Person: DEMİRCİOĞLU, SERAP
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DEMİRCİOĞLU
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SERAP
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Publication Metadata only Clinical Significance of Hypophosphatasemia in Children(SPRINGER, 2020) BEREKET, ABDULLAH; Bayramli, Rana; Cevlik, Tulay; Guran, Tulay; Atay, Zeynep; Bas, Serpil; Haklar, Goncagul; Bereket, Abdullah; Turan, SerapLow serum alkaline phosphatase (sALP)-hypophosphatasemia-is a characteristic of hypophosphatasia (HPP), but related to several clinical conditions. Here, we evaluated the frequency, persistency and the etiology of hypophosphatasemia in children. In retrospective analyses of sALP measurements from children, evaluated according to in-house constructed age- and sex-specific reference ranges, patients with no normal sALP measurement (Unresolved hypophosphatasemia) were invited for reanalysis. Prospectively, ALP substrates, pyridoxal-5-phosphate (PLP), and phosphoethanolamine (PEA) were measured in patients with persistent hypophosphatasemia. Radiographs and ALPL gene sequencing for HPP were performed to the cases with elevated PEA and/or PLP. From 130,340 sALP measurements of 93,162 patients, hypophosphatasemia was detected in 1404 samples from 867 patients (0.9%). Among them, 745 had at least one normal sALP values in laboratory records, grouped as transient hypophosphatasemia. 75 out of 122 patients with unresolved hypophosphatasemia could be reanalyzed for sALP, of whom PLP and PEA measurements were required in 37 due to persistent hypophosphatasemia. Both PEA and PLP were elevated in 4 patients, and ALPL gene analysis showed heterozygous mutations in 3 patients and homozygous in 1 patient. Elevated PEA with normal PLP were detected in 3 patients, and one had a heterozygous ALPL mutation. Anemia was the most common diagnosis, and upper respiratory tract infections and chronic diseases were more common in transient and unresolved hypophosphatasemia, respectively. In conclusion, reflected persistent hypophosphatasemia frequency was 1/1552 (0.06%) in this large pediatric cohort and, ALPL gene mutations were detected in 13.5% (5/37) of the studied cases. Although biochemical hypophosphatasemia is not uncommon, clinically significant HPP is rare.Publication Metadata only The role of leptin, soluble leptin receptor, resistin, and insulin secretory dynamics in the pathogenesis of hypothalamic obesity in children(SPRINGER, 2009) BEREKET, ABDULLAH; Guran, Tulay; Turan, Serap; Bereket, Abdullah; Akcay, Teoman; Unluguzel, Goksenin; Bas, Firdevs; Gunoz, Hulya; Saka, Nurcin; Bundak, Ruveyde; Darendeliler, Feyza; Isguven, Pinar; Yildiz, Metin; Adal, Erdal; Sarikaya, Sevil; Baygin, Leyla Akin; Memioglu, Nihal; Onal, Hasan; Ercan, Oya; Haklar, GoncagulIn this study, we have investigated the role of leptin, soluble leptin receptor(sOb-R), resistin, and insulin secretory dynamics in the development of hypothalamic obesity. Children who had hypothalamo-pituitary tumor were divided into two groups. First group included obese-overweight (hypothalamic obese = HOB group, n = 23) and second group included non-obese children (hypothalamic non-obese = HNOB group, n = 16). Exogenously obese-overweight children (OB group, n = 22) were included as controls. Basal and second-hour serum glucose and insulin in oral glucose tolerance test (OGTT), basal serum leptin, sOb-R, resistin levels, and homeostasis model assessment (HOMA) indexes were compared between the groups. Age, sex, and pubertal status were similar in study groups. Median and interquartile ranges of body mass index (BMI) z scores were similar in HOB and OB groups (2.0 (1.5-2.1) and 2.1 (1.8-2.3), respectively). Serum