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Background Maturity-onset diabetes of the young (MODY) is a common form of monogenic diabetes. Fourteen genes have been identified, each leading to cause a different type of MODY. The aims of this study were to reveal both known and novel variants in MODY genes in patients with MODY using targeted next generation sequencing (NGS) and to present the genotype-phenotype correlations. Methods Mutation analysis of MODY genes ( GCK , HNF1A , HNF4A , HNF1B , ABCC8 , INS and KCNJ11 ) was performed using targeted NGS in 106 patients with a clinical diagnosis of MODY. The variants were evaluated according to American College of Medical Genetics and Genomics (ACMG) Standards and Guidelines recommendations. Results A total of 18 (17%) variants were revealed among all patients. Seven variants in GCK , six in HNF4A , four in HNF1A and one in ABCC8 genes were found. Eight of them were previously published and 10 of them were assessed as novel pathogenic or likely pathogenic variants. Conclusions While the most frequent mutations are found in the HNF1A gene in the literature, most of the variants were found in the GCK gene in our patient group using the NGS method, which allows simultaneous analysis of multiple genes in a single panel.

Background Diabetes mellitus is a metabolic disorder. However, dental caries and periodontal health have not attracted much interest in diabetic patients. This study was carried out to assess the dental caries status and gingival health status in children with type 1 diabetes mellitus (T1DM). Methods The study group consisted of 80 children, aged 6–18 years, with T1DM. The dental caries status was recorded using the World Health Organisation (WHO) criteria. Gingival health was assessed using the Loe and Silness gingival index (GI). Data obtained were subjected to statistical analysis. Results The mean dental caries status for primary (decayed, extracted, filled teeth [deft]) and permanent dentition (decayed, missing, filled teeth [DMFT]) scores in diabetic children were 0.44±1.28 and 1.26±2.49, respectively. The GI scores of diabetic children were 0.33±0.48. GI in the study group significantly correlated with DMFT (p<0.001) and deft (p≤0.05). Conclusions Dental caries in primary dentition was lower in diabetic children but was not statistically significant, whereas dental caries in permanent dentition was significantly higher. The gingival condition of diabetic children was healthy.

Background Prader-Willi syndrome (PWS) is associated with marked obesity that can lead to severe complications such as diabetes mellitus. Early adiposity rebound (AR) is associated with future obesity and an increased risk of diabetes mellitus and metabolic syndrome. Previous reports have shown that the onset of AR occurred earlier in diseases that cause obesity. However, there have been no studies focusing on the timing of AR in PWS, or on the effect of growth hormone (GH) treatment on AR. The aim of this study was to explore AR in PWS patients and to analyze the effect of GH treatment on AR. Methods This retrospective study evaluated 48 patients, with 16 of the patients found to have AR prior to GH treatment. AR was constructed for each patient using Microsoft Excel, and the exact point of the nadir of body mass index (BMI) following the initial peak was determined. We additionally analyzed the relationship between GH treatment and the timing of AR onset. Results AR onset for patients found to have AR before starting GH treatment was 16.0 (13.0–21.0) months. In contrast, AR onset for patients found to have AR after starting GH treatment was 27.5 (23.8–36.3) months. The difference between the two groups was statistically significant (p=0.0001). A positive correlation was found between the GH treatment period and AR (p=0.00013). Conclusion The median age of AR onset in PWS patients was 16.0 (13.0–21.0) months, and GH treatment might delay the early AR onset.

Background Cardiovascular disease (CVD) is the end result of vascular aging and atherosclerosis, having its origins in childhood. The aim of our study was to compare arterial stiffness (AS) and intima-media thickness (IMT) as markers of an early vascular damage between obese adolescents, adolescents with diabetes type 1 (T1D) and lean control subjects. Methods We analyzed AS and IMT in 68 obese adolescents (13.27±2.31 years), 42 adolescents with T1D (14.95±2.35 years) lasting over 5 years and 38 controls (15.02±1.94 years). AS (measured by pulse wave velocity [PWV], arterial compliance [AC] and β-stiffness) and IMT were assessed using an e-tracking ultrasound method. Results A significant difference between the groups was found for AC (p=0.022) and PWV (p=0.010), with the lowest compliance and higher velocities in T1D patients. When corrected for age, the difference in AC among the groups did not reach a statistical difference (p=0.059). Correlation analysis in the obese adolescents showed lower AC in females (p=0.041), with higher systolic blood pressure (SBP) (p=0.032). In T1D adolescents, disease duration was the strongest determinant of AS (AC p=0.028, β p=0.029 and PWV p=0.003), followed by body mass index (BMI; PWV p=0.008; β p=0.033), SBP (AC p<0.001; PWV p=0.023), diastolic BP (AC p=0.049; PWV p=0.048) and HbA 1c (PWV p=0.048). No significant correlations were found for AS measures or IMT with sex, age, BMI, Tanner stage or BP levels in controls. Conclusions Early vascular damage is more pronounced in T1D adolescents than in obese or lean adolescents, which may emphasize the impact of hyperglycemia as a major threat for cardiovascular health.

