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Cardiovascular diseases (CVD) are the most important cause of morbidity and mortality in patients with type 1 diabetes (T1D). Children with T1D have a similar or higher prevalence of being overweight (OW) or obese (Ob) compared to healthy peers. The aim of this study was to determine the prevalence of CVD risk factors in children and adolescents with T1D and the impact of obesity and sex differences on these factors. Data of patients aged 10-21 years and who had been using intensive insulin therapy with a diagnosis of T1D for at least three years were evaluated. Patients were divided into normal weight (NW), OW and Ob groups based on body mass index percentiles. Risk factors for CVD (obesity, dyslipidemia, hypertension) were compared between groups, and impact of gender was also analyzed. Data of 365 patients (200 girls, 54.8%), were evaluated. Prevalence of OW/Ob was 25.9% and was significantly higher in girls (30.6% vs 20.1%, p<0.001). Rate of hypertension was highest in OW/Ob girls followed by OW/Ob boys, and similar in NW girls and boys (p=0.003). Mean low density lipoprotein cholesterol (LDL-c) and triglyceride (TG) levels were highest in OW/Ob girls, followed by OW/Ob boys, NW girls and NW boys, respectively (p<0.001 and p<0.001, respectively). Mean high density lipoprotein-cholesterol (HDL-c) levels were similar among groups. Rates of high LDL-c and TG were similar between OW/Ob girls and boys and higher than NW girls, followed by NW boys (p<0.001 and p<0.001, respectively). The rate of low HDL-c was similar in OW/Ob girls and boys, and higher than NW girls, followed by NW boys (p<0.001). Overall, girls were 1.9 times more likely than boys to have two or more risk factors for CVD. Factors associated with risk for CVD in multiple logistic regression analyses were being a girl, followed by higher daily insulin dose, higher hemoglobin A1c, and longer duration of diabetes (r=0.856; p<0.001). In spite of the increased prevalence for obesity in both sexes, the trend for CVD risk factors was greater in Ob girls, followed by Ob boys and NW girls. Girls with T1D are more likely to be OW/Ob and to have CVD risk than boys, highlighting the need for early intervention and additional studies to elucidate the causes.

Background Global variations in epidemiology of type 1 diabetes mellitus (T1DM) exist. This study is designed to examine demographic and clinical features of T1DM over the past 3 decades as well as evolving trends in epidemiology over last 50 years. Methods Clinical characteristics of 925 patients with T1DM over last 30 years (1990–2019) were evaluated and compared to previously published data of 477 patients diagnosed between 1969 and 1990 from one of the major referral centers for diabetes in Turkey. Results Mean age at diagnosis decreased from 9.5 ± 4.0 to 7.1 ± 3.6 years within the past 50 years (p < .001). Age at diagnosis peaked at 12–14 years between 1969 and 1990, then fell to 10–11.9 years between 1990 and 1999, and to 4–5.9 years between 2000–2009 and 2010–2019 (p = .005). Although the percentage of patients diagnosed <6 years of age is gradually increasing, the percentage between the ages of 6 and 11.9 years is decreasing, and the percentage diagnosed ≥12 years remained stable. A total of 47.5% of patients had ketoacidosis, 38.2% had ketosis, and 14.3% had only hyperglycemia. 23% of patients had severe diabetic ketoacidosis (DKA), whereas 42% had moderate. Over last 3 decades, there has been no change in frequency of ketoacidosis at presentation, but there has been significant decline in severity (p = .865, and p < .001, respectively). Although the frequency of patients with mild DKA increased over time, frequency of patients with moderate DKA decreased; however, no significant difference was observed among patients with severe ketoacidosis. DKA was more frequent and severe in patients <6 years of age (p = .005, and p < .001, respectively). Conclusion Age at diagnosis shifted to younger ages in T1DM in the past 50 years. Half of patients had ketoacidosis at diagnosis and frequency of presentation with DKA did not decrease, but severity decreased slightly. Increase in prevalence of T1DM in the younger age group and the fact that half of patients present with DKA indicate that awareness should be increased in terms of early diagnosis and treatment. Highlights This study provides important data from a single quarternary reference center where cases with type 1 diabetes mellitus (T1DM) come from a wide range of geographical distribution over 50 years and may well reflect secular trends in T1DM in Turkey. The mean age at diagnosis was 9.5 ± 4.0 years from 1969 to 1990, and it significantly decreased to 7.1 ± 3.6 years over the subsequent 50 years. Similarly, age at diagnosis peaked at 12–14 years between 1969 and 1990, then fell to 10–11.9 years between 1990 and 1999, and to 4–5.9 years between 2000–2009 and 2010–2019. Although the percentage of patients diagnosed <6 years of age is gradually increasing, the percentage diagnosed between ages of 6 and 11.9 years is decreasing, and the percentage diagnosed ≥12 years remained stable. Approximately half of the patients had ketoacidosis at the time of diagnosis and the frequency of presentation with DKA did not decrease, but the severity decreased slightly. Although the frequency of patients with mild DKA increased over time, frequency of patients with moderate DKA decreased; however, no significant difference was observed among patients with severe ketoacidosis.

