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Free access

Feyza Darendeliler, Sukran Poyrazoglu, Firdevs Bas, Ozlem Sancakli, and Gulbin Gokcay

Background

Ghrelin is the natural ligand of GH secretagogue receptor. It has several metabolic functions including regulation of food intake, energy homeostasis, and body weight. An inverse relationship between fasting plasma ghrelin and insulin concentrations has been shown. Being born large for gestational age (LGA) has an increased risk of developing insulin resistance.

Objective

The aim of this study was to evaluate ghrelin levels in LGA born children who have no obesity at prepubertal ages and the effect of intrauterine and postnatal growth on ghrelin levels.

Patients and methods

Thirty-two (17F, 15M) LGA born non-obese children (mean (±s.e.m.) age 4.4±0.3 years) were evaluated with respect to glucose, insulin, and ghrelin levels. Their data were compared with that of non-obese 45 (19F, 26M) appropriate for gestational age (AGA) children (mean (±s.e.m.) age 4.0±0.1 years).

Results

LGA children, who had similar age and body mass index (BMI) standard deviation score (SDS) as AGA children, had significantly higher insulin (P=0.044) and at a borderline significance higher homeostasis model assessment-insulin resistance levels (P=0.054) than AGA children. Ghrelin level was significantly lower in LGA born than AGA born children (P=0.001) even after controlling for age, sex, and BMI (P=0.006). There were no differences between genders in insulin and ghrelin levels. Multivariate analysis revealed that birth weight was the only significant parameter influencing ghrelin levels (R 2=0.13, B=−0.007, P=0.002).

Conclusions

LGA born non-obese prepubertal children have lower ghrelin levels when compared with age and BMI matched AGA children. Birth weight seems to have the only significant effect on the reduced ghrelin levels.

Open access

Dilek Cicek, Nick Warr, Gozde Yesil, Hatice Kocak Eker, Firdevs Bas, Sukran Poyrazoglu, Feyza Darendeliler, Gul Direk, Nihal Hatipoglu, Mehmet Eltan, Zehra Yavas Abali, Busra Gurpinar Tosun, Sare Betul Kaygusuz, Tuba Seven Menevse, Didem Helvacioglu, Serap Turan, Abdullah Bereket, Richard Reeves, Michelle Simon, Matthew Mackenzie, Lydia Teboul, Andy Greenfield, and Tulay Guran

Context

Homozygous and heterozygous variants in PPP2R3C are associated with syndromic 46,XY complete gonadal dysgenesis (Myo-Ectodermo-Gonadal Dysgenesis (MEGD) syndrome), and impaired spermatogenesis, respectively. This study expands the role of PPP2R3C in the aetiology of gonadal dysgenesis (GD).

Method

We sequenced the PPP2R3C gene in four new patients from three unrelated families. The clinical, laboratory, and molecular characteristics were investigated. We have also determined the requirement for Ppp2r3c in mice (C57BL6/N) using CRISPR/Cas9 genome editing.

Results

A homozygous c.578T>C (p.L193S) PPP2R3C variant was identified in one 46,XX girl with primary gonadal insufficiency, two girls with 46,XY complete GD, and one undervirilised boy with 46,XY partial GD. The patients with complete GD had low gonadal and adrenal androgens, low anti-Müllerian hormone, and high follicle-stimulating hormone and luteinizing hormone concentrations. All patients manifested characteristic features of MEGD syndrome. Heterozygous Ppp2r3c knockout mice appeared overtly normal and fertile. Inspection of homozygous embryos at 14.5, 9.5, and 8.5 days post coitum(dpc) revealed evidence of dead embryos. We conclude that loss of function of Ppp2r3c is not compatible with viability in mice and results in embryonic death from 7.5 dpc or earlier.

Conclusion

Our data indicate the essential roles for PPP2R3C in mouse and human development. Germline homozygous variants in human PPP2R3C are associated with distinctive syndromic GD of varying severity in both 46,XY and 46,XX individuals.

Open access

Irina Bacila, Nicole Freeman, Eleni Daniel, Marija Sandrk, Jillian Bryce, Salma Rashid Ali, Zehra Yavas Abali, Navoda Atapattu, Tania A Bachega, Antonio Balsamo, Niels Birkebæk, Oliver Blankenstein, Walter Bonfig, Martine Cools, Eduardo Correa Costa, Feyza Darendeliler, Silvia Einaudi, Heba Hassan Elsedfy, Martijn Finken, Evelien Gevers, Hedi L Claahsen-van der Grinten, Tulay Guran, Ayla Güven, Sabine E Hannema, Claire E Higham, Violeta Iotova, Hetty J van der Kamp, Marta Korbonits, Ruth E Krone, Corina Lichiardopol, Andrea Luczay, Berenice Bilharinho Mendonca, Tatjana Milenkovic, Mirela C Miranda, Klaus Mohnike, Uta Neumann, Rita Ortolano, Sukran Poyrazoglu, Ajay Thankamony, Jeremy W Tomlinson, Ana Vieites, Liat de Vries, S Faisal Ahmed, Richard J Ross, and Nils P Krone

Objective

Despite published guidelines no unified approach to hormone replacement in congenital adrenal hyperplasia (CAH) exists. We aimed to explore geographical and temporal variations in the treatment with glucocorticoids and mineralocorticoids in CAH.

