CNS pathologies in boys were hamartomas (5%) and suprasellar arachnoid cysts (3.3%); which were significantly lower in girls (0.8 and 0.8% respectively). Onset of organic CPP was before six years in girls, and seven years in boys.

Conclusions: Organic CPP was 3.5 times more common in boys compared to girls. It is possible to detect an underlying CNS pathology in one out of every five boys with CPP. Frequency and distribution of organic etiology also differ between girls and boys, hypothalamic hamartomas and suprasellar arachnoid cysts being more common in boys than girls. The likelihood of novel intracranial pathology associated with CPP is quite low in girls with an onset after six years of age and in boys with an onset after seven years of age.
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http://dx.doi.org/10.24953/turkjped.2020.05.007DOI Listing
January 2020

Treatment response to long term antiresorptive therapy in osteogenesis imperfecta type VI: does genotype matter?

J Pediatr Endocrinol Metab 2020 Dec 8;33(12):1617-1624. Epub 2020 Oct 8.

Division of Pediatric Endocrinology, Department of Pediatrics, Hacettepe University Medical School, Ankara, Turkey.

Objectives: Osteogenesis imperfecta type VI (OI VI) follows a progressive and severe course, yet unlike other forms of severe OI it has a later onset of fractures, and extra-skeletal findings are not part of the clinical picture. Another difference is that there is an increase in unmineralized osteoid tissue in OI VI, which hinders the effect of bisphosphonates-the current standard of treatment for OI. Therefore, the response to standard treatments in OI VI is not satisfactory. Herein, we report long-term follow-up of two cases with novel mutations, who show great variation in their treatment response to bisphosphonates.

Case Presentation: The first case was given pamidronate at the age of 15 months when he could sit independently, followed a fluctuating course under treatment, fracture rate did not decrease, however he was able to mobilize with walker at the age of 10 years. On the other hand, the second case developed severe deformities and became wheelchair-bound under pamidronate, thus the treatment was switched to denosumab. Unfortunately, there was no improvement under denosumab after 15 months too, and since bone pain increased, denosumab treatment was stopped. He was put on zoledronic acid instead.

Conclusion: transcript amount may be an important factor to explain the variation in response to pamidronate therapy. In OI VI patients, the factors affecting the clinical course should be identified and new or combined treatment options should be established.
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http://dx.doi.org/10.1515/jpem-2020-0260DOI Listing
December 2020

Obstructive sleep apnea in children with hypothalamic obesity: Evaluation of possible related factors.

Pediatr Pulmonol 2020 12 6;55(12):3532-3540. Epub 2020 Oct 6.

Department of Pediatrics, Division of Pediatric Pulmonology, Faculty of Medicine, Hacettepe University, Ankara, Turkey.

Introduction: Hypothalamic obesity (HO) is a type of obesity that is caused by hypothalamic damage. HO can be complicated by obstructive sleep apnea syndrome (OSAS) due to anatomical narrowing of the upper airway and hypothalamic damage-induced dysfunction of the sleep control mechanisms. We aimed to explore the presence and severity of OSAS in children with HO and hypothesized that OSAS is more severe and frequent in HO than exogenous obesity (EO).

Methods: This cross-sectional study was conducted among children aged 6.6-17.9 years. Subjects with HO (n = 14) and controls with EO (n = 19) were consecutively recruited through an endocrinology clinic. All patients underwent full-night polysomnography. The primary outcomes were obstructive apnea-hypopnea index (OAHI) and the severity of OSAS. We analyzed the polysomnography findings, biochemical parameters, Brodsky and modified Mallampati scores, and blood pressure compared with the controls. We explored the different obesity types and these variables in association with OAHI using multiple linear regression (MLR).

Results: Age and body mass index z scores (BMI-z) were similar between the EO and HO groups. The OAHI of HO (5.8) was higher than that of EO (2.2). In MLR, the predicted OAHI was formulated as an equation using regression coefficients of obesity type (HO), age, and BMI-z (R  = .41). In the logistic regression analysis, the odds ratio of moderate/severe OSA was 5.6 for HO.

Conclusions: Children with HO have a higher risk of moderate/severe OSAS than children with EO. Polysomnography should be considered in all patients with HO.
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http://dx.doi.org/10.1002/ppul.25097DOI Listing
December 2020

Novel insights into diabetes mellitus due to DNAJC3-defect: Evolution of neurological and endocrine phenotype in the pediatric age group.

Pediatr Diabetes 2020 Nov 10;21(7):1176-1182. Epub 2020 Sep 10.

Department of Medical Genetics, Hacettepe University, Ankara, Turkey.

Background: A number of inborn errors of metabolism caused by abnormal protein trafficking that lead to endoplasmic reticulum storage diseases (ERSD) have been defined in the last two decades. One such disorder involves biallelic mutations in the gene encoding endoplasmic reticulum resident co-chaperone DNAJC3 (P58 ) that leads to diabetes in the second decade of life, in addition to multiple endocrine dysfunction and nervous system involvement.

Objective: The aim of this study was to define the natural history of this new form of diabetes, especially the course of abnormalities related to glucose metabolism.

Methods: Whole-exome and Sanger sequencing was used to detect DNAJC3 defect in two patients. Detailed analysis of their clinical history as well as biochemical, neurological and radiological studies were carried out to deduce natural history of neurological and endocrine phenotype.

Results: DNAJC3 defect led to beta-cell dysfunction causing hyperinsulinemichypoglycemia around 2 years of age in both patients, which evolved into diabetes with insulin deficiency in the second decade of life, probably due to beta cell loss. Endocrine phenotype involved severe early-onset growth failure due to growth hormone deficiency, and hypothyroidism of central origin. Neurological phenotype involved early onset sensorineural deafness discovered around 5 to 6 years, and neurodegeneration of central and peripheral nervous system in the first two decades of life.

