Molecular Genetic Diagnosis with Targeted Next Generation Sequencing in a Cohort of Turkish Osteogenesis Imperfecta Patients and Their Genotype-phenotype Correlation.

Introduction: Osteogenesis imperfecta (OI) is a group of phenotypically and genetically heterogeneous connective tissue disorders that share similar skeletal anomalies causing bone fragility and deformation. This study aimed to investigate the molecular genetic etiology and determine the relationship between genotype and phenotype in OI patients with targeted next-generation sequencing (NGS). Method: In patients with OI, a targeted NGS analysis panel (Illumina TruSight One) containing genes involved in collagen/bone synthesis was performed on the Illumina Nextseq550 platform. Results: Fifty-six patients (female/male: 25/31) from 46 different families were enrolled in the study. Consanguinity between parents was noted in 15 (32.6%) families. Clinically according to Sillence classification; 18(33.1%) patients were considered to type I, 1(1.7%) type II, 26(46.4%) type III and 11(19.6%) type IV. Median body weight was -1.1 (-6.8, - 2.5) SDS, and height was -2.3 (-7.6, - 1.2) SDS. Bone deformity was detected in 30 (53.5%) of the patients, while 31 (55.4%) were evaluated as mobile. Thirty-six (60.7%) patients had blue sclera, 13 (23.2%) had scoliosis, 12 (21.4%) had dentinogenesis imperfecta (DI), and 2 (3.6%) had hearing loss. Disease-causing variants in COL1A1 and COL1A2 genes were found in 24 (52.1%) and 6 (13%) families, respectively. In 8 (17.3%) of the remaining 16 (34.7%) families, the NGS panel revealed disease-causing variants in three different genes (FKBP10, SERPINF1, and P3H1). Nine (23.6%) of the variants detected in all investigated genes were not previously reported in the literature and were classified to be pathogenic according to ACMG guidelines pathogenity scores. In ten (21.7%) families, a disease-related variant was not found in a total of 13 OI genes included in the panel. Conclusion: Genetic etiology was found in 38 (82.6%) of 46 families by targeted NGS analysis. In addition, 9 new variants were assessed in known OI genes which is a significant contribution to the literature.

Effect of Continuous Glucose Monitoring Device Assistance on Glycemic Control of 2023 Kahramanmaras Doublet Earthquake Survivors with Type 1 Diabetes in Adana, Turkey.

OBJECTIVE: The aim of this study was to investigate the effects of the devastating 2023 Kahramanmaras earthquake on the glycemic control of children with type 1 diabetes (T1DM) in Adana, Turkey. Additionally, the study aimed to assess the impact of continuous glucose monitoring (CGM) device assistance on glycemic control after the earthquake. MATERIALS AND METHODS: A retrospective study was conducted involving 134 children with T1DM receiving intensive insulin treatment. Participants were divided into 2 groups: CGM (+) (n = 58), who benefited from CGM device assistance, and CGM (-) (n = 76), who did not utilize CGM device after the earthquake. Glycated hemoglobin (HbA1c) levels were recorded before and after the earthquake. RESULTS: Following the earthquake, the median HbA1c for all participants changed insignificantly from 8.9% to 8.6% (P = .491). However, in the CGM (+) group, HbA1c levels significantly improved post earthquake (P = .001). Conversely, the CGM (-) group experienced a deterioration in glycemic control (P = .027). A 2-way repeated measures ANOVA revealed a significant interaction effect between CGM device usage and the earthquake on HbA1c levels (F = 17.257, P <.001). Subgroup analysis based on age indicated that the effectiveness of CGM was more pronounced in adolescents (≥12 years) than in younger children (<12 years). CONCLUSION: This study highlights the adverse impact of the earthquake on glycemic control in children with T1DM and underscores the effectiveness of CGM in improving glycemic control, particularly among adolescents. The provision of CGM devices following the earthquake led to enhanced outcomes, mitigating the negative effects of the disaster on glycemic control.

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 value of mid-upper arm circumference for malnutrition screening in pediatric celiac disease.

