Person: HALİLOĞLU, BELMA
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HALİLOĞLU
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BELMA
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Publication Open Access GCK gene mutations are a common cause of childhood-onset MODY (maturity-onset diabetes of the young) in Turkey(WILEY-BLACKWELL, 2016-09) BEREKET, ABDULLAH; Haliloglu, Belma; Hysenaj, Gerald; Atay, Zeynep; Guran, Tulay; Abali, Saygin; Turan, Serap; Bereket, Abdullah; Ellard, SianObjectiveInactivating heterozygous mutations in the GCK gene are a common cause of MODY and result in mild fasting hyperglycaemia, which does not require treatment. We aimed to identify the frequency, clinical and molecular features of GCK mutations in a Turkish paediatric cohort. Design and PatientsFifty-four unrelated probands were selected based on the following criteria: age of diagnosis 17years, family history of diabetes in at least two generations, anti-GAD/ICA negative, BMI<95.p and follow-up with diet, oral antidiabetic drug or low-dose insulin treatment (05U/kg/d). A MODY probability score () was calculated and 21 patients with a score 75%, HbA1c levels 75% (585mmol/mol) and fasting blood glucose (FBG) levels 99-145mg/dl (55-80mmol/l) were selected for Sanger sequencing of the GCK gene. Targeted next-generation sequencing for all known monogenic diabetes genes was undertaken for any patient without a GCK gene mutation. ResultsGCK gene mutations (pathogenic or likely pathogenic variants) and a novel intronic variant of uncertain significance (c.208+3A>T) were identified in 13/54 probands (24%). Twelve of these patients had a MODY probability score 75%. FBG level and 2-h glucose level in OGTT were 12314mg/dl (68 +/- 07mmol/l) (107-157mg/dl) and 181 +/- 30mg/dl (101 +/- 16mmol/l) (136-247mg/dl), respectively. Average of glucose increment in OGTT was 58 +/- 27mg/dl (32 +/- 15mmol/l) (19-120mg/dl), and mean HbA1c level was 65 +/- 05% (475 +/- 55mmol/mol) (59-76%). Five novel missense mutations were identified (p.F123S, p.L58P, p.G246A, p.F419C, and p.S151C). Two patients treated with low-dose insulin before the molecular analysis were able to stop treatment. ConclusionsApproximately 1 in 4 MODY cases in this Turkish paediatric cohort have a GCK mutation. Selection of patients for GCK gene analysis using the MODY probability score was an effective way of identifying most (11/12) patients with a GCK mutation.Publication Open Access Risk factors for mortality caused by hypothalamic obesity in children with hypothalamic tumours(WILEY-BLACKWELL, 2016-10) BEREKET, ABDULLAH; Haliloglu, B.; Atay, Z.; Guran, T.; Abali, S.; Bas, S.; Turan, S.; Bereket, A.BackgroundHypothalamic obesity (HyOb) is a common complication of childhood hypothalamic tumours. Patients with HyOb probably have a higher mortality rate than those with other types of obesity due in many cases to obstructive sleep apnoea/hypoventilation. ObjectivesTo identify predictive factors for mortality caused by HyOb in children. MethodsTwenty children with HyOb secondary to hypothalamic tumours that were followed-up for 3 years and aged <15 years at diagnosis, and received supraphysiological glucocorticoid treatment for 1 month. ResultsMean age at diagnosis was 6.363.60 years. Mean body mass index (BMI) Standard deviation of the samples (SDS) increased from 0.77 +/- 1.26 to 2.66 +/- 1.45 during the first 6 months, but slowed from month 6-12 (2.73 +/- 1.35). BMI SDS at 0-6 months was significantly higher in patients aged <6 years at diagnosis than in those aged >6 years at diagnosis (3.71 +/- 1.96 vs. 0.83 +/- 0.73, P<0.001). Maximum BMI SDS was also significantly higher in the younger group (3.88 +/- 1.39 vs. 2.79 +/- 0.64, P<0.05). In all, four patients died and the mortality rate was significantly higher in the patients with a further increase in BMI SDS>1 SDS after 6 months of therapy (RR: 8.4, P<0.05). Both overall mortality and obesity-related mortality rates were higher in the patients aged <6 years at diagnosis (4.5-fold, 7.2-fold higher, respectively, P>0.05). The mortality rate was also 3.7-fold higher in the patients with a maximum BMI SDS3 at any time during the first 3 years after therapy(P>0.05). ConclusionsAn increase in BMI SDS after 6 months of therapy was observed to be a risk factor for mortality caused by HyOb. In addition, age <6 years at diagnosis and a maximum BMI SDS3 were associated with a higher mortality rate, indicating that earlier and more aggressive treatment of obesity is required.Publication Open Access An Atypical Case