Molecular genetic etiology by whole exome sequence analysis in cases with familial type 1 diabetes mellitus without HLA haplotype predisposition or incomplete predisposition.

OBJECTIVES: Familial transmission is observed in approximately 10% of cases with type 1 diabetes mellitus (T1DM). The most important gene determining susceptibility is the human leukocyte antigen complex (HLA) located on chromosome 6. More than 50 susceptible loci are associated with T1DM susceptibility have been identified in genes other than HLA. In this study, it was aimed to investigate the molecular genetic etiology by whole-exome sequence (WES) analysis in cases with familial T1DM with no or weakly detected HLA tissue type susceptibility. We aimed to identify new genes responsible for the development of type 1 diabetes and to reveal new genes that have not been shown in the literature before. METHODS: Cases with at least one T1DM diagnosis in first-degree relatives were included in the study. In the first step, HLA DQ2 and DQ8 loci, which are known to be associated with T1DM susceptibility, were investigated by. In the second step, the presence of variants that could explain the situation was investigated by WES analysis in patients who were negative for both HLA DQ2 and HLA DQ8 haplotypes, HLA DQ2 negative, HLA DQ8 positive, and HLA DQ2 positive and HLA DQ8 negative patients. RESULTS: The mean age and duration of diabetes of the 30 cases (Girl/Male: 17/13) were 14.9 ± 6 and 7.56 ± 3.84 years, respectively. There was consanguineous marriage in 5 (16%) of the families. As a result of filtering all exome sequence analysis data of two cases with DQ2 (DQB1*02) (-) and DQ8 (DQB1*03:02) (-), seven cases with DQ2 (DQB1*02) (+) and DQ8 (DQB1*03:02) (-), and one case with DQ2 (DQB1*02) (-) and DQ8 (DQB1*03:02) (+), seven different variants in seven different genes were detected in five cases. The pathogenicity of the detected variants were determined according to the "American College of Medical Genetics and Genomics (ACMG)" criteria. These seven variants detected were evaluated as high-score VUS (Variants of unknown/uncertain significance). In the segregation study conducted for the mutation in the POLG gene detected in case 5, this variant was detected in the mother of the case and his brother with T1DM. Segregation studies are ongoing for variants detected in other affected individuals in the family. CONCLUSIONS: In conclusion, in this study, seven different variants in seven different genes were detected in five patients by WES analysis in familial T1DM patients with no or weak HLA tissue type susceptibility. These seven variants detected were evaluated as high-score VUS. POLG might be a novel candidate gene responsible for susceptibility to T1DM. Non-HLA genes directly responsible for the development of T1DM were not detected in any of the cases.

Increased deficits in emotion recognition and regulation in children and adolescents with exogenous obesity.

OBJECTIVES: In this study we aimed to evaluate emotion recognition and emotion regulation skills of children with exogenous obesity between the ages of 11 and 18 years and compare them with healthy controls. METHODS: The Schedule for Affective Disorders and Schizophrenia for School Aged Children was used for psychiatric evaluations. Emotion recognition skills were evaluated using Faces Test and Reading the Mind in the Eyes Test. The Difficulties in Emotions Regulation Scale was used for evaluating skills of emotion regulation. RESULTS: Children with obesity had lower scores on Faces Test and Reading the Mind in the Eyes Test, and experienced greater difficulty in emotional regulation skills. CONCLUSIONS: Improved understanding of emotional recognition and emotion regulation in young people with obesity may improve their social adaptation and help in the treatment of their disorder. To the best of our knowledge, this is the first study to evaluate both emotional recognition and emotion regulation functions in obese children and obese adolescents between 11 and 18 years of age.

Neonatal Hyperglycemia, which threshold value, diagnostic approach and treatment?: Turkish Neonatal and Pediatric Endocrinology and Diabetes Societies consensus report.

Hyperglycemia has become an important risk factor for mortality and morbidity in the neonatal period, especially with increased survival rates of very low birth weight neonates. Hyperglycemia in the neonatal period develops as a result of various mechanisms including iatrogenic causes, inability to supress hepatic glucose production, insulin resistance or glucose intolerance, specifically in preterm neonates. Initiation of parenteral or enteral feeding in the early period in preterm babies increases insulin production and sensitivity. The plasma glucose is targeted to be kept between 70 and 150 mg/dL in the newborn baby. While a blood glucose value above 150 mg/dL is defined as hyperglycemia, blood glucose values measured with an interval of 4 hours of >180-200 mg/dL and +2 glucosuria require treatment. Although glucose infusion rate is reduced in treatment, use of insulin is recommended, if two blood glucose values measured with an interval of 4 hours are >250 mg/dL and glucosuria is present in two separate urine samples.

