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Öğe Adrenocortical hormone profiles do not predict the molecular etiology in non-CAH primary adrenal insufficiency(Karger, 2021) Seven Menevşe, Tuba; Kendir Demirkol, Yasemin; Gürpınar Tosun, Büşra; Bayramoğlu, Elvan; Yıldız, Melek; Acar, Sezer; Erişen Karaca, Seda; Orbak, Zerrin; Önder, Asan; Söbü, Elif; Anık, Ahmet; Atay, Zeynep; Buğrul, Fuat; Demir, Korcan; Doğan, Durmuş; Emeksiz, Hamdi Cihan; Kırmızıbekmez, Heves; Özcan Murat, Nurhan; Yaman, Akan; Turan, Serap; Bereket, Abdullah; Güran, TülayBackground: Primary adrenal insufficiency other than congenital adrenal hyperplasia (non-CAH PAI) is very uncommon in children but associated with a variety of molecular defects. Biosynthesis of adrenocortical hormones is reduced although the relation of steroid profiles with underlying molecular etiology is not yet studied. Objective: Investigation of clinical and steroid hormone profiles of a multicenter cohort of children with non-CAH PAI. Design: Patients with CAH, adrenoleukodystrophy, autoimmune adrenal insufficiency or obvious syndromic PAI on clinical and biochemical assessment were excluded. Genetic analysis was performed using either targeted gene panel or whole-exome sequencing. Plasma adrenal steroids were quantified by liquid chromatography-mass spectrometry and compared to that of controls. Setting: Sixteen tertiary pediatric endocrinology clinics. Patients: Forty-one children (19 females, median age: 3 months, range: 0-8 years) with non-CAH PAI of unknown etiology. Results: A genetic diagnosis was obtained in 29 (68%) patients by targeted gene panel. Further molecular diagnosis could not be achieved by WES. The range of etiologies was: MC2R (n = 6), StAR (n = 6), NNT (n = 3), NR0B1 (n = 3), CYP11A1 (n = 2), MRAP (n = 2), SGPL1 (n = 2), ABCD1 (n = 1), AIRE (n = 1), AAAS (n = 1), HSD3B2 (n = 1). Steroid profiling demonstrated low levels in all adrenocortical steroid hormones irrespective of age and not varied among the genetic etiologies except two patients with new-onset symptoms of PAI due to homozygous c.518T>A(p.Leu173Gln) SGPL1, and hemizygous c.1772G>T(p.Arg591Leu) ABCD1 defects, and another patient with non-classic non-CAH PAI due to homozygous c.1351C>T (p.Arg451Trp) variant in CYP11A1. Compared to age-matched healthy control group in whom steroid hormone concentrations are physiologically low, the patient group had even lower steroid concentrations, most significantly in cortisone, cortisol, and corticosterone (P < 0.0001, area under the ROC curve: 0.96, 0.88, 0.87, respectively). Plasma cortisol<4 ng/ml, cortisone<11 ng/ml, and corticosterone<0.11 ng/ml had >95% specificity to segregate non-CAH PAI patients compared to control groups. Conclusion: Adrenocortical hormone profiles are highly sensitive for the diagnosis of non-CAH PAI, while, in contrast to CAH, they are unlikely to point out a specific molecular diagnosis. Targeted gene panel sequencing is an undisputed optimal approach in the molecular diagnosis of non-CAH PAI with low cost and high efficacy, while little additional benefit is expected from whole-exome sequencing. Further progress can be made, mainly by more collaboration and exchanging knowledge for delineation of rare causes of primary adrenal insufficiency.Öğe Change of menarcheal age in schoolgirls living in Istanbul over the last 12 years(Karger, 2022) Güran, Tülay; Alır, Fahriye; Arslan, Yusuf Taha; Molla, Giasim; Şahin, Berk; Sayar, Mehmet Emir; Atay, Zeynep; Helvacıoğlu, Didem; Gürpınar Tosun, Büşra; Haliloğlu, Belma; Turan, Serap; Hıdıroğlu, Seyhan; Bereket, Abdullah[Abstract Not Available]Öğe Decline in the age of menarche in İstanbul schoolgirls over the last 12 years(Galenos Publishing House, 2023) Güran, Tülay; Helvacıoğlu, Didem; Gürpınar Tosun, Büşra; Yavaş Abalı, Zehra; Alır, Fahriye; Arslan, Yusuf Taha; Molla, Giasim; Şahin, Berk; Sayar, Mehmet Emir; Atay, Zeynep; Haliloğlu, Belma; Demir, Korcan; Turan, Serap; Hıdıroğlu, Seyhan; Bereket, AbdullahObjective: Menarche is the endpoint of a sequence of maturational events of female puberty. The timing of menarche is a strongly heritable trait. However, secular trends suggest that lifestyle and environmental factors are important. To assess the trend in age at menarche (AAM), and its associated factors in İstanbul over the last 12 years. Methods: A cross-sectional study was carried out between March and April 2022 on