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Monogenic defects of beta cell function refer to a group of rare disorders that are characterized by early-onset diabetes mellitus due to a single gene mutation affecting insulin secretion. It accounts for up to 5% of all pediatric diabetes cases and includes transient or permanent neonatal diabetes, maturity-onset diabetes of the young (MODY), and various syndromes associated with diabetes. Causative mutations have been identified in genes regulating the development or function of the pancreatic beta cells responsible for normal insulin production and/or release. To date, more than 40 monogenic diabetes subtypes have been described, with those caused by mutations in HNF1A and GCK genes being the most prevalent. Despite being caused by a single gene mutation, each type of monogenic diabetes, especially MODY, can appear with various clinical phenotypes, even among members of the same family. This clinical heterogeneity, its rarity, and the fact that it shares some features with more common types of diabetes, can make the clinical diagnosis of monogenic diabetes rather challenging. Indeed, several cases of MODY or syndromic diabetes are accurately diagnosed in adulthood, after having been mislabeled as type 1 or type 2 diabetes. The recent widespread use of more reliable sequencing techniques has improved monogenic diabetes diagnosis, which is important to guide appropriate treatment and genetic counselling. The current review aims to summarize the latest knowledge on the clinical presentation, genetic confirmation, and therapeutic approach of the various forms of monogenic defects of beta cell function, using three imaginary clinical scenarios and highlighting clinical and laboratory features that can guide the clinician in reaching the correct diagnosis. [ABSTRACT FROM AUTHOR]

Metabolic dysfunction-associated steatotic liver disease (MASLD), previously known as nonalcoholic fatty liver disease (NAFLD), is the main cause of chronic liver disease in children and adolescents. Indeed, epidemiological studies have shown that MASLD affects up to 40% of children with obesity. Despite the recent approval of medications that target weight loss in adolescents that could have benefits on pediatric MASLD, lifestyle interventions, such as diet and exercise, remain the mainstay of our therapeutic approach. More specifically, studies on diet alone have focused on the possible role of carbohydrate or fat restriction, albeit without a definite answer on the best approach. Weight loss after dietary intervention in children with obesity and MASLD has a beneficial effect, regardless of the diet used. In relation to the role of exercise in MASLD reversal, indirect evidence comes from studies showing that a sedentary lifestyle leading to poor fitness, and low muscle mass is associated with MASLD. However, research on the direct effect of exercise on MASLD in children is scarce. A combination of diet and exercise seems to be beneficial with several studies showing improvement in surrogate markers of MASLD, such as serum alanine aminotransferase and hepatic fat fraction, the latter evaluated with imaging studies. Several dietary supplements, such as vitamin E, probiotics, and omega-3 fatty acid supplements have also been studied in children and adolescents with MASLD, but with equivocal results. This review aims to critically present available data on the effects of lifestyle interventions, including diet, exercise, and dietary supplements, on pediatric MASLD, thus suggesting a frame for future research that could enhance our knowledge on pediatric MASLD management and optimize clinicians' approach to this vexing medical condition. [ABSTRACT FROM AUTHOR]

Aim: Newborn thyroid screening tests are carried out during the first days after birth in many parts of the world. The aim of this review was to assess whether additional thyroid function tests of neonates born to mothers with hypothyroidism are necessary to diagnose newborns with congenital hypothyroidism (CH) missed by the usual screening test. Methods: A search in PubMed and Google Scholar databases was conducted for pertinent studies, using relevant keywords. All studies that were published in any language from 1 January 2000 to 30 June 2023 were included. Observational cohort studies were included in the analysis, while case reports and studies not referring to neonates were excluded. Results: Thirteen studies were identified comprising more than 4400 infants with CH. Studies with the larger study populations recommended against additional testing in healthy infants of hypothyroid mothers. Similar were the results of some smaller retrospective studies. Few studies identified in total 16 infants with CH that were missed on neonatal screening without, though, a definite causative link between the mother's and the infant's thyroid dysfunction. Conclusion: Based on available data, additional thyroid function tests seem redundant in identifying undiagnosed cases of CH. Larger studies are needed to reach a definite conclusion. [ABSTRACT FROM AUTHOR]