BACKGROUND: Malnutrition rates in pediatric celiac disease (CD) patients range from 20.2% to 67.3%. OBJECTIVES: To investigate the prevalence of malnutrition in pediatric CD patients in Turkey using different anthropometric measurements, including mid-upper arm circumference (MUAC). MATERIAL AND METHODS: This prospective study included 124 patients aged 1-18 years with a diagnosis of CD, admitted to the Pediatric Gastroenterology Outpatient Clinic of Adana City Training and Research Hospital, Turkey. The anthropometric measurements, including weight-for-age (WFA) Z-score, height-for-age (HFA) Z-score, body mass index (BMI)-for-age Z-score, MUAC [cm], and MUAC Z-score were calculated. RESULTS: The study analyzed 75 female (60.5%) and 49 male (39.5%) patients with a mean age of 9.83 ±4.1 years. While 44 patients (35.5%) had malnutrition according to their BMI Z-scores, 60 patients (48.4%) had malnutrition based on their MUAC Z-scores. The number of patients with stunting (HFA value below -2) was 24 (19.4%), and the WFA value was below -2 in 27 (21.8%) patients. Furthermore, the BMI Z-score failed to identify chronic malnutrition in 70.9% of patients. There was a positive linear correlation (r = 0.396) between the BMI value and the MUAC value (p < 0.001). However, the degree of agreement between the BMI Z-scores and MUAC Z-scores was weak (κ: 0.300). CONCLUSIONS: The MUAC Z-score successfully detected acute and chronic malnutrition and should be included in standard anthropometric measurements at follow-up nutritional assessments in CD patients.

An unusual manifestation in a pediatric patient with MAFB mutation: Sacroiliitis in multicentric carpotarsal osteolysis syndrome.

Multicentric carpotarsal osteolysis (MCTO) syndrome, is typically characterized by progressive bone resorption in especially carpal and tarsal bones, in addition to abnormal facial appearance and proteinuria. This disorder is caused by monoallelic pathogenic MAFB mutations, which result in excessive osteoclastogenesis via aberrant receptor activator of nuclear factor kappa-B ligand activation. Most cases are sporadic with de-novo mutations, and it is still unclear why carpal and tarsal bones are predominantly affected. The early phases of MCTO resemble juvenile idiopathic arthritis (JIA) with ankle and wrist swelling and pain, even with inflammatory changes in magnetic resonance imaging. Herein we report a pediatric patient, previously treated with antirheumatic drugs, and eventually diagnosed with MCTO. This case was a descriptive case with exophthalmos, significant proteinuria, and total loss of carpal and tarsal bones at the time of genetic diagnosis. Similar to the literature, our case had typical radiological findings despite methotrexate and anti-tumor necrosis factor-alpha treatment. However, while arthritis affecting joints other than wrists and ankles has not been reported so far in the literature, our case had bilateral sacroiliitis which completely resolved after adalimumab treatment. We cannot be sure if sacroiliitis was incidental or occurred as a component of the disease, nonetheless, we think that sharing our experience may lead to easy and early recognition of MCTO, with more knowledge on rare manifestations of MCTO, and thus we may be able to clarify the benefits of denosumab, which is the most promising agent in early phases of the disease.

The Effect of the SARS-CoV-2 Pandemic on Presentation with Diabetic Ketoacidosis in Children with New Onset Type 1 Diabetes Mellitus