Background Congenital central hypoventilation syndrome (CCHS) is a rare disorder of autonomic control. A hypoglycaemic seizure in a 4-year-old girl with CCHS led to a more detailed examination of glycaemic control in a cohort of children with CCHS. Methods We conducted an observational cohort study of glucose homeostasis in seven children (3 months to 12 years) with genetically confirmed CCHS using a combination of continuous glucose monitoring (CGM), fasting studies and oral glucose tolerance test (OGTT). CGM was used to compare the effect of diazoxide and dietary intervention in the index patient. Results Hypoglycaemia was not elicited by fasting in any of the patients. Increased postprandial glycaemic variability was evident in all patients using CGM, with seven of seven patients demonstrating initial postprandial hyperglycaemia (plasma-glucose concentration >7.8 mmol/L), followed by asymptomatic hypoglycaemia (plasma-glucose concentration ≤2.8 mmol/L) in two of seven patients that was also demonstrated on OGTT. Both diazoxide and low Glycaemic Index (GI) dietary intervention reduced the proportion of CGM readings <4 mmol/L; however, diazoxide also increased the proportion of readings in the hyperglycaemic range. Conclusions Glucose variability associated with autonomic dysfunction may be unrecognised in CCHS, particularly in children with more severe phenotypes. This report highlights the occurrence of hyperglycaemia as well as hypoglycaemia in CCHS. Given the challenges of recognising hypoglycaemia based on clinical symptomatology, the use of CGM may facilitate its identification allowing appropriate management. The observed normoglycaemia during fasting combined with increased postprandial plasma blood glucose level (BGL) variability is more consistent with dumping syndrome than persistent hyperinsulinism. Dietary modifications therefore may be more effective than diazoxide in managing hypoglycaemia.

Background Parents of children with metabolic diseases report more parenting stress, anxiety, depression and dysfunctional parenting styles than parents of children without metabolic diseases. In addition, their children have more behavioral problems. Beside the fact that metabolic diseases are rare, they form a relatively large proportion in the morbidity and mortality of chronically ill children. Methods In this pilot study 14 parents of children with metabolic diseases, aged between 2.5 and 13 years, participated in a quasi-experimental pre-post-follow-up study. Results After participating in the Level 4 Group Triple P-program there were small effects in decreasing child behavioral problems and large effects in decreasing dysfunctional parenting styles. There was a moderate to large reduction of parental stress and a large reduction of parental anxiety. Only the effects on the behavioral problems and the parenting style ‘laxness’ were no longer significant at 6 months follow-up. Conclusions In summary it can be said that the existing Triple P-program has good effects, with a great degree of satisfaction, for parents of children with metabolic diseases in reducing dysfunctional parenting styles, parenting stress and behavioral problems of their children. One should not wait for a specialized program to reach these parents, but further research is necessary as a greater effect can be expected when this program is adapted to these parents.

Background With conventional enzyme replacement therapy (ERT), the clinical prognosis of classic Pompe disease is often unsatisfactory. About half the patients treated with ERT at the recommended dosage (20 mg/kg every other week) require ventilatory support within the first years of life. The heterogeneous response to ERT has been related to different factors, including cross-reactive immunologic material (CRIM) status and age at ERT initiation. Early treatment with a standard dosage of ERT improves clinical outcome and avoids mechanical ventilation in CRIM-positive patients detected at newborn screening, not preventing persistent hyperCKemia and muscle weakness. Later treatment with higher dosages of ERT was shown to provide similar benefits in CRIM-positive patients. Here, we report the clinical and biochemical outcomes of six patients with classic Pompe disease treated with different dosages of alglucosidase alpha at different ages. Methods A standard dosage of ERT was employed in five patients, sharing a poor prognosis after transient clinical improvements, even in the case of early treatment (four died at 22.2±11.9 months and one survived but required tracheostomy and gastrostomy). Early higher dosage of alglucosidase alpha (40 mg/kg/week from 14 days) was administered to one CRIM-positive patient with fetal persistent bradycardia. Results Early higher dosage of alclucosidase alpha not only achieved normal neuromotor development but also the full correction of biochemical markers of muscle damage until 3 years of age, an unmet target with the standard dosage. Speech delay was not prevented by this approach. Conclusions We suggest that early treatment with a higher dosage of ERT may further improve clinical prognosis in classic Pompe disease.

