Systematic genetic testing for recessively inherited monogenic diabetes: a cross-sectional study in paediatric diabetes clinics.

AIMS/HYPOTHESIS: Current clinical guidelines for childhood-onset monogenic diabetes outside infancy are mainly focused on identifying and testing for dominantly inherited, predominantly MODY genes. There are no systematic studies of the recessively inherited causes of monogenic diabetes that are likely to be more common in populations with high rates of consanguinity. We aimed to determine the contribution of recessive causes of monogenic diabetes in paediatric diabetes clinics and to identify clinical criteria by which to select individuals for recessive monogenic diabetes testing. METHODS: We conducted a cross-sectional study of 1093 children from seven paediatric diabetes clinics across Turkey (a population with high rates of consanguinity). We undertook genetic testing of 50 known dominant and recessive causes of monogenic diabetes for 236 children at low risk of type 1 diabetes. As a comparison, we used monogenic diabetes cases from UK paediatric diabetes clinics (a population with low rates of consanguinity). RESULTS: Thirty-four children in the Turkish cohort had monogenic diabetes, equating to a minimal prevalence of 3.1%, similar to that in the UK cohort (p = 0.40). Forty-one per cent (14/34) had autosomal recessive causes in contrast to 1.6% (2/122) in the UK monogenic diabetes cohort (p < 0.0001). All conventional criteria for identifying monogenic diabetes (parental diabetes, not requiring insulin treatment, HbA1c ≤ 58 mmol/mol [≤7.5%] and a composite clinical probability of MODY >10%) assisted the identification of the dominant (all p ≤ 0.0003) but not recessive cases (all p ≥ 0.2) in Turkey. The presence of certain non-autoimmune extra-pancreatic features greatly assisted the identification of recessive (p < 0.0001, OR 66.9) but not dominant cases. CONCLUSIONS/INTERPRETATION: Recessively inherited mutations are a common cause of monogenic diabetes in populations with high rates of consanguinity. Present MODY-focused genetic testing strategies do not identify affected individuals. To detect all cases of monogenic paediatric diabetes, it is crucial that recessive genes are included in genetic panels and that children are selected for testing if they have certain non-autoimmune extra-pancreatic features in addition to current criteria.

Pediatricians' COVID-19 experiences and views on the willingness to receive COVID-19 vaccines: a cross-sectional survey in Turkey.

Developing an effective and safe vaccine against Covid-19 will facilitate return to normal. Due to hesitation toward the vaccine, it is crucial to explore the acceptability of the COVID-19 vaccine to the public and healthcare workers. In this cross-sectional survey, we invited 2251 pediatricians and 506 (22%) of them responded survey and 424 (84%) gave either nasopharyngeal swap or antibody assay for COVID-19 and 71 (14%) of them got diagnosis of COVID-19. If the effective and safe COVID-19 vaccine was launched on market, 420 (83%) of pediatrician accepted to get vaccine shot, 422 (83%) of them recommended vaccination to their family members, 380 (75%) of them accepted to vaccine their children and 445 (85%) of them offered vaccination to their pediatric patients. Among the participated pediatricians 304 (60%) of them thought COVID-19 vaccine should be mandatory. We found that there are high COVID-19 vaccine willingness rates for pediatricians for themselves, their own children, family members and their pediatric patients. We also found that being a pediatric subspecialist, believing in achieving an effective vaccine, willingness to participate in the phase 1-2 clinical vaccine trial, willingness to get an influenza shot this season, believing a vaccine and vaccine passport should be mandatory were significant factors in accepting the vaccine. It is important to share all information about COVID-19 vaccines, especially effectiveness and safety, with the public in a clear communication and transparency. The opposite will contribute to vaccine hesitancy and anti-vaccine movement.

Distribution of α-actinin-3 rs1815739 and angiotensin-1 converting enzyme InDel polymorphisms in Turkish bodybuilders.