Objective: Diabetic ketoacidosis (DKA) is a life-threatening, acute complication of type 1 diabetes mellitus (T1DM). Infection is the most common precipitating factor for DKA, being responsible for more than 50% of such complications. The frequency and severity of DKA in children with T1DM, before and during the coronavirus disease 2019 outbreak were evaluated and compared with pre-pandemic presentation and severity rates. Methods: In total, 199 patients younger than 18 years were included in the study. Patients were divided into two groups: the Coronavirus disease-2019 (COVID-19) pandemic group (new onset T1DM presenting from March 2020 to March 2021; the control group included new onset T1DM from March 2016 to March 2020. Results: The rate of DKA at presentation was similar (p=0.393) during the pandemic period (58.3%) compared to the pre-pandemic years (44.8-64.3%). Although the percentage of DKA was similar, the rate of severe DKA in the COVID-19 group was higher than previous years. Although not significant, the duration of diabetes symptoms was longer in the COVID-19 period than the previous years. Conclusion: This study suggests that the rate of severe DKA, but not the overall rate of DKA, has increased during the COVID-19 pandemic compared to the prior four years. This may be due to the behavior of the parents of sick children and the limited access to the healthcare system. Despite this limited access, parental concern may have been sufficiently high to seek medical attention for their children, avoiding an increased frequency of DKA as the first presentation of new-onset T1DM.

Electrocardiographic Findings in Children With Growth Hormone Deficiency.

Introduction It has been shown that cardiac functions begin to deteriorate in growth hormone (GH) deficiency even in childhood. However, little is known about how GH deficiency affects arrhythmogenesis. The aim of this study was to evaluate the parameters of P wave dispersion (Pd), QT dispersion (QTd), corrected QT (QTc) dispersion (QTcd), T wave peak-to-end (Tp-e) interval, Tp-e/QT ratio, and Tp-e/QTc ratio in children with GH deficiency. This study also aimed to evaluate the relationship of these parameters with insulin-like growth factor 1 (IGF-1) and insulin-like growth factor binding protein 3 (IGFBP-3). Method In the study, records of children diagnosed with GH deficiency in Adana City Training and Research Hospital Pediatric Endocrine Outpatient Clinic between September 2021 and December 2022 were retrospectively reviewed. The control group consisted of children in the same age group who applied to the Emergency Outpatient Clinic with a complaint of chest pain and no pathological finding was detected. The electrocardiograms (ECGs) of all patients were retrospectively evaluated. Results There were a total of 82 children in the study, 41 of whom were diagnosed with GH deficiency and 41 in the healthy control group. The age and male/female ratio of children with GH deficiency were similar to those in the control group (p>0.05). There were 27 (66%) children with complete GH deficiency and 14 (34%) children with partial GH deficiency. P wave dispersion was similar in both GH-deficient children and control group children. It was also similar in children with complete and partial GH deficiency (p>0.05). QT and QTc dispersions were found to be increased in children with GH deficiency, although not statistically significant, compared to the control group (p>0.05). Tp-e interval, Tp-e/QTmax (longest QT interval), and Tp-e/QTcmax (longest QTc interval) ratios were increased in children with GH deficiency compared to the control group (p=0.001, p=0.003, and p=0.001, respectively). QT and QTc dispersion, Tp-e interval, Tp-e/QTmax, and Tp-e/QTcmax ratios were found to be increased in children with complete GH deficiency compared to children with partial GH deficiency, but the difference was not significant (p>0.05). No correlation was found between these ECG parameters and IGF-1, IGFBP-3, and peak GH levels after stimulation tests (p>0.05). Conclusion We found in our study that the Tp-e interval was longer and Tp-e/QT and Tp-e/QTc ratios were increased in children with GH deficiency. These results suggest that the risk of ventricular arrhythmias in children with GH deficiency may start to increase from childhood. However, further prospective studies are needed to confirm our results.

The Screening of Celiac Serology in Pediatric Patients Diagnosed with Type 1 Diabetes Mellitus.