Biofilm-related infections pose significant challenges in neonatal and pediatric care, contributing to increased morbidity and mortality rates. These complex microbial communities, comprising bacteria and fungi, exhibit resilience against antibiotics and host immune responses. Bacterial species such as Enterococcus faecalis, Pseudomonas aeruginosa, Staphylococcus aureus, and Staphylococcus epidermidis commonly form biofilms on medical devices, exacerbating infection risks. Neonates and children, particularly those in intensive care units, are highly susceptible to biofilm-associated infections due to the prolonged use of invasive devices, such as central lines and endotracheal tubes. Enteral feeding tubes, crucial for neonatal nutritional support, also serve as potential sites for biofilm formation, contributing to recurrent microbial contamination. Moreover, Candida species, including Candida pelliculosa, present emerging challenges in neonatal care, with multi-drug resistant strains posing treatment complexities. Current antimicrobial therapies, while important in managing infections, often fall short in eradicating biofilms, necessitating alternative strategies. The aim of this review is to summarize current knowledge regarding antibiofilm strategies in neonates and in children. Novel approaches focusing on biofilm inhibition and dispersal show promise, including surface modifications, matrix-degrading enzymes, and quorum-sensing inhibitors. Prudent use of medical devices and exploration of innovative antibiofilm therapies are imperative in mitigating neonatal and pediatric biofilm infections. [ABSTRACT FROM AUTHOR]

Basal insulin analogs, typically administered once or twice daily, have been one of the two pillars of the multiple daily injection (MDI) insulin therapy of patients with type 1 diabetes (T1D) for the last twenty years. Recently, once-weekly basal insulin analogs have been developed and are in late-phase clinical trials. One of these analogs is insulin icodec (icodec), appropriately developed to bind reversibly to albumin and to be gradually released into the patient's circulation. Icodec has been tried mostly in clinical trials of adult patients with type 2 diabetes. A recent phase 3a clinical trial comprising adult patients with T1D was designed to evaluate icodec's efficacy and safety compared with a daily basal insulin analog (degludec) after a 26-week main phase plus a safety extension of another 26 weeks. Icodec showed non-inferiority to once-daily degludec in glycated hemoglobin (HbA1c) reduction at week 26, and no significant differences in time in range (TIR) (70–180 mg/dL) and in time above range (TAR) (>180 mg/dL). On the other hand, it was associated with increased rates of clinically significant hypoglycemia (blood glucose < 54 mg/dL) and severe hypoglycemia (external assistance need for recovery), remaining either below or close to the internationally recommended targets for hypoglycemia. Another once-weekly insulin analog, basal insulin Fc (BIF), has been investigated in a phase 2 clinical trial comprising adult patients with T1D, with equally promising results. These preliminary data suggest that once-weekly insulin analogs could be of use for some patients with T1D, for example, patients not taking insulin regularly or those who are on MDI and wish for fewer injections. In addition, due to its prolonged mode of action, it could decrease the risk of diabetic ketoacidosis and the need for hospitalization. Additionally, patients with T1D that struggle with wearing diabetes mellitus devices/closed-loop insulin pumps either due to the cost or due to skin issues may also benefit from long-acting insulin. There is increasing evidence of the benefits of adjunctive therapies to insulin in T1D patients, but these therapies are not FDA-approved due to a possible higher risk of diabetic ketoacidosis. These long-acting insulin analogues could be used with adjunctive therapies in selected patients. This review aims to present available data on the mode of action, clinical trial results, and possible benefits of once-weekly insulin analogs for patients with T1D. In addition, it intends to suggest a future research framework for important clinical questions, such as once-weekly insulin analog use and exercise, sick days, or surgery, that will enhance our knowledge regarding this indisputable innovation in insulin management. [ABSTRACT FROM AUTHOR]