The determination of the genetic profiles of successful athletes and the effects of these genetic parameters on athletic performance is gaining increasing interest. The majority of studies assessing the genetics of athletes usually analyse the most well-known genetic variations in athletes associated with the different specialties. The aim of the present study was to analyse the ACE InDel and ACTN3 rs1815739 polymorphisms in Turkish bodybuilders. A total of 11 male bodybuilders were recruited and genotyped for these polymorphisms. The respective percentage of the ACE II, ID and DD genotypes were 18, 73 and 9. For the ACTN3 genotype, the respective frequencies were 55 and 45 for the RX and RR genotypes. No XX genotype was detected. The allelic counts were 12 (55%) for I and 10 (45%) for the D alleles of ACE; and 12 (55%) and 10 (45%) for R and X alleles, respectively, for the ACTN3 genotype. Additionally, 5 athletes had ID + RX genotypes in terms of ACE InDel and ACTN3 rs1815739 polymorphisms, respectively. These results indicate the importance of endurance related alleles of ACE and ACTN3 in bodybuilders. The results of the present are in agreement with previous studies, highlighting a potential association between specific polymorphisms and the endurance-related nature of bodybuilders. Further studies with larger cohorts are required to understand the association between these polymorphisms and specific parameters performance in bodybuilders.

The Use of Social Network in Daily Pediatric Practice and Education: Turkish Pediatric Atelier.

Using social media applications in pediatric education is not outdated, and its effectiveness has not been tested yet. For this reason, we shared the first results of the Pediatric Atelier experience that we realized through telegram application. We make an online survey to investigate the needs, requirements, pleasure, and suggestions of members through a web-based questionnaire. This cross-sectional survey study was delivered only to participants who were members of the workshop via their email addresses. Online questionnaires organized using Google Forms were sent to pediatric workshop members between March and June 2019. The questionnaire consisted of questions that measured the participants' basic demographic data, the use of the workshop, and the overall impact of the workshop on their professional behavior. While the institutions and positions of the participants were recorded, no other personal data (such as address and telephone) were collected. Among the 997 members, 417 (42%) of them answered the questionnaire. Respondents included 300 (72%) pediatrician, 21 (5%) pediatric subspeciality fellows, and 75 (18%) pediatric subspecialists. Of the 417 respondents, 217 (52%) were working in Istanbul, and 200 (48%) were working in other cities of Turkey. Among the responders, 233 (56%) were working in private hospitals or doctor offices. A total of 520 cases were consulted in 241 days of study period. Most consultations (n = 309, %59) were made from the Istanbul metropolitan area, and 203 (40%) consultations were from other cities of Turkey. The most frequently consulted departments were Pediatric infectious diseases: 166 (32%), Pediatric hematology and oncology: 56 (11%), and Neonatology: 43 (8%). Of the 520 consulted cases, 44 (8%) were related to life-threatening events, and 25 of them were hospitalized in the intensive care units, and 6 of them were required surgical operations. Of the 94% of responders thought this platform was useful and 82% of them stated that the case counseling part of the atelier was the most useful part. We think that the development of technology and artificial intelligence may lead to the usage of on-line platforms or systems in clinical medical practice. Clinical Trial Registration (if any). Registry name, registration number, web link to study on registry, and data sharing statement.

Revisiting Classical 3ß-hydroxysteroid Dehydrogenase 2 Deficiency: Lessons from 31 Pediatric Cases.

CONTEXT: The clinical effects of classical 3ß-hydroxysteroid dehydrogenase 2 (3ßHSD2) deficiency are insufficiently defined due to a limited number of published cases. OBJECTIVE: To evaluate an integrated steroid metabolome and the short- and long-term clinical features of 3ßHSD2 deficiency. DESIGN: Multicenter, cross-sectional study. SETTING: Nine tertiary pediatric endocrinology clinics across Turkey. PATIENTS: Children with clinical diagnosis of 3ßHSD2 deficiency. MAIN OUTCOME MEASURES: Clinical manifestations, genotype-phenotype-metabolomic relations. A structured questionnaire was used to evaluate the data of patients with clinical 3ßHSD2 deficiency. Genetic analysis of HSD3B2 was performed using Sanger sequencing. Novel HSD3B2 mutations were studied in vitro. Nineteen plasma adrenal steroids were measured using LC-MS/MS. RESULTS: Eleven homozygous HSD3B2 mutations (6 novel) were identified in 31 children (19 male/12 female; mean age: 6.6 ±â€…5.1 yrs). The patients with homozygous pathogenic HSD3B2 missense variants of > 5% of wild type 3ßHSD2 activity in vitro had a non-salt-losing clinical phenotype. Ambiguous genitalia was an invariable feature of all genetic males, whereas only 1 of 12 female patients presented with virilized genitalia. Premature pubarche was observed in 78% of patients. In adolescence, menstrual irregularities and polycystic ovaries in females and adrenal rest tumors and gonadal failure in males were observed. CONCLUSIONS: Genetically-documented 3ßHSD2 deficiency includes salt-losing and non-salt-losing clinical phenotypes. Spared mineralocorticoid function and unvirilized genitalia in females may lead to misdiagnosis and underestimation of the frequency of 3ßHSD2 deficiency. High baseline 17OHPreg to cortisol ratio and low 11-oxyandrogen concentrations by LC-MS/MS unequivocally identifies patients with 3ßHSD2 deficiency.