Management of Childhood Thyroid Nodules: Surgical and Endocrinological Findings in a Large Group of Cases.

OBJECTIVE: The management of childhood thyroid nodules is still a big challenge for clinicians. In this study, we aimed to present our surgical and endocrinological experience in more than one hundred pediatric cases. METHODS: A retrospective analysis of patients admitted with a thyroid nodule between 2006 and 2014 was performed. Detailed ultrasonography and fine-needle aspiration biopsy (FNAB) were the cornerstones of the diagnostic approach. RESULTS: One hundred-three children (72 female, 31 male) with a mean age of 13.1±3.6 years (3-18 years) were admitted to our center. Management strategy was surgery in 58 patients and follow-up in 45 patients. Mean nodule size was 17±12.7 mm (2-45 mm). The diagnoses were listed as benign solitary nodule (48 patients), thyroid carcinoma (26 patients), multinodular goiter (23 patients), Hashimoto thyroiditis (4 patients), and Graves' disease (2 patients). Surgical procedures were nodulectomy/lobectomy (32 patients), total thyroidectomy (TT) (13 patients), or TT+ neck dissection (13 patients). The rate of malignancy was 25% in the total group and 44% in the surgery group. The malignancy rate was higher in patients younger than 12 years compared to older children (41% vs. 17%, p=0.040). Metastasis was seen in 38% of the malignant nodules. Postoperative complications were transient hypocalcemia (8%), permanent hypocalcemia (1.7%), and unilateral vocal cord paralysis (1.7%). Recurrence or mortality was not encountered in the 5.4±1.2-year follow-up period. CONCLUSION: Thyroid nodule in a child requires an aggressive diagnostic approach due to increased risk of malignancy and metastasis. Intraoperative frozen section examination must be done as a useful adjunct to determine the surgical strategy. Incidence of complications is small in thyroid surgery when performed by experienced surgeons.

Evaluation of therapeutics management patterns and glycemic control of pediatric type 1 diabetes mellitus patients in Turkey: A nationwide cross-sectional study.

AIMS: To evaluate the management strategies, glycemic control and complications of pediatric type 1 diabetes mellitus (T1DM) patients in Turkey. METHODS: Study included 498 patients with T1DM between the ages 1-18. Data provided from patients' hospital files were recorded on standard case report forms by applicant clinicians within the 3months of data collection period between October 2012 and July 2013. RESULTS: Mean age of patients was 11.3±3.8years. Mean duration of DM was determined as 3.7±3.1years. Majority of patients (85.5%) used basal/bolus injection (BBI), and 6.5% used continuous subcutaneous insulin infusion pump. Assessment of glycemic control based on HbA1c levels showed that 29.1% of patients had an HbA1c value <7.5% (58mmol/mol), 16.1% had a value between 7.5% (58mmol/mol) and 8% (64mmol/mol), 19.1% had a value between 8.1% (64mmol/mol) and 9%(75mmol/mol) and 35.7% a value >9%(75mmol/mol). Hypoglycemia was reported in 145 (29.1%) patients and the number of severe hypoglycemic attacks in the last 3months was 1.0±2.4. Taking into consideration the carbohydrate count and insulin correction dose and parents with high socioeconomic status was related to have better glycemic control. The most common comorbidities were Hashimoto's thyroiditis/hypothyroidism (6.2%) followed by celiac disease (3.8%), epilepsy(1.2%), and asthma(1.0%). CONCLUSIONS: BBI insulin therapy is widely used among pediatric T1DM patients in Turkey. However, despite improvements in treatment facilities and diabetic care, glycemic control is not at a satisfactory level. Therefore, new and comprehensive initiatives require for pediatric T1DM patients with poor glycemic control. Promoting use of carbohydrate count and insulin correction doses may improve the glycemic control of pediatric T1DM in Turkey.

Difficulties experienced by caregivers of patients diagnosed with osteogenesisimperfecta (OI): example of a hospital.