Background The aim of the study was to investigate whether there is insulin resistance in children with familial hyperlipidemia (FHL) and to determine the factors affecting insulin resistance. Methods Hyperlipidemic children aged between 4 and 18 years and followed up with an FHL diagnosis were included in the study. The children of adults followed up with an FHL diagnosis were also recruited after the screening period. The scanned children were divided into two groups as hyperlipidemic and normolipidemic. A total of 77 patients of whom 52 were hyperlipidemic and 25 were normolipidemic were assessed in the study. Insulin resistance was evaluated (homeostatic model assessment of insulin resistance [HOMA-IR]) by performing the oral glucose tolerance test (OGTT). Results Of the patients, 36 were male and 41 were female; the average age was 11.6±3.9 years, and the body mass index (BMI) was established to be 20.3±4.4. In hyperlipidemic and normolipidemic patients, the following were determined: fasting insulin: 10.6 (±0.89) μU/mL, 4.9 (±0.45) μU/mL (p=0.000); 2-h insulin: 28.7 (±12.7) μU/mL, 18.9 (±10.5) μU/mL (p=0.000); and HOMA-IR: 1.9 (±0.17), 0.86 (±0.7) (p=0.000). No relationship was identified between lipid profiles and insulin resistance. Nevertheless, there was a positive correlation between insulin resistance and apolipoprotein B (Apo B) levels (0.52), and a negative correlation was determined in carnitine levels (−0.64). Conclusions Insulin resistance was established to be higher in children with FHL compared to normolipidemic children. Insulin resistance was not related to lipid phenotypes, but to Apo B levels and carnitine levels. Insulin resistance should be a routine method of evaluation in the follow-up of children with FHL.

Background Turner syndrome (TS) patients have increased cardiovascular risk. This cardiovascular risk is famously attributed to structural abnormalities of the left side of the heart such as aortic stenosis and aortic coarctation. However, due to insulin resistance and subsequent pathogenic mechanisms, normotensive TS patients without structural abnormalities may develop varying degrees of myocardial dysfunction. The aim of this research was to examine the role of speckle tracking echocardiography in early detection of Turner cardiomyopathy and to correlate this myocardial dysfunction with measures of insulin resistance. Methods This cross-sectional case control study included 30 children with TS and 30 age-matched healthy controls. TS patients were excluded if: hypertensive, with major structural abnormalities of the heart or other systemic diseases that may affect myocardial function. Conventional speckle tracking echocardiography and glucose-insulin ratio were performed for all study subjects. Results Routine echocardiographic parameters of left ventricular systolic function were similar in cases and controls while global longitudinal and circumferential strain (GLS and GCS) were lower in patients with TS than controls: (−13.2±1.1 vs. −18.3±2.4, p-value<0.000) and (−11.3±1.1 vs. −16.3±2.1, p-value<0.000), respectively. Fasting glucose:insulin ratio (FGIR) proved to be the best predictor of myocardial dysfunction in TS patients by multivariate analysis. Conclusions This study points towards the potential role of two-dimensional (2D) speckle tracking echocardiography in early detection of subtle systolic myocardial dysfunction in TS patients. It also points towards the implication of insulin resistance in precipitation of the observed dysfunction in TS patients.

Background Almost 30% of the premature infants have low body weight and bone mineral density due to prematurity. There is no consensus of screening premature neonates for metabolic bone disease; therefore, it is important to investigate the use of bone biochemical parameters. Latest studies involved the activity of acetylcholinesterase as a mediator in bone remodeling. It is hypothesized that there is a possible correlation of bone biochemical biomarkers and acetylcholinesterase (AChE) activity in premature infants. Methods We studied 50 neonates (26 preterm with gestational age <32 weeks, 24 full-term). Clinical data (sex, gestational week) and anthropometric parameters (body weight) were recorded. We directly measured the bone biochemical markers in serum such as alkaline phosphatase (ALP), calcium (Ca), phosphorus (P), magnesium (Mg) and parathyroid hormone (PTH). In addition, we measured the AChE activity. Results ALP and parathyroid hormone levels were higher, but Ca, P and AChE were lower in premature neonates group compared with full-term ones. There is a significant positive correlation of gestational age with body weight, Ca and AChE. A significant negative correlation was observed for ALP and PTH with gestational age. Conclusions We found a gestational age-related increase of AChE activity. There were significant relationships between AChE activity with P and PTH.