leptin levels corrected for BMI were highest and total leptin/sOb-R ratios (free leptin index (FLI)) tended to be higher in HOB than HNOB and OB groups, indicating leptin resistance (leptin/BMI, 4.0 (1.6-5.2), 1.5 (0.8-3.1), and 2.5 (1.8-3.5); FLI, 2.0 (0.8-3.5), 0.6 (0.3-1.2), and 1.5 (1-2.3) in HOB, HNOB, and OB groups; respectively). Serum resistin levels were similar in groups (2.6 (1.9-3.1), 2.8 (1.7-3.4), and 3.0 (2.2-3.5) ng/ml in HOB, HNOB, and OB groups, respectively). Basal serum glucose, basal and second-hour insulin levels in OGTT, and HOMA index were higher in OB group than the HOB and HNOB groups, indicating insulin resistance in simple obesity; however, increment of insulin to same glycemic load in OGTT was highest in the HOB group indicating insulin dysregulation (p < 0.05). Hypothalamic obesity seems to be related to both dysregulated afferent (leptin) and efferent (insulin) neural outputs through the autonomic nervous system resulting in energy storage as fat.Publication Metadata only Revisiting Classical 3 beta-hydroxysteroid Dehydrogenase 2 Deficiency: Lessons from 31 Pediatric Cases(ENDOCRINE SOC, 2020) BEREKET, ABDULLAH; Guran, Tulay; Kara, Cengiz; Yildiz, Melek; Bitkin, Eda C.; Haklar, Goncagul; Lin, Jen-Chieh; Keskin, Mehmet; Barnard, Lise; Anik, Ahmet; Catli, Gonul; Guven, Ayla; Kirel, Birgul; Tutunculer, Filiz; Onal, Hasan; Turan, Serap; Akcay, Teoman; Atay, Zeynep; Yilmaz, Gulay C.; Mamadova, Jamala; Akbarzade, Azad; Sirikci, Onder; Storbeck, Karl-Heinz; Baris, Tugba; Chung, Bon-Chu; Bereket, AbdullahContext: The clinical effects of classical 3 beta-hydroxysteroid dehydrogenase 2 (3 beta HSD2) deficiency are insufficiently defined due to a limited number of published cases. Objective: To evaluate an integrated steroid metabolome and the short- and long-term clinical features of 3 beta HSD2 deficiency. Design: Multicenter, cross-sectional study. Setting: Nine tertiary pediatric endocrinology clinics across Turkey. Patients: Children with clinical diagnosis of 3 beta HSD2 deficiency. Main Outcome Measures: Clinical manifestations, genotype-phenotype-metabolomic relations. A structured questionnaire was used to evaluate the data of patients with clinical 3 beta HSD2 deficiency. Genetic analysis of HSD3B2 was performed using Sanger sequencing. Novel HSD3B2 mutations were studied in vitro. Nineteen plasma adrenal steroids were measured using LC-MS/MS. Results: Eleven homozygous HSD3B2 mutations (6 novel) were identified in 31 children (19 male/12 female; mean age: 6.6 +/- 5.1 yrs). The patients with homozygous pathogenic HSD3B2 missense variants of > 5% of wild type 3 beta HSD2 activity in vitro had a non-salt-losing clinical phenotype. Ambiguous genitalia was an invariable feature of all genetic males, whereas only 1 of 12 female patients presented with virilized genitalia. Premature pubarche was observed in 78% of patients. In adolescence, menstrual irregularities and polycystic ovaries in females and adrenal rest tumors and gonadal failure in males were observed. Conclusions: Genetically-documented 3 beta HSD2 deficiency includes salt-losing and non-salt-losing clinical phenotypes. Spared mineralocorticoid function and unvirilized genitalia in females may lead to misdiagnosis and underestimation of the frequency of 3 beta HSD2 deficiency. High baseline 17OHPreg to cortisol ratio and low 11-oxyandrogen concentrations by LC-MS/MS unequivocally identifies patients with 3 beta HSD2 deficiency.Publication Metadata only Persistent Mullerian Duct Syndrome: A Rare But Important Etiology of Inguinal Hernia and Cryptorchidism(KARGER, 2020) BEREKET, ABDULLAH; Bugrul, Fuat; Abali, Zehra Yavas; Kirkgoz, Tarik; Cerit, Kivilcim