Clinical features, diagnosis and treatment outcomes of Cushing's disease in children: A multicenter study.

OBJECTIVE: Since Cushing's disease (CD) is less common in the paediatric age group than in adults, data on this subject are relatively limited in children. Herein, we aim to share the clinical, diagnostic and therapeutic features of paediatric CD cases. DESIGN: National, multicenter and retrospective study. PATIENTS: All centres were asked to complete a form including questions regarding initial complaints, physical examination findings, diagnostic tests, treatment modalities and follow-up data of the children with CD between December 2015 and March 2017. MEASUREMENTS: Diagnostic tests of CD and tumour size. RESULTS: Thirty-four patients (M:F = 16:18) from 15 tertiary centres were enroled. The most frequent complaint and physical examination finding were rapid weight gain, and round face with plethora, respectively. Late-night serum cortisol level was the most sensitive test for the diagnosis of hypercortisolism and morning adrenocorticotropic hormone (ACTH) level to demonstrate the pituitary origin (100% and 96.8%, respectively). Adenoma was detected on magnetic resonance imaging (MRI) in 70.5% of the patients. Transsphenoidal adenomectomy (TSA) was the most preferred treatment (78.1%). At follow-up, 6 (24%) of the patients who underwent TSA were reoperated due to recurrence or surgical failure. CONCLUSIONS: Herein, national data of the clinical experience on paediatric CD have been presented. Our findings highlight that presenting complaints may be subtle in children, the sensitivities of the diagnostic tests are very variable and require a careful interpretation, and MRI fails to detect adenoma in approximately one-third of cases. Finally, clinicians should be aware of the recurrence of the disease during the follow-up after surgery.

Investigation of the molecular genetic causes of non-syndromic primary ovarian ınsufficiency by next generation sequencing analysis

ABSTRACT Objective: The aim of this study is to investigate the molecular genetic causes of non-syndromic primary ovarian insufficiency (POI) cases with the gene panel based on next generation sequencing analysis and to establish the relationship between genotype and phenotype. Subjects and methods: Twenty three cases aged 14-40 years followed up with POI were included. Patients with a karyotype of 46, XX, primary or secondary amenorrhea before the age of 40, with elevated FSH (>40 IU/mL) and low AMH levels (<0.03 ng/mL) were included in the study. Molecular genetic analyzes were performed by the next generation sequencing analysis method targeted with the TruSightTM Exome panel. Results: Median age of the cases was 17.8 (14.0-24.3) years, and 12 (52%) cases admitted before the age of 18. Fifteen (65%) patients had consanguineous parents. In 2 (8.6%) cases, variants detected were in genes that have been previously proven to cause POI. One was homozygous variant in FIGLA gene and the other was homozygous variant in PSMC3IP gene. Heterozygous variants were detected in PROK2, WDR11 and CHD7 associated with hypogonadotropic hypogonadism, but these variants are insufficient to contribute to the POI phenotype. Conclusion: Genetic panels based on next generation sequencing analysis technologies can be used to determine the molecular genetic diagnosis of POI, which has a highly heterogeneous genetic basis.

Investigation of the molecular genetic causes of non-syndromic primary ovarian insufficiency by next generation sequencing analysis.

Objective: The aim of this study is to investigate the molecular genetic causes of non-syndromic primary ovarian insufficiency (POI) cases with the gene panel basedon next generation sequencing analysis and to establish the relationship between genotype and phenotype. Materials and methods: Twenty three cases aged 14-40 years followed up with POI were included. Patients with a karyotype of 46, XX, primary or secondary amenorrhea before the age of 40, with elevated FSH (>40 IU/mL) and low AMH levels (<0.03 ng/mL) were included in the study. Molecular genetic analyzes were performed by the next generation sequencing analysis method targeted with the TruSight TM Exome panel. Results: Median age of the cases was 17.8 (14.0-24.3) years, and 12 (52%) cases admitted before the age of 18. Fifteen (65%) patients had consanguineous parents. In2 (8.6%) cases, variants detected were in genes that have been previously proven to cause POI. One was homozygous variant in FIGLA gene and the other was homozygous variant in PSMC3IP gene. Heterozygous variants were detected in PROK2, WDR11 and CHD7 associated with hypogonadotropic hypogonadism, but these variants are insufficient to contribute to the POI phenotype. Conclusion: Genetic panels based on next generation sequencing analysis technologies can be used to determine the molecular genetic diagnosis of POI, which has a highly heterogeneous genetic basis.