BACKGROUND: This study aims to detect the rate of celiac antibody test positivity in pediatric patients diagnosed with type 1 diabetes mellitus (T1DM) and determine the characteristics of the patient groups diagnosed with and without celiac disease (CD). METHODS: This study was conducted retrospectively in Adana City Training and Research Hospital, Pediatric Endocrinology Outpatient Clinic with the patients diagnosed with T1DM between September 17, 2017, and January 1, 2022. The patients were examined by 3 different groups. Group 1: celiac patient group, group 2: serology false positive group, and group 3: serology negative group. RESULTS: The study included 418 patients, 228 (54.5%) males and 190 (45.5%) females. About 6% of the patients (25 patients) were in the celiac patient group, 12.6% (53 patients) in the serology false positive group, and 81.3% (340 patients) in the serology negative group. The age at diagnosis was 10 (7.2-12.9) years in the celiac patient group and 8.8 (6.2-12.00) years in the serology false positive group (P = .559). Among 53 patients in the serology false positive group, spontaneous normalization was observed in 66% (35 patients), and positivity was continued during the test follow-up period in 34% (18 patients). There was no significant difference in terms of sex (P = .101), and HbA1c values at diagnosis (P = .557). Tissue transglutaminase IgA titer was 20× Upper limit of normal (ULN) in the celiac patient group and 2.52× ULN in the serology false positive group. CONCLUSION: T1DM and CD are both autoimmune diseases concurrently seen together. CD antibody positivity may be observed at the first presentation of T1DM. While the majority of these antibodies become negative during the follow-up, we wanted to highlight the false positive antibody titers and emphasize that these patients should be followed by endocrinologists and gastroenterologists together.

In vivo evaluation of macular microvasculature in childhood malnutrition using optical coherence tomography angiography.

BACKGROUND: To evaluate the microvascular alterations and foveal avascular zone (FAZ) changes in the foveal and parafoveal region in malnourished children. METHODS: This cross-sectional study analyzed 168 eyes of 85 patients. The subjects were split into 3 groups based on their body mass index (BMI) percentiles and defined as Group 1 (BMI percentiles ≥95th, overnutrition group), Group 2 (BMI <5th percentile, undernutrition group) and Group 3 (BMI ≥5th and <85th percentile, control group). All subjects were examined with optical coherence tomography angiography (OCTA) to evaluate superficial capillary plexus (SCP), deep capillary plexus (DCP) vessel density (VD) and FAZ parameters. The retinal nerve fiber layer (RNFL), average macular ganglion cell-inner plexiform layer (GCL-IPL), inner limiting membrane-retinal pigment epithelium (ILM-RPE) thickness were evaluated using SD-OCT device. RESULTS: Age and gender did not statistically differ across groups (p = 0.12 and p = 0.92). Groups 1 and 2 were found to have significantly higher VD of the superior-hemisphere of the DCP levels than the control group (p = 0.001). The control group's foveal VD of SCP was statistically higher than group 1's (p = 0.012). Parafoveal VD was significantly increased in the superior of the SCP of group 1 and the lower hemisphere of the SCP of group 2 compared with the control group (p = 0.02 and p = 0.02, respectively). The mean FAZ perimeter, choriocapillaris flow area, RNFL, GCL-IPL and ILM-RPE thickness were similar between all groups. CONCLUSION: The childhood undernutrition and overnutrition may affect the density of retinal capillaries. Although the FAZ area and choriocapillary flow did not change, retinal capillary density tended to increase in malnutrition.

Association between clinical variations and copy number variations in cases with Turner syndrome.

OBJECTIVES: Turner syndrome (TS) is one of the most common chromosomal abnormalities with an incidence of approximately one in 2,500 live births. Short stature and primary ovarian insufficiency are two most important characteristic findings of TS. Turner syndrome karyotypes include monosomy X, mosaic structure and X chromosome structural anomalies. Genotypic and phenotypic characteristics vary among cases. This study aimed to evaluate the clinical variations observed in TS cases with the copy number variations (CNV) detected by microarray study. METHODS: Fifty-three patients diagnosed with TS, between the ages of 0-18 were included in the study. Peripheral blood samples were taken from 36 cases for microarray study. RESULTS: Karyotypes were as follows: thirty-three of cases were 45,X, 7 were 45,X/46,XX, 6 were 45,X/46,Xi(Xq), 2 were 46,Xi(Xq), 2 were 45,X/46,r(X), 1 was 45,X/46,Xi(Xp), 1 was 45,X/46,XY and 1 was 45,X/46,X+mar(idicY) karyotype. A significant correlation was found between karyotype groups and FSH values of the cases (p=0.034). In monosomy X and mosaic isochromosome Xq cases, the FSH value was found to be significantly higher than those with 45,X/46,XX mosaic karyotype. CNVs were found in 8 (22.2%) out of 36 cases whose microarray study was performed. Unexpected atypical findings were discussed in the light of the characteristics of CNVs. CONCLUSIONS: In conclusion, the microarray method has a great contribution in explaining many unexpected findings in TS cases. Moreover, those CNV findings may contribute for the explanation of the underlying mechanisms of those anomalies.