K.; Canmemis, Arzu; Turan, Serap; Tugtepe, Halil; Picard, Jean-Yves; Bereket, Abdullah; Guran, TulayHomozygous loss of function mutations in genes encoding anti-Mullerian hormone (AMH) or its receptor (AMHRII) lead to persistent Mullerian duct syndrome (PMDS). PMDS is characterized by the presence of a uterus, fallopian tubes, cervix, and upper vagina in fully virilised 46,XY males. Both surgical management and long-term follow-up of these patients are challenging. Four cases with PMDS presented with cryptorchidism and inguinal hernia, and laparoscopic inguinal exploration revealed Mullerian remnants. Three of the patients had homozygous mutations in the AMH gene, one with a novel c.1673G>A (p.Gly558Asp) mutation, and one patient had an AMHRII mutation. All patients underwent a single-stage laparotomy in which the fundus of the uterus was split along the midline to release testes and to avoid damaging the vas deferens or the deferential artery. Biopsy of Mullerian remnants did not reveal any malignancy. The cases presented here expand the clinical and molecular presentation of PMDS. Cryptorchidism and inguinal hernia in the presence of Mullerian structures in an appropriately virilised 46,XY individual should suggest PMDS. Long-term reproductive and endocrinological surveillance is necessary.Publication Metadata only Breast ultrasonography: How useful in the diagnosis of precocious puberty?(2022-09-15) BIYIKLI, ERHAN; BUĞDAYCI, ONUR; DEMİRCİOĞLU, SERAP; GÜRAN, TÜLAY; BEREKET, ABDULLAH; HELVACIOĞLU D., BIYIKLI E., BUĞDAYCI O., DEMİRCİOĞLU S., GÜRAN T., BEREKET A.Publication Metadata only T4 plus T3 Treatment in Children with Hypothyroidism and Inappropriately Elevated Thyroid-Stimulating Hormone despite Euthyroidism on T4 Treatment(KARGER, 2010) BEREKET, ABDULLAH; Akcay, Teoman; Turan, Serap; Guran, Tulay; Unluguzel, Goksenin; Haklar, Goncagul; Bereket, AbdullahAims: To evaluate the effect of addition of T3 to L-T4 treatment in children with congenital hypothyroidism (CH) who have inappropriately elevated thyroid-stimulating hormone (TSH) levels despite high normal serum T4 levels on L-T4 treatment. Methods: Ten children (age 7.1 +/- 2 years) with CH whose TSH levels were persistently high despite euthyroidism and can only be normalized with hyperthyroidism were included. L-T4 treatment was switched to T3+L-T4 combination (Bitiron (R) tablet 50 mu g L-T4 + 12.5 mu g triiodothyronine). The patients received 50% of their usual L-T4 dose as L-T4 and the remaining half as T3 in a 4: 1 ratio. The dose of T3+L-T4 was titrated to achieve normal TSH levels. Thyroid hormones and biochemical markers were followed for 1 year. Results: Euthyrotropinemia was achieved at the 7th month (mean) of combination (T3+L-T4) treatment. Serum T4 and fT4 were lower and T3 was higher during combination compared to L-T4 treatment. LDL-cholesterol decreased and ALP increased in the euthyrotropinemic state. Vital signs were similar at hyperthyrotropinemia and euthyrotropinemia. Conclusion: T3+L-T4 treatment provides euthyrotropinemia without causing hyperthyroidism in children with CH and inappropriate hyperthyrotropinemia. Our data strongly suggest that decreased negative feedback due to lower T3 levels at the pituitary level is the main reason for persistent hyperthyrotropinemia. Copyright (C) 2010 S. Karger AG, BaselPublication Metadata only Does Genotype-Phenotype Correlation Exist in Vitamin D-Dependent Rickets Type IA: Report of 13 New Cases and Review of the Literature(SPRINGER, 2021) BEREKET, ABDULLAH; Kaygusuz, Sare Betul; Alavanda, Ceren; Kirkgoz, Tarik; Eltan, Mehmet; Yavas Abali, Zehra; Helvacioglu, Didem; Guran, Tulay; Ata, Pinar; Bereket, Abdullah; Turan, SerapVitamin D-dependent rickets type IA (VDDR-IA) is caused by biallelic mutations in CYP27B1. Data regarding genotype-phenotype correlation in VDDR-IA are scarce. Here, we aimed to investigate clinical/genotypic features and long-term follow-up of 13 new cases with VDDR-IA and genotype-phenotype correlation of reported cases in the literature. Thirteen patients with VDDR-IA were evaluated. Eight patients had reached their final height at the time of the study and, for whom, long-term outcome data were analyzed. Further, all VDDR-IA patients in the literature (n:183) were analyzed and clinical-genetic features were recorded. The median age of diagnosis was 2.55 +/- 1.13 (1.0-12) years. Initial diagnoses before referral to our clinic were nutritional rickets (n:7), hypophosphatemic rickets (n:2), and pseudohypoparathyroidism (n:1). All had biochemical evidence suggestive of VDDR-IA; except one with elevated 1,25(OH)(2)D3 and another with hyperphosphatemia, in whom pseudohypoparathyroidism was excluded with molecular tests. Combined analyses of our cohort and other series in the literature demonstrated that three most common CYP27B1 mutations are p.F443Pfs*24, c.195 + 2T > G, and p.V88Wfs*71. In Turkish population, p.K192E mutation along with the former two is the most common mutations. Comparison of clinical features demonstrated that c.195 + 2T > G mutation causes the most severe and p.K192E mutation causes the least severe phenotype with respect to age and height at presentation and calcitriol requirement. We found a clear genotype-phenotype correlation in VDDR-IA, notably CYP27B1 intronic c.195 + 2T > G mutation causes a more severe phenotype with lower height SDS at presentation and, higher calcitriol requirement, while less severe phenotype occurs in p.K192E mutation.Publication Metadata only Restoration of Height after 11 Years of Letrozole Treatment in 11 beta-Hydroxylase Deficiency(KARGER, 2020) BEREKET, ABDULLAH; Atay, Zeynep; Turan, Serap; Bugdayci, Onur; Guran, Tulay; Bereket, Abdullah11 beta-hydroxylase deficiency (11 beta-OHD) is the second most common form of congenital adrenal hyperplasia (CAH). Males with 11 beta-OHD CAH are often diagnosed late with a significantly advanced bone age leading to a poor height prognosis due to early closure of epiphysis. Delaying epiphyseal fusion by treatment of aromatase inhibitors (AIs) might be a useful strategy in patients with very advanced bone ages. However, there are limited data regarding the effect on final height and long-term safety of this approach. We report our experience with 11 years of letrozole treatment and 17 years of follow-up in a boy with 11 beta-OHD. He presented at 2 years and 11 months of age with a bone age of 13 years (predicted adult height, PAH, 129.5 cm). Letrozole was added after 1 year of glucocorticoid treatment due to no improvement in height prognosis (130 cm), and continued until the age of 14 years and 11 months. He also received GnRH analog treatment at 10 years and 3 months of age for 2.5 years due to central activation of puberty. He reached a final height of 165.2 cm (35.2 cm above his PAH). This long-term treatment with letrozole was associated with changes in vertebral morphology such as vertebral body end-plate changes, Schmorl nodes, and mild protrusions in the intervertebral discs. Testicular volumes, gonadotropins, testosterone, and anti-Mullerian hormone were normal at age 20 years. A spermiogram showed a normal count but impaired sperm motility and morphology. This unique case represents the longest duration of AI treatment reported in CAH and the first case in which letrozole was started before puberty with the final height reported. We conclude that AIs may restore height in selected patients with CAH with