Variant characterisation and clinical profile in a large cohort of patients with Ellis-van Creveld syndrome and a family with Weyers acrofacial dysostosis.

BACKGROUND: Ellis-van Creveld syndrome (EvC) is a recessive disorder characterised by acromesomelic limb shortening, postaxial polydactyly, nail-teeth dysplasia and congenital cardiac defects, primarily caused by pathogenic variants in EVC or EVC2. Weyers acrofacial dysostosis (WAD) is an ultra-rare dominant condition allelic to EvC. The present work aimed to enhance current knowledge on the clinical manifestations of EvC and WAD and broaden their mutational spectrum. METHODS: We conducted molecular studies in 46 individuals from 43 unrelated families with a preliminary clinical diagnosis of EvC and 3 affected individuals from a family with WAD and retrospectively analysed clinical data. The deleterious effect of selected variants of uncertain significance was evaluated by cellular assays. MAIN RESULTS: We identified pathogenic variants in EVC/EVC2 in affected individuals from 41 of the 43 families with EvC. Patients from each of the two remaining families were found with a homozygous splicing variant in WDR35 and a de novo heterozygous frameshift variant in GLI3, respectively. The phenotype of these patients showed a remarkable overlap with EvC. A novel EVC2 C-terminal truncating variant was identified in the family with WAD. Deep phenotyping of the cohort recapitulated 'classical EvC findings' in the literature and highlighted findings previously undescribed or rarely described as part of EvC. CONCLUSIONS: This study presents the largest cohort of living patients with EvC to date, contributing to better understanding of the full clinical spectrum of EvC. We also provide comprehensive information on the EVC/EVC2 mutational landscape and add GLI3 to the list of genes associated with EvC-like phenotypes.

Development and psychometric evaluation of the type 1 diabetes mellitus self-management scale for parents.

BACKGROUND/AIM: Diabetes has become a global epidemic, necessitating effective self-management strategies. This is particularly crucial for parents of children with type 1 diabetes mellitus, as they must make numerous daily decisions and perform complex care activities. Therefore, the aim of this study was to develop a comprehensive diabetes self-management scale specifically for parents of children with type 1 diabetes. This scale aims to holistically address behaviors impacting diabetes self-management and to evaluate its psychometric properties. MATERIALS AND METHODS: A methodological, correlational, and cross-sectional study was conducted with a sample of 190 parents of children with type 1 diabetes mellitus. The scale items were reviewed by five experts to ensure they adequately covered the parents' evaluation of their children's diabetes self-management. Following this, a Turkish language expert assessed the draft scale for language accuracy, comprehensibility, and grammar. The data were analyzed using descriptive statistics (numbers and percentages), Cronbach's α reliability coefficient, factor analysis, and correlation analysis. RESULTS: The Cronbach's alpha for the overall scale was 0.893, and the Cronbach's alpha for the subscales was between 0.757 and 0.845. The item-total score correlations ranged between 0.408 and 0.660 (p < .05). The exploratory factor analysis showed that the scale explained 61.427% of the total variance, and the factor loadings of items ranged from 0.574 to 0.859. The confirmatory factor analysis also showed that the factor loadings of the scale items ranged from 0.574 to 0.859. CONCLUSION: The validity and reliability analyses revealed that the scale is a valid and reliable measurement tool for the Turkish culture.

Anthropometric findings from birth to adulthood and their relation with karyotpye distribution in Turkish girls with Turner syndrome.

To evaluate the anthropometric features of girls with Turner syndrome (TS) at birth and presentation and the effect of karyotype on these parameters. Data were collected from 842 patients with TS from 35 different centers, who were followed-up between 1984 and 2014 and whose diagnosis age ranged from birth to 18 years. Of the 842 patients, 122 girls who received growth hormone, estrogen or oxandrolone were excluded, and 720 girls were included in the study. In this cohort, the frequency of small for gestational age (SGA) birth was 33%. The frequency of SGA birth was 4.2% (2/48) in preterm and 36% (174/483) in term neonates (P < 0.001). The mean birth length was 1.3 cm shorter and mean birth weight was 0.36 kg lower than that of the normal population. The mean age at diagnosis was 10.1 ± 4.4 years. Mean height, weight and body mass index standard deviation scores at presentation were -3.1 ± 1.7, -1.4 ± 1.5, and 0.4 ± 1.7, respectively. Patients with isochromosome Xq were significantly heavier than those with other karyotype groups (P = 0.007). Age at presentation was negatively correlated and mid-parental height was positively correlated with height at presentation. Mid-parental height and age at presentation were the only parameters that were associated with height of children with TS. The frequency of SGA birth was found higher in preterm than term neonates but the mechanism could not be clarified. We found no effect of karyotype on height of girls with TS, whereas weight was greater in 46,X,i(Xq) and 45,X/46,X,i(Xq) karyotype groups.