of Familial Glucocorticoid Deficiency without Pigmentation Caused by Coexistent Homozygous Mutations in MC2R (T152K) and MC1R (R160W)(ENDOCRINE SOC, 2012-05-01) BEREKET, ABDULLAH; Turan, Serap; Hughes, Claire; Atay, Zeynep; Guran, Tulay; Haliloglu, Belma; Clark, Adrian J. L.; Bereket, Abdullah; Metherell, Louise A.Context: Familial glucocorticoid deficiency (FGD) is a rare autosomal recessive disorder characterized by isolated cortisol deficiency. Mutations in the gene encoding the ACTH receptor (MC2R) account for 25% of cases. One significant feature is generalized skin hyperpigmentation, which is thought to be due to elevated ACTH acting on the melanocortin 1 receptor (MC1R). Objective: The aim of the study was to determine the cause of a nonhyperpigmented case of FGD. Patients: The patient presented at 4 yr of age with hypoglycemia after prolonged fasting during a respiratory tract infection. She had further hypoglycemic attacks and was diagnosed with isolated glucocorticoid deficiency at 6 yr of age. Her parents were consanguineous, and she had two unaffected sisters. Her physical examination was normal, except that her height and weight were greater than the 97th centile for a sex-and age-matched reference population. Interestingly, she had no hyperpigmentation despite very high ACTH levels. Results: Nucleotide sequence analysis revealed homozygous mutations c.478C>T in MC1R and c.455C>A in MC2R leading to R160W and T152K changes in the amino acid sequences, respectively. The R160W MC1R change has previously been implicated in a red hair/pale skin phenotype, and MC2R-T152K is trafficking defective. Both parents and two unaffected sisters were heterozygous for the MC1R mutation; additionally, one unaffected sister was heterozygous for the MC2R mutation, and the other was wild-type. Conclusion: We report an unusual case of FGD without hyperpigmentation due to coexistent MC1R/MC2R mutations. This case is important because it demonstrates for the first time that the assumption that the action of ACTH on MC1R causes skin hyperpigmentation is correct. (J Clin Endocrinol Metab 97: E771-E774, 2012)Publication Open Access Cathepsin K analysis in a pycnodysostosis cohort: demographic, genotypic and phenotypic features(BIOMED CENTRAL LTD, 2014-12) BEREKET, ABDULLAH; Arman, Ahmet; Bereket, Abdullah; Coker, Ajda; Kiper, Pelin Ozlem Simsek; Guran, Tulay; Ozkan, Behzat; Atay, Zeynep; Akcay, Teoman; Haliloglu, Belma; Boduroglu, Koray; Alanay, Yasemin; Turan, SerapBackground: To characterize cathepsin K (CTSK) mutations in a group of patients with pycnodysostosis, who presented with either short stature or atypical fractures to pediatric endocrinology or dysmorphic features to pediatric genetics clinics. Methods: Seven exons and exon/intron boundaries of CTSK gene for the children and their families were amplified with PCR and sequenced. Sixteen patients from 14 families with pycnodysostosis, presenting with typical dysmorphic features, short stature, frequent fractures and osteosclerosis, were included in the study. Results: We identified five missense mutations (M1I, I249T, L7P, D80Y and D169N), one nonsense mutation (R312X) and one 301 bp insertion in intron 7, which is revealed as Alu sequence; among them, only L7P and I249 were described previously. The mutations were homozygous in all cases, and the families mostly originated from the region where consanguineous marriage rate is the highest. Patients with M1I mutation had fractures, at younger ages than the other pycnodysostosis cases in our cohort which were most probably related to the severity of mutation, since M1I initiates the translation, and mutation might lead to the complete absence of the protein. The typical finding of pycnodysostosis, acroosteolysis, could not be detected in two patients, although other patients carrying the same mutations had acroosteolysis. Additionally, none of the previously described hot spot mutations were seen in our cohort; indeed, L7P and R312X were the most frequently detected mutations. Conclusions: We described a large cohort of pycnodysostosis patients with genetic and phenotypic features, and, first Alu sequence insertion in pycnodysostosis.Publication Open Access Clinical Characteristics and Long-term Follow-up of Patients with Diabetes Due To PTF1A Enhancer Mutations(2020-12-01) BEREKET, ABDULLAH; Demirbilek, Huseyin; Cayir, Atilla; Flanagan, Sarah E; Yıldırım, Ruken; Kor, Yılmaz; Gurbuz, Fatih; Haliloğlu, Belma; Yıldız, Melek; Baran, Rıza Taner; Akbas, Emine