Glucocorticoid deficiency causes transcriptional and post-transcriptional reprogramming of glutamine metabolism.

Background: Deficient glucocorticoid biosynthesis leading to adrenal insufficiency is life-threatening and is associated with significant co-morbidities. The affected pathways underlying the pathophysiology of co-morbidities due to glucocorticoid deficiency remain poorly understood and require further investigation. Methods: To explore the pathophysiological processes related to glucocorticoid deficiency, we have performed global transcriptional, post-transcriptional and metabolic profiling of a cortisol-deficient zebrafish mutant with a disrupted ferredoxin (fdx1b) system. Findings: fdx1b−/− mutants show pervasive reprogramming of metabolism, in particular of glutamine-dependent pathways such as glutathione metabolism, and exhibit changes of oxidative stress markers. The glucocorticoid-dependent post-transcriptional regulation of key enzymes involved in de novo purine synthesis was also affected in this mutant. Moreover, fdx1b−/− mutants exhibit crucial features of primary adrenal insufficiency, and mirror metabolic changes detected in primary adrenal insufficiency patients. Interpretation: Our study provides a detailed map of metabolic changes induced by glucocorticoid deficiency as a consequence of a disrupted ferredoxin system in an animal model of adrenal insufficiency. This improved pathophysiological understanding of global glucocorticoid deficiency informs on more targeted translational studies in humans suffering from conditions associated with glucocorticoid deficiency. Fund: Marie Curie Intra-European Fellowships for Career Development, HGF-programme BIFTM, Deutsche Forschungsgemeinschaft, BBSRC.

-174 G/C polymorphism of interleukin 6 gene is not significantly different in Turkish professional short and long distance runners.

Interleukin-6 (IL-6) is a kind of multifunctional cytokine and involved in mediating muscle repair metabolism, and therefore athletic capacity.  Muscular and circulating IL-6 levels increase in response to physical exercise. Responsible gene coding for IL-6 has a functional polymorphism in its promoter region, -174 G/C (rs1800795). We aimed to analyze the association of G allele and GG genotype in Turkish professional athletes and compare the allelic and genotypic difference between short distance and long distance runners. For this purpose, we enrolled 40 (24 short distance runners and 16 long distance runners) Turkish professional athletes to the study. Real time genotyping procedure was carried out to determine the -174 G/C polymorphism. G allele and GG genotype was more prevalent than the others in our cohort. We found no statistically significant difference between short and long distance runners in the terms of genotype (p=0.07). Our study suggests that-174 G/C polymorphism of IL-6 gene differs in athletes, G allele and GG genotype is higher than the other ones, at least in Turkish athletes, and therefore should be taken into consideration when determining genetic aspects of athletes. Further studies are necessary to confirm our results and show the effect of the given polymorphism in sports science.

Incidence of Type 1 Diabetes in Children Aged Below 18 Years during 2013-2015 in Northwest Turkey

Objective: To assess the incidence of type 1 diabetes mellitus (T1DM) in children under 18 years of age in the northwest region of Turkey during 2013-2015. Methods: All newly diagnosed T1DM cases were recorded prospectively during 2013-2015. Total, as well as gender and age group specific (0-4, 5-9, 10-14 and 15-17 age) mean incidences per 100,000 per year were calculated. Results: There were 1,773 patients diagnosed during 2013-2015 (588 cases in 2013, 592 cases in 2014, 593 cases in 2015). Of these, 862 (48.6%) were girls and 911 (51.4%) were boys. The mean age at diagnosis was 9.2±4.2 years and it was not significantly different between girls (9.0±4.1 years) and boys (9.4±4.4 years) (p=0.052). The crude mean incidence was 8.99/100.000 confidence interval (CI) (95% CI: 8.58-9.42). Although mean incidence was similar between boys [8.98/100.000 (CI: 8.40 to 9.58)] and girls [9.01/100.000 (CI: 8.42 to 9.63)], there was male predominance in all groups except for 5-9 year age group. The standardized mean incidence was 9.02/100.000 according to the World Health Organization standard population. The mean incidence for the 0-4, 5-9, 10-14 and 15-17 age groups was 6.13, 11.68, 11.7 and 5.04/100.000 respectively. The incidence of T1DM was similar over the course of three years (p=0.95). A significant increase in the proportion of cases diagnosed was observed in the autumn-winter seasons. Conclusion: The northwest region of Turkey experienced an intermediate incidence of T1DM over the period of the study.