The relationship of periaortic fat thickness and cardiovascular risk factors in children with Turner syndrome.

Children with Turner syndrome (TS) have a broad range of later health problems, including an increased risk of cardiovascular morbidity and mortality. The aim of this study was to evaluate the relationship between periaortic fat thickness (PAFT) and metabolic and cardiovascular profiles in children with TS. Twenty-nine TS and 29 healthy children and adolescents were enrolled in the study. Anthropometric measurements, pubertal staging, and blood pressure measurements were performed. Fasting serum glucose, insulin, and lipid profile were measured. Periaortic fat thickness was measured using an echocardiography method, which has not previously been applied in children with TS. No difference was found between TS and control subject (CS) in age, weight, waist/hip ratio, HDL cholesterol and LDL cholesterol levels. However, in TS subjects, total cholesterol (p = 0.045) was greater than that in controls. It was determined that 13.7 % (N: 4) of TS subjects had dyslipidemia. Mean fasting glucose, fasting insulin, QUICK-I, HOMA, and FGIR index were similar in TS and in CS, whereas 17.2 % (N: 5) of TS subjects had insulin resistance (IR) and 13.7 % (N: 4) had impaired glucose tolerance. Six subjects (20.6 %) were diagnosed as hypertensive. Periaortic fat thickness was significantly higher in the TS group (p < 0.001) (0.1694 ± 0.025 mm in the TS group and 0.1416 ± 0.014 mm in the CS group) In children with TS, PAFT was positively correlated with fasting insulin, body mass index, and diastolic blood pressure. Our results provide additional evidence for the presence of subclinical cardiovascular disease in TS. In addition to existing methods, we recommend the measurement of periaortic fat thickness in children with TS to reveal the presence of early atherosclerosis.

Ambulatory blood pressure and subclinical cardiovascular disease in children with turner syndrome.

Patients with Turner syndrome (TS) have an increased risk of cardiovascular morbidity. 29 TS and 25 healthy control subjects (CS) were included in the study. We investigated body mass index, waist circumference, fasting glucose and insulin, homeostatic model assessment (HOMA) index, serum lipids, oral glucose tolerance test, 24-h ambulatory blood pressure (BP) monitoring, and carotid intima-media thickness (CIMT) and compared them with CS. 28 % (N = 7) of TS had insulin resistance (IR), and 36 % (N = 9) had IGT. Mean systolic BP and diastolic BP (DBP) dip were 7.24 ± 3.97 % and 11.84 ± 6.2 %, respectively. CIMT was greater in TS than in CS (p = 0.00). CIMT was correlated positively with fasting insulin, HOMA index, and insulin-sensitivity check index (r = 0.563, p = 0.015; r = 0.603, p = 0.008; and r = 0.623, p = 0.006, respectively) and negatively with fasting glucose-to-insulin ratio and DBP dipping (r = -0.534, p = 0.022; r = -0.534, p = 0.00, respectively) in the two groups combined. These results provide additional evidence for the presence of subclinical cardiovascular disease and its relation to hypertension in TS. They also indicate a significant relation between DBP dipping and increased arterial stiffness. It is also important to note that our findings show significant relationships between insulin sensitivity and cardiovascular changes and underline the importance of insulin resistance for predicting cardiovascular disease.

17α Hydroxylase/17,20 lyase deficiency: clinical features and genetic insights from a large Turkey cohort.