The Impact of the CEDD-NET on the Evaluation of Rare Disorders: A Multicenter Scientific Research Platform in the Field of Pediatric Endocrinology

Objective: The database http://cedd.saglik-network.org (CEDD-NET) has been operating since 2013 in Turkey. All pediatric endocrinologists can propose projects to this network. The aim of our study was to determine the impact of CEDD-NET on the transformation of multicenter studies into scientific publications and assess the academic characteristics of the studies that have been transcribed into publication. Methods: All the studies that were opened to patient admission on the website between August 26, 2013 and March 1, 2021 were reviewed. Results: A total of 30 studies were accepted and opened for data entry. The median data collection period was 12 (1.5-24) months, while the median number of researchers participated was 23 (3-180), the median number of cases was 120 (26-192). The average cost was $2113 (1370-3118). Out of 30 studies, data entry was completed for 27. Sixteen publications were produced from 14 studies, 13 ot them have not published yet. The median time from the end of data entry to publication of the study was 686 (168-1608) days. While the median impact factor of the journals in which the studies were published was 1.803 (1.278-5.399), the median number of citations was 6.5 (0-49), and cited by 99 times in Web of Science indexed journals in total. Conclusion: CEDD-NET appears to be productive and effective as all the publications are of high quality that have been published in the Q1-Q2 categories. This study demonstrated the benefits and necessity of establishing nationwide databases, even covering more than one country, in specialized branches, such as pediatric endocrinology where rare diseases are of concern.

Does COVID-19 predispose patients to type 1 diabetes mellitus?

The novel coronavirus disease (COVID-19) has emerged as a global pandemic. This was a prospective, case-control study conducted in Izmir, Turkey. The aim of this study was to assess the relationship between COVID-19 and new-onset T1DM. We included pediatric patients (aged 6 mo-18 yr) with new-onset type-1 diabetes mellitus (T1DM) diagnosed during the COVID-19 pandemic, between April 2020 and January 2021. Polymerase chain reaction was used to diagnose COVID-19 after hospital admission. An enzyme-linked immunoassay for IgM and IgG against SARS-CoV-2 was performed after the diagnosis was confirmed. In the control group, the blood antibody test was conducted as close as possible to the time of the T1DM patient referral. A total of 118 participants were included in the study, comprising 57 (48%) patients with new-onset T1DM and 61 (52%) healthy controls. Of the 57 patients, 36 (63.2%) presented with DKA, 17 (29.7%) with diabetic ketosis, and four (7%) incidentally. The SARS-CoV-2 antibody test was positive in five (8.7%) patients with T1DM and six (10%) controls. The rate of positivity did not differ between the two groups (p = 0.901). It was not possible to demonstrate a clear association between SARS-CoV-2 infection and new-onset T1DM. Whether SARS-CoV-2 increases susceptibility to diabetes by triggering islet cell autoimmunity and affects the timing of overt diabetes in patients with existing autoimmunity should be studied in large cohorts.

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.

A large cohort of disorders of sex development and their genetic characteristics: 6 novel mutations in known genes.