Background: The prevailing etiological model of both acute and chronic urticaria implicates specific allergen exposure that triggers the local release of vasoactive factors and inflammatory adhesion molecules, including vascular cell adhesion molecule 1 (VCAM-1), intercellular adhesion molecule 1 (ICAM-1), endothelial leukocyte adhesion molecule 1 (ELAM-1), P-selectin and E-selectin in the superficial dermis. This study focused on the possible role of VCAM-1 and ICAM-1 as biomarkers in children with acute and chronic urticaria. Methods: This study involved 184 children, 40 with acute urticaria, 71 with chronic urticaria, and 73 matched comparison subjects. The serum levels of ICAM-1 and VCAM-1 were determined in venous blood in all the participants on enrollment. Antihistamine treatment was administered to all the patients. In the children with chronic urticaria, the Urticaria Activity Score Questionnaire (UAS7) was completed daily by the parents. In 16 of the patients with acute urticaria and 43 with chronic urticaria, the serum levels of ICAM-1 and VCAM-1 were determined at follow-up after 6–8 weeks of treatment. Results: The mean serum levels of both VCAM-1 and ICAM-1 were higher in both groups of children with urticaria than in the comparison subjects at the start of the study. In the chronic urticaria group, the levels decreased significantly (p = 0.03 and p = 0.01, respectively) following treatment. Similarly, the acute urticaria group exhibited significant reduction in the mean levels of VCAM and ICAM (p < 0.001). In both groups, the mean level of ICAM after treatment was comparable with that of the comparison group. Conclusions: VCAM-1 and ICAM-1 are suggested as promising biomarkers for monitoring both acute and chronic urticaria in children. Future research should explore their utility in larger cohorts and investigate their role in personalized treatment strategies. [ABSTRACT FROM AUTHOR]

Neonatal sepsis is a leading cause of morbidity and mortality in neonates, particularly in low- and middle-income countries. The emergence of antimicrobial resistance is a rapidly growing global problem. A significant proportion of the pathogens that commonly cause neonatal sepsis are resistant to multiple antibiotics. Therefore, for the empirical treatment of neonatal sepsis, the repurposing of older antibiotics that are effective against multidrug-resistant pathogens is being investigated. This review aims to provide an overview of current research and experience using the repurposed antibiotics colistin and fosfomycin for the empirical treatment of neonatal sepsis. Based on current knowledge, colistin and fosfomycin may be potentially helpful for the empirical treatment of sepsis in neonates due to their efficacy against a wide range of pathogens and acceptable safety profile. [ABSTRACT FROM AUTHOR]

Early-onset sepsis (EOS) is a global health issue, considered one of the primary causes of neonatal mortality. Diagnosis of EOS is challenging because its clinical signs are nonspecific, and blood culture, which is the current gold-standard diagnostic tool, has low sensitivity. Commonly used biomarkers for sepsis diagnosis, including C-reactive protein, procalcitonin, and interleukin-6, lack specificity for infection. Due to the disadvantages of blood culture and other common biomarkers, ongoing efforts are directed towards identifying innovative molecular approaches to diagnose neonates at risk of sepsis. This review aims to gather knowledge and recent research on these emerging molecular methods. PCR-based techniques and unrestricted techniques based on 16S rRNA sequencing and 16S–23S rRNA gene interspace region sequencing offer several advantages. Despite their potential, these approaches are not able to replace blood cultures due to several limitations; however, they may prove valuable as complementary tests in neonatal sepsis diagnosis. Several microRNAs have been evaluated and have been proposed as diagnostic biomarkers in EOS. T2 magnetic resonance and bioinformatic analysis have proposed potential biomarkers of neonatal sepsis, though further studies are essential to validate these findings. [ABSTRACT FROM AUTHOR]

Background: Neurofibromatosis type 1 (NF1) is an autosomal dominant disorder typified by various combination of numerous Café-au-lait macules, cutaneous and plexiform neurofibromas, freckling of inguinal or axillary region, optic glioma, Lisch nodules and osseous lesions. Cherubism is a rare genetic syndrome described by progressive swelling of the lower and/or upper jaw due to replacement of bone by fibrous connective tissue. Patients are reported in the literature with NF1 and cherubism-like phenotype due to the NF1 osseous lesions in the jaws. The purpose of this case report is the description of a young male genetically diagnosed with both NF1 and cherubism. Methods and results: A 9 years and six month old patient with clinical findings of NF1 and cherubism in whom both diseases were genetically confirmed, is presented. The patient was evaluated by a pediatrician, a pediatric endocrinologist, an ophthalmologist, and an oral and maxillofacial surgeon. A laboratory and hormonal screening, a histological examination, a chest X-ray, a magnetic resonance imaging (MRI) of the orbit and a digital panoramic radiography were performed. Genetic testing applying Whole Exome Sequencing was conducted. Conclusions: A novel and an already reported pathogenic variants were detected in NF1 and SH3BP2 genes, respectively. This is the first described patient with coexistence of NF1 and cherubism. The contribution of Next Generation Sequencing (NGS) in gene variant identification as well as the importance of close collaboration between laboratory scientists and clinicians, is highlighted. Both are essential for optimizing the diagnostic approach of patients with a complex phenotype. [ABSTRACT FROM AUTHOR]