PURPOSE: 17α Hydroxylase/17,20 lyase deficiency (17OHD) is a rare form of congenital adrenal hyperplasia, typically diagnosed in late adolescence with symptoms of pubertal delay and hypertension. This study aimed to determine the clinical and laboratory characteristics of 17OHD cases and gather data on disease management. METHODS: Data from 97 nationwide cases were analyzed using the CEDD-NET web system. Diagnostic, follow-up findings, and final heights of patients were evaluated. RESULTS: Mean age at admission was 13.54 ± 4.71 years, with delayed puberty as the most common complaint. Hypertension was detected in 65% at presentation; hypokalemia was present in 34%. Genetic analysis revealed Exon 1-6 homozygous deletion as the most frequent mutation, identified in 42 cases. Hydrocortisone replacement was universal; pubertal replacement was administered to 66 cases. Antihypertensive treatment was required in 57 (90%) patients. Thirty-seven cases reached final height, with an average SD of 0.015 in 46,XX and -1.43 in 46,XY. Thelarche and pubarche did not develop properly in some cases despite estradiol treatment. CONCLUSION: This study represents the largest cohort of pediatric cases of 17-hydroxylase deficiency (17OHD) documented in the literature. Hypertension and hypokalemia can serve as guiding indicators for early diagnosis.The final height is typically considered to be normal. The relationship between genotype and phenotype remains elusive. The initial genetic test for exon 1-6 deletions may be MLPA in our region.

Pentoxifylline treatment for protecting diabetic retinopaty in children with type 1 diabetes.

OBJECTIVE: The purpose of this study was to determine whether oral pentoxifylline (PTX) would improve retinal microvascular hemodynamics in children with type 1 diabetes mellitus (DM). PATIENTS AND METHODS: Non-invasive ultrasonographic measurements were made in 56 type 1 diabetic patients. The diabetic patients were matched first in terms of age, diabetes duration, then one individual within each pair was randomized into a pentoxifylline group and a control group. Pentoxifylline was administered for 6 months. We investigated the change of peak systolic velocity (PSV), end diastolic velocity (EDV), pulsatility index (PI), and resistivity index (RI) of central retinal artery (CRA) at 6 months after pentoxifylline. We investigated the relationship between PI, RI and carotide cross-sectional compliance (C-CSC). RESULTS: In comparison to changes in CRA measurements between the two groups, the pentoxifylline treatment group had significantly lower PI values (p=0.01). The RI, PSV and EDV were lower in pentoxifylline group but not statistically different. There was a positive correlation between CRA PSV and carotid Vmax (cm/s) (r=0.29, p=0.02) and also C-CSC (r=0.27, p=0.03). In addition, there was a positive correlation between PI and C-CSC (r=0.3, p=0.02). In the pentoxifylline group there was a significant reduction in systolic blood pressure, diastolic blood pressure, microalbuminuria and an increase in HDL level. CONCLUSION: Our results suggest that pentoxifylline may have a protective action for diabetic retinopathy and might modulate risk factors for atherosclerosis in type 1 diabetes.

Serum ischemia-modified albumin level and its association with cardiovascular risk factors in obese children and adolescents.

BACKGROUND: Serum ischemia modified albumin (IMA) levels have been previously studied and found to correlate with some anthropometric and laboratory measurements in adult obesity. IMA had not been studied in obese children and adolescents. OBJECTIVE: The aim of the study is to analyze serum IMA levels and to evaluate their correlation with cardiovascular risk factors in obese children and adolescents with and without metabolic syndrome (MS). SUBJECTS AND METHODS: Sixty-one obese children/adolescents and 33 healthy children were included in the study. The obese group was divided into four subgroups, including MS (n=25), non-MS (n=36), liver steatosis (n=19) and non-liver steatosis (n=42) groups. Blood was collected to analyze biochemical parameters and IMA. Epicardial adipose tissue thickness was measured with echocardiography, and liver steotosis was determined with ultrasonography for each subject. RESULTS: Body mass index (BMI), waist circumferences (WC), left ventricular mass (LVM) and epicardial adipose tissue (EAT) thickness were significantly higher in obese subjects. Serum IMA levels were significantly higher in the metabolic syndrome (MS) and hepatosteotosis groups. Additionally, LVM and EAT thickness were found to be correlated with serum IMA levels in these groups. CONCLUSIONS: Our study suggests that serum IMA levels may be used to predict cardiovascular risk in obese children with MS and hepatosteotosis. This may be related to the duration of obesity in childhood ending in adulthood.