schoolgirls aged 9-18 years. A predesigned and self-administered questionnaire was filled out anonymously by the students. The data of AAM was included in the statistical analysis if the time of AAM is remembered in both months and years. A probit model was used to calculate the median AAM. The findings were compared with those from a study performed 12 years ago in the same region of İstanbul. Results: Among 9000 girls to whom the questionnaire was distributed, 1749 (19.5%) responded. The median AAM of 1374 girls whose AAM information was considered valid was 12.04 years (95% confidence interval: 12.01-12.13), 0.7 years lower than was reported 12 years ago (p<0.0001). AAM was correlated positively with maternal AAM, and negatively with body mass index (BMI) standard deviation score and maternal educational status (p<0.0001, p<0.0001 and p=0.002), respectively. There was no correlation between the AAM and birth weight. Girls with BMI percentile ?85% (n=251) had earlier menarche than the ones with BMI percentile <85% (n=1072) (11.5 vs. 12.1 years, p<0.0001). Among the mother-daughter pairs (n=1162), AAM of girls was 0.91 years (median 0.94 years) earlier than their mothers. Conclusion: The present study demonstrates a significant downward trend in the menarcheal age in İstanbul over the last twelve years. These findings support a strong contribution from genetic factors and BMI on AAM.Öğe Evaluation of brain MRI lesions in 381 girls with central precocious puberty(Karger, 2019) Helvacıoğlu, Didem; Güran, Tülay; Kırkgöz, Tarık; Atay, Zeynep; Yavaş Abalı, Zehra; Eltan, Mehmet; Kaygusuz, Sare Betül; Seven, Tuba; Gürpınar, Büşra; Turan, Serap; Bereket, AbdullahCentral precocious puberty (CPP) in girls is a diagnosis increasingly made by the Pediatric Endocrinologists worldwide. Although it is most frequently of idiopathic origin, magnetic resonance imaging (MRI) of the brain is recommended to rule out organic lesions causing CPP. However, controversy exists regarding the age limits for routinely performing MRI in girls with CPP. Objective: To evaluate the outcome of brain MRI in girls diagnosed with CPP and its relationship with age and clinical and biochemical parameters. Method: A single-center, study of 381 girls with CPP who had brain imaging performed between 2008-2018. The results of imaging were categorised as Group 1:Normal, Group 2: incidental CNS lesions, Group 3: previously known CNS lesions Group 4: newly identified CNS lesions. Clinical and biochemical features of four groups were compared. Additionally, MRI lesion frequency was determined based on three age categories (<6 y, 6-8, >8 years) Results: MRI findings were abnormal in 73 patients (19%). 18 girls (4.7%) had well known brain pathologies at the time of referral. In the remaining 363 girls with CPP, who had no CNS symptoms, MRI revealed CNS abnormalities in 55 girls. In 34 girls (8.9%) MRI findings were considered as incidental findings, which were not related to the early puberty. Another 21 girls (5.5%) had newly identified MRI abnormalities which were considered to be causally related to CPP. Among these, 19 lesions were non-neoplastic and included arachnoid cysts (6) pineal cysts (4) hydrocephaly (2) Chiari Type2 malformation (1) Dandy-Walker malformation(1) and others (5) not requiring surgical intervention during follow-up. There were only 2 tumoral lesions (0.5%) in the cohort (1 hamartoma and 1 glioma) and they required surgical intervention. These two cases were the youngest of the entire cohort (1.0 and 2.7 years of age respectively) and had the highest baseline LH and Estradiol levels. Otherwise, clinical and biochemical parameters were similar in 4 groups. Newly identified CNS lesions were detected throughout all ages including those above 8 years (Table). Conclusion: Although CNS lesions can be detected throughout all age categories in girls with CPP, only 5.5 % are causally related and most of them do not require intervention. CPP due to neoplastic lesions are detected in younger patients who also had a robust activation of pituitary-gonadal axis.