Conclusion: Biallelic loss-of-function in the ER co-chaperone DNAJC3 leads to a new form of diabetes with early onset hyperinsulinemic hypoglycemia evolving into insulin deficiency as well as severe growth failure, hypothyroidism and diffuse neurodegeneration.
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http://dx.doi.org/10.1111/pedi.13098DOI Listing
November 2020

Adequacy of basal luteinizing hormone levels in the diagnosis of central precocious puberty.

Turk Pediatri Ars 2020 19;55(2):131-138. Epub 2020 Jun 19.

Division of Pediatric Endocrinology, Department of Pediatrics, Hacettepe University Faculty of Medicine, Ankara, Turkey.

Aim: To determine the clinical, anthropometric, and laboratory parameters that could be used for differentiating central precocious puberty from premature thelarche in girls who had breast development between the ages of 3 and 8 years.

Material And Methods: The study included 344 girls (196 girls with idiopathic central precocious puberty, 148 girls with premature thelarche) who underwent gonadotropin- releasing hormone stimulation tests for breast development. Age at diagnosis, bone age, anthropometric measurements, basal/stimulated hormone levels were recorded. Univariate regression analysis was performed to determine the parameters that could be used for differentiating precocious puberty from premature thelarche. Significant parameters in univariate analyses were grouped according to the thresholds determined using receiver operating characteristic curves and reevaluated through multivariate analysis.

Results: The bone age, height-standard deviation score, body mass index-standard deviation score, and growth velocity-standard deviation score at diagnosis were found to be higher; pubertal stages were found to be more advanced; uterus and ovary volumes were found to be larger; and the basal/peak luteinizing hormone, follicle-stimulating hormone, luteinizing hormone/follicle-stimulating hormone levels were found to be higher in the subjects with precocious puberty. There was no difference between estradiol levels between the two groups. The best thresholds to differentiate the two groups were found as 0.65 IU/L (78% sensitivity, 100% specificity), 1.9 IU/L (100% sensitivity, 72% specificity), 0.25 (67% sensitivity, 100% specificity) and 1.1 (69% sensitivity, 71% specificity), respectively, for basal luteinizing hormone, follicle-stimulating hormone, luteinizing hormone/follicle-stimulating hormone ratio, and the growth velocity-standard deviation score.

Conclusion: In girls presenting with early breast development, a basal luteinizing hormone level of ≥0.65 IU/L and a luteinizing hormone/follicle-stimulating hormone ratio of ≥0.25 are sensitive ways to demonstrate activation of the hypothalamo-pituitary-gonadal axis. Among these, the variable that gives the best sensitivity and specificity is the measurement of basal luteinizing hormone levels (≥0.65 IU/L), which can be used as a screening test in the diagnosis of central precocious puberty.
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http://dx.doi.org/10.14744/TurkPediatriArs.2019.03708DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7344123PMC
June 2020

Effect of long-term glucocorticoid therapy on bone mineral density of the patients with congenital adrenal hyperplasia.

Turk J Pediatr 2020 ;62(3):359-366

Division of Pediatric Endocrinology, Department of Pediatrics, Hacettepe University Faculty of Medicine, Ankara.

Background And Objectives: Congenital adrenal hyperplasia (CAH) is characterized by androgen excess which should be treated with life-long glucocorticoid therapy, thus can affect bone mineralization. We aimed to evaluate the bone mineral density (BMD) and determine the factors affecting bone mineralization in patients with CAH.

Method: This prospective case-control study was conducted in children, adolescents and young adults with classical 21-hydroxylase CAH, and age-, sex-, and pubertal stage matched healthy controls. Lumbar1-4 BMD was determined by dual-energy X-ray absorptiometry. BMD z-score was calculated using national standards with respect to height age and was referred as `low BMD` if z-score < -1 SD. Univariate analyses were performed between low BMD and normal BMD groups, and multivariate logistic regression analysis was performed to assess the independent predictors of low BMD. Correlations of Body Mass Index (BMI)-z-score, average serum 17-hydroxyprogesterone level, duration of treatment, average and cumulative glucocorticoid doses with BMD z-score were evaluated with Spearman analyses.

Results: Each group included 37 cases. BMD z-score of patients with CAH [0.47 (-0.04 - 1.56)] was higher than control group [-0.43 (-0.82 -0.05)]; p= < 0.001. Number of patients with low BMD was similar in both groups; [CAH: 6(16.2%), control: 5(13.5%); p= 0.744]. BMI- z-score was higher in patients with CAH when compared to control group; p= < 0.001. BMI z-score was lower in low BMD group as comparison to normal BMD group; p= 0.041. Each 1.0 decrease in BMI z-score, risk of having low BMD was found to increase by 1.79 (%95 CI: 1.03- 3.12, p= 0.040). BMI-z-score, average serum 17-hydroxyprogesterone level, duration of treatment, average and cumulative glucocorticoid doses were not found to be correlated with BMD z-score.

Conclusion: Long-term glucocorticoid therapy did not have negative effect on BMD of patients with CAH. Higher BMI z-score in patients with CAH may have a positive effect on preserving bone health. Precautions should be taken for increased risk of obesity.
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http://dx.doi.org/10.24953/turkjped.2020.03.002DOI Listing
January 2020

Neonatal Screening for Congenital Adrenal Hyperplasia in Turkey: Outcomes of Extended Pilot Study in 241,083 Infants

J Clin Res Pediatr Endocrinol 2020 09 11;12(3):287-294. Epub 2020 Mar 11.