Effect of metabolic control on cognitive functions in children and adolescents with type 1 diabetes mellitus.

OBJECTIVES: Neurocognitive functions of children with type 1 diabetes mellitus (T1D) are reported to be poorer than those of healthy peers. The aim was to investigate the effects of age of onset of diabetes, metabolic control, and type of insulin regimen on neurocognitive functions in children and adolescents with T1D. METHODS: Forty-seven children aged 6-18 years, with T1D for at least five years, were included. Children with a known psychiatric disorder or chronic diseases other than T1D were excluded. Intelligence via the Wechsler children's intelligence scale (WISC-R), short-term memory via the audio-auditory digits form B (GISD-B) test, visual motor perception via the Bender Gestalt test, and attention via the Moxo continuous attention and performance test, timing, hyperactivity, and impulsivity (Moxo-dCPT) were assessed. RESULTS: Compared with the T1D group, healthy controls had higher scores in terms of verbal intelligence quotient (IQ), performance IQ, and total IQ mean scores on WISC-R (p=0.01, p=0.05 and p=0.01, respectively). On the MOXO-dCPT test, the T1D group had higher impulsivity compared to the control group (p=0.04). Verbal IQ was better in the moderate control group than in the poorer metabolic control (p=0.01). Patients with no history of diabetic ketoacidosis (DKA) had higher performance, verbal and total intelligence scores than the group with history of DKA. CONCLUSIONS: Poor metabolic control and a history of DKA in children with T1D adversely affected neurocognitive functions. It would be beneficial to consider the assessment of neurocognitive functions in T1D and to take the necessary precautions in follow-up.

The Relationship Between Lipid Profile and Non-alcoholic Fatty Liver Disease in Children and Adolescents with Obesity.

OBJECTIVE: To determine the relationship between lipid profile and non-alcoholic fatty liver disease in obese children and adolescents. STUDY DESIGN: A comparative cross-sectional study. PLACE AND DURATION OF STUDY: Department of Pediatrics, Kastamonu Training and Research Hospital, Turkey, from March 2018 to April 2021. METHODOLOGY: Clinical, laboratory and ultrasound findings of 290 children and adolescents diagnosed with obesity were analysed. Children and adolescents were divided into two groups as those who were diagnosed with NAFLD by ultrasonography (USG) and those who did not were diagnosed. Two groups were compared in terms of clinical and biochemical findings. RESULTS: The body mass index (BMI), bodyweight for height (BWH), insulin, alanine aminotransferase (ALT), aspartate aminotransferase (AST), free T4, total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), triglyceride (TG), hemoglobin A1c (HbA1c) and HOMA-IR (Homeostatic Model Assessment for Insulin Resistance) levels were found to be significantly higher (p<0.05) in the children and adolescents with NAFLD In obese children and adolescents; there was a significant correlation between the increase in TC, LDL-C and TG levels in the blood and the development of NAFLD (p<0.05). Blood ALT level ≥37 U/L in obese boys and ≥23.5 U/L in obese girls was found to be a strong diagnostic biomarker in determining the presence of NAFLD. CONCLUSION: In obese children and adolescents, there was a significant relationship between the increase in BWH and blood lipid levels, insulin resistance and the development of NAFLD. ALT had high specificity and sensitivity to predict non-alcoholic fatty liver disease. KEY WORDS: Obesity, Children, Hepatosteatoz.

Pilot-Scale Test Results of Electrodialysis Bipolar Membrane for Reverse-Osmosis Concentrate Recovery.

