Browsing by Author "Özbek, Mehmet Nuri"

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Clinical characteristics of patients presented with primary adrenal insufficiency due to a p.R451W mutation in the CYP11A1 gene
(Karger, 2023) Çayır, Atilla; Demirbilek, Hüseyin; Özbek, Mehmet Nuri; Kurt, İlknur; Karaoğlan, Murat; Albayrak, Serpil; Dündar, Bumin Nuri; Güran, Tülay
Background and objective: The first and rate-limiting step of steroidogenesis is the conversion of cholesterol to pregnanolone which is catalyzed by the P450scc side chain cleavage enzyme (encoded by CYP11A1 gene-SCC). Homozygous recessive mutations of the CYP11A1 gene cause a global steroid hormone deficiency thereby disorders of sexual development in 46, XY individuals with a variable phenotype depending on the mutation characteristics. About 60 cases of SCC deficiency due to CYP11A1 gene mutation have been reported so far. The most common mutation is the c.1351C>T (p.R451W) mutation, which has been detected in 12 cases. We, herein, present the clinical characteristics of 14 cases presented with adrenal insufficiency due to p.R451W mutation in the CYP 11A1 gene. Design and method: Data were retrospectively collected from tertiary pediatric endocrine centers using a standardized proforma. Family history, presenting age, clinical, biochemical, and hormonal characteristics, treatment options, and the follow-up characteristics obtained during their latest follow-up visits were recorded. Results: 14 patients (M/F:7/7) from 10 consanguineous Turkish families were recruited. The mean age of the diagnosis was 3.8±2.4(Range: 1.04-8.5 years). All of the male subjects were completely virilized with no sign of DSD. The main presenting complaints were signs and symptoms of primary adrenal insufficiency. However, despite having signs and symptoms 3 subjects were diagnosed when investigated due to the history of their affected siblings. While glucocorticoid deficiency (elevated ACTH, low cortisol) was present in all cases, none of the male cases had undervirilization excluding androgen deficiency. Mild mineralocorticoid (MC) deficiency was detected in 10/14 of the cases which were recovered in 2 subjects during follow-up. More strikingly, one patient with no MC deficiency at presentation had developed a salt-wasting adrenal crisis during acute illness. Although a deterioration was detected in height SDS, there was not a statistically significant difference between height SDS at presentation (-0.64±1.4), at the latest follow-up visit(-0.90±1.4), and target height SDS (-0.63±0.6). Conclusion: In the present largest case series with a p.R451W mutation in the CYP11A1 gene our results confirmed a milder phenotype for all steroid hormones. Particularly lack of virilization defect in male subjects, and lack of salt-wasting crisis until a relatively late age of diagnosis suggested mild MC and androgen deficiency. Nevertheless, lack of MC deficiency at presentation does not exclude the risk of developing a salt-wasting adrenal crisis. Therefore special caution requires for patients with no MC replacement, particularly during acute illnesses.
Clinical features of generalized lipodystrophy in Turkey: a cohort analysis
(Wiley Online Library, 2023) Özbek, Mehmet Nuri; Yildirim Simsir, Ilgin; Tuysuz, Beyhan; Tanrikulu, Seher; Celik Guler, Merve; Akinci, Baris
Aim: To describe the Turkish generalized lipodystrophy (GL) cohort with the frequency of each complication and the death rate during the period of the follow-up. Methods: This study reports on 72 patients with GL (47 families) registered at different centres in Turkey that cover all regions of the country. The mean ± SD follow-up was 86 ± 78 months. Results: The Kaplan-Meier estimate of the median time to diagnosis of diabetes and/or prediabetes was 16 years. Hyperglycaemia was not controlled in 37 of 45 patients (82.2%) with diabetes. Hypertriglyceridaemia developed in 65 patients (90.3%). The Kaplan-Meier estimate of the median time to diagnosis of hypertriglyceridaemia was 14 years. Hypertriglyceridaemia was severe (≥ 500 mg/dl) in 38 patients (52.8%). Seven (9.7%) patients suffered from pancreatitis. The Kaplan-Meier estimate of the median time to diagnosis of hepatic steatosis was 15 years. Liver disease progressed to cirrhosis in nine patients (12.5%). Liver disease was more severe in congenital lipodystrophy type 2 (CGL2). Proteinuric chronic kidney disease (CKD) developed in 32 patients (44.4%) and cardiac disease in 23 patients (31.9%). Kaplan-Meier estimates of the median time to diagnosis of CKD and cardiac disease were 25 and 45 years, respectively. Females appeared to have a more severe metabolic disease, with an earlier onset of metabolic abnormalities. Ten patients died during the follow-up period. Causes of death were end-stage renal disease, sepsis (because of recurrent intestinal perforations, coronavirus disease, diabetic foot infection and following coronary artery bypass graft surgery), myocardial infarction, heart failure because of dilated cardiomyopathy, stroke, liver complications and angiosarcoma. Conclusions: Standard treatment approaches have only a limited impact and do not prevent the development of severe metabolic abnormalities and early onset of organ complications in GL.