İstanbul University İstanbul Faculty of Medicine, Department of Paediatric Endocrinology, İstanbul, Turkey

Objective: Turkish Directorate of Public Health introduced the first pilot screening program for congenital adrenal hyperplasia (CAH) in four Turkish cities in 2017, and in 2018 extended the program, with a slight change in screening strategy, to fourteen cities. To evaluate the performance of the extended study and update previously reported outcomes.

Methods: Retrospective, descriptive study. Neonates of ≥32 gestational weeks and ≥1500 gr birth weight from fourteen cities, born between May-December 2018, were included. Screening protocol included one sample, two-tier testing as applied in the previous pilot study. In the first step, 17α-hydroxyprogesterone (17-OHP) was measured by fluoroimmunoassay in dried blood spots (DBS) obtained at 3-5 days of life. Cases with positive initial screening underwent second tier testing by steroid profiling in DBS using liquid chromatographyt-andem mass spectrometry to measure 17-OHP, 21-deoxycortisol (21-S), cortisol (F), 11-deoxycortisol and androstenedione. The babies with a steroid ratio (21-S+17-OHP)/F of ≥0.7 (increased from ≥0.5 in the earlier pilot study) were referred to pediatric endocrinology clinics for diagnostic assessment.

Results: In the evaluated period, 241,083 newborns were screened. 12,321 (5.11%) required second-tier testing and 880 (0.36%) were referred for clinical assessment, twenty of whom were diagnosed with CAH (10 females, 10 males). Sixteen were diagnosed as classical 21-hydroxylase deficiency (21-OHD) CAH (12 with salt-wasting and four with simple virilising CAH), and four cases were identified with 11β-OHD CAH. No case of salt-wasting CAH was missed by neonatal screening (sensitivity was 100%). The incidence of classical 21-OHD and 11β-OHD in the screened population was 1:15,067 and 1:60,270, respectively.

Conclusion: Turkish neonatal CAH screening effectively led to earlier diagnosis of 21-OHD and 11β-OHD, using steroid profiling as a second-tier test. This will result in improved care of these patients in the future.
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http://dx.doi.org/10.4274/jcrpe.galenos.2020.2019.0182DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7499135PMC
September 2020

Treatment with Depot Leuprolide Acetate in Girls with Idiopathic Precocious Puberty: What Parameter should be Used in Deciding on the Initial Dose?

J Clin Res Pediatr Endocrinol 2020 03 26;12(1):37-44. Epub 2019 Jul 26.

Hacettepe University Faculty of Medicine, Department of Pediatrics, Division of Pediatric Endocrinology, Ankara, Turkey

Objective: Doses of gonadotropin releasing hormone (GnRH) analogues used to treat idiopathic central precocious puberty (iCPP) vary among clinicians. Study aims were to evaluate the efficacy of a monthly 3.75 mg dose of leuprolide acetate (LA) to suppress the hypothalamo-pituitary-gonadal (HPG) axis in girls with iCPP and to determine factors that may have an impact on the supressing dose.

Methods: Study subjects were 220 girls receiving LA for iCPP. LA was started at a dose of 3.75 mg/28 days. Suppression was assessed using the GnRH test at the third month. To assess clinical suppression signs and symptoms of puberty were also evaluated. The dose of LA was increased to 7.5 mg/28 days in those who had a peak luteinising hormone (LH) ≥2 IU/L and in whom adequate clinical suppression of puberty was absent. Receiver operating characteristic curves were used to determine thresholds for clinical and hormonal factors affecting the suppressing dose of LA. Logistic regression analyses were used to investigate thresholds which might differentiate between those requiring high dose for suppression and those in whom lower dose LA was adequate.

Results: Peak stimulated LH <2 IU/L was achieved in 88.6% with a dose of LA of 3.75 mg (0.11±0.03 mg/kg). Significant variables for differentiating the two doses were body weight (Wt) of 36.2 kg and/or body mass index (BMI)-standard deviation scores (SDS) of 1.64 (p<0.001). Multiple logistic regressions showed that Wt and BMI-SDS values above thresholds indicated requirement of LA at a dose of 7.5 mg/28 days (p<0.001).

Conclusion: Monthly injections of 3.75 mg LA is an effective treatment in the majority of girls with iCPP. However, a higher initial dose may be preferred in patients with a Wt ≥36 kg or BMI-SDS ≥1.6 for effective suppression of the HPG axis.
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http://dx.doi.org/10.4274/jcrpe.galenos.2019.2019.0060DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7127887PMC
March 2020

Neonatal effects of thyroid diseases in pregnancy and approach to the infant with increased TSH: Turkish Neonatal and Pediatric Endocrinology and Diabetes Societies consensus report.

Turk Pediatri Ars 2018 25;53(Suppl 1):S209-S223. Epub 2018 Dec 25.

Pediatric Endocrinolgy Unit, Memorial Kayseri Hospital, Kayseri, Turkey.

Thyroid functions in the fetus and newborn carry importance in terms of the baby's health and development of the central nervous system. Maternaliodine deficiency, exposure to iodine, thyroid diseases (Hashimoto thyroiditis, Graves') and drugs used by the mother affect thyroid functions in the fetus. Reflections of these effects are observed immediately after delivery. Investigation of the mother in terms of thyroid diseases during pregnancy, recognition and appropriate assessment of the required conditions, screening of all newborns in the first days of life in terms of congenital hypothyroidism, timely and appropriate evaluation of the screening results, early diagnosis and appropriate treatment of cases of congenital hypothyroidism, assessment and management of cases of transient thyroid hormone disorders and close monitoring of the thyroid functions and development of patients in whom treatment has been initiated with a diagnosis of hypothyroidism are crucial in terms of developmental outcomes of the babies who have thyroid function disorders or hypothyroidism. This guideline was written with the objective of guiding pediatricians, neonatologists and pediatric endocrinologists in the issue of assessment, diagnosis and management of thyroid function disorders and thyroid diseases concerning the fetus and baby during gestation and neonatal period.
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http://dx.doi.org/10.5152/TurkPediatriArs.2018.01819DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6568290PMC
December 2018

Further expanding the mutational spectrum and investigation of genotype-phenotype correlation in 3M syndrome.