Background: Handling of the dawn phenomenon (DP) with multiple daily insulin injection (MDII) regimen is a real challenge. Objective: We aimed to demonstrate the effectiveness of a dual-basal-insulin (a long-acting glargine and an intermediate-acting neutral protamine Hagedorn (NPH)) regimen for the management of DP in children with type 1 diabetes mellitus (T1DM). The primary efficacy outcome was to overcome morning hyperglycemia without causing hypoglycemia during the non-DP period of the night. Design: Retrospective cohort study. Method: Charts of 28 children with T1DM (12 female; 42.8%, mean age 13.7 ± 2.1 years) treated with MDII were retrospectively reviewed. The median duration of diabetes was 4.5 years (range 2–13.5 years). DP was diagnosed using a threshold difference of 20 mg/dL (0.1 mmol/L) between fasting capillary blood glucose at 3 a.m. and prebreakfast. NPH was administered at midnight in addition to daily bedtime (08.00–09.00 p.m.) glargine (dual-basal-insulin regimen). Midnight, 03:00 a.m., prebreakfast and postprandial capillary blood glucose readings, insulin–carbohydrate ratios, and basal-bolus insulin doses were recorded the day before the dual-basal-insulin regimen was started and the day after the titration of the insulin doses was complete. Body mass index standard deviation scores (BMI SDS) at the onset–3rd–12th month of treatment were noted. Results: Before using dual basal insulin, prebreakfast capillary blood glucose levels were greater than those at midnight and at 03:00 a.m. (F = 64.985, p < 0.01). After titration of the dual-basal-insulin doses, there were significant improvements such that there were no statistically significant differences in the capillary blood glucose measurements at the three crucial time points (midnight, 03.00 a.m., and prebreakfast; F = 1.827, p = 0.172). No instances of hypoglycemia were reported, and the total daily insulin per kilogram of body weight did not change. The BMI SDS remained steady over the course of the 1-year follow-up. Conclusion: In this retrospective cohort study, the dual-basal-insulin regimen, using a long-acting glargine and an intermediate-acting NPH, was effective in overcoming early morning hyperglycemia due to insulin resistance in the DP. However, the effectiveness of the dual-basal-insulin regimen needs to be verified by prospective controlled studies using continuous glucose monitoring metrics or frequent blood glucose monitoring.