OBJECTIVE: To identify the difficulties experienced by medical caregivers of inpatients diagnosed with osteogenesisimperfecta. METHODS: The descriptive, cross-sectional study was conducted at a university hospital in western Turkey from April to May, 2012, and comprised relatives providing care to patients who were diagnosed with osteogenesisimperfecta and were being treated in the paediatric endocrinology unit. Data was collected via face-to-face interviews with patient relatives. The 35-itemquestionnaire had 16 open-ended and 19 close-ended questions. RESULTS: The mean age of the 46 caregivers was 35.52±6.65 years, and 43(93.5%) of them were mothers. All of them said they felt anxious (100%), while 44(95.7%) felt sad/sorrow, 41(89.1%) puzzled, 40(87.0%) nervous, 40(87.0%) frightened, 39(84.8%) disappointed, 29(63%) shocked, and 28(60.9%) depressed when they first heard the diagnosis. Overall, 26(56.5%) experienced physical, 45(97.8%) psychological, 45(97.8%) social, and 35(76.1%) economic changes and difficulties, while 24(52.1%) had no social support. Of all the patient relatives, 38(82.6%) were unable to obtain adequate information about the disorder from the healthcare team. CONCLUSIONS: Caregivers of patients diagnosed with osteogenesisimperfecta experienced psychological and social difficulties..

Multiple cutaneous hemangiomas in a patient with combined pituitary hormone deficiency.

Combined pituitary hormone deficiency (CPHD) refers to a rare heterogeneous group of conditions in which there is a deficiency in at least two anterior pituitary hormones. Patients with POU1F1 mutations show a combined pituitary deficiency with low or absent levels of growth hormone, prolactin, and thyroid-stimulating hormone. In this study, a 7-month-old girl with a CPHD is presented. She had facial dysmorphologic features, hypertrichosis, and hypotonia. Additionally, she also presented with multiple cutaneous hemangioma that until now has not been reported in association with this disorder.

Diabetes care, glycemic control, complications, and concomitant autoimmune diseases in children with type 1 diabetes in Turkey: a multicenter study.

OBJECTIVE: Epidemiologic and clinical features of type 1 diabetes mellitus (T1DM) may show substantial differences among countries. The primary goal in the management of T1DM is to prevent micro- and macrovascular complications by achieving good glycemic control. The present study aimed to assess metabolic control, presence of concomitant autoimmune diseases, and of acute and long-term complications in patients diagnosed with T1DM during childhood and adolescence. The study also aimed to be a first step in the development of a national registry system for T1DM, in Turkey. METHODS: Based on hospital records, this cross-sectional, multicenter study included 1 032 patients with T1DM from 12 different centers in Turkey, in whom the diagnosis was established during childhood. Epidemiological and clinical characteristics of the patients were recorded. Metabolic control, diabetes care, complications, and concomitant autoimmune diseases were evaluated. RESULTS: Mean age, diabetes duration, and hemoglobin A1c level were 12.5 ± 4.1 years, 4.7 ± 3.2 years, and 8.5 ± 1.6%, respectively. Acute complications noted in the past year included ketoacidosis in 5.2% of the patients and severe hypoglycemia in 4.9%. Chronic lymphocytic thyroiditis was noted in 12%, Graves' disease in 0.1%, and celiac disease in 4.3% of the patients. Chronic complications including neuropathy, retinopathy, and persistent microalbuminuria were present in 2.6%, 1.4%, and 5.4% of the patients, respectively. Diabetic nephropathy was not present in any of the patients. Mean diabetes duration and age of patients with neuropathy, retinopathy and microalbuminuria were significantly different from the patients without these long-term complications (p<0.01). A significant difference was found between pubertal and prepubertal children in terms of persistent microalbuminuria and neuropathy (p=0.02 and p<0.001, respectively). Of the patients, 4.4% (n:38) were obese and 5% had short stature; 17.4% of the patients had dyslipidemia, and 14% of the dyslipidemic patients were obese. CONCLUSIONS: Although the majority of the patients in the present study were using insulin analogues, poor glycemic control was common, and chronic complications were encountered.

Effects of pesticides used in agriculture on the development of precocious puberty.