Early puberty paradox: an investigation of anxiety levels of mothers and children, children's quality of life, and psychiatric diagnoses
(SpringerLink, 2023) Kardaş, Burcu; Kardaş, Ömer; Demiral, Meliha; Özbek, Mehmet Nuri
Early puberty signs lead to an increase in anxiety levels of parents and children. The aim of this study was to investigate the quality of life and anxiety levels of girls and their mothers who were admitted to a pediatric endocrinology clinic with concerns about early puberty. Girls and their mothers who were admitted to endocrinology outpatient clinic with concerns about early puberty were compared to healthy control group. Screen for Child Anxiety Related Emotional Disorders (SCARED) parent form, Quality of Life for Children Scale (PedsQL) parent form, and Beck Anxiety Inventory (BAI) were administered to the mothers. Children were evaluated with the Schedule for Afective Disorders and Schizophrenia for School-Age Children (Kiddie-SADS Lifetime Version) (K-SADS-PL). The study sample consisted of 92 girls and 62 of them were administered to clinic with concerns about early puberty. There were 30 girls in early puberty group (group 1), 32 girls were in the normal development group (group 2), and 30 were in the healthy control group (group 3). The anxiety level of group 1 and group 2 was signifcantly higher, and their quality of life was signifcantly lower when compared to group 3 (p<0.001). Mother’s anxiety level was found signifcantly higher in group 2 (p<0.001). It has shown that anxiety level and quality of life of children were associated with anxiety level of mothers and the current Tanner stage (r=0.302, p<0.005). Conclusion: Mothers and children who have concerns about early puberty are negatively afected when early puberty is a possibility. For this reason, educating parents will prevent negative impacts of this situation on children. At the same time, it will decrease health burden.
Evaluation and management of neonatal onset hyperinsulinemic hypoglycemia: a single neonatal center experience
(Taylor & Francis, 2023) Bezirganoğlu, Handan; Okur, Nilifer; Feryal Taş, Funda; Çelik, Kıymet; Özbek, Mehmet Nuri
Objectives: To evaluate the clinical characteristics and treatment options of neonates requiring prolonged hospitalization due to persistent hyperinsulinemic hypoglycemia (HH). Methods: This retrospective cohort study included infants >34 weeks of gestation at birth who were born in our hospital between 2018 and 2021, diagnosed with HH, and required diazoxide within the first 28 days of life. The baseline clinical characteristics, age at the time of diagnosis and treatment options in diazoxide resistance cases were recorded. Genetic mutation analysis, if performed, was also included. Results: A total of 32 infants diagnosed with neonatal HH were followed up. Among the cohort, 25 infants were classified as having transient form of HH and seven infants were classified as having congenital hyperinsulinemic hypoglycemia (CHI). Thirty-one percent of the infants had no risk factors. The median birth weight was significantly higher in the CHI group, whereas no differences were found in other baseline characteristics. Patients diagnosed with CHI required higher glucose infusion rate, higher doses, and longer duration of diazoxide treatment than those in the transient HH group. Eight patients were resistant to diazoxide, and six of them required treatment with octreotide and finally sirolimus. Sirolimus prevented the need of pancreatectomy in five of six patients without causing major side effects. Homozygous mutations in the ABCC8 gene were found in four patients with CHI. Conclusions: The risk of persistent neonatal hyperinsulinism should be considered in hypoglycemic neonates particularly located in regions with high rates of consanguinity. Our study demonstrated sirolimus as an effective treatment option in avoiding pancreatectomy in severe cases.