What is already known on this topic? Classical congenital adrenal hyperplasia (CAH) occurs in 1:13,000 to 1:15,000 live births. 21-hydroxylase enzyme deficiency (21-OHD) occurs in 90 to 95% of all cases of CAH. In contrast to 21-OHD, the carrier rate for 11[beta]-OHD is fairly low, the rate of compound heterozygosity of CYP11B1 mutations in the pathogenesis is less frequent and the estimated overall frequency is 1 in 100,000 live births. However, the prevalence of 11[beta]-OHD is relatively higher in the Middle East and North Africa. Neonatal screening for CAH is effective in detecting the salt-wasting form and thereby reducing mortality. The estimated incidence of classical 21-OHD was 1:7,787 in an initial pilot study of newborn screening for CAH, in which 38,935 neonates were screened in Turkey. What this study adds? The incidence of classical 21-OHD and 11[beta]-OHD CAH in Turkey in the screened population of 241,083 neonates was 1:15,067 and 1:60,270, respectively. Turkish neonatal CAH screening led to the early and effective diagnosis of 21-OHD and 11[beta]-OHD by the use of steroid profiling as a second-tier test Objective: Turkish Directorate of Public Health introduced the first pilot screening program for congenital adrenal hyperplasia (CAH) in four Turkish cities in 2017, and in 2018 extended the program, with a slight change in screening strategy, to fourteen cities. To evaluate the performance of the extended study and update previously reported outcomes. Methods: Retrospective, descriptive study. Neonates of [greater than or equal to]32 gestational weeks and [greater than or equal to]1500 gr birth weight from fourteen cities, born between May-December 2018, were included. Screening protocol included one sample, two-tier testing as applied in the previous pilot study. In the first step, 17[alpha]-hydroxyprogesterone (17-OHP) was measured by fluoroimmunoassay in dried blood spots (DBS) obtained at 3-5 days of life. Cases with positive initial screening underwent second tier testing by steroid profiling in DBS using liquid chromatography-tandem mass spectrometry to measure 17-OHP, 21-deoxycortisol (21-S), cortisol (F), 11-deoxycortisol and androstenedione. The babies with a steroid ratio (21-S+17-OHP)/F of [greater than or equal to]0.7 (increased from [greater than or equal to]0.5 in the earlier pilot study) were referred to pediatric endocrinology clinics for diagnostic assessment. Results: In the evaluated period, 241,083 newborns were screened. 12,321 (5.11%) required second-tier testing and 880 (0.36%) were referred for clinical assessment, twenty of whom were diagnosed with CAH (10 females, 10 males). Sixteen were diagnosed as classical 21-hydroxylase deficiency (21-OHD) CAH (12 with salt-wasting and four with simple virilising CAH), and four cases were identified with 11[beta]-OHD CAH. No case of salt-wasting CAH was missed by neonatal screening (sensitivity was 100%). The incidence of classical 21-OHD and 11[beta]-OHD in the screened population was 1:15,067 and 1:60,270, respectively. Conclusion: Turkish neonatal CAH screening effectively led to earlier diagnosis of 21-OHD and 11[beta]-OHD, using steroid profiling as a second-tier test. This will result in improved care of these patients in the future. Keywords: Neonatal screening, congenital adrenal hyperplasia, second-tier, steroid profiling, incidence, 11[beta]-hydroxylase deficiency

Objective: Phosphomannomutase 2 deficiency (PMM2-CDG) is a disorder of protein N-glycosylation with a wide clinical spectrum. Hypoglycemia is rarely reported in PMM2-CDG. In this study, we evaluated cause, treatment options and outcomes in cases with hypoglycemia in the course of PMM2-CDG. Methods: Clinical records of patients followed with PMM2-CDG within the last two decades were reviewed. Medical data of patients with hypoglycemia were evaluated in more detail. Demographic and clinical findings, organ involvement and laboratory investigations at time of hypoglycemia were recorded. Time of first attack of hypoglycemia, cause, treatment modalities, duration of hypoglycemia (permanent/transient), and duration of treatment, as well as outcome were also recorded. Other published cases with PMM2-CDG and hypoglycemia are also reviewed in order to elucidate characteristics as well as pathophysiology of hypoglycemia. Results: Nine patients with PMM2-CDG were reviewed, and hypoglycemia was present in three cases. All three had hyperinsulinism as the cause of hypoglycemia. In the first two cases reported here, serum insulin level concurrent with hypoglycemic episodes was elevated, and glucose response was exaggerated during glucagon test, favoring hyperinsulinism. However, in the third case, the serum insulin level at time of hypoglycemia was not so high but hypoglycemia responded well to diazoxide. Hyperinsulinism was permanent in two of these three cases. No genotype-phenotype correlation was observed with respect to hyperinsulinism. Conclusion: The main cause of hypoglycemia in PMM2-CDG appears to be hyperinsulinism. Although insulin levels at the time of hypoglycemia may not be very high, hypoglycemia in patients with PMM2 responds well to diazoxide. Keywords: Congenital disorders of glycosylation, diazoxide, hyperinsulinism, hypoglycemia, phosphomannomutase 2 deficiency