Öğe Incidence of type 1 diabetes in children aged below 18 years during 2013-2015 in northwest Turkey(Galenos Yayıncılık, 2018) Poyrazoğlu, Şükran; Bundak, Rüveyde; Yavaş Abalı, Zehra; Önal, Hasan; Sarıkaya, Sevil; Akgün, Abdurrahman; Baş, Serpil; Abalı, Saygın; Bereket, Abdullah; Eren, Erdal; Tarım, Ömer; Güven, Ayla; Yıldız, Metin; Karaman Aksakal, Derya; Yüksel, Ayşegül; Seymen Karabulut, Gülcan; Hatun, Şükrü; Özgen, Tolga; Cesur, Yaşar; Azizoğlu, Mehmet; Dilek, Emine; Tütüncüler, Filiz; Çakır, Esra Papatya; Özcabı, Bahar; Evliyaoğlu, Olcay; Karadeniz, Songül; Dursun, Fatma; Bolu, Semih; Arslanoğlu, İlknur; Yeşiltepe Mutlu, Gül; Kırmızıbekmez, Heves; İşgüven, Pınar; Üstyol, Ala; Adal, Erdal; Uçar, Ahmet; Cebeci, Nurcan; Bezen, Didem; Binay, Çiğdem; Semiz, Serap; Korkmaz, Hüseyin Anıl; Memioğlu, Nihal; Sağsak, Elif; Peltek, Havva Nur; Yıldız, Melek; Akçay, Teoman; Turan, Serap; Güran, Tülay; Atay, Zeynep; Akcan, Neşe; Çizmecioğlu, Filiz; Ercan, Oya; Dağdeviren, Aydilek; Baş, Firdevs; İşsever, Halim; Darendeliler, FeyzaObjective: To assess the incidence of type I diabetes mellitus (T1DM) in children under 18 years of age in the northwest region of Turkey during 2013-2015. Methods: All newly diagnosed T1DM cases were recorded prospectively during 2013-2015. Total, as well as gender and age group specific (0-4, 5-9. 10-14 and 15-17 age) mean incidences per 100,000 per year were calculated. Results: There were 1,773 patients diagnosed during 2013-2015 (588 cases in 2013, 592 cases in 2014, 593 cases in 2015). Of these, 862 (48.6 %) were girls and 911 (51.4%) were boys. The mean age at diagnosis was 9.2 +/- 4.2 years and it was not significantly different between girls (9.0 +/- 4.1 years) and boys (9.4 +/- 4.4 years) (p = 0.052). The crude mean incidence was 8.99/100.000 confidence interval (CI) (95% CI: 8.58-9.42). Although mean incidence was similar between boys [8.98/100.000 (CI: 8.40 to 9.58)] and girls [9.01/100.000 (CI: 8.42 to 9.63)], there was male predominance in all groups except for 5-9 year age group. The standardized mean incidence was 9.02/100.000 according to the World Health Organization standard population. The mean incidence for the 0-4, 5-9, 10-14 and 15-17 age groups was 6.13, 11.68, 11.7 and 5.04/1 00.000 respectively. The incidence of T1DM was similar over the course of three years (p = 0.95). A significant increase in the proportion of cases diagnosed was observed in the autumn-winter seasons. Conclusion: The northwest region of Turkey experienced an intermediate incidence of T1DM over the period of the study.Öğe PPP2R3C gene variants cause syndromic 46,XY gonadal dysgenesis and impaired spermatogenesis in humans(Bioscientifica Ltd, 2019) Güran, Tülay; Yeşil, Gözde; Turan, Serap; Atay, Zeynep; Bozkurtlar, Emine; Aghayev, AghaRza; Gül, Sinem; Tinay, İlker; Aru, Başak; Arslan, Sema; Köroğlu, Mustafa Kutay; Ercan, Feriha; Yanıkkaya Demirel, Gülderen; Tanay Eren, Funda; Karademir, Betül; Bereket, AbdullahContext: Most of the knowledge on the factors involved in human sexual development stems from studies of rare cases with disorders of sex development. Here, we have described a novel 46, XY complete gonadal dysgenesis syndrome caused by homozygous variants in PPP2R3C gene. This gene encodes B '' gamma regulatory subunit of the protein phosphatase 2A (PP2A), which is a serine/threonine phosphatase involved in the phospho-regulation processes of most mammalian cell types. PPP2R3C gene is most abundantly expressed in testis in humans, while its function was hitherto unknown. Patients and methods: Four girls from four unrelated families with 46, XY complete gonadal dysgenesis were studied using exome or Sanger sequencing of PPP2R3C gene. In total, four patients and their heterozygous parents were investigated for clinical, laboratory, immunohistochemical and molecular characteristics. Results: We have identified three different homozygous PPP2R3C variants, c.308T>C (pL103P), c.578T>C (pL193S) and c.1049T>C (pF350S), in four girls with 46, XY complete gonadal dysgenesis. Patients also manifested a unique syndrome of extragonadal anomalies, including typical facial gestalt, low birth weight, myopathy, rod and cone dystrophy, anal atresia, omphalocele, sensorineural hearing loss, dry and scaly skin, skeletal abnormalities, renal agenesis and neuromotor delay. We have shown a decreased SOX9-Phospho protein expression in the dysgenetic gonads of the patients with homozygous PPP2R3C variants suggesting impaired SOX9 signaling in the pathogenesis of gonadal dysgenesis. Heterozygous males presented with abnormal sperm morphology and impaired fertility. Conclusion: Our findings suggest that PPP2R3C protein is involved in the ontogeny of multiple organs, especially critical for testis development and spermatogenesis. PPPR3C provides insight into pathophysiology, as well as emerging as a potential therapeutic target for male infertility.