The present study aims to evaluate the effects of pesticides on premature breast development. Forty-five girls (group 1) with premature breast development living in the Menderes region, where greenhouse cultivation is the main income, 16 girls (group 2) living in Izmir city with early puberty, and 33 girls (group 3) who had no signs of puberty were included in the study. Endosulphan 1, endosulphan 2, endosulphan sulphate, methoxychlor, vinclozolin, 4,4-dichlorodiphenyldichlorethylene (DDE), 4,-dichlorodiphenyltrichloroethane (DDT), and 2,4-DDT were evaluated in the serum and adipose tissues of the groups by using a gas chromatography-mass spectrometry method. With the exception of 4,4'-DDE, the pesticides studied were undetectable in the serum and adipose tissue samples. The levels of basal luteinizing hormone (LH), stimulated LH, follicle-stimulating hormone, and the long axis of the uterus and both ovaries were significantly different in the girls who had premature thelarche and detectable 4,4'-DDE levels compared to the girls who had premature thelarche and undetectable 4,4'-DDE levels in serum and adipose tissues. The presence and levels of pesticides in serum and adipose tissues were not related to precocious puberty (PP). The mechanisms that lead to PP may also result in obesity, and obesity may be the underlying cause for PP in this group.

Clinical course of Hashimoto's thyroiditis and effects of levothyroxine therapy on the clinical course of the disease in children and adolescents.

OBJECTIVE: The aim of this study was to evaluate the clinical course of Hashimoto's thyroiditis (HT) in children and adolescents and the effects of levothyroxine therapy on the clinical course and laboratory findings. METHODS: The clinical and laboratory data of 101 patients with HT at presentation and during a three-year follow-up period were retrospectively evaluated using patient records. RESULTS: The mean age of the patients at the time of diagnosis was 12.3 ± 2.90 years and female/male ratio was 5.7/1. The complaint at the time of hospital presentation was goiter in 57.8% of the patients. At baseline, 36.7% of the patients were euthyroid, whereas 32.7% had subclinical hypothyroidism, 16.6 % of subjects were evaluated as hypothyroid. Twelve of the 28 patients who were initially euthyroid and not receiving therapy developed subclinical or overt hypothyroidism during the first 18 months of the follow-up period and were started on thyroid medication. At presentation, the mean anti-thyroglobulin (anti-Tg) and anti-thyroperoxidase antibody levels were 450 ± 725 IU/mL and 392 ± 428 IU/mL, respectively and at the end of the follow-up period, a significant decrease was observed in the anti-Tg levels of patients receiving levothyroxine from the beginning. CONCLUSIONS: Thyroid functions of the patients with HT should be monitored periodically for hypothyroidism. Levothyroxine therapy may positively affect the clinical course of the disease and the antibody titers.

Primary hyperparathyroidism in a young adult presenting with severe hypertension.

Hypertension is a significant cause of morbidity and mortality in childhood. Endocrine-related hypertension is rare in children. Hypercalcmia due to hyperparathyroidism is a rare cause of endocrine-related hypertension in childhood. We present a patient with severe headache, who was diagnosed with hypertension due to hyperparathyroidism. Hyperparathyroidism should be kept in mind in children with hypertension accompanied by hypercalcemia and hypophosphatemia.

Ghrelin levels in children with constitutional delay of growth and puberty.

OBJECTIVE: In this study, we aimed to show the role of ghrelin in growth delay in children with constitutional delay of growth and puberty (CDGP). METHODS: Thirty male children with CDGP constituted the study group and fifteen healthy children with normal growth of similar ages-the control group. In both groups, fasting and postprandial plasma ghrelin levels, serum insulin-like growth factor-1 (IGF-1) and IGF-binding protein-3 (IGFBP-3) levels were determined. RESULTS: There were no differences in fasting and postprandial ghrelin levels (824.23±523.46 pg/mL and 447.26±259.92 pg/mL, respectively) in children with CDGP compared to the levels in the control group (687.38±481.43 pg/mL and 365.59±260.43 pg/mL, respectively; p>0.05). Differences in fasting and postprandial ghrelin levels were also similar in the two groups (394.44±369.10 pg/mL and 346.55±338.67 pg/mL, respectively; p>0.05). Serum IGF-1 levels were significantly depressed in children with CDGP compared to those in the control group (239.5±83.95 ng/mL and 339.20±63.08 ng/mL, respectively; p<0.05). CONCLUSION: Decreased appetite and feeding problems in children with CDGP were not related to depressed ghrelin levels. In addition, ghrelin levels did not increase to compensate for the decreased appetite and feeding problems in CDGP.

Many admissions to the emergency departments with recurrent syncope attacks and seizures in an adolescent boy.

A 16-year-old boy presented with tonic-clonic seizure after he woke up early in the morning. He had experienced 5-6 episodes of syncope, fatigue, weakness and somnolence one year before admission. On admission, physical examination was normal and first line laboratory tests were normal except capillary blood glucose which was 16 mg/dl.