Background: Neurofibromatosis type 1 (NF1) is an autosomal dominant disorder typified by various combination of numerous Café-au-lait macules, cutaneous and plexiform neurofibromas, freckling of inguinal or axillary region, optic glioma, Lisch nodules and osseous lesions. Cherubism is a rare genetic syndrome described by progressive swelling of the lower and/or upper jaw due to replacement of bone by fibrous connective tissue. Patients are reported in the literature with NF1 and cherubism-like phenotype due to the NF1 osseous lesions in the jaws. The purpose of this case report is the description of a young male genetically diagnosed with both NF1 and cherubism. Methods and results: A 9 years and six month old patient with clinical findings of NF1 and cherubism in whom both diseases were genetically confirmed, is presented. The patient was evaluated by a pediatrician, a pediatric endocrinologist, an ophthalmologist, and an oral and maxillofacial surgeon. A laboratory and hormonal screening, a histological examination, a chest X-ray, a magnetic resonance imaging (MRI) of the orbit and a digital panoramic radiography were performed. Genetic testing applying Whole Exome Sequencing was conducted. Conclusions: A novel and an already reported pathogenic variants were detected in NF1 and SH3BP2 genes, respectively. This is the first described patient with coexistence of NF1 and cherubism. The contribution of Next Generation Sequencing (NGS) in gene variant identification as well as the importance of close collaboration between laboratory scientists and clinicians, is highlighted. Both are essential for optimizing the diagnostic approach of patients with a complex phenotype. [ABSTRACT FROM AUTHOR]

Data regarding the nutritional management of preterm small for gestational age (SGA) infants are scarce. In the recent report of ESPGHAN, the recommended energy for very preterm infants during hospitalization has been increased, yet this may not fit the needs of all preterm infants. It is important to distinguish fetal growth-restricted (FGR) infants from constitutional SGA infants, as well as preterm SGA from preterm AGA infants, since they may have different nutritional needs. Preterm FGR infants, and specifically infants < 29 weeks' gestation, accumulate nutrient deficits due to intrauterine malnutrition, prematurity, morbidities, delayed initiation of feeding, and feeding intolerance. Therefore, these infants may need more aggressive nutrition for optimal catch-up growth and neurologic development. However, a balance should be kept between optimal and excessive catch-up growth, since the combination of intrauterine malnutrition and excessive postnatal growth has been linked with later adverse metabolic consequences. Furthermore, multiple gestation is often complicated by FGR and prematurity. There is controversy in the definition of FGR in multiple gestations, and it should be noted that FGR in multiple gestation usually differs etiologically from FGR in singletons. The aim of this review is to summarize existing knowledge regarding the nutritional needs of preterm FGR and FGR infants of multiple gestation. [ABSTRACT FROM AUTHOR]

Despite being classified as benign tumors, craniopharyngiomas (CPs) are associated with significant morbidity and mortality due to their location, growth pattern, and tendency to recur. Two types can be identified depending on age distribution, morphology, and growth pattern, adamantinomatous and papillary. The adamantinomatous CP is one of the most frequently encountered central nervous system tumors in childhood. Our aim was to review the relevant literature to identify clinical, morphological, and immunohistochemical prognostic factors that have been implicated in childhood-onset CP recurrence. Lack of radical surgical removal of the primary tumor by an experienced neurosurgical team and radiotherapy after a subtotal excision has been proven to significantly increase the recurrence rate of CP. Other risk factors that have been consistently recognized in the literature include younger age at diagnosis (especially <5 years), larger tumor size at presentation, cystic appearance, difficult tumor location, and tight adherence to surrounding structures, as well as the histological presence of whorl-like arrays. In addition, several other risk factors have been studied, albeit with conflicting results, especially in the pediatric population. Identifying risk factors for CP recurrence is of utmost importance for the successful management of these patients in order to ultimately ensure the best prognosis. [ABSTRACT FROM AUTHOR]