Am J Med Genet A 2019 07 13;179(7):1157-1172. Epub 2019 Apr 13.

Department of Pediatric Genetics, Hacettepe University Faculty of Medicine, Ankara, Turkey.

3M syndrome is characterized by severe pre- and postnatal growth retardation, typical facial features, and normal intelligence. Homozygous or compound heterozygous mutations in either CUL7, OBSL1, or CCDC8 have been identified in the etiology so far. Clinical and molecular features of 24 patients (23 patients and a fetus) from 19 unrelated families with a clinical diagnosis of 3M syndrome were evaluated and genotype-phenotype correlations were investigated with the use of DNA sequencing, chromosomal microarray, and whole exome sequencing accordingly. A genetic etiology could be established in 20 patients (n = 20/24, 83%). Eleven distinct CUL7 or OBSL1 mutations, among which eight was novel, were identified in 18 patients (n = 18/24, 75%). Ten patients had CUL7 (n = 10/18, 56%) while eight had OBSL1 (n = 8/18, 44%) mutations. Birth weight and height standard deviation scores at admission were significantly (p < 0.05) lower in patients with CUL7 mutation compared to that of patients with OBSL1 mutation. Two patients with a similar phenotype had a de novo 20p13p deletion involving BMP2. No genetic etiology could be established in four patients (n = 4/28, 17%). This study yet represents the largest cohort of 3M syndrome patients from a single center in Turkey. Microdeletions involving BMP2 may cause a phenotype similar to 3M syndrome with some distinctive features. Larger cohort of patients are required to establish genotype-phenotype correlations in 3M syndrome.
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http://dx.doi.org/10.1002/ajmg.a.61154DOI Listing
July 2019

Neonatal Screening for Congenital Adrenal Hyperplasia in Turkey: A Pilot Study with 38,935 Infants

J Clin Res Pediatr Endocrinol 2019 02 14;11(1):13-23. Epub 2018 Aug 14.

İstanbul University İstanbul Faculty of Medicine, Department of Paediatric Endocrinology and Diabetes, İstanbul, Turkey

Objective: Congenital adrenal hyperplasia (CAH) is the most common form of primary adrenal insufficiency in children. Neonatal screening for CAH is effective in detecting the salt-wasting (SW) form and in reducing mortality. In this study, our aim was to estimate the incidence of CAH in Turkey and to assess the characteristics and efficacy of the adopted newborn CAH screening strategy.

Methods: A pilot newborn CAH screening study was carried out under the authority of the Turkish Directorate of Public Health. Newborn babies of ≥32 gestational weeks and ≥1500 gr birth weight from four cities, born between March 27-September 15, 2017 were included in the study. Screening protocol included one sample two-tier testing. In the first step, 17α-hydroxyprogesterone (17-OHP) was measured by fluoroimmunoassay in dried blood spots (DBS) obtained at 3-5 days of life. The cases with positive initial screening were tested by steroid profiling in DBS using a liquid chromatography-tandem mass spectrometry method to measure 17-OHP, 21-deoxycortisol (21-S), cortisol (F), 11-deoxycortisol and androstenedione as a second-tier test. The babies with a steroid ratio (21-S+17-OHP)/F of ≥0.5 were referred to pediatric endocrinology clinics for diagnostic assessment.

Results: 38,935 infants were tested, 2265 (5.82%) required second-tier testing and 212 (0.54%) were referred for clinical assessment, six of whom were diagnosed with CAH (four males, two females). Four cases were identified as SW 21-hydroxylase deficiency (21-OHD) (two males, two females). One male baby had simple virilizing 21-OHD and one male baby had 11-OHD CAH. The incidence of classical 21-OHD in the screened population was 1:7,787.

Conclusion: The incidence of CAH due to classical 21-OHD is higher in Turkey compared to previous reports. We, therefore, suggest that CAH be added to the newborn screening panel in Turkey. The use of steroid profiling as a second-tier test was found to improve the efficacy of the screening and reduce the number of false-positives.
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http://dx.doi.org/10.4274/jcrpe.galenos.2018.2018.0117DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6398187PMC
February 2019

Can having a sibling with type 1 diabetes cause disordered eating behaviors?

J Pediatr Endocrinol Metab 2018 Jul;31(7):711-716

Department of Pediatrics, Division of Adolescent Medicine, Hacettepe University, Ankara, Turkey.

Background Adolescents with type 1 diabetes mellitus (T1DM) are at an increased risk of eating disturbances. The aim of this study was to evaluate whether the risk of a disordered eating behavior (DEB) also applies to the well sibling sharing the same environment. Methods Well siblings were included if they were 10-18 years old, had a sibling with a T1DM diagnosis for at least 6 months and lived with the sibling during the illness. The control group was comprised of healthy participants recruited from the outpatient clinic with no family history of T1DM. Participants completed a four-part questionnaire concerning their eating behaviors that was developed by the study team. This survey aimed to evaluate the dietary habits and eating patterns. All participants completed the Eating Attitudes Test-26 (EAT-26) and a 24-h food dietary recall. Any participant with a high EAT-26 score or that seemed to be at risk according to the questionnaire was re-evaluated. Results Eight cases (33.3%) in the well sibling group had either a total and/or subgroup pathological score. Three of them were found to have DEB and one case was diagnosed with anorexia nervosa (AN). In the control group, five cases (17.2%) had either a total and/or subgroup pathological score. Three of these cases were found to have DEB, no cases were diagnosed with an eating disorder. There were no statistically significant differences in the EAT-26 scores between the groups. Conclusions Although a direct relationship was not observed, the probability of having a pathologic EAT-26 score was higher in the group with a sibling with T1DM.
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http://dx.doi.org/10.1515/jpem-2017-0533DOI Listing
July 2018

A pheochromocytoma case diagnosed as adrenal incidentaloma.