Evaluation of patients diagnosed with congenital hypothyroidism by newborn screening between 2011-2019 in Diyarbakir, Turkey
(LWW, 2023) Toktaş, İzzettin; Erdem, Özgür; Sarıbaş, Seyfettin; Özbek, Mehmet Nuri
This study aimed to determine the incidence of congenital hypothyroidism in Turkey’s Diyarbakir Province and assess the development and growth conditions of people with congenital hypothyroidism. Patients born between 2011-2019 and diagnosed with congenital hypothyroidism within the scope of the newborn screening program were included. The medical records of these patients were retrospectively reviewed. The length and weight for age, weight for length, and body mass index standard deviation scores were calculated. We investigated the treatment status of the patients, whether their relatives had a similar disorder, and the presence of consanguinity between parents. Blood samples were collected from 380,592 newborns. As a result of further tests, 498 newborns were diagnosed with congenital hypothyroidism (incidence: 1/764). Demographic and anthropometric data of 241 patients were analyzed. The patients comprised 46.9% (n = 113) females and 53.1% (n = 128) males. It was determined that 44.4% of the individuals had transient congenital hypothyroidism and 53.6% had permanent congenital hypothyroidism. The parents of 29.8% of the individuals diagnosed with transient congenital hypothyroidism and 44.2% of the individuals diagnosed with permanent congenital hypothyroidism were consanguineous (P = .02). According to the latest anthropometric assessment, 6.8% of individuals diagnosed with congenital hypothyroidism had a weight z-score below −2 SD and 16.9% had a length z-score below −2 SD. The incidence of congenital hypothyroidism was higher in our region. The ratio of consanguinity between parents was higher in patients diagnosed with permanent congenital hypothyroidism than in those diagnosed with transient congenital hypothyroidism. According to the most recent follow-up, weight and age were found to be similar in patients with transient and permanent congenital hypothyroidism.
Evaluation of patients diagnosed with phenylketonuria and biotinidase deficiency by the newborn screening program: a ten-year retrospective study
(The Turkish Journal of Pediatrics, 2022) Toktaş, İzzettin; Sarıbaş, Seyfettin; Canpolat, Semih; Erdem, Özgür; Özbek, Mehmet Nuri
Background. Phenylketonuria (PKU) and biotinidase deficiency (BD) are autosomal recessive diseases. If they are not identified and treated early, severe intellectual disability and developmental delay occur. This study was conducted to calculate the ten-year incidence of PKU and BD in the Diyarbakır province of Turkey. Methods. This cross-sectional study included patients born between 2011-2020 and diagnosed with PKU and BD. Patients with a clear diagnosis had their records evaluated retrospectively. Results. Between 2011 and 2020, blood was taken from 417,525 newborns’ heels in Diyarbakir province. As a result of further diagnostic testing, 53 PKU (Incidence: 1:7878) and 177 BD (Incidence: 1:2359) were detected. Of the patients with BD, 56% had profound BD and 44% had partial BD. The records of a total of 269 patients (PKU: 25; BD: 123; Hyperphenylalaninemia: 121) were examined. Parents of 65% (n=15) of the patients diagnosed with PKU and 46.6% (n=55) of the patients diagnosed with BD were consanguineous. Conclusions. The incidence of both PKU and BD was found to be high in our region. The high number of consanguineous marriages was regarded as the most important explanation for the high frequency of these illnesses.