Design

This retrospective multi-center study, including 31 centers (16 countries), analyzed data from the International-CAH Registry.

Methods

Data were collected from 461 patients aged 0–18 years with classic 21-hydroxylase deficiency (54.9% females) under follow-up between 1982 and 2018. Type, dose and timing of glucocorticoid and mineralocorticoid replacement were analyzed from 4174 patient visits.

Results

The most frequently used glucocorticoid was hydrocortisone (87.6%). Overall, there were significant differences between age groups with regards to daily hydrocortisone-equivalent dose for body surface, with the lowest dose (median with interquartile range) of 12.0 (10.0–14.5) mg/m2/day at age 1–8 years and the highest dose of 14.0 (11.6–17.4) mg/m2/day at age 12–18 years. Glucocorticoid doses decreased after 2010 in patients 0–8 years (P < 0.001) and remained unchanged in patients aged 8–18 years. Fludrocortisone was used in 92% of patients, with relative doses decreasing with age. A wide variation was observed among countries with regards to all aspects of steroid hormone replacement.

Conclusions

Data from the I-CAH Registry suggests international variations in hormone replacement therapy, with a tendency to treatment with high doses in children.

Open access

Angela K Lucas-Herald, Jillian Bryce, Andreas Kyriakou, Marie Lindhardt Ljubicic, Wiebke Arlt, Laura Audi, Antonio Balsamo, Federico Baronio, Silvano Bertelloni, Markus Bettendorf, Antonia Brooke, Hedi L Claahsen van der Grinten, Justin H Davies, Gloria Hermann, Liat de Vries, Ieuan A Hughes, Rieko Tadokoro-Cuccaro, Feyza Darendeliler, Sukran Poyrazoglu, Mona Ellaithi, Olcay Evliyaoglu, Simone Fica, Lavinia Nedelea, Aneta Gawlik, Evgenia Globa, Nataliya Zelinska, Tulay Guran, Ayla Güven, Sabine E Hannema, Olaf Hiort, Paul-Martin Holterhus, Violeta Iotova, Vilhelm Mladenov, Vandana Jain, Rajni Sharma, Farida Jennane, Colin Johnston, Gil Guerra Junior, Daniel Konrad, Odile Gaisl, Nils Krone, Ruth Krone, Katherine Lachlan, Dejun Li, Corina Lichiardopol, Lidka Lisa, Renata Markosyan, Inas Mazen, Klaus Mohnike, Marek Niedziela, Anna Nordenstrom, Rodolfo Rey, Mars Skaeil, Lloyd J W Tack, Jeremy Tomlinson, Naomi Weintrob, Martine Cools, and S Faisal Ahmed

Objectives

To determine trends in clinical practice for individuals with DSD requiring gonadectomy.

Design

Retrospective cohort study.

Methods

Information regarding age at gonadectomy according to diagnosis; reported sex; time of presentation to specialist centre; and location of centre from cases reported to the International DSD Registry and who were over 16 years old in January 2019.

Results

Data regarding gonadectomy were available in 668 (88%) individuals from 44 centres. Of these, 248 (37%) (median age (range) 24 (17, 75) years) were male and 420 (63%) (median age (range) 26 (16, 86) years) were female. Gonadectomy was reported from 36 centres in 351/668 cases (53%). Females were more likely to undergo gonadectomy (n = 311, P < 0.0001). The indication for gonadectomy was reported in 268 (76%). The most common indication was mitigation of tumour risk in 172 (64%). Variations in the practice of gonadectomy were observed; of the 351 cases from 36 centres, 17 (5%) at 9 centres had undergone gonadectomy before their first presentation to the specialist centre. Median age at gonadectomy of cases from high-income countries and low-/middle-income countries (LMIC) was 13.0 years (0.1, 68) years and 16.5 years (1, 28), respectively (P < 0.0001) with the likelihood of long-term retention of gonads being higher in LMIC countries.

Conclusions

The likelihood of gonadectomy depends on the underlying diagnosis, sex of rearing and the geographical setting. Clinical benchmarks, which can be studied across all forms of DSD will allow a better understanding of the variation in the practice of gonadectomy.