Turk J Pediatr 2017 ;59(2):200-206

Division of Pediatric Endocrinology Departments of Pediatrics, Hacettepe University Faculty of Medicine, Ankara, Turkey.

Vurallı D, Kandemir N, Clark G, Orhan D, Alikaşifoğlu A, Gönç N, Ekinci S, Özön A. A pheochromocytoma case diagnosed as adrenal incidentaloma. Turk J Pediatr 2017; 59: 200-206. There are two problems that needs to be addressed in cases of an adrenal incidentaloma. The first is to decide whether the adrenal mass is benign or malignant, and the second is to determine whether the mass is hormonally active or not. A 17-year-old male was admitted with the complaint of progressive weight gain. Abdominal ultrasonography was performed for elevation in transaminases which revealed a hypoechoic mass located in the left adrenal gland. Hormonal investigations revealed an increase in fractionated catecholamine and metanephrine levels in 24-hour urine. Surgery was performed and pathological examination was in accordance with pheochromocytoma. Mutation analysis was carried out. This is a rare case of pheochromocytoma presenting as adrenal incidentaloma during adolescence. In view of this case, we review the approach to incidentally discovered adrenal masses and the approach to pheochromocytoma. A mutation analysis should be performed on all cases with pheochromocytoma that are diagnosed below age 20.
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http://dx.doi.org/10.24953/turkjped.2017.02.015DOI Listing
November 2018

Long-Term Follow-up of a Case with Proprotein Convertase 1/3 Deficiency: Transient Diabetes Mellitus with Intervening Diabetic Ketoacidosis During Growth Hormone Therapy.

J Clin Res Pediatr Endocrinol 2017 09 7;9(3):283-287. Epub 2017 Jun 7.

Hacettepe University Faculty of Medicine, Department of Pediatric Endocrinology, Ankara, Turkey

Proprotein convertase 1/3 (PC1/3) deficiency is a very rare disease characterized by severe intractable diarrhea in the first years of life, followed by obesity and several hormonal deficiencies later. Diabetes mellitus requiring insulin treatment and diabetic ketoacidosis have not been reported in this disorder. We herein present a girl with PC1/3 deficiency who has been followed from birth to 17 years of age. She developed deficiencies of all pituitary hormones over time as well as diabetes mellitus while receiving growth hormone (GH) therapy. She was complicated with diabetic ketoacidosis during dietary management of diabetes mellitus, thus insulin treatment was initiated. Insulin requirement to regulate hyperglycemia was short-lived. Repeat oral glucose tolerance test five years later was normal. The findings of this patient show that diabetes mellitus can develop at any time during follow-up of cases with proportein convertase 1/3 deficiency especially under GH therapy.
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http://dx.doi.org/10.4274/jcrpe.3986DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5596812PMC
September 2017

Clinical and laboratory parameters predicting a requirement for the reevaluation of growth hormone status during growth hormone treatment: Retesting early in the course of GH treatment.

Growth Horm IGF Res 2017 06 10;34:31-37. Epub 2017 May 10.

Hacettepe University, Faculty of Medicine, Department of Pediatric Endocrinology, Ankara, Turkey.

Objective: We aimed to define the predictive criteria, in the form of specific clinical, hormonal and radiological parameters, for children with growth hormone deficiency (GHD) who may benefit from the reevaluation of GH status early in the course of growth hormone (GH) treatment.

Design And Methods: Two hundred sixty-five children with growth hormone deficiency were retested by GH stimulation at the end of the first year of GH treatment. The initial clinical and laboratory characteristics of those with a normal (GH≥10ng/ml) response and those with a subnormal (GH<10ng/ml) response were compared to predict a normal GH status during reassessment.

Results: Sixty-nine patients (40.6%) out of the 170 patients with isolated growth hormone deficiency (IGHD) had a peak GH of ≥10ng/ml during the retest. None of the patients with multiple pituitary hormone deficiency (MPHD) had a peak GH of ≥10ng/ml. Puberty and sex steroid priming in peripubertal cases increased the probability of a normal GH response. Only one patient with IGHD who had an ectopic posterior pituitary without stalk interruption on MRI analysis showed a normal GH response during the retest. Patients with a peak GH between 5 and 10ng/ml, an age at diagnosis of ≥9years or a height gain below 0.61 SDS during the first year of treatment had an increased probability of having a normal GH response at the retest.

Conclusion: Early reassessment of GH status during GH treatment is unnecessary in patients who have MPHD with at least 3 hormone deficiencies. Retesting at the end of the first year of therapy is recommended for patients with IGHD who have a height gain of <0.61 SDS in the first year of treatment, especially those with a normal or 'hypoplastic' pituitary on imaging. Priming can increase the likelihood of a normal response in patients in the pubertal age group who do not show overt signs of pubertal development.
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http://dx.doi.org/10.1016/j.ghir.2017.05.003DOI Listing
June 2017

Clinical, genetic, and structural basis of congenital adrenal hyperplasia due to 11β-hydroxylase deficiency.

Proc Natl Acad Sci U S A 2017 03 22;114(10):E1933-E1940. Epub 2017 Feb 22.