Glutaric aciduria and L-2-hydroxyglutaric aciduria: Clinical and molecular findings of 35 patients from Turkey
(ScienceDirect, 2023) Özbek, Mehmet Nuri; Ergül Bozaci, Ayse; Er, Esra; Ünal, Aysel Tekmenuray; Tas, Ibrahim; Ayaz, Ercan; Durmaz, Asude; Aykut , Ayçe; Kose, Melis
Background: Cerebral organic acid disorders are progressive neurometabolic diseases characterized by neurologic dysfunction. Glutaric aciduria type I (GA-I) and L-2-hydroxyglutaric aciduria (L2HGA) are the main cerebral organic acid disorders. They are both classified as, and it is suggested that these two disorders may share a common metabolic pathway. Current treatment strategies are based on levocarnitine, vitamin B2, and diet. Recent guidelines recommend a lysine-restricted diet up to six years of age, but there is no consensus for patients over the age of six. Vitamin B2 is exists in the blood as riboflavin and its cofactors, flavin mononucleotide and flavin adenine dinucleotide (FAD). FAD, the cofactor of L2HGD, accelerates the conversion of L-2-hydoxy glutarate to alpha-ketoglutarate. Levocarnitine stimulates the formation and excretion of derivatives of glutaric acid. Also, lysine-associated organic acidurias some results provide principal proof for the beneficial effects of riboflavin in GA-I. It has been previously reported that combination therapy with riboflavin and levocarnitine is effective for L2HGA as well as GA-I. Riboflavin and levocarnitine have been reported to improve not only clinical symptoms but also urinary 2-HGA levels. In our study, we aimed to evaluate the effect of the current treatment strategies and genotype on urinary metabolites and IQ scores in GA-I and L2HGA patients. Methods: The presented retrospective multicenter study included patients followed up in Diyarbakir Children's Hospital and Izmir Katip Celebi University Faculty of Medicine, Division of Pediatric Metabolism. Between 2016 and 2021, we retrospectively evaluated 35 patients with confirmed diagnosis of GA-I and L-2HGA. We analyzed the clinical, biochemical, neuroradiological, molecular data and treatment of the patients. The follow-up period was every 2 months until 12 months old, every 3 months until 6 years of age, and every 6 months thereafter. Therapy monitoring was undertaken during follow-up visits that included evaluation of clinical parameters, laboratory parameters, and dietary consumption records. Denver II was applied in order to evaluate children aged 0–6 years in terms of development. Patients between 6 and 16 years of age were evaluated using the Wechsler Intelligence Scale for Children-Revised. Results: We identified 25 with GA-I and 10 with L2HGA. The most common clinical symptoms were developmental delay, intellectual disability, and movement disorders. Behavioural problems were more common in L2HGA than in GA-I patients. In the same family, there were patients with severe developmental delay despite early diagnosis and treatment and individuals with normal IQ scores. In our study group, we used diet (lysine restricted or protein controlled), levocarnitine and vitamin B2 for GA-I patients. The mean urinary glutaric acid levels were decreased with treatment in GA-I patients. Group I consisted of 14/25 patients receiving lysine restricted diet and levocarnitine, Group II (8/25) received protein-controlled diet and levocarnitine. Group III (3/25) patients whom had p.Pro248Leu (P248L) variant, received riboflavin in combination with protein-controlled diet and levocarnitine. When we evaluated according to the treatment groups, a significant decrease was observed in urinary glutaric acid levels in group I. But there were no significant difference in Group II and III. The patients with c.1018C > T variant in GCDH gene had higher pre-treatment urinary metabolites and significant reduction in urinary metabolites with treatment was detected. In L2HGA patients, we used levocarnitine and vitamin B2. In all L2HGA patients, there was a significant decrease in the mean urinary 2- hydoxy glutarate with treatment. However, there was no significant difference between the c.164G > A and c.1115delT variants. The mean pre- and post-treatment IQ scores of GA-I patients, no significant difference was observed. Relative neurologic improvement was seen in three L2HGA patients. We found two novel variants, including the c.221A > G (p.Tyr74Cys) in the GCDH gene and the c.738 + 5A > G splice variant in the L2HGDH gene. Conclusions: Glutaric aciduria type I and L2HGA are the most common cerebral organic acidurias. Early and correct diagnosis is crucial. Poor prognosis based on metabolic crises and progressive deterioration still appears. In countries where newborn screening is not performed, a clinical suspicion index is required for cerebral organic aciduria. GA-I and L-2HGA are difficult to examine by medical evidence standards because of the small sample size, regional differences in newborn screening, and medical care limits. More clinical studies are needed to identify effective treatments. However, the significant decrease in urinary glutaric acid levels after treatment in patients on lysine-restricted diet raises the question of whether lysine-restricted diet should be continued after six years of age. We also reported our experience in order to contribute to the literature.