Evaluation of nutritional status and related factors in children with cystic fibrosis.

BACKGROUND: This study aimed to evaluate the nutritional status and body composition in children with cystic fibrosis (CF), in accordance with the new nutritional targets defined by European Society for Clinical Nutrition and Metabolism (ESPEN), the European Society for Paediatric Gastroenterology, Hepatology and Nutrition (ESPGHAN) and the European Cystic Fibrosis Society (ECFS) 2016. METHODS: In this cross-sectional study, data were collected prospectively in a single centre. A record was made for a total of 95 patients with CF of clinical data. Anthropometric data were evaluated using the World Health Organization growth standards. The bone mineral density (BMD) z-score was adjusted for height by measuring dual-energy X-ray absorptiometry (DXA). The speed of sound z-score values were measured with quantitative ultrasound (QUS). RESULTS: The nutritional status was normal in 37.9% of patients aged < 2 years and 33.3% of patients aged 2-18 years. When the DXA BMD z-score values were corrected for height, it was determined that the BMD deficit was less. The calcaneus QUS SOS z-score mean value was lower than the mean height for age z-score adjusted BMD (BMDHAZ). CONCLUSIONS: The malnutrition rates of CF patients were higher than the rates previously reported in literature. As there are insufficient nutritional data in Turkey, there is a need for multi-centre studies to determine the frequency of malnutrition according to the new classifications. It is clear that QUS measurements cannot replace DXA in the diagnosis of osteopenic bone disease. However, when low values are determined with QUS as the first recommended measurement in the screening of bone status, it can be considered appropriate to confirm the status with DXA.

A Stk4-Foxp3-NF-κB p65 transcriptional complex promotes Treg cell activation and homeostasis.

The molecular programs involved in regulatory T (Treg) cell activation and homeostasis remain incompletely understood. Here, we show that T cell receptor (TCR) signaling in Treg cells induces the nuclear translocation of serine/threonine kinase 4 (Stk4), leading to the formation of an Stk4-NF-κB p65-Foxp3 complex that regulates Foxp3- and p65-dependent transcriptional programs. This complex was stabilized by Stk4-dependent phosphorylation of Foxp3 on serine-418. Stk4 deficiency in Treg cells, either alone or in combination with its homolog Stk3, precipitated a fatal autoimmune lymphoproliferative disease in mice characterized by decreased Treg cell p65 expression and nuclear translocation, impaired NF-κB p65-Foxp3 complex formation, and defective Treg cell activation. In an adoptive immunotherapy model, overexpression of p65 or the phosphomimetic Foxp3S418E in Stk3/4-deficient Treg cells ameliorated their immune regulatory defects. Our studies identify Stk4 as an essential TCR-responsive regulator of p65-Foxp3-dependent transcription that promotes Treg cell-mediated immune tolerance.

Investigation of the effect of epicardial adipose tissue thickness on cardiac conduction system in children with type 1 diabetes mellitus.

Objectives Investigation of the association between epicardial adipose tissue thickness (EATT) and P-wave dispersion (Pd), QT dispersion (QTd), corrected QT dispersion (QTcd) and Tp-e interval in children with Type 1 Diabetes Mellitus (T1DM) was aimed. Methods Forty-one children with T1DM and 41 age- and gender-matched healthy children were included in the study. Demographical characteristics of all cases were examined. In echocardiography; in addition to conventional echocardiographic measurements, end-systolic EATT was measured from right ventricular free wall. In electrocardiogram; Pd, QTd, QTcd and Tp-e interval durations, as well as Tp-e/QT and Tp-e/QTc ratios were calculated. Correlation values between EATT and electrocardiographic parameters were also noted. Results Mean age of the patient group was determined to be 12.43 ± 3.04 years and that of the control group was determined to be 12.08 ± 2.56 years. There was no significant difference between the groups in regard to age, gender, body weight, height and body mass index. In the patient group; EATT, Pd, QTd, QTcd and Tp-e interval were determined to be significantly higher compared to the control group. In the patient group, no significant correlation was determined between EATT and Pd, QTd, QTcd and Tp-e. However, when both patient and control groups were evaluated together, a statistically significant positive correlation was determined between EATT and Pd, QTd, QTcd and Tp-e. Conclusions In children with T1DM, an increase in epicardial adipose tissue thickness and in risk of cardiac arrhythmias has been demonstrated. To reveal the possible unfavorable effects of EATT on cardiac conduction system in T1DM patients needs further studies.