Doses of gonadotropin releasing hormone (GnRH) analogues used to treat idiopathic central precocious puberty (iCPP) vary among clinicians. Study aims were to evaluate the efficacy of a monthly 3.75 mg dose of leuprolide acetate (LA) to suppress the hypothalamo-pituitary-gonadal (HPG) axis in girls with iCPP and to determine factors that may have an impact on the supressing dose. Study subjects were 220 girls receiving LA for iCPP. LA was started at a dose of 3.75 mg/28 days. Suppression was assessed using the GnRH test at the third month. To assess clinical suppression signs and symptoms of puberty were also evaluated. The dose of LA was increased to 7.5 mg/28 days in those who had a peak luteinising hormone (LH) ≥2 IU/L and in whom adequate clinical suppression of puberty was absent. Receiver operating characteristic curves were used to determine thresholds for clinical and hormonal factors affecting the suppressing dose of LA. Logistic regression analyses were used to investigate thresholds which might differentiate between those requiring high dose for suppression and those in whom lower dose LA was adequate. Peak stimulated LH <2 IU/L was achieved in 88.6% with a dose of LA of 3.75 mg (0.11±0.03 mg/kg). Significant variables for differentiating the two doses were body weight (Wt) of 36.2 kg and/or body mass index (BMI)-standard deviation scores (SDS) of 1.64 (p<0.001). Multiple logistic regressions showed that Wt and BMI-SDS values above thresholds indicated requirement of LA at a dose of 7.5 mg/28 days (p<0.001). Monthly injections of 3.75 mg LA is an effective treatment in the majority of girls with iCPP. However, a higher initial dose may be preferred in patients with a Wt ≥36 kg or BMI-SDS ≥1.6 for effective suppression of the HPG axis.

Congenital adrenal hyperplasia (CAH) is the most common form of primary adrenal insufficiency in children. Neonatal screening for CAH is effective in detecting the salt-wasting (SW) form and in reducing mortality. In this study, our aim was to estimate the incidence of CAH in Turkey and to assess the characteristics and efficacy of the adopted newborn CAH screening strategy. A pilot newborn CAH screening study was carried out under the authority of the Turkish Directorate of Public Health. Newborn babies of ≥32 gestational weeks and ≥1500 gr birth weight from four cities, born between March 27-September 15, 2017 were included in the study. Screening protocol included one sample two-tier testing. In the first step, 17α-hydroxyprogesterone (17-OHP) was measured by fluoroimmunoassay in dried blood spots (DBS) obtained at 3-5 days of life. The cases with positive initial screening were tested by steroid profiling in DBS using a liquid chromatography-tandem mass spectrometry method to measure 17-OHP, 21-deoxycortisol (21-S), cortisol (F), 11-deoxycortisol and androstenedione as a second-tier test. The babies with a steroid ratio (21-S+17-OHP)/F of ≥0.5 were referred to pediatric endocrinology clinics for diagnostic assessment. 38,935 infants were tested, 2265 (5.82%) required second-tier testing and 212 (0.54%) were referred for clinical assessment, six of whom were diagnosed with CAH (four males, two females). Four cases were identified as SW 21-hydroxylase deficiency (21-OHD) (two males, two females). One male baby had simple virilizing 21-OHD and one male baby had 11-OHD CAH. The incidence of classical 21-OHD in the screened population was 1:7,787. The incidence of CAH due to classical 21-OHD is higher in Turkey compared to previous reports. We, therefore, suggest that CAH be added to the newborn screening panel in Turkey. The use of steroid profiling as a second-tier test was found to improve the efficacy of the screening and reduce the number of false-positives.