very advanced bone age and severely compromised height prognosis.Publication Metadata only Effects of leukemia inhibitory receptor gene mutations on human hypothalamo-pituitary-adrenal function(SPRINGER, 2015) BEREKET, ABDULLAH; Guran, Tulay; Guran, Omer; Paketci, Cem; Kipoglu, Osman; Firat, Irfan; Turan, Serap; Atay, Zeynep; Haliloglu, Belma; Bereket, AbdullahStuve-Wiedemann syndrome (STWS) (MIM #601559) is a rare autosomal recessive disorder caused by mutations in the leukemia inhibitory factor receptor (LIFR) gene. STWS has a diverse range of clinical features involving hematopoietic, skeletal, neuronal and immune systems. STWS manifests a high mortality due to increased risk of sudden death. Heterodimerization of the LIFR mediates leukemia inhibitory factor (LIF) signalling through the intracellular Janus kinase (JAK)/STAT3 signalling cascade. The LIF/LIFR system is highly expressed in and regulates the hypothalamo-pituitary-adrenal (HPA) axis. HPA function was investigated in three STWS patients to characterise consequences of impaired LIF/LIFR signalling on adrenal function. Six genetically proven STWS patients from four unrelated Turkish families were included in the study. Sudden death occurred in three before 2 years of age. Basal adrenal function tests were performed by measurement of early morning serum cortisol and plasma ACTH concentrations on at least two different occasions. Low dose synacthen stimulation test and glucagon stimulation tests were performed to explore adrenal function in three patients who survived. All patients carried the same LIFR (p.Arg692X) mutation. Our oldest patient had attenuated morning serum cortisol and plasma ACTH levels at repeated measurements. Two of three patients had attenuated cortisol response (< 18 mu g/dl) to glucagon, one of whom also had borderline cortisol response to low dose (1 mu g) ACTH stimulation consistent with central adrenal insufficiency. STWS patients may develop central adrenal insufficiency due to impaired LIF/LIFR signalling. LIF/LIFR system plays a role in human HPA axis regulation.Publication Metadata only The prevalence and risk factors of premature thelarche and pubarche in 4-to 8-year-old girls(WILEY, 2012) BEREKET, ABDULLAH; Atay, Zeynep; Turan, Serap; Guran, Tulay; Furman, Andrzej; Bereket, AbdullahAim: To assess the prevalence of premature thelarche (PT) and pubarche in healthy 4- to 8-year-old girls and to investigate factors associated with early pubertal development. Method: Eight hundred and twenty girls were examined by two paediatric endocrinologists to determine Tanner staging. The effects of body mass index, gestational age, intrauterine growth status, age at the first tooth eruption, socio-economical status, maternal age of menarche and consumption of certain food items on early pubertal development were analysed through parametric and nonparametric tests. Results: The prevalence of PT and of premature pubarche was 8.9% and 4.3%, respectively. We found a strong association between the prevalence of PT and the body mass index standard deviation scores (BMI SDS). There were more girls with BMI SDS values above 1 in the PT group (56.1%) than among the remaining subjects (22.9%). Premature thelarche was not significantly associated with intrauterine growth, premature birth, socioeconomic status, age of first tooth eruption or maternal age of menarche. Similarly, the amount of milk, eggs, chicken or fish consumed was not associated with PT. None of the investigated factors were associated with premature pubarche. Conclusion: Occurrence of PT is strongly associated with BMI SDS. Studies investigating secular trends in pubertal development must consider a secular change in body mass index.