Demet; Demiral, Meliha; Ünal, Edip; Arslan, Gulcin; Vuralli, Dogus; Buyukyilmaz, Gonul; Al-Khawaga, Sara; Saeed, Amira; Al Maadheed, Maryam; Khalifa, Amel; Onal, Hasan; Yuksel, Bilgin; Ozbek, Mehmet Nuri; Bereket, Abdullah; Hattersley, Andrew T; Hussain, Khalid; De Franco, ElisaAbstract Context Biallelic mutations in the PTF1A enhancer are the commonest cause of isolated pancreatic agenesis. These patients do not have severe neurological features associated with loss-of-function PTF1A mutations. Their clinical phenotype and disease progression have not been well characterized. Objective To evaluate phenotype and genotype characteristics and long-term follow-up of patients with PTF1A enhancer mutations. Setting Twelve tertiary pediatric endocrine referral centers. Patients Thirty patients with diabetes caused by PTF1A enhancer mutations. Median follow-up duration was 4 years. Main Outcome Measures Presenting and follow-up clinical (birthweight, gestational age, symptoms, auxology) and biochemical (pancreatic endocrine and exocrine functions, liver function, glycated hemoglobin) characteristics, pancreas imaging, and genetic analysis. Results Five different homozygous mutations affecting conserved nucleotides in the PTF1A distal enhancer were identified. The commonest was the Chr10:g.23508437A>G mutation (n = 18). Two patients were homozygous for the novel Chr10:g.23508336A>G mutation. Birthweight was often low (median SDS = –3.4). The majority of patients presented with diabetes soon after birth (median age of diagnosis: 5 days). Only 2/30 presented after 6 months of age. All patients had exocrine pancreatic insufficiency. Five had developmental delay (4 mild) on long-term follow-up. Previously undescribed common features in our cohort were transiently elevated ferritin level (n = 12/12 tested), anemia (19/25), and cholestasis (14/24). Postnatal growth was impaired (median height SDS: –2.35, median BMI SDS: –0.52 SDS) with 20/29 (69%) cases having growth retardation. Conclusion We report the largest series of patients with diabetes caused by PTF1A enhancer mutations. Our results expand the disease phenotype, identifying recurrent extrapancreatic features which likely reflect long-term intestinal malabsorption.Publication Open Access The Distribution of Different Types of Diabetes in Childhood: A Single Center Experience(GALENOS YAYINCILIK, 2018-05-18) BEREKET, ABDULLAH; Haliloglu, Belma; Abali, Saygin; Bugrul, Fuat; Celik, Enes; Bas, Serpil; Atay, Zeynep; Guran, Tulay; 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.Publication Open Access Evidence of hormone resistance in a pseudo-pseudohypoparathyroidism patient with a novel paternal mutation in GNAS(ELSEVIER SCIENCE INC, 2015-02) BEREKET, ABDULLAH; Turan, Serap; Thiele, Susanne; Tafaj, Olta; Brix, Bettina; Atay, Zeynep; Abali, Saygin; Haliloglu, Belma; Bereket, Abdullah; Bastepe, MuratContext: Loss-of-function GNAS mutations lead to hormone resistance and Albright's hereditary osteodystrophy (AHO) when maternally inherited, i.e. pseudohypoparathyroidism-Ia (PHPIa), but cause AHO alone when located on the paternal allele, i.e. pseudoPHP (PPHP). Objective: We aimed to establish the molecular diagnosis in a patient with AHO and evidence of hormone resistance. Case: The patient is a female who presented at the age of 13.5 years with short stature and multiple AHO features. No evidence for TSH or gonadotropin-resistance was present. Serum calcium and vitamin D levels were normal. However, serum PTH was elevated on multiple occasions (64-178 pg/mL, normal: 9-52) and growth hormone response to clonidine or L-DOPA was blunted, suggesting hormone resistance and PHP-Ia. The patient had diminished erythrocyte Gm activity and a novel heterozygous GNAS mutation (c.328 G>C; p.A109P). The mother lacked the mutation, and the father's DNA was not available. Hence, a diagnosis of PPHP also appeared possible, supported by low birth weight and a lack of AHO features associated predominantly with PHP-Ia, i.e. obesity and cognitive impairment. To determine the parental origin of the mutation, we amplified the paternally expressed A/B and biallelically expressed Gs alpha transcripts from the patient's peripheral blood RNA. While both wild-type and mutant nucleotides were detected in the Gs alpha amplicon, only the mutant nucleotide was present in the A/B amplicon, indicating that the mutation was paternal. Conclusion: These findings suggest that PTH and other hormone resistance may not be an exclusive feature of PHP-Ia and could also be observed in patients with PPHP. (C) 2014 Elsevier Inc. All rights reserved.