Division of Adrenal Steroid Disorders, Department of Pediatrics, Icahn School of Medicine at Mount Sinai, New York, NY 10029;

Congenital adrenal hyperplasia (CAH), resulting from mutations in , a gene encoding 11β-hydroxylase, represents a rare autosomal recessive Mendelian disorder of aberrant sex steroid production. Unlike CAH caused by 21-hydroxylase deficiency, the disease is far more common in the Middle East and North Africa, where consanguinity is common often resulting in identical mutations. Clinically, affected female newborns are profoundly virilized (Prader score of 4/5), and both genders display significantly advanced bone ages and are oftentimes hypertensive. We find that 11-deoxycortisol, not frequently measured, is the most robust biochemical marker for diagnosing 11β-hydroxylase deficiency. Finally, computational modeling of 25 missense mutations of revealed that specific modifications in the heme-binding (R374W and R448C) or substrate-binding (W116C) site of 11β-hydroxylase, or alterations in its stability (L299P and G267S), may predict severe disease. Thus, we report clinical, genetic, hormonal, and structural effects of gene mutations in the largest international cohort of 108 patients with steroid 11β-hydroxylase deficiency CAH.
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http://dx.doi.org/10.1073/pnas.1621082114DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5347606PMC
March 2017

Results of intraoperative gamma probe survey and frozen section in surgical treatment of parathyroid adenoma in children.

J Pediatr Surg 2016 09 22;51(9):1492-5. Epub 2016 Apr 22.

Hacettepe University Faculty of Medicine, Department of Pediatric Surgery, Ankara, Turkey.

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http://dx.doi.org/10.1016/j.jpedsurg.2016.04.007DOI Listing
September 2016

Novel and prevalent CYP11B1 gene mutations in Turkish patients with 11-β hydroxylase deficiency.

J Steroid Biochem Mol Biol 2017 01 5;165(Pt A):57-63. Epub 2016 Mar 5.

Hacettepe University, Pediatric Metabolism Unit, Institute of Child Health, Ankara, Turkey.

11β-Hydroxylase deficiency is the second most frequent type of congenital adrenal hyperplasia and is more common in those of Turkish descent than in other populations. The purpose of this study is to examine the spectrum of CYP11B1 gene mutations in Turkish patients with 11β-hydroxylase deficiency. Twenty-eight patients from 24 families, ages ranging from 0.1 to 7 years, were included in the study. Clinical diagnosis was based on virilization and high levels of 11-deoxycortisol. Twenty-six cases exhibited the classical and 2 cases the non-classical form. Mutation screening of 9 CYP11B1 exons was performed by direct DNA sequence analysis, specifically amplifying CYP11B1 gene fragments while avoiding simultaneous amplification of homologous CYP11B2 gene sequences. Seventeen different mutations were detected, 6 of which are novel (p.Gln189Hisfs*70, p.Glu198Gly, p.Thr318Lys, p.Gly446Ser, IVS8+5G>C and exon 3-5 del). All of the identified mutations resulted in the classical form with severe virilization, except for the p.Gly446Ser mutation, which caused a late-onset type of 11β-hydroxylase deficiency. The c.954G>A;p.Thr318Thr mutation was the most common in our cohort, with an allele frequency of 14.6%.Of the CYP11B1 gene mutations detected, 75% were found in exons 3, 5 and 7 and the half of the mutations were nonsense, splice site, deletion or insertion mutations, causing severe virilization in female patients. The findings are important for genetic counseling and the prenatal diagnosis of Turkish patients with 11β-hydroxylase deficiency.
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http://dx.doi.org/10.1016/j.jsbmb.2016.03.006DOI Listing
January 2017

Severe Undervirilisation in a 46,XY Case Due to a Novel Mutation in HSD17B3 Gene.

J Clin Res Pediatr Endocrinol 2015 Sep;7(3):249-52

Hacettepe University Faculty of Medicine, Department of Pediatrics, Division of Pediatric Endocrinology, Ankara, Turkey Phone: +90 312 305 11 24 E-mail:

17-β-hydroxysteroid dehydrogenase type 3 (17β-HSD3) is an important enzyme involved in the final steps of androgen synthesis and is required for the development of normal male external genitalia. 46,XY individuals with deficiency of this enzyme present a wide clinical spectrum from a female appearance of the external genitalia through ambiguous genitalia to a predominantly male genitalia with micropenis or hypospadias. This paper reports a one-year-old 46,XY patient with 17β-HSD3 deficiency who presented with female external genitalia and bilaterally palpable gonads in the inguinal region. The low T/Δ4 ratio after human chorionic gonadotropin (hCG) stimulation suggested 17β-HSD3 deficiency. A homozygous mutation, c.761_762delAG, was determined at the intron 9/exon 10 splice site of the HSD17B3 gene. To the best of our knowledge, this mutation has not been reported thus far, but its localization and type would imply a complete disruption of the 17β-HSD3 which may explain the phenotype of our patient.
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http://dx.doi.org/10.4274/jcrpe.2069DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4677563PMC
September 2015

Hyperthyroidism After Allogeneic Hematopoietic Stem Cell Transplantation: A Report of Four Cases.

J Clin Res Pediatr Endocrinol 2015 Dec;7(4):349-54

Hacettepe University Faculty of Medicine, Department of Pediatrics, Ankara, Turkey Phone: +90 312 305 11 68 E-mail:

Hematopoietic stem cell transplantation (HSCT) is the only curative treatment for many hematological disorders, primary immunodeficiencies, and metabolic disorders. Thyroid dysfunction is one of the frequently seen complications of HSCT. However, hyperthyroidism due to Graves' disease, autoimmune thyroiditis, and thyrotoxicosis are rare. Herein, we report a series of 4 patients who were euthyroid before HSCT but developed hyperthyroidism (3 of them developed autoimmune thyroid disease) after transplantation.
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http://dx.doi.org/10.4274/jcrpe.2295DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4805214PMC
December 2015

Growth Hormone Deficiency in a Child with Neurofibromatosis-Noonan Syndrome.