Background Limited information is available regarding baseline characteristics of children and adolescents with gender dysphoria (GD). The purpose of this retrospective study was to describe baseline characteristics of pediatric patients referred for GD. Methods A retrospective chart review of pediatric patients with GD referred to the pediatric endocrine clinic between 2002 and 2017 was conducted. Body mass index (BMI) percentiles and z-scores were calculated based on height and weight at the initial visit. Results Seventy-eight patients aged 14.9±2.37 years were identified. Of these, affirmed gender was more often male than female (63% vs. 37%, p=0.024). Although no difference was seen in average BMI z-scores between female to male (FTM) and male to female (MTF) patients, approximately 50% were overweight or obese. A higher incidence of anxiety was present in FTM compared with MTF youth (p=0.05). Fifty-six patients were referred in January 2014 or later, of whom 27% had a history of early expression of GD compared with 55% of those seen prior to 2014 (p=0.061). Conclusions The high prevalence of overweight in TG youth at baseline represents a potential risk for adverse health consequences. There appears to be a change in the age of first manifestation of GD over time.

Background Hypertrophic cardiomyopathy (HCM) in childhood is a rare diagnosis, and associations with adrenocortical tumors (ACTs) have been rarely reported in the pediatric literature. Case presentation We present a case of a 5-month-old who presented with HCM and during the evaluation for hypertension was found to have elevated glucocorticoids, mineralocorticoids, androgens and urine metanephrines. During preoperative evaluation, he developed shock followed by cardiogenic collapse requiring extracorporeal membrane oxygenation (ECMO); however, he did not survive. Pathology revealed an ACT with hormone production that contributed to his demise. Conclusions Adrenocortical tumors associated with hypertrophic cardiomyopathy can be life-threatening. We discuss the complex interplay of unrestricted cortical hormone production in the setting of hypertrophic cardiomyopathy that may lead to rapid decline and poor clinical outcomes.

Background Although hepatic infantile hemangioma (IH) may correlate with consumptive hypothyroidism consequent to the overexpression of thyroid hormone inactivating enzyme by hemangioma cells, hypothyroidism has been rarely recognized in infants with cutaneous hemangioma. Case presentation A male infant born at 28 weeks of gestational age with an extremely low birth weight (775 g) developed a massive cutaneous hemangioma on his neck and severe abdominal distension. Imaging examinations detected a small mass lesion in the brain but no hepatic hemangioma. Laboratory findings at the age of 26 days revealed hypothyroidism. Although high-dose levothyroxine therapy failed to normalize the thyroid function, hypothyroidism improved and cutaneous hemangioma regressed after initiating propranolol therapy. Conclusions Our findings suggest that consumptive hypothyroidism should be considered as a critical comorbidity in patients with massive cutaneous IH. Propranolol therapy can effectively normalize thyroid function and cause hemangioma regression.

Background Peutz-Jeghers syndrome (PJS) is characterized by gastrointestinal polyposis, mucocutaneous pigmentation and cancer predisposition. Patients with PJS can develop large calcifying Sertoli cell tumors (LCSTs). Case presentation A patient presented at 3 years of age with delayed development, hypermobility and later also with tall stature and advanced bone age. Extensive endocrine evaluation, mutation analysis of genes associated with connective tissue disorders and a single nucleotide polymorphism (SNP) array showed no abnormalities. At 8 years of age, gynecomastia developed as well as pigmentations on the lips, both of which are associated with PJS. Mutation analysis showed a heterozygous deletion of the whole STK11 gene confirming PJS. Testicular ultrasound confirmed the presence of LCSTs. Interestingly, the previously performed SNP array did not report deletion of the STK11 gene. Conclusions We advise excluding LCSTs in children with tall stature and advanced bone age where more common causes have been eliminated. Although STK11 deletions are documented in control databases, reporting the deletion of this gene even in the absence of a phenotype is advised for patient management.