In this study, it is aimed to investigate the potential of electrodialysis bipolar membrane (EDBM) systems for the recovery of the concentrate originating from an organized industrial estate (OIE) wastewater treatment system with reverse osmosis (RO). Acids and bases were obtained from a pilot-scale treatment plant as a result of the research. Furthermore, the sustainability and affordability of acids and bases obtained by EDBM systems were investigated. Six cycles were carried out in continuous-flow mode with the EDBM system as batch cycles in the disposal of the concentrate and the production of acids and bases with the EDBM system. For each cycle, the EDBM system was operated for 66, 48, 66, and 80 min, respectively, and the last two cycles were operated for a total of 165 min (70 + 90) with 5 min of waiting. In the EDBM system, a working method was determined such that the cycle flow rate was 180 L/hour, energy to be given to the system was 25 V, and the working pressure was in the range of 0.8-2.5 bar. In the six cycles with the EDBM system, the concentrate, acid and base, conductivity, pH, and pressure increase values were investigated depending on time. Throughout all these studies, the cycles were continued over the products formed in the acid and base chamber. As a result of all the cycles, acid (HCl) production at a level of 1.44% and base (NaOH) production at a level of 2% were obtained.

Local complications of insulin administration sites and effect on diabetes management.

BACKGROUND: Administration of insulin may be associated with substantial cutaneous adverse effects, such as lipoatrophy and lipohypertrophy (LH), which can cause glycemic excursions above and below the target levels for blood glucose. Our aim was to evaluate the effect on compliance with the use of insulin administration site, dermatological complications and diabetes management in children with type 1 diabetes (T1D). METHODS: Patients aged 0 - 21 years who were followed up with the diagnosis of T1D for at least one year were included. A 14-question survey including demographic characteristics and a subjective opinion of skin-related complications of insulin administration was given. Data were obtained from the medical records to evaluate the effect of dermatological complications on diabetes management. This study was checked with the STROBE checklist. RESULTS: Two hundred and fifty-four patients were included and 53% of these were female. The mean age was 14.9 ± 4.7 years and the duration of T1D was 7.3 ± 4.1 years. The mean HbA1c level was 8 ± 1.4% and the mean total insulin dose was 0.84 ± 0.25 units/kg/day. More than half of the individuals (57%) were receiving multiple daily injections (MDI) and 43% were on insulin pump therapy (IPT). Of the participants, 11.8% reported LH, 7.5% wound, 21.7% allergy, 55.5% bleeding, 41.3% bruising and 47.2% pain. LH rates varied significantly by regimen, 17.1% in MDI and 4.6% with IPT (p = .001). Those with LH were using higher median doses of insulin (0.97 U/kg/day) than those who did not (0.78 U/kg/day; p = .016). LH was reported more frequently (18.3%) in patients with frequent hypoglycemia (p = .007). Positive correlation between BMI-SDS and LH in patients aged <18 years was found (p = .043). LH rates by site were: right arm 20.8%, left arm 26.4%, right abdomen 26.4%, left abdomen 22.6% and 1% in the right and left leg. CONCLUSIONS: Local complications of insulin therapy are common in young patients with T1D. The complication with the most impact on metabolic control was LH, present in nearly 12% of patients. Users of IPT have a significantly lower risk of LH. The results emphasise the importance of individualised education for young T1D patients and their families about injection site preference and rotation techniques. RELEVANCE TO CLINICAL PRACTICE: The diabetes team should check the insulin administration sites of children with type 1 diabetes at each visit and provide repeated education about the dermatological complications of insulin.