Emergence of insulin resistance following empirical glibenclamide therapy: a case report of neonatal diabetes with a recessive INS gene mutation.

BACKGROUND: As KATP channel mutations are the most common cause of neonatal diabetes mellitus (NDM) and patients with these mutations can be treated with oral sulfonylureas, empiric therapy is a common practice for NDM patients. CASE PRESENTATION: A non-syndromic, small for gestational age baby born to first-degree consanguineous parents was diagnosed with NDM. Because of hypo- and hyperglycemic episodes and variability in insulin requirement, we initiated a trial of glibenclamide, with a presumptive diagnosis of NDM caused by a KATP channel mutation. However, this empiric sulfonylurea trial did not improve the patient's glycemic control and resulted in resistance to exogenous insulin. Genetic testing identified a previously reported homozygous INS promoter mutation (c.-331C>G), which was not responsive to sulfonylurea therapy. CONCLUSIONS: In light of our results, we recommend to confirm the genetic diagnosis as soon as possible and decide on sulfonylurea treatment after a genetic diagnosis is confirmed.

Association Between Endocrine Diseases and Serous Otitis Media in Children.

OBJECTIVE: Otitis media with effusion (OME) is a condition in which fluid is retained in the middle ear cavity. The association between endocrine disorders and OME has not yet been determined. This study aimed to investigate the presence of OME in children diagnosed with an endocrine disease and the relationship between these two conditions. METHODS: The study was conducted on 918 pediatric patients (440 boys, 478 girls; mean age: 8.40, range 3-15 years) and 158 healthy controls (76 boys, 79 girls; mean age: 8.31, range 3-15 years). All children underwent an ear examination and a tympanometry performed by an otorhinolaryngologist. Tympanometry results were used to diagnose OME. RESULTS: OME was detected in 205 (22.3%) of 918 patients and in 19 (12.0%) of 158 subjects in the control group. The difference in frequency of OME between the two groups was statistically significant (p=0.003). CONCLUSION: The results of the study reveal that there may be a tendency towards the occurrence of OME in pediatric endocrinology patients.

Autosomal-Recessive Mutations in SLC34A1 Encoding Sodium-Phosphate Cotransporter 2A Cause Idiopathic Infantile Hypercalcemia.

Idiopathic infantile hypercalcemia (IIH) is characterized by severe hypercalcemia with failure to thrive, vomiting, dehydration, and nephrocalcinosis. Recently, mutations in the vitamin D catabolizing enzyme 25-hydroxyvitamin D3-24-hydroxylase (CYP24A1) were described that lead to increased sensitivity to vitamin D due to accumulation of the active metabolite 1,25-(OH)2D3. In a subgroup of patients who presented in early infancy with renal phosphate wasting and symptomatic hypercalcemia, mutations in CYP24A1 were excluded. Four patients from families with parental consanguinity were subjected to homozygosity mapping that identified a second IIH gene locus on chromosome 5q35 with a maximum logarithm of odds (LOD) score of 6.79. The sequence analysis of the most promising candidate gene, SLC34A1 encoding renal sodium-phosphate cotransporter 2A (NaPi-IIa), revealed autosomal-recessive mutations in the four index cases and in 12 patients with sporadic IIH. Functional studies of mutant NaPi-IIa in Xenopus oocytes and opossum kidney (OK) cells demonstrated disturbed trafficking to the plasma membrane and loss of phosphate transport activity. Analysis of calcium and phosphate metabolism in Slc34a1-knockout mice highlighted the effect of phosphate depletion and fibroblast growth factor-23 suppression on the development of the IIH phenotype. The human and mice data together demonstrate that primary renal phosphate wasting caused by defective NaPi-IIa function induces inappropriate production of 1,25-(OH)2D3 with subsequent symptomatic hypercalcemia. Clinical and laboratory findings persist despite cessation of vitamin D prophylaxis but rapidly respond to phosphate supplementation. Therefore, early differentiation between SLC34A1 (NaPi-IIa) and CYP24A1 (24-hydroxylase) defects appears critical for targeted therapy in patients with IIH.