INTRODUCTION: Disorders of sex development (DSD) constitutes a group of congenital conditions that affect urogenital differentiation and are associated with chromosomal, gonadal and phenotypic sex abnormalities. OBJECTIVE: To evaluate the clinical and genetic features of childhood DSD cases. MATERIALS AND METHODS: DSD patients followed up between the years of 2002-2018 were evaluated in terms of their complaints, demographic, clinical features and genetic diagnoses. RESULTS: Out of 289 patients, 143(49.5%) were classified as 46XY DSD, 62(21.5%) as 46XX DSD and 84(29%) as sex chromosomal DSD. Genetic diagnosis was achieved in 150 patients (51.9%). The distribution of the molecular diagnosis of the 46XY DSD patients were; 12 (26.6%) SRD5A2, 10 (22.2%) AR, 7 (15.5%) HSD17B3, 3 (6.6%) WT-1, 2 (4.4%) AMHR2, 2 (4.4%) AMH, 2 (4.4%) LHCGR, 2 (4.4%) HSD3B2, 1 (2.2%) NR5A1, 1 (2.2%) CYP17A1 and 1 (2.2%) SRY mutation. Fifty (80.6%) of the 46XX DSD patients received a diagnosis with clinical and laboratory findings. Twenty-four (38.7%) of them were 21-hydroxylase deficiency, 9(14.5%) Rokitansky-Küster-Hauser Syndrome, 4 (6.5%) 11-ß hydroxylase deficiency, 3 (4.8%) gonadal dysgenesis and 2 (3.2%) aromatase deficiency. In 46XX group pathogenic mutations were detected in 21(33.8%) of the patients. Eighty-four (29%) patients were diagnosed as sex chromosomal disorder. Of these 66 (78.5%) were Turner Syndrome, 6 (7.2%) Klinefelter Syndrome and 10 (11.9%) mix gonadal dysgenesis. Gender re-assignment was decided in 11 patients. Malignant and pre-invasive lesions was diagnosed in 8 (2.7%) patients. CONCLUSION: Many of DSD's are clinically similar and etiology of numerous of them still cannot be established. A multi-disciplinary approach and new rapid genetic diagnostic methods are needed in the process from diagnosis to gender assignment and follow-up.

A New Cause of Obesity Syndrome Associated with a Mutation in the Carboxypeptidase Gene Detected in Three Siblings with Obesity, Intellectual Disability and Hypogonadotropic Hypogonadism

Objective: Carboxypeptidase E (CPE) plays a critical role in the biosynthesis of peptide hormones and neuropeptides in the endocrine system and central nervous system. CPE knockout mice models exhibit disorders such as diabetes, hyperproinsulinaemia, low bone mineral density and neurodevelopmental disorders. Only one patient is described with morbid obesity, intellectual disability, abnormal glucose homeostasis and hypogonadotropic hypogonadism, which was associated with a homozygous frameshift deletion in CPE. Methods: Herein are described three siblings with obesity, intellectual disability and hypogonadotropic hypogonadism. Whole exome sequencing (WES) was performed in the index case. Candidate variants were prioritised and segregation of the variant, consistent with the phenotype of the index case, was assessed by Sanger sequencing in affected siblings and parents. Results: WES analysis revealed a homozygous nonsense c.405C>A (p.Y135*) mutation in CPE. Validation and segregation analysis confirmed the homozygous mutation in the index case and his affected siblings. The parents were phenotypically normal heterozygous mutation carriers. Conclusion: This study provides additional evidence of the association between a homozygous nonsense mutation in CPE and a clinical phenotype consisting of obesity, intellectual disability and hypogonadotropic hypogonadism, which may be considered as a new monogenic obesity syndrome.

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.

A Remarkable Coexistence of Systemic Capillary Leak Syndrome and Diabetes in an 11-Year-Old Boy: A Case Report and Review of the Literature.