Evaluation of Periaortic Adiposity and Metabolic Disorders in Obese Children.

OBJECTIVE: To evaluate the relationship between periaortic fat thickness (PAFT) and parameters involved in the development of metabolic complications of the cardiovascular system in obese children and to assess the usefulness of echocardiographic measurements of PAFT in correlation with cardiovascular risk factors. METHODS: The study was conducted with 263 obese and 100 healthy children and adolescents. PAFT was measured with echocardiography method which was recently performed in obese children and adolescents. RESULTS: PAFT was significantly higher in the obese group (0.258±0.031 mm) than in the control group (0.137±0.032 mm) (p<0.001). In multivariable regression analysis, body mass index-standard deviation score and total body fat were predictors of PAFT. The area under the receiver operating characteristic curve was 0.989 and was quite significant at p<0.001. PAFT above 0.179 mm was determined as the cut-off value in obese children and adolescents (sensitivity=1, specificity=0.97). CONCLUSION: The measurement of PAFT in obese children and adolescents may be a good method to reveal the presence of early cardiovascular risk.

Prediabetes and Cardiovascular Parameters in Obese Children and Adolescents.

OBJECTIVE: In this study, our aim was to determine cardiovascular risk and cardiac function in prediabetic obese children and adolescents. METHODS: The study was conducted on 198 obese children and adolescents 6-18 years of age. Anthropometric measurements, blood pressure measurements, oral glucose tolerance test, lipid profile, and HbA1c levels of patients were assessed. Prediabetes was defined according to American Diabetes Association criteria. Left ventricular mass index (LVMi), carotid intima-media thickness (c-IMT), and tissue Doppler measurements records were used. RESULTS: LVMi was found to be significantly higher in the prediabetes group (p=0.03). There were no statistically significant differences in right ventricular tissue Doppler measurements between the prediabetic and non-prediabetic groups. Left ventricular tissue Doppler measurements were significantly higher in the prediabetes group: LVEEM (left ventricular E/e ratio) (p=0.04); LVEM (left ventricular myocardial velocity cm/s) (p=0.035). LVMi was found to positively correlate with triglyceride level, diastolic blood pressure, waist circumference, body weight standard deviation score and to negatively correlate with high-density lipoprotein cholesterol (p=0.043, r=0.15; p=0.039, r=0.15; p=0.025, r=0.17; p=0.009, r=0.19; p=0.038, r=-0.15, respectively). LVEM was correlated with glucose (p=0.046, r=0.15) and LVEEM was correlated with systolic blood pressure (p=0.035, r=0.15). In linear regression analysis for clinical cardiovascular risk factors, fasting glucose level was the best predictor of LVEM. CONCLUSION: In this study, deterioration of cardiac function in prediabetic obese children and adolescents was shown. We recommend determining cardiovascular risk and cardiac dysfunction at early stages in prediabetic obese children and adolescents.

Is there a relationship between cardiovascular risk factors and dehydroepiandrosterone sulfate levels in childhood obesity?

AIM: In this study, parameters of metabolic syndrome and dehydroepiandrosterone sulfate (DHEAS) levels in obese children and adolescents were evaluated and the associations between these factors were analyzed. METHOD: One hundred obese and 40 healthy children/adolescents were included in the study. Pubertal stages, anthropometric and blood pressure measurements were recorded. Levels of fasting serum lipids, glucose, insulin, and DHEAS, and liver function tests were determined. Carotid intima-media thickness (CIMT) was measured using two-dimensional echocardiography. Steatorrhoeic hepatosis was evaluated using abdominal ultrasonography in the obese group. RESULTS: Mean body weight, body mass index, waist, hip circumference, waist/hip ratio, homeostatic model assessment of insulin resistance, triglycerides, high-density lipoprotein cholesterol, alanine transferase, DHEAS, and CIMT values were significantly higher in the obese group than in the controls. DHEAS levels were found to be positively correlated with waist circumference, waist/hip ratio, and CIMT. CONCLUSION: Early determination of metabolic and cardiac dysfunction in obese children is important for the prevention of future complications. Since in this study we found a strong association between DHEAS levels and obesity-related metabolic and cardiovascular risk factors, we believe that this may lead to increased interest in further studies of DHEAS in the search for new treatment approaches.