J Clin Res Pediatr Endocrinol 2016 Mar 18;8(1):96-100. Epub 2015 Dec 18.

Hacettepe University Faculty of Medicine, Department of Pediatric Endocrinology, Ankara, Turkey, E-mail:

Neurofibromatosis-Noonan syndrome (NFNS) is a distinct entity which shows the features of both NF1 (neurofibromatosis 1) and Noonan syndrome (NS). While growth hormone deficiency (GHD) has been relatively frequently identified in NF1 and NS patients, there is limited experience in NFNS cases. The literature includes only one case report of a NFNS patient having GHD and that report primarily focuses on the dermatological lesions that accompany the syndrome and not on growth hormone (GH) treatment. Here, we present a 13-year-old girl who had clinical features of NFNS with a mutation in the NF1 gene. The case is the first NFNS patient reported in the literature who was diagnosed to have GHD and who received GH treatment until reaching final height. The findings in this patient show that short stature is a feature of NFNS and can be caused by GHD. Patients with NFNS who show poor growth should be evaluated for GHD.
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http://dx.doi.org/10.4274/jcrpe.2070DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4805056PMC
March 2016

Variable Phenotype of Diabetes Mellitus in Siblings with a Homozygous PTF1A Enhancer Mutation.

Horm Res Paediatr 2015 14;84(3):206-11. Epub 2015 Jul 14.

Department of Pediatric Endocrinology, Hacettepe University, Ankara, Turkey.

Neonatal diabetes is a rare form of diabetes, characterized by onset in the first 6 months of life. A number of cases are due to pancreas agenesis. Recently, PTF1A enhancer mutations have been shown to cause neonatal diabetes associated with pancreatic agenesis. Herein, we report the clinical features of two siblings with PTF1A enhancer mutations, one of whom had neonatal diabetes, whereas the elder sister had a milder form of the disease with onset of diabetes at 9 years of age.
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http://dx.doi.org/10.1159/000435782DOI Listing
June 2016

Prevalence of nasal carriage of methicillin-resistant Staphylococcus aureus in children with diabetes mellitus: Trends between 2005 and 2013.

Am J Infect Control 2015 09 3;43(9):1015-7. Epub 2015 Jun 3.

Pediatric Infectious Disease Unit, Department of Pediatrics, Hacettepe University Faculty of Medicine, Ankara, Turkey.

The aim of this prospective study was to establish the methicillin-resistant Staphylococcus aureus (MRSA) colonization rates in pediatric outpatients with type 1 diabetes mellitus, while also evaluating changes in colonization rates over time. There was no significant difference between 2005 and 2013 patients in terms of demographic and clinical findings. MRSA colonization rates were 0.7% (in 101 patients) and 0.9% (in 134 patients) (P = .84). Although increased MRSA colonization has become a significant problem worldwide, it does not seem to be a major issue in our diabetic outpatient population.
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http://dx.doi.org/10.1016/j.ajic.2015.04.206DOI Listing
September 2015

Changing Etiological Trends in Male Precocious Puberty: Evaluation of 100 Cases with Central Precocious Puberty over the Last Decade.

Horm Res Paediatr 2015 19;83(5):340-4. Epub 2015 Mar 19.

Department of Pediatric Endocrinology, Hacettepe University, Ankara, Turkey.

Background/aims: There are few studies in the literature that have evaluated the etiological factors in boys with central precocious puberty (CPP), and these studies are limited in terms of the sample size. In the present study, we aimed to evaluate the etiological factors in male CPP cases.

Methods: One hundred male CPP subjects, aged between 9 months and 10.5 years, were included. The medical records were screened, and age at diagnosis, bone age, body weight, height, pubertal stage, imaging findings of the pituitary gland, testosterone, and basal and stimulated gonadotropin levels were recorded.

Results: There was no underlying cause in 74% of the cases, and an organic cause was determined in only 26%. Most of the organic cases had been diagnosed before the age of 7 years, whereas most of the idiopathic cases had been diagnosed after the age of 7 years.

Conclusion: An organic cause was determined in 26% of the male patients with CPP. This rate is one of the lowest rates in the literature and indicates that the number of idiopathic male CPP cases is increasing over time. When a boy is diagnosed with CPP above the age of 7 years, the odds of detecting an underlying pathology are very low, and these cases are mostly idiopathic.
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http://dx.doi.org/10.1159/000377678DOI Listing
March 2016

Effects of GH/IGF-I Axis on Retinal Vascular Morphology: Retinal Vascular Characteristics in a Clinical Setting with Severe IGF-I Deficiency.

Ophthalmic Genet 2016 31;37(1):53-8. Epub 2014 Jul 31.

c Pediatric Endocrinology, Faculty of Medicine, Hacettepe University , Ankara , Turkey.

Background: The purpose of this study was to assess retinal vascular characteristics of patients with Laron syndrome (LS) as a genetic model of IGF-I deficiency before and after rhIGF1/IGFBP3 treatment and to compare them with healthy controls.

Methods: A total of 28 subjects (11 LS, and 17 controls) were enrolled. Patients with LS received combined rhIGF1/rhIGFBP3 1-2 mg/kg/d in a single dose and digital fundus imaging was performed. The number of branching points and tortuosity of retinal vessels were studied. Pre- and post-treatment findings were compared with each other and with controls.