Rare Causes of Primary Adrenal Insufficiency: Genetic and Clinical Characterization of a Large Nationwide Cohort.

CONTEXT: Primary adrenal insufficiency (PAI) is a life-threatening condition that is often due to monogenic causes in children. Although congenital adrenal hyperplasia occurs commonly, several other important molecular causes have been reported, often with overlapping clinical and biochemical features. The relative prevalence of these conditions is not known, but making a specific diagnosis can have important implications for management. OBJECTIVE: The objective of the study was to investigate the clinical and molecular genetic characteristics of a nationwide cohort of children with PAI of unknown etiology. DESIGN: A structured questionnaire was used to evaluate clinical, biochemical, and imaging data. Genetic analysis was performed using Haloplex capture and next-generation sequencing. Patients with congenital adrenal hyperplasia, adrenoleukodystrophy, autoimmune adrenal insufficiency, or obvious syndromic PAI were excluded. SETTING: The study was conducted in 19 tertiary pediatric endocrinology clinics. PATIENTS: Ninety-five children (48 females, aged 0-18 y, eight familial) with PAI of unknown etiology participated in the study. RESULTS: A genetic diagnosis was obtained in 77 patients (81%). The range of etiologies was as follows: MC2R (n = 25), NR0B1 (n = 12), STAR (n = 11), CYP11A1 (n = 9), MRAP (n = 9), NNT (n = 7), ABCD1 (n = 2), NR5A1 (n = 1), and AAAS (n = 1). Recurrent mutations occurred in several genes, such as c.560delT in MC2R, p.R451W in CYP11A1, and c.IVS3ds+1delG in MRAP. Several important clinical and molecular insights emerged. CONCLUSION: This is the largest nationwide study of the molecular genetics of childhood PAI undertaken. Achieving a molecular diagnosis in more than 80% of children has important translational impact for counseling families, presymptomatic diagnosis, personalized treatment (eg, mineralocorticoid replacement), predicting comorbidities (eg, neurological, puberty/fertility), and targeting clinical genetic testing in the future.

Is Metabolic Syndrome Associated with Obstructive Sleep Apnea in Obese Adolescents?

OBJECTIVE: To investigate whether there is an association between metabolic syndrome and obstructive sleep apnea syndrome (OSAS) in obese adolescents. METHODS: In total, 240 pubertal children or prepubertal children older than 11 y recruited consecutively from the pediatric endocrinology unit, obesity clinic. Patients with tonsillar and adenoid hypertrophy (grade 3/4), systemic illnesses, or chronic drug usage were excluded. After anthropometric measurement and laboratory study, patients were divided into two groups according to metabolic syndrome (MS): MS and non-MS. Overnight polysomnographic evaluation was performed and 104 subjects were included for statistical analysis. The two groups were compared in terms of sleep efficiency, number of awakenings per night, oxygen desaturation index, snoring time, and obstructive/central/ mixed apnea-hypopnea index (AHI). RESULTS: Of the obese adolescents, 51 had MS and 53 did not. The AHI was ≥ 1 in 25 of the 53 non-MS children (47.2%) and in 25 of the 51 MS children (49%). The median obstructive AHI value was 0.9 (0.2-2.4) and total AHI was 0.9 (0.2-2.5) in the MS group; these values were 0.9 (0.25-3.55) and 0.9 (0.3-3.55), respectively, in the non-MS group. Obstructive, central, mixed, and total AHI values in the MS and non-MS groups were not statistically significantly different (p > 0.05). CONCLUSIONS: In our study, we did not find an association between MS and sleep apnea in obese adolescents.

Current practice in diagnosis and treatment of growth hormone deficiency in childhood: a survey from Turkey.