Diagnostic Value of Bilateral Petrosal Sinus Sampling in Children with Cushing Disease: A Multi-center Study

Objective: Although the sensitivity and specificity of bilateral inferior petrosal sinus sampling (BIPSS) were shown to be quite high in adult patients, pediatric studies are limited in number and have conflicting results, since BIPSS is much less commonly performed in children. The aim of this study was to assess the role of BIPSS in the detection and accuracy of lateralization of pituitary adenomas in pediatric patients with Cushing disease (CD) and its possible advantage over other diagnostic methods. Methods: This was a multicenter, nationwide, web-based study. The diagnostic value of BIPSS in 16 patients, aged between four and 16.5 years with a confirmed diagnosis of CD, was evaluated retrospectively. The sensitivity and specificity of BIPSS and magnetic resonance imaging (MRI) were calculated, and compared statistically. Results: Standard tests, except for morning cortisol level, were effective in proving the presence of Cushing syndrome. While MRI findings were consistent with microadenoma in eight cases (50%), CD presence and lateralization was successfully predicted in 14 of 16 patients using BIPSS. BIPSS compared with MRI examination was significantly more accurate, both in pre-stimulation and post-stimulation results (p=0.047 and p=0.041, respectively). BIPSS showed a significantly higher sensitivity (92.8%) than MRI in detecting the pituitary source of adrenocorticotropic hormone secretion. Conclusion: These results suggest that BIPSS is superior to MRI for diagnostic work-up to confirm the diagnosis of CD. Moreover, in line with previous studies, BIPSS was shown to provide better information about adenoma location, which is vital for possible surgical intervention.

Molecular Diagnosis of Monogenic Diabetes and Their Clinical/Laboratory Features in Turkish Children

Objective: Monogenic diabetes is a heterogeneous disease that causes functional problems in pancreatic beta cells and hyperglycemia. The aim of this study was to determine the clinical and laboratory features, the admission characteristics and distribution of monogenic form of diabetes in childhood in Turkey. Methods: Patients aged 0-18 years, who were molecularly diagnosed with monogenic diabetes, and consented to participate, were included in the study. Results: Seventy-seven (45.6%) female and 92 male cases with a mean age of 8.18±5.05 years at diagnosis were included. 52.7% of the cases were diagnosed with monogenic diabetes by random blood glucose measurement. The reason for genetic analysis in 95 (56.2%) of cases was having a family member diagnosed with diabetes under the age of 25. At the time of diagnosis, ketone was detected in urine in 16.6% of the cases. Mean hemoglobin A1c on admission, fasting blood glucose, fasting insulin, and c-peptide values were 7.3±2.1%, 184.9±128.9 mg/dL, 9.4±22.9 IU/L, 1.36±1.1 and ng/L respectively. GCK-MODY was found in 100 (59.2%), HNF1A-MODY in 31 (18.3%), and variants in ABCC8 in 6 (3.6%), KCNJ11 in 5 (3%), HNF4A in 2 (1.2%), and HNF1B in 2 (1.2%). Conclusion: Recent studies have indicated HNF1A-MODY is the most frequent of all the MODY-monogenic diabetes cases in the literature (50%), while GCK-MODY is the second most frequent (32%). In contrast to these reports, in our study, the most common form was GCK-MODY while less than 20% of cases were diagnosed with HNF1A-MODY.

Treatment and long-term follow-up of patients diagnosed with type 1 diabetes mellitus before age 5.

OBJECTIVES: This study aimed to determine the effects of continuous subcutaneous insulin infusion (CSII) treatment on anthropometric measurements, mean HbA1c, and insulin dosage in patients diagnosed under 5 years of age and compare with multiple-dose injection therapy (MDI). METHODS: Children with type 1 diabetes mellitus, diagnosed <5 years since 2000 and their 19-year follow-up were evaluated retrospectively. Weight, height, body mass index (BMI), blood pressure, and HbA1c values were recorded for each visit. RESULTS: Hundred and five patients (58.1% female, 41.9% male) were included in the study. Sixty-three (60 %) patients were treated by CSII and 42 (40%) by MDI. Mean age at diagnosis was 2.68 ± 1.42 and 3.29 ± 1.30 years respectively. Mean follow-up was 7.42 ± 4.76 and 6.01 ± 4.41 years respectively. For each group, weight standard deviation score (SDS) increased significantly in the first year after the diagnosis (p<0.001), and with the onset of puberty weight SDS decreased significantly (p<0.001). The trend of weight and BMI SDS changes over the years showed similar characteristics in both groups. During follow-up height SDS was similar in both groups except in Tanner stage 5. When puberty was completed, mean height SDS was 0.51 ± 1.03 in CSII and -0.31 ± 0.75 in the MDI group (p: 0.029). Mean HbA1c was significantly lower in the CSII group (7.62 ± 0.82 and 8.17 ± 1.22 respectively). Systolic and diastolic blood pressure change trends during the follow-up were also similar in both groups. CONCLUSIONS: CSII treatment had positive effects on metabolic control and height SDS in patients with early-onset diabetes without increasing BMI.