Traditionally a disease of adults, type 2 diabetes (T2D) has been increasingly diagnosed in youth, particularly among adolescents and young adults of minority ethnic groups. Especially, during the recent COVID-19 pandemic, obesity and prediabetes have surged not only in minority ethnic groups but also in the general population, further raising T2D risk. Regarding its pathogenesis, a gradually increasing insulin resistance due to central adiposity combined with a progressively defective β-cell function are the main culprits. Especially in youth-onset T2D, a rapid β-cell activity decline has been observed, leading to higher treatment failure rates, and early complications. In addition, it is well established that both the quantity and quality of food ingested by individuals play a key role in T2D pathogenesis. A chronic imbalance between caloric intake and expenditure together with impaired micronutrient intake can lead to obesity and insulin resistance on one hand, and β-cell failure and defective insulin production on the other. This review summarizes our evolving understanding of the pathophysiological mechanisms involved in defective insulin secretion by the pancreatic islets in youth- and adult-onset T2D and, further, of the role various micronutrients play in these pathomechanisms. This knowledge is essential if we are to curtail the serious long-term complications of T2D both in pediatric and adult populations. [ABSTRACT FROM AUTHOR]

The orexin system is related to food behavior, energy balance, wakefulness and the reward system. It consists of the neuropeptides orexin A and B, and their receptors, orexin 1 receptor (OX1R) and orexin 2 receptor (OX2R). OX1R has selective affinity for orexin A, and is implicated in multiple functions, such as reward, emotions, and autonomic regulation. This study provides information about the OX1R distribution in human hypothalamus. The human hypothalamus, despite its small size, demonstrates a remarkable complexity in terms of cell populations and cellular morphology. Numerous studies have focused on various neurotransmitters and neuropeptides in the hypothalamus, both in animals and humans, however, there is limited experimental data on the morphological characteristics of neurons. The immunohistochemical analysis of the human hypothalamus revealed that OX1R is mainly found in the lateral hypothalamic area, the lateral preoptic nucleus, the supraoptic nucleus, the dorsomedial nucleus, the ventromedial nucleus, and the paraventricular nucleus. The rest of the hypothalamic nuclei do not express the receptor, except for a very low number of neurons in the mammillary bodies. After identifying the nuclei and neuronal groups that were immunopositive for OX1R, a morphological and morphometric analysis of those neurons was conducted using the Golgi method. The analysis revealed that the neurons in the lateral hypothalamic area were uniform in terms of their morphological characteristics, often forming small groups of three to four neurons. A high proportion of neurons in this area (over 80%) expressed the OX1R, with particularly high expression in the lateral tuberal nucleus (over 95% of neurons). These results were analyzed, and shown to represent, at the cellular level, the distribution of OX1R, and we discuss the regulatory role of orexin A in the intra-hypothalamic areas, such as its special role in the plasticity of neurons, as well as in neuronal networks of the human hypothalamus. [ABSTRACT FROM AUTHOR]

Thyroid cancer represents the prominent endocrine cancer in children. Papillary thyroid cancer (PTC) constitutes its most frequent (>90%) pediatric histological type. Mutations energizing the mitogen-activated-protein kinase (MAPK) pathway are definitely related to PTC. Its most common genetic alteration is in proto-oncogene B-Raf (BRAF). Mutated BRAF is proposed as a prognostic tool in adult PTC. We conducted a systematic review and meta-analysis evaluating the association of mutated BRAF gene and prognostic clinicopathological characteristics of PTC in children/adolescents. Systematic search for relevant studies included PubMed, MEDLINE, Scopus, clinicaltrials.gov and Cochrane Library. Pooled estimates of odds ratios for categorical data and mean difference for continuous outcomes were calculated using random/fixed-effect meta-analytic models. BRAFV600E mutation presents a pooled pediatric/adolescent prevalence of 33.12%. Distant metastasis is significantly associated with mutated BRAF gene (OR = 0.32, 95% CI = 0.16–0.61, p = 0.001). Tumor size (MD = −0.24, 95% CI = −0.62–0.135, p = 0.21), multifocality (OR = 1.13, 95% CI = 0.65–2.34, p = 0.74), vascular invasion (OR = 1.17, 95% CI = 0.67–2.05, p = 0.57), lymph node metastasis (OR = 0.92, 95% CI = 0.63–1.33, p = 0.66), extra-thyroid extension (OR = 0.78, 95% CI = 0.53–1.13, p = 0.19) and tumor recurrence (OR = 1.66, 95% CI = 0.68–4.21, p = 0.376) presented no association or risk with BRAF mutation among pediatric/adolescent PTC. Mutated BRAF gene in children and adolescents is less common than in adults. Mutation in BRAF relates significantly to distant metastasis among children/adolescents with PTC. [ABSTRACT FROM AUTHOR]