OBJECTIVE: Approaches to diagnosis and treatment of growth hormone deficiency (GHD) in children vary among countries and even among centers in the same country. This survey, aiming to facilitate the process of preparing the new consensus on GHD by the Turkish Pediatric Endocrinology and Diabetes Society, was designed to evaluate the current practices in diagnosis and treatment of GHD in different centers in Turkey. METHODS: A questionnaire covering relevant items for diagnosis and treatment of GHD was sent out to all pediatric endocrinology centers. RESULTS: Twenty-four centers returned the questionnaire. The most frequently used GH stimulation test was L-dopa, followed by clonidine. Eighteen centers used a GH cut-off value of 10 ng/mL for the diagnosis of GHD; this value was 7 ng/mL in 4 centers and 5 ng/mL in 2 centers. The most frequently used assay was immunochemiluminescence for determination of GH, insulin-like growth factor-1 and insulin-like growth factor binding protein-3 concentrations. Sex steroid priming in both sexes was used by 19 centers. The most frequently used starting dose of recombinant human GH (rhGH) in prepubertal children was 0.025-0.030 mg/kg/day and 0.030-0.035 mg/kg/day in pubertal children. Growth velocity was used in the evaluation for growth response to rhGH therapy in all centers. Anthropometric measurements of patients every 3-6 months, fasting blood glucose, bone age and thyroid panel evaluation were used by all centers at follow-up. Main indications for cessation of therapy were decreased height velocity and advanced bone age. Fourteen centers used combined treatment (rhGH and gonadotropin-releasing analogues) to increase final height. CONCLUSION: Although conformity was found among centers in Turkey in current practice, it is very important to update guideline statements and to modify, if needed, the approach to GHD over time in accordance with new evidence-based clinical studies.

The frequency and the effects of 21-hydroxylase gene defects in congenital adrenal hyperplasia patients.

Congenital adrenal hyperplasia (CAH) is a group of genetic endocrine disorders, caused by enzyme deficiencies in the conversion of cholesterol to cortisol. More than 90% of the cases have 21-hydroxylase deficiency (21-OHD). The clinical phenotype of the disease is classified as classic, the severe form, and nonclassic, the mild form. In this study, it was planned to characterize the mutations that cause 21-OHD in Turkish CAH patients by direct sequencing and multiplex ligation-dependent probe amplification (MLPA) analysis and to investigate the type of CAH (classic or nonclassic type) that these mutations cause. A total of 124 CAH patients with 21-OHD and 100 healthy volunteers were recruited to the study. Most of the mutations were detected by direct sequencing. Large gene deletions/duplications/conversions were investigated with MLPA analysis. Results were evaluated statistically. At the end of our study, 66 different variations were detected including SNPs and deletions/duplications/conversions. Of these variations, 18 are novel, of which three cause amino acid substitutions. In addition, 15 SNPs which cause amino acid changes were identified among these variations. If similar results are obtained in different populations, these mutations, in particular the novel mutation 711 G>A, may be used as markers for prenatal diagnosis.

Non-alcoholic fatty liver disease in obese children and the relationship between metabolic syndrome criteria.

AIM: To investigate metabolic syndrome (MetS) and MetS criteria, and to establish whether metabolic syndrome criteria were associated with non-alcoholic fatty liver disease (NAFLD) in obese children. METHODS: A total of 451 pubertal obese children (8-18 years old) were enrolled in the study. Patients were divided into three groups according to the degree of steatosis. Antropometric and laboratory measurements of the participants were recorded. RESULTS: Of 451 obese children, 217 (48.1%) were diagnosed as having NAFLD and 96 (21.3%) as having MetS. The frequency of abdominal obesity, hypertension, impaired fasting glucose, hyperinsulinemia, dyslipidemia and type 2 diabetes mellitus (T2DM) were 61.8% (279), 25.7% (116), 4.4% (20), 54.3% (245), 41% (185) and 2.2% (10), respectively. The prevalence of NAFLD among patients with MetS [73% (70/96)], was significantly higher than the frequency of hypertension [55% (53/96)] and abnormalities of glucose metabolism [23% (22/96)], but almost equal to the frequency of dyslipidemia [78% (75/96)]. The prevalence of MetS criteria were higher in patients with NAFLD than those without NAFLD. Except impaired fasting glucose, blood pressure and T2DM significant difference was found between groups for all. It was observed that the number of MetS criteria increased in parallel with the severity of steatosis. CONCLUSION: NAFLD in obese children is strongly associated with multiple MetS criteria. In addition to NAFLD is not only a liver disease, but also early mediator that reflects metabolic disorder, and liver ultrasound can be a useful tool for MetS screening.

Phenotypic severity of homozygous GCK mutations causing neonatal or childhood-onset diabetes is primarily mediated through effects on protein stability.