The Value of Telemedicine for the Follow-up of Patients with New Onset Type 1 Diabetes Mellitus During COVID-19 Pandemic in Turkey: A Report of Eight Cases

The current Coronavirus disease-2019 (COVID-19) pandemic has forced health care teams to look for alternative approaches to manage a great number of children with diabetes, not only in rural but also in urban locations. The aim was to assess the provision of information about follow-up of new-onset pediatric type 1 diabetes (T1D) patients, and to investigate the integration of telemedicine into routine clinical care in the long term. The changes in coefficient of variation (CV), standard deviation and percentages of time in range (TIR), time below range (TBR) and time above range were evaluated in eight children with new-onset T1D, diagnosed during the COVID-19 pandemic. The study period was two-months of follow-up using a telemedicine system. Median follow-up time was 51 (24-66) days. Two of the patients were using low glucose suspend system and six were on multiple daily injection therapy. Target TIR values were achieved in seven patients in the last televisit and, in line with recent guidelines, a TBR <70 mg/dL (<3.9 mmol/L) (level 1 hypoglycemia) of <4% and a TBR <54 mg/dL (<3.0 mmol/L) (level 2 hypoglycemia) of <1% were achieved in all patients. Seven patients achieved a CV of <36% at their last televisit. Telemedicine as an alternative follow-up tool during unusual circumstances such pandemics, even in countries where it is not routinely used, could be beneficial to achieve optimum glycemic control in patients with new-onset T1D.

Glycated hemoglobin variability and microvascular complications in patients with type 1 diabetes mellitus.

OBJECTIVES: Glycated hemoglobin (HbA1c) has proven to be indicative in the development of microvascular complications. In this study, the contribution of HbA1c variability to microvascular complications was evaluated. METHODS: Twenty-one cases with type 1 diabetes mellitus (T1DM) who developed microvascular complications and 39 cases without complications, that were similar in terms of gender, age of diagnosis, insulin treatment, insulin doses (U/kg), and mean HbA1c levels were included. RESULTS: Mean age of T1DM diagnosis was 5.87 ± 3.93 years in the complication group and 4.63 ± 3.33 years in the control group. Nephropathy was detected in 17 cases, neuropathy in 8 cases, and retinopathy in 1 case. Nephropathy occurred at a mean age of 11.52 ± 4.12 years and neuropathy at 14.13 ± 5.68 years. The mean HbA1c during follow-up was similar in the group with complications and the control group (8.60 ± 0.63 vs. 8.84 ± 1.32). Adjusted HbA1c-standard deviation (SD) and HbA1c-variation coefficient (CV) values were 1.30 ± 0.65 and 14.36 ± 6.23 in the group with complications (p=0.014), and 0.91 ± 0.37 and 10.59 ± 4.01 in the control group (p=0.013). In the Receiver Operating Characteristic (ROC)-analysis for microvascular complications, the limit value HbA1c-CV was 11.99 (sensitivity: 61.9%, specificity: 71.9%). This value for HbA1c-SD was 0.9699 (sensitivity: 71.43%, specificity: 66.67%). CONCLUSIONS: This study has shown that long-term fluctuations in HbA1c are associated with the development of microvascular complications in type 1 diabetes.