Systemic capillary leak syndrome (ISCLS) is a rare disease characterized by unexplained reversible capillary hyperpermeability followed by hypoperfusion, hemoconcentration, and either hypoalbuminemia or total hypoproteinemia. An 11-year-old boy was admitted with vomiting, generalized edema, and hyperglycemia, which was preceded by 5 days of coryzal symptoms, lethargy, and oral aft, without fever. On physical examination, he had tachycardia and hypotension, with severe generalized systemic nonitchy edema, and the laboratory tests supported the conclusion that he had severe hemoconcentration with hemoglobin: 184 g/L, hematocrit: 51.3 %, urea: 20 mmol/L, blood glucose: 11.1 mmol/L, and albumin: 19 gr/L, with normal urine analysis. On the fourth day, the patient was diagnosed with ISCLS, by ruling out other causes of shock and hypoalbuminemia. Intravenous immunoglobulin (IVIG) treatment regimen was administered on two consecutive days (day five and day six). His edema decreased on the fifth day, and the patient was deemed clinically well. There was no compartment syndrome, rhabdomyolysis, or pulmonary edema in the recovery period. However, respiratory virus panel PCR was positive for respiratory syncytial virus (RSV) and enterovirus, which were thought to be the triggering cause of ISCLS. For the differential diagnosis of diabetes, his fasting serum glucose was 13.4 mmol/L, simultaneous C-peptide was 0.44 nmol/L, and HbA1c was 64 mmol/mol, and urine ketone was positive. However, antiglutamic acid decarboxylase, anti-insulin antibody, and islet cell antibody were negative. At the last outpatient visit, 22 months after the diagnosis, his insulin dose was still 0.4 IU/kg/day and HbA1c was 40 mmol/mol, and without prophylaxis, there was no ISCLS attack. Conclusion. Early recognition of ISCLS is important for therapeutic awareness, since it is very rare in childhood and occurs usually without any prior provoking factors in healthy children. With the increase in awareness of the disease, knowledge and experiences about pediatric patients may also increase. We think that our case will contribute to the literature since there have been no pediatric diabetic patients with ISCLS reported.

Melanocortin 4 receptor (MC4R) gene variants in children and adolescents having familial early-onset obesity: genetic and clinical characteristics.

Melanocortin 4 receptor gene plays an important role in food intake, energy balance, and weight control. The autosomal dominantly inherited MC4R variants cause obesity by causing hyperphagia and decreased sense of satiety. Homozygous variants are rarely reported, and they cause earlier/severe obesity. Our objective is to determine the MC4R gene variant frequency in children and adolescents with familial early-onset obesity. One hundred thirty-nine children and adolescents (57 girls/82 boys) whose weight increase started before the age of 5 years and who had early-onset obesity in at least one of their first-degree relatives were included in the study. Obesity is defined as body mass index (BMI) of ≥ 95th percentile, and as extreme obesity is defined if the BMI ≥ 120% of the 95th percentile or ≥ 35 kg/m2. Children having genetic syndromes associated with obesity and mental retardation or taking drugs that promote changes in eating behavior or weight were excluded from the study. Coding region of the MC4R gene was sequenced by using the Illumina MiSeq Next Generation Sequencing System. The mean age of the patients was 7.3 ± 3.7 years, and the mean BMI SDS was 3.7 ± 0.7. While 118 patients (85%) were prepubertal, 21 patients (15%) were pubertal. Seven different variants were identified in 12 patients by giving a variant detection rate of 8.6%, of these five were previously identified missense variants p.N274S, p.S136F, p.V166I, p.R165W, and p.I291SfsX10. One homozygous variant p.I291SfsX10 (c.870delG) was detected in a severely obese 2-year-old boy, and other variants were heterozygous. Two novel variants were found: p.M200del and p.S188L. By using the in silico analysis software, these novel variants were predicted to be disease causing.Conclusion: MC4R gene variants are quite common in childhood obesity in Turkish population. Screening the variants in MC4R gene is necessary in patients with severe childhood-onset obesity. In such patients, comorbidities of obesity can be seen from early years. What is known • The frequency of MC4R mutations in obese patients was approximately 0-6.3%. What is new • In obese Turkish pediatric population, unlike other European countries, MC4R gene variants are quite common as we found a variant rate of 8.6% • We believe it is necessary to screen the variants in MC4R gene in patients with severe childhood-onset obesity and who had early-onset obesity in at least one of their first-degree relatives in Turkish population.

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.