Results: The number of branching points was significantly lower in patients with LS in comparison to controls (12.73 ± 3.41, and 17.47 ± 5.82 respectively, p = 0.012). This difference persisted after treatment (12.09 ± 2.66 post-treatment LS versus controls, p = 0.017). Tortuosity indices of nasal arteries (NA) were significantly less in LS than that of controls (upper NA 1.07 ± 0.04 and 1.12 ± 0.06 respectively p = 0.022; lower NA 1.07 ± 0.03 and 1.13 ± 0.07 respectively, p = 0.004). This difference also persisted following treatment (p < 0.05). Remaining vessels did not differ in tortuosity index. There was no significant difference of tortuosity index and number of branching points before and after treatment in patients with LS.

Conclusion: Retinal vascular development may be adversely affected in the setting of severe IGF-I deficiency confirming a major role for GH/IGF-I axis during retinal vascular development in humans antenatally. Resolution of IGF-I deficiency following birth using rhIGF1, however, may not reverse these changes, suggesting that IGF-I may be necessary but insufficient by itself for postnatal angiogenesis.
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http://dx.doi.org/10.3109/13816810.2014.942918DOI Listing
September 2016

Clinical characteristics of type 1 diabetes over a 40 year period in Turkey: secular trend towards earlier age of onset.

J Pediatr Endocrinol Metab 2014 Jul;27(7-8):635-41

Unlabelled: OBJective: To determine the demographic and clinical characteristics of type 1 diabetes (T1D) in the past two decades, and to analyze changing trends over the past 40 years.

Methods: Patients with a diagnosis of T1D in 1990-2010 were included. Patients diagnosed in the first half of the period comprised Period I, and those from the second half comprised Period II. Age at onset, gender, seasonal distribution, infectious etiology, and clinical picture at onset are analyzed and compared in two periods. In addition, we compared these data with that of the preceding two decades (1969-1991), which was reported in a previous publication.

Results: A total of 354 children with T1D were included in the study. The median age at diagnosis of T1D was 7 years in the period 1990-2010 in comparison to 9.5 years during the period 1969-1991. Patients were diagnosed mostly in winter and autumn, and 32.3% of the children had an infection at the time of diagnosis. Frequency of diabetic ketoacidosis was 50.8% at diagnosis. The peak age at onset was 4 to 6 years.

Conclusions: Our study provides substantial information about the clinical characteristics of Turkish children. The age of onset of T1D decreased in the past 20 years, as observed in other parts of the world. Our findings also suggest seasonality at onset of T1D. This study shows the changes of demographic and clinical characteristics of T1D in central and northeastern parts of our country over a 40 year period.
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http://dx.doi.org/10.1515/jpem-2013-0320DOI Listing
July 2014

Carotid intima media thickness in adolescents with increased risk for atherosclerosis.

Turk J Pediatr 2013 Sep-Oct;55(5):510-8

Department of Pediatrics, Hacettepe University Faculty of Medicine, Ankara, Turkey.

In this study, we aimed to analyze early-onset atherosclerotic changes in adolescents with risk of cardiovascular disease in comparison to healthy controls using carotid intima media thickness (CIMT), homocysteine and markers of endothelial function as indicators. Children aged 10 years or older, all pubertal, with type 1 diabetes mellitus (T1DM), obesity, or obesity with glucose intolerance and age- and sex-matched healthy controls were included in the study. Endothelial markers (von Willebrand factor [vWF], tissue plasminogen activator [tPA], plasminogen activator inhibitor [PAI]-1), CIMT, homocysteine, folic acid, and vitamin B12 levels were measured in all subjects. Mean CIMT of the obese subjects were significantly higher than that of lean diabetic children and healthy controls (p=0.024). There was an independent relationship between CIMT and homocysteine level (b=0.76, p<0.0001). Further, homocysteine was negatively correlated with vitamin B12 (r=-0.20, p<0.001) and folic acid (r=-0.44, p<0.001). Homocysteine is an independent risk factor for early atherosclerosis in adolescents, which may be controlled by supplementation with vitamin B12 and folic acid.
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January 2015

Evaluation of hypothalamic-pituitary function in children following acute bacterial meningitis.

Pituitary 2015 Feb;18(1):1-7

Department of Pediatric Infectious Disease, Faculty of Medicine, Hacettepe University, Sıhhiye, 06100, Ankara, Turkey,

Background: Previous studies in adults and case reports in children have shown increased frequency of hypothalamo-pituitary dysfunction after infectious diseases of the central nervous system. The aim of this study was to evaluate the function of hypothalamo-pituitary axis in children with a history of bacterial meningitis.

Methods: Patients diagnosed with bacterial meningitis between April 2000 and June 2011 was included. Baseline and stimulated hormonal tests were performed as required for hormonal evaluations following a diagnosis of meningitis.

Results: Pituitary function was assessed following a period of 8-135 months (mean 53 months) after bacterial meningitis. Thirty-seven cases (27 male, 15 pubertal) with mean age of 11.1 ± 4.4 years were included. Mean height SDS was 0.01 ± 1.07 and mean BMI SDS was 0.54 ± 1.15 all patients had a SDS above -2 SD. Baseline cortisol and low dose ACTH stimulation revealed normal adrenal functions in all patients. Gonadotropin deficiency was not detected in any of the pubertal cases. Four cases (10.8%) had low IGF1 and IGFBP3 z-scores (<-2 SD) according to age, sex and Tanner stage, but peak GH response in clonidin test was >10 ng/ml in three of them suggesting neurosecretary dysfunction of GH in these cases. The fourth case has died before the test. No one had TSH deficiency and diabetes insipidus, only one case had mild hyperprolactinemia.

Conclusions: Our findings suggest that hypothalamo-pituitary dysfunction is not as common in childhood as in adulthood. The most remarkable finding was neurosecretary dysfunction of GH in some cases.
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http://dx.doi.org/10.1007/s11102-013-0547-4DOI Listing
February 2015