Antibiotics are the most frequently prescribed drugs in neonatal intensive care units (NICUs) due to the severity of complications accompanying neonatal sepsis. However, antimicrobial drugs are often used inappropriately due to the difficulties in diagnosing sepsis in the neonatal population. The reckless use of antibiotics leads to the development of resistant strains, rendering multidrug-resistant pathogens a serious problem in NICUs and a global threat to public health. The aim of this narrative review is to provide a brief overview of neonatal sepsis and an update on the data regarding indications for antimicrobial therapy initiation, current guidance in the empirical antimicrobial selection and duration of therapy, and indications for early discontinuation. [ABSTRACT FROM AUTHOR]

Wolfram syndrome 1 (WS1) is a rare autosomal recessive neurodegenerative disease caused by mutations in WFS1 and WFS2 genes that produce wolframin, a protein involved in endoplasmic reticulum calcium homeostasis and cellular apoptosis. Its main clinical features are diabetes insipidus (DI), early-onset non-autoimmune insulin-dependent diabetes mellitus (DM), gradual loss of vision due to optic atrophy (OA) and deafness (D), hence the acronym DIDMOAD. Several other features from different systems have been reported such as urinary tract, neurological, and psychiatric abnormalities. In addition, endocrine disorders that can appear during childhood and adolescence include primary gonadal atrophy and hypergonadotropic hypogonadism in males and menstrual cycle abnormalities in females. Further, anterior pituitary dysfunction with deficient GH and/or ACTH production have been described. Despite the lack of specific treatment for the disease and its poor life expectancy, early diagnosis and supportive care is important for timely identifying and adequately managing its progressive symptoms. The current narrative review focuses on the pathophysiology and the clinical features of the disease, with a special emphasis on its endocrine abnormalities that appear during childhood and adolescence. Further, therapeutic interventions that have been proven to be effective in the management of WS1 endocrine complications are discussed. [ABSTRACT FROM AUTHOR]

Purpose: A phenotype of metabolically healthy obesity (MHO) has been described in youth with obesity, but data are still scarce in this age group. The aim of the current study was to describe and compare clinical and laboratory parameters related to obesity among three different groups of youth, namely youth with normal weight (NW), with MHO, and with metabolically unhealthy obesity (MUO). Methods: One hundred and three youngsters with obesity were divided according to 2018 consensus-based criteria into those with MHO [n = 49, age (±SD): 10.9 ± 2.9 years] and those with MUO [n = 54, 11.5 ± 2.7 years] and were compared to age-, sex- and Tanner-matched NW [n = 69, 11.3 ± 2.9 years]. Several obesity-related parameters were investigated for all three groups of children. Comparisons were made by analysis of variance (ANOVA) followed by the Fisher's PLSD test. Results: Youth with MHO had lower systolic (p < 0.001) and diastolic (p < 0.01) blood pressure z-score and triglycerides (p < 0.01), but higher HDL-C (p < 0.001), total cholesterol (p < 0.05), and apo-A1 (p < 0.05) compared to those with MUO. Compared to controls, both children with MHO and MUO showed higher fasting insulin (p < 0.05), HOMA-IR (p < 0.05), and QUICKI (p < 0.001). Similarly, both groups had higher hsCRP, fibrinogen, uric acid, and leptin compared to controls (for all, p < 0.001), while their adiponectin was lower (p < 0.05). Visfatin was higher in children with MUO compared to controls (p < 0.01), and it showed a trend to be lower in children with MHO compared to those with MUO (p = 0.1). Conclusion: This study provides evidence that children identified as having MHO by the consensus-based criteria had better metabolic profiles than youth with MUO, but worse than NW. Further research is needed in pediatric populations both regarding MHO criteria and the nature of the MHO phenotype per se. [ABSTRACT FROM AUTHOR]

The concept of metabolic syndrome (MetS) as a cluster of cardiovascular risk factors (obesity, altered glucose metabolism, dyslipidemia, and hypertension) has been around for more