Assessment of Cardiovascular Parameters in Obese Children and Adolescents with Non-Alcoholic Fatty Liver Disease.

OBJECTIVE: The aim of this study was to evaluate the periaortic fat thickness (PAFT) using conventional echocardiography in obese children and adolescents with non-alcoholic fatty liver disease (NAFLD). METHODS: Two hundred and ninety-seven obese children and adolescents were included in the study. Anthropometric measurements were made in all subjects, and fasting venous blood samples were taken for determination of glucose, insulin, total cholesterol, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, triglycerides, alanine aminotransferase (ALT) and aspartate aminotransferase (AST) levels. Ultrasonography of the liver was used for assessment of NAFLD and the subjects were grouped as NAFLD and non-NAFLD. Echocardiography was performed in all subjects. RESULTS: PAFT was higher in patients with NAFLD compared with the non-NAFLD group. In patients with NAFLD, PAFT was positively correlated with waist circumference and with total cholesterol levels. In multiple regression analysis, waist circumference (ß=0.28, p=<0.001) was found to be the best predictor of PAFT. CONCLUSION: Conventional echocardiography may be used to determine increased PAFT at an early stage in obese children and adolescents with NAFLD for careful monitoring of cardiovascular risk.

Ambulatory blood pressure and subclinical cardiovascular disease in patients with congenital adrenal hyperplasia: a preliminary report.

OBJECTIVE: There is an increased risk of cardiovascular morbidity in children and adolescents with classical congenital adrenal hyperplasia (CAH), presumably associated with obesity, hypertension, impaired glucose tolerance and dyslipidemia. This study was designed to evaluate the metabolic and cardiovascular profile of a group of children with classical CAH from the perspective of cardiovascular risk. METHODS: Twenty-five CAH patients and 25 healthy controls were included in the study. Metabolic and anthropometric parameters were investigated and compared in these two groups. RESULTS: Subjects in the CAH group were shorter than the controls (p=0.001) and had higher body mass index values (p=0.033). Diastolic blood pressure (DBP) (p=0.027) and carotid intima-media thickness (CIMT) values (p=0.006) were also higher in the patient group. In 24% (n=6) of CAH patients, 24-h ambulatory BP monitoring showed arterial hypertension. CIMT was significantly higher in the hypertensive patients than in those with no hypertension (p=0.013). Twenty percent (n=5) of CAH patients had nocturnal hypertension. CIMT was significantly greater in the nocturnal hypertensive group (p=0.02). Mean systolic BP (SBP) and DBP dipping were significantly different in the CAH patients (p<0.001). CIMT correlated negatively with DBP dipping (r=-0632, p=0.037) in these patients. CONCLUSION: These results provide additional evidence for the presence of subclinical cardiovascular disease in classical CAH patients and its relationship with hypertension.

Growth curves for Turkish Girls with Turner Syndrome: Results of the Turkish Turner Syndrome Study Group.

OBJECTIVE: Children with Turner syndrome (TS) have a specific growth pattern that is quite different from that of healthy children. Many countries have population-specific growth charts for TS. Considering national and ethnic differences, we undertook this multicenter collaborative study to construct growth charts and reference values for height, weight and body mass index (BMI) from 3 years of age to adulthood for spontaneous growth of Turkish girls with TS. METHODS: Cross-sectional height and weight data of 842 patients with TS, younger than 18 years of age and before starting any therapy, were evaluated. RESULTS: The data were processed to calculate the 3rd, 10th, 25th, 50th, 75th, 90th and 97th percentile values for defined ages and to construct growth curves for height-for-age, weight-for-age and BMI-for-age of girls with TS. The growth pattern of TS girls in this series resembled the growth pattern of TS girls in other reports, but there were differences in height between our series and the others. CONCLUSION: This study provides disease-specific growth charts for Turkish girls with TS. These disease-specific national growth charts will serve to improve the evaluation of growth and its management with growth-promoting therapeutic agents in TS patients.