Hyperinsulinemic Hypoglycemia in Childhood
(2023) Özbek, Mehmet Nuri; Orhan, Özhan
ABSTRACT Hyperinsulinemic Hypoglycemia (HH) is the most common cause of permanent hypoglycemia, especially in the neonatal period. Childhood HH is mostly related to genes encoding proteins in the insulin secretion pathways, and may also be seen in syndromes such as Beckwidth Wiedemann, Kabuki, and Turner. The majority of congenital HH cases are the result of KATP channel gene defect. Most of these cases are unresponsive to diazoxide treatment. In this review, recent genetic studies and recent updates in treatment options in childhood HH are reviewed.
Investigation of the effect of comorbid psychopathologies on glycemic control in children and adolescents with type 1 diabetes mellitus
(Turkish J Clinical Psychiatry, 2022) Kardaş, Burcu; Kardaş, Ömer; Demiral, Meliha; Özbek, Mehmet Nuri
Objective: The presence of comorbid psychiatric conditions in chronic diseases makes the management of the disease difficult. Our study, we aimed to examine the relationship between psychiatric comorbid conditions and glycemic control in children and adolescents with Type 1 Diabetes. Method: In our study, depending on the number of patients, good and moderate controls were evaluated as a single group, and HbA1c levels of 8.5 and below were included in this group. Children for Depression Inventory (CDI), Screen for Child Anxiety-Related Emotional Disorders (SCARED), Turgay Child and Adolescent Behavioral Disorders Based on DSM-IV Screening and Evaluation Scale were applied. The case and parents were evaluated with K-SADS-PL.Among 778 diabetic patients who were followed up in the pediatric endocrinology clinic, 73 cases between the ages of 8 and 17 who were followed up regularly, who did not have any comorbidities and who accepted to participate in the study were evaluated psychiatrically. Results: Of the 73 cases included in the study, 29 were accepted as the patients with good glycemic control (HbA1c <= 8.5 mg / dl), and 44 as with poor glycemic control (HbA1c>8.5mg / dl). In cases with poor glycemic control, parents' education level and income level were significantly lower, while the rate of attention deficit and hyperactivity disorder, major depressive disorder, social anxiety disorder and psychopathology was significantly higher. Discussion: The findings of this study revealed that there are many factors affecting glycemic control and there is a strong relationship between glycemic control and psychopathologies.
MOLECULAR DIAGNOSIS IN PATIENTS WITH MONOGENIC DIABETES MELLITUS, AND DETECTION OF A NOVEL CANDIDATE GENE
(Elsevier, 2023) Gökşen, Damla; Evin, Ferda; Işık, Esra; Özen, Samim; Atık, Tahir; Özkınay, Ferda; Akcan, Neşe; Özkan, Behzat; Büyükinan, Muammer; Özbek, Mehmet Nuri; Darcan, Şükran; Onay, Hüseyin
Aim: We aimed to investigate molecular genetic basis of monogenic diabetes (DM) and novel responsible candidate genes with targeted Next Generation Sequencing (NGS) and Whole Exome Sequencing (WES). Methods: A hundred cases presenting with clinical findings and a family history of monogenic DM were included in the study. Molecular analysis was performed using an NGS panel including 14 genes. Following targeted NGS, WES was planned in cases in whom no variant was detected. Results: Thirty different disease-causing variants in seven different genes were detected in thirty-five (35%) cases with targeted NGS approach. Most common pathogenic variant was found in GCK gene in 25 (25%) cases. Four different variants were detected in 4 (4%) patients in ABCC8 gene. In 45 of 65 cases; WES analyses were done. A heterozygous c.2635C>T(p.Gln879Ter) variant was detected in IFIH1 gene in a patient with incidental hyperglycemia. In the segregation analysis affected mother was shown to be heterozygous for the same variant. Conclusion: Molecular etiology was determined in 35% cases with the NGS targeted panel. Seventeen novel variants in monogenic DM genes have been identified. A candidate gene determined by WES analysis in a case that could not be diagnosed with NGS panel in this study.