Low density lipoprotein apheresis in pediatric patients with homozygous familial hypercholesterolemia.

The aim of the present study is to clarify the low density lipoprotein apheresis procedure for pediatric patients with homozygous familial hypercholesterolemia (FH) in terms of efficacy, adverse effects and difficulties. The follow-up was carried out using an open, prospective uncontrolled clinical design. Data were collected from 10 patients (with an average age of 8.4 +/- 4.7 years) with FH treated with double filtration plasmapheresis. The total time span of follow-up covered five years (30.2 +/- 17.8 months [range 9-60 months]) and more than 600 sessions (62.1 +/- 35.5 sessions per patient [range 18-120 sessions]) were evaluated. The mean low density lipoprotein cholesterol (LDL-C) pre-treatment value was 375.5 +/- 127.5 mg/dL, and the post-treatment value was 147.5 +/- 73.9 mg/dL. This corresponded to a 62.8 +/- 10.3% (43-73%) acute reduction of LDL-C, while the mean high density lipoprotein cholesterol losses amounted to 41%. The chronic reduction in LDL-C ranged from 18 to 52%, with a mean level of 36.4 +/- 11.7%. The most frequently occurring technical problems were related to blood lines: puncture difficulties (4.5%), insufficient blood flow (3.5%), and obturation of the blood lines (2.4%). The main clinical adverse effects were hypotension (0.2%), chills/feeling cold (0.1%), and nausea and vomiting (0.2%). We observed that the low pediatric patient tolerance is the main problem in compliance with treatment. In conclusion, LDL apheresis, started under the age of eight years, combined with lipid-lowering drugs, provides a safe and effective lowering of the mean LDL-C levels in pediatric homozygous FH; and there are more problems with compliance for pediatric LDL apheresis than in the adult population.

A cross-sectional, mono-centric pilot study of insulin resistance in enzyme replacement therapy patients with Gaucher type I without overweight.

Insulin resistance have been demonstrated in untreated patients with Gaucher type I disease. It was implied in overweight enzyme replacement therapy (ERT) treated patients with Gaucher type I disease. In present study we investigate whether insulin resistance is presented in fourteen ERT treated patients with Gaucher type I disease and without overweight in comparison to normal subjects. This work illustrates the presence of insulin resistance in non-overweight ERT treated patients with Gaucher type I disease.

A randomized clinical trial comparing breakfast and bedtime administration of insulin glargine in children and adolescents with type 1 diabetes.

BACKGROUND: Insulin glargine provides effective glycemic control when administered at bedtime in adults. OBJECTIVE: This study aims to investigate whether insulin glargine is equally effective if administered in the morning or at bedtime in combination with preprandial anologue insulin. METHODS: Twenty-eight patients that have been treated with an intensified insulin regimen for at least one year were randomized to insulin glargine injection at breakfast (06:00-09:00) (12 patients) or bedtime (21:00-24:00) (16 patients), plus meal-time anologue insulin in the two groups. Glucose data from each day were analyzed at four different times: between 9:00 and 21:00 (t1), between 21:00 and 24:00 (t2), between 24:00 and 04:00 (t3),04:00 and 09:00 (t4) by the Minimed continuous glucose monitoring system. RESULTS: Baseline characteristics were similar in the two groups. The sensor values were lower before breakfast in the bedtime group (180.5 ± 49.0 vs 223.8 ± 47.3 mg/dl, p=0.03). There were 13.7 events.patient (-1).day(-1) in the bedtime group and 6.9 events.patient (-1).day(-1) in the breakfast group in which glucose levels fell below 60 mg/dl (p=0.3). There were 121.6 events.patient (-1).day(-1) in the bedtime group and 162.4 events.patient (-1).day(-1) in the breakfast group in which glucose levels exceeded 180 mg/dl (p=0.05). Nighttime hypoglycemia only reached to a statistical significance between the two groups between 24:00 and 04:00. There were no significant correlations between the duration of nocturnal hypoglycemia, age, duration of diabetes, gender and HbA1c levels. CONCLUSION: Breakfast group is hyperglycemic during the day and hyperglycemia starts in the morning at 04:00. There is no significant difference in the frequency or duration of hypo/hyper glycemia during the day and night irrespective of the timing of glargine injection except pre-breakfast levels are significantly better in the bedtime group and hypoglycemia occurs between midnight and 04:00 in the bedtime group.