Mutations in glucokinase (GCK) cause a spectrum of glycemic disorders. Heterozygous loss-of-function mutations cause mild fasting hyperglycemia irrespective of mutation severity due to compensation from the unaffected allele. Conversely, homozygous loss-of-function mutations cause permanent neonatal diabetes requiring lifelong insulin treatment. This study aimed to determine the relationship between in vitro mutation severity and clinical phenotype in a large international case series of patients with homozygous GCK mutations. Clinical characteristics for 30 patients with diabetes due to homozygous GCK mutations (19 unique mutations, including 16 missense) were compiled and assigned a clinical severity grade (CSG) based on birth weight and age at diagnosis. The majority (28 of 30) of subjects were diagnosed before 9 months, with the remaining two at 9 and 15 years. These are the first two cases of a homozygous GCK mutation diagnosed outside infancy. Recombinant mutant GCK proteins were analyzed for kinetic and thermostability characteristics and assigned a relative activity index (RAI) or relative stability index (RSI) value. Six of 16 missense mutations exhibited severe kinetic defects (RAI ≤ 0.01). There was no correlation between CSG and RAI (r(2) = 0.05, P = 0.39), indicating that kinetics alone did not explain the phenotype. Eighty percent of the remaining mutations showed reduced thermostability, the exceptions being the two later-onset mutations which exhibited increased thermostability. Comparison of CSG with RSI detected a highly significant correlation (r(2) = 0.74, P = 0.002). We report the largest case series of homozygous GCK mutations to date and demonstrate that they can cause childhood-onset diabetes, with protein instability being the major determinant of mutation severity.

Cathepsin K analysis in a pycnodysostosis cohort: demographic, genotypic and phenotypic features.

BACKGROUND: To characterize cathepsin K (CTSK) mutations in a group of patients with pycnodysostosis, who presented with either short stature or atypical fractures to pediatric endocrinology or dysmorphic features to pediatric genetics clinics. METHODS: Seven exons and exon/intron boundaries of CTSK gene for the children and their families were amplified with PCR and sequenced. Sixteen patients from 14 families with pycnodysostosis, presenting with typical dysmorphic features, short stature, frequent fractures and osteosclerosis, were included in the study. RESULTS: We identified five missense mutations (M1I, I249T, L7P, D80Y and D169N), one nonsense mutation (R312X) and one 301 bp insertion in intron 7, which is revealed as Alu sequence; among them, only L7P and I249 were described previously. The mutations were homozygous in all cases, and the families mostly originated from the region where consanguineous marriage rate is the highest. Patients with M1I mutation had fractures, at younger ages than the other pycnodysostosis cases in our cohort which were most probably related to the severity of mutation, since M1I initiates the translation, and mutation might lead to the complete absence of the protein. The typical finding of pycnodysostosis, acroosteolysis, could not be detected in two patients, although other patients carrying the same mutations had acroosteolysis. Additionally, none of the previously described hot spot mutations were seen in our cohort; indeed, L7P and R312X were the most frequently detected mutations. CONCLUSIONS: We described a large cohort of pycnodysostosis patients with genetic and phenotypic features, and, first Alu sequence insertion in pycnodysostosis.

Effects of ACE inhibitors on insulin resistance and lipid profile in children with metabolic syndrome.

OBJECTIVE: The aim of this study was to evaluate the effects of using ACE inhibitors on insulin resistance, glucose metabolism, body fat composition, and lipid profile in children over 10 years of age with obesity-associated metabolic syndrome (MS). METHODS: A total of 53 children with MS, who had been followed for at least one year were included in the study. The sample was divided into two groups: Group 1-30 obese children (13 female, 17 male) who were not using an ACE inhibitor and Group 2-23 obese children (13 female, 10 male) who were using an ACE inhibitor. Anthropometric and laboratory data obtained at baseline and at the 3rd, 6th, and 12th months of follow-up were compared in the two groups. RESULTS: Comparison of the data in the two groups at 3rd, 6th, and 12th months revealed no statistically significant differences in terms of weight standard deviation score (SDS), body mass index SDS, weight for height percentile, body fat percentage, and very low-density lipoprotein (VLDL)values. However, there were statistically significant differences in mean glucose and insulin levels, homeostasis model assessment for insulin resistance, LDL and high-density lipoprotein values, and highly significant differences in mean triglyceride values. CONCLUSIONS: The positive effects of ACE inhibitor drugs, particularly on hypertriglyceridemia and insulin resistance, might bring them forth as first-line drugs in the treatment of obese and hypertensive children. Randomized, controlled, double-blind, and long-term studies are needed for a definitive conclusion.