Browsing by Author "Demirbilek, Huseyin"

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Clinical Characteristics and Phenotype-Genotype Analysis in Turkish Patients With Congenital Hyperinsulinism; Predominance of Recessive Katp Channel Mutations
(Bioscientifica Ltd, 2014) Demirbilek, Huseyin; Arya, Ved Bhushan; Ozbek, Mehmet Nuri; Akinci, Aysehan; Dogan, Murat; Demirel, Fatma; Hussain, Khalid
Objective: Congenital hyperinsulinism (CHI) is the commonest cause of hyperinsulinaemic hypoglycaemia in the neonatal, infancy and childhood periods. Its clinical presentation, histology and underlying molecular biology are extremely heterogeneous. The aim of this study was to describe the clinical characteristics, analyse the genotype phenotype correlations and describe the treatment outcome of Turkish CHI patients. Design and methods: A total of 35 patients with CHI were retrospectively recruited from four large paediatric endocrine centres in Turkey. Detailed clinical, biochemical and genotype information was collected. Results: Diazoxide unresponsiveness was observed in nearly half of the patients (n= 17; 48.5%). Among diazoxide-unresponsive patients, mutations in ABCC8/KCNJ11 were identified in 16 (94%) patients. Among diazoxide-responsive patients (n=18), mutations were identified in two patients (11%). Genotype phenotype correlation revealed that mutations in ABCC8/KCNJ11 were associated with an increased birth weight and early age of presentation. Five patients had p.L1171fs (c.3512de1) ABCC8 mutations, suggestive of a founder effect. The rate of detection of a pathogenic mutation was higher in consanguineous families compared with non-consanguineous families (87.5 vs 21%; P<0.0001). Among the diazoxide-unresponsive group, ten patients were medically managed with octreotide therapy and carbohydraterich feeds and six patients underwent subtotal pancreatectomy. There was a high incidence of developmental delay and cerebral palsy among diazoxide-unresponsive patients. Conclusions: This is the largest study to report genotype phenotype correlations among Turkish patients with CHI. Mutations in ABCC8 and KCNJ11 are the commonest causes of CHI in Turkish patients (48.6%). There is a higher likelihood of genetic diagnosis in patients with early age of presentation, higher birth weight and from consanguineous pedigrees.
Clinical Characteristics, Molecular Genetics Analysis Results and Long-Term Follow-Up of a Large Cohort of Congenital Hyperinsulinism From Turkey: a Nationwide Cross-Sectional Study
(Karger, 2023) Demirbilek, Huseyin; Ozbek, M. Nuri; Yildiz, Melek; Houghton, Jayne L. A.; Onal, Hasan; Gurbuz, Fatih; Flanagan, Sarah E.
Normosmic Idiopathic Hypogonadotropic Hypogonadism Due To a Novel Homozygous Nonsense C.c969a (P.y323x) Mutation in the Kiss1r Gene in Three Unrelated Families
(Wiley, 2015) Demirbilek, Huseyin; Ozbek, M. Nuri; Demir, Korcan; Kotan, L. Damla; Cesur, Yasar; Dogan, Murat; Topaloglu, A. Kemal
ObjectiveThe spectrum of genetic alterations in cases of hypogonadotropic hypogonadism continue to expand. However, KISS1R mutations remain rare. The aim of this study was to understand the molecular basis of normosmic idiopathic hypogonadotropic hypogonadism. MethodsClinical characteristics, hormonal studies and genetic analyses of seven cases with idiopathic normosmic hypogonadotropic hypogonadism (nIHH) from three unrelated consanguineous families are presented. ResultsOne male presented with absence of pubertal onset and required surgery for severe penoscrotal hypospadias and cryptorchidism, while other two males had absence of pubertal onset. Two of four female cases required replacement therapy for pubertal onset and maintenance, whereas the other two had spontaneous pubertal onset but incomplete maturation. In sequence analysis, we identified a novel homozygous nonsense (p.Y323X) mutation (c.C969A) in the last exon of the KISS1R gene in all clinically affected cases. ConclusionsWe identified a homozygous nonsense mutation in the KISS1R gene in three unrelated families with nIHH, which enabled us to observe the phenotypic consequences of this rare condition. Escape from nonsense-mediated decay, and thus production of abnormal proteins, may account for the variable severity of the phenotype. Although KISS1R mutations are extremely rare and can cause a heterogeneous phenotype, analysis of the KISS1R gene should be a part of genetic analysis of patients with nIHH, to allow better understanding of phenotype-genotype relationship of KISS1R mutations and the underlying genetic basis of patients with nIHH.