The present study was performed to determine the prevalence of metabolic syndrome (MS) and its risk factors in obese children and adolescents. The study included 352 obese children and adolescents (body mass index [BMI] ≥ 95th percentile) aged between 2 and 19 years. The diagnosis of MS was made according to the criteria adapted from the World Health Organization (WHO) and the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) guidelines. BMI z -scores were calculated to assess the degree of obesity. The prevalence of MS and risk factors were determined. Determinants of MS were examined using regression analysis. The prevalence of MS was 41.8%. The age at onset of obesity, sedentary life-span, fasting blood levels of glucose, insulin, triglyceride, very-low-density lipoprotein (VLDL) cholesterol, and alanine aminotransferase (ALT) were higher, while levels of high-density lipoprotein (HDL) cholesterol and the number of actively spent hours were lower in cases with MS ( p  < 0.05). The most important determinant of MS was BMI z -score ( r  = 0.31, p  < 0.0001). A one-point increase in BMI z -score yielded a 2-fold increase in the prevalence of MS. The prevalence of MS increased from 27.6% to 60.7% when the BMI z -score increased from 2.3 to 3.3. The risk of developing MS was 2.6-fold higher in cases with BMI z -score > 3 when compared to those with z -scores between 2 and 3. The results from this study indicate that, although the correlation between MS and the BMI z -score was weak, the BMI z -score may be an effective parameter in identifying obese children and adolescents at risk for MS. Screening the cases with BMI z -scores ≥ 2 for MS is important for establishing an early diagnosis.

摘要 背景:残余β细胞功能和通过逆转葡萄糖毒性改善胰岛素敏感性被认为是与部分缓解(PR)相关的两种现象。体脂质量是胰岛素敏感性的主要决定因素。本研究旨在调查1型糖尿病(T1DM)诊断后体重增加率与其他临床因素之间的关系，以确定PR的发生和持续时间 方法:将新发T1DM儿童(2‐16岁)(n=99)根据胰岛素剂量调整后的HbA1c值分为缓解组和非缓解组。记录实验室和临床数据以及诊断时和每次随访时每千克体重的每日胰岛素需求量，确定PR持续时间。以每六个月收集的生长发育数据，计算体重指数标准差评分(BMI‐SDS)的变化 结果:47名患者(47.5%)病情缓解，52名患者(52.5%)病情未缓解。诊断后前6个月，病情未缓解患者的BMI‐SDS平均增加值高于病情缓解患者(p=0.04)。PR持续时间与诊断后第6个月至第12个月BMI‐SDS的变化呈负相关。多元回归分析显示男性、年轻、青春期前状态和较低的HbA1c是病情缓解的预测因素，其中男性的可能性最大 结论:T1DM诊断后早期体重快速增加可能在对难以缓解和PR持续时间较短起作用。预防早期体重快速增加的干预措施可能有助于维持和延长缓解

Insulin-like growth factor-1 (IGF-1) is the main driver of growth during prenatal life and acts through IGF-1 receptor ( ). Patients with defects exhibit variable phenotypic features. A 10.9-year-old boy presented with severe short stature, microcephaly, minor dysmorphic features and mental retardation. Genetic analysis for revealed heterozygous deletion of the complete . At the age of 12.3 years, daily subcutaneous recombinant human growth hormone (rhGH) was started and continued for a total of 5.7 years in two courses with improvement of height velocity as well as final height. Puberty was delayed and eventually he did not achieve full puberty, suggesting partial hypogonadotropic hypogonadism. Hypothyroidism initially developed during rhGH therapy. However, low T4 levels persisted after cessation of rhGH therapy and thus central hypothyroidism is a likely diagnosis. rhGH has partial effect for induction of growth in cases with defects. However, long-term treatment with an early initiation may have more beneficial effects. In addition, patients with defects should be followed for delayed puberty-hypogonadism, and hypothyroidism.