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 Open Access A Rare Cause of Hypophosphatemia: Raine Syndrome Changing Clinical Features with Age(SPRINGER, 2020-07) DAĞÇINAR, ADNAN; Eltan, Mehmet; Alavanda, Ceren; Yavas Abali, Zehra; Ergenekon, Pinar; Yalindag Ozturk, Nilufer; Sakar, Mustafa; Dagcinar, Adnan; Kirkgoz, Tarik; Kaygusuz, Sare Betul; Gokdemir, Yasemin; Elcioglu, Huriye Nursel; Guran, Tulay; Bereket, Abdullah; Ata, Pinar; Turan, SerapRaine Syndrome (RS) is caused by biallelic loss-of-function mutations in FAM20C gene and characterized by hypophosphatemia, typical facial and skeletal features. Subperiosteal bone formation and generalized osteosclerosis are the most common radiological findings. Here we present a new case with RS. A 9-month-old male patient on a home-type ventilator was referred for hypophosphatemia. He was born with a weight of 3800 g to non-consanguineous parents. Prenatal ultrasound had demonstrated nasal bone agenesis. A large anterior fontanel, frontal bossing, exophthalmos, hypoplastic nose, high arched palate, low set ears, triangular mouth, and corneal opacification were detected on physical examination. Serial skeletal X-rays revealed diffuse osteosclerosis at birth which was gradually decreased by the age of 5 months with subperiosteal undermineralized bone formation and medullary space of long bone could be distinguishable with bone-within-a-bone appearance. At 9 months of age, hand X-ray revealed cupping of the ulna with loose radial bone margin with minimal fraying and osteopenia. Cranial computed tomography scan showed bilateral periventricular calcification and hydrocephalus in progress. The clinical, laboratory, and radiological examinations were consistent with RS. Molecular analyses revealed a compound heterozygous mutation in FAM20C gene (a known pathogenic mutation, c.1645C > T, p.Arg549Trp; and a novel c.863 + 5 G > C variant). The patient died due to respiratory failure at 17 months of age. This case allowed us to demonstrate natural progression of skeletal features in RS. Furthermore, we have described a novel FAM20C variant causing RS. Previous literature on RS is also reviewed.Publication Open Access Familial Hypomagnesemia with Hypercalciuria and Nephrocalcinosis Due to CLDN16 Gene Mutations: Novel Findings in Two Cases with Diverse Clinical Features(SPRINGER, 2021-11-11) BEREKET, ABDULLAH; Eltan, Mehmet; Abali, Zehra Yavas; Turkyilmaz, Ayberk; Gokce, Ibrahim; Abali, Saygin; Alavanda, Ceren; Arman, Ahmet; Kirkgoz, Tarik; Guran, Tulay; Hatun, Sukru; Bereket, Abdullah; Turan, SerapBiallelic loss of function mutations in the CLDN16 gene cause familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC), and chronic kidney disease. Here we report two cases of FHHNC with diverse clinical presentations and hypercalcemia in one as a novel finding. Pt#1 initially presented with urinary tract infection and failure to thrive at 5.5 months of age to another center. Bilateral nephrocalcinosis, hypercalcemia (Ca: 12.2 mg/dl), elevated parathyroid hormone (PTH) level, and hypercalciuria were detected. Persistently elevated PTH with high/normal Ca levels led to subtotal-parathyroidectomy at the age of 2.5. However, PTH levels remained elevated with progressive deterioration in renal function. At 9-year-old, she was referred to us for evaluation of hyperparathyroidism and, hypomagnesemia together with hypercalciuria, elevated PTH with normal Ca levels, and medullary nephrocalcinosis were detected. Compound heterozygosity of CLDN16 variants (c.715G>A, p.G239R; and novel c.360C>A, p.C120*) confirmed the diagnosis. Pt#2 was a 10-month-old boy, admitted with irritability and urinary crystals. Hypocalcemia, hypophosphatemia, elevated PTH and ALP, low 25(OH)D levels, and radiographic findings of rickets were detected. However, additional findings of hypercalciuria and bilateral nephrocalcinosis were inconsistent with the nutritional rickets. Low/normal serum Mg levels suggested the diagnosis of FHHNC which was confirmed genetically as a homozygous missense (c.602G > A; p.G201E) variant in CLDN16. Yet, hypocalcemia and hypomagnesemia persisted in spite of treatment. In conclusion, FHHNC may present with diverse clinical features with mild hypomagnesemia leading to secondary hyperparathyroidism with changing Ca levels from low to high. Early and accurate clinical and molecular genetic diagnosis is important for proper management.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 Open Access Homozygosity for a novel INHA mutation in two male siblings with hypospadias, primary hypogonadism, and high-normal testicular volume(2022-03-23) ŞAHİN, BAHADIR; DEMİRCİOĞLU, SERAP; BEREKET, ABDULLAH; GÜRAN, TÜLAY; Arslan Ateş E., Eltan M., Sahin B., Gurpinar Tosun B., Seven Menevse T., Geckinli B. B., Greenfield A., Turan S., Bereket A., Güran T.Background: The human INHA gene encodes the inhibin subunit alpha protein, which is common to both inhibin A and B. The functional importance of inhibins in male sex development, sexual function, and reproduction remain largely unknown. Objective: We report for the first time two male siblings with homozygous INHA mutations. Methods: The medical files were examined for clinical, biochemical, and imaging data. Genetic analysis was performed using next-generation and Sanger sequencing methods. Results: Two brothers complained of gynecomastia, testicular pain, and had a history of hypospadias. Biochemistry revealed low serum testosterone, high gonadotropin and anti-Mullerian hormone, and very low/undetectable inhibin concentrations, where available. Both patients had azoospermia in the spermiogram. We have identified a homozygous 2 bp deletion (c.208_209delAG, R70Gfs*3) variant, which leads to a truncated INHA protein in both patients, and confirmed heterozygosity in the parents. The external genital development, pubertal onset and progression, reproductive functions, serum gonadotropins, and sex hormones of mother and father, who were heterozygous carriers of the identified mutation, were normal. Conclusion: Homozygosity for INHA mutations causes decreased prenatal and postnatal testosterone production and infertility in males, while the heterozygous female and male carriers of INHA mutations do not have any abnormality in sex development and reproduction.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 Open Access Biallelic and monoallelic ESR2 variants associated with 46,XY disorders of sex development(2018-07) BEREKET, ABDULLAH; Baetens, Dorien; Güran, Tülay; Mendonca, Berenice B.; Gomes, Nathalia L.; De Cauwer, Lode; Peelman, Frank; Verdin, Hannah; Vuylsteke, Marnik; Van der Linden, Malaïka; Stoop, Hans; Looijenga, Leendert H.; De Bosscher, Karolien; Cools, Martine; De Baere, Elfride; Atay, Zeynep; Bereket, Abdullah; de Krijger, Ronald R.; Preter, Katleen de; Domenice, Sorahia; Turan, SerapPublication 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, Basel