Öğe Restoration of height after 11 years of letrozole treatment in 11?-hydroxylase deficiency(Karger, 2020) Atay, Zeynep; Turan, Serap; Bu?daycı, Onur; Güran, Tülay; Bereket, Abdullah11?-hydroxylase deficiency (11?-OHD) is the second most common form of congenital adrenal hyperplasia (CAH). Males with 11?-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?-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-Müllerian 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.Öğe Steroid hormone profiles and molecular diagnostic tools in pediatric patients with non-CAH primary adrenal insufficiency(National Library of Medicine's (NLM) Medline, 2022) Seven Menevşe, Tuba; Kendir Demirkol, Yasemin; Gürpınar Tosun, Büşra; Bayramoğlu, Elvan; Yıldız, Melek; Acar, Sezer; Erişen Karaca, Seda; Orbak, Zerrin; Önder, Asan; Söbü, Elif; Anık, Ahmet; Atay, Zeynep; Buğrul, Fuat; Buluş, Ayşe Derya; Demir, Korcan; Doğan, Durmuş; Emeksiz, Hamdi Cihan; Kırmızıbekmez, Heves; Özcan Murat, Nurhan; Yaman, Akan; Turan, Serap; Bereket, Abdullah; Güran, TülayCONTEXT: There is a significant challenge of attributing specific diagnoses to patients with primary adrenal insufficiency of unknown etiology other than congenital adrenal hyperplasia (non-CAH PAI). Specific diagnoses per se may guide personalized treatment or may illuminate pathophysiology. OBJECTIVE: This work aimed to investigate the efficacy of steroid hormone profiles and high-throughput sequencing methods in establishing the etiology in non-CAH PAI of unknown origin. METHODS: Pediatric patients with non-CAH PAI whose etiology could not be established by clinical and biochemical characteristics were enrolled. Genetic analysis was performed using targeted-gene panel sequencing (TPS) and whole-exome sequencing (WES). Plasma adrenal steroids were quantified by liquid chromatography-mass spectrometry and compared to that of controls. This study comprised 18 pediatric endocrinology clinics with 41 patients (17 girls, median age: 3 mo, range: 0-8 y) with non-CAH PAI of unknown etiology. RESULTS: A genetic diagnosis was obtained in 29 (70.7%) patients by TPS. Further molecular diagnosis could not be achieved by WES. Compared to a healthy control group, patients showed lower steroid concentrations, most statistically significantly in cortisone, cortisol, and corticosterone (P?Öğe The distribution of different types of diabetes in childhood: A single center experience(Galenos Yayıncılık, 2018) Haliloğlu, Belma; Abalı, Saygın; Buğrul, Fuat; Çelik, Enes; Baş, Serpil; Atay, Zeynep; Güran, Tülay; Turan, Serap; Bereket, AbdullahObjective: Type I diabetes (T1D) is the most common cause of diabetes in childhood but type 2 diabetes (T2D) and maturity onset diabetes of the young (MODY) are emerging as noteworthy causes of diabetes at young ages. The aim is to determine the distribution, trends and clinical features of the different types of diabetes in childhood in one tertiary center. Methods: The records of children and adolescents aged 0-18 years who were diagnosed as "diabetes/persistent hyperglycemia" between January 1999 and December 2016, were reviewed. Clinical and laboratory characteristics of the patients at diagnosis and type of diabetes were recorded. Results: The mean +/- standard deviation age of 835 patients (48.7% females) at diagnosis was 8.8 +/- 4.4 years. Eighty-four percent of the patients were diagnosed as T1D, 5.7% as T2D, 5.3% as clinical MODY and 5% as being cases of other types of diabetes. The frequency of diabetic ketoacidosis (DKA) and severe DKA in T1D were 48.4% and 11.6%, respectively. Fourteen patients (29.2 %) with T2D presented with ketosis and two of them (4.2 %) had DKA at diagnosis. Antibody positivity was 83.1 % in T1D and 14.8% in T2D. A statistically significant increase in the frequency of T2D has clearly been demonstrated in recent years with a frequency of 1.9%, 2.4% and 7.9% in 1999-2004, 2005-2010 and 2011-2016, respectively (p <0.001). In MODY, genetic analysis was performed in 26 (59%) patients and NNF1A and GCK gene mutations were detected in 3 (11.5%) and 14 (53.8%) patients, respectively. Conclusion: Although the most frequent cause of DM is T1D in childhood, a trend towards increase in the frequency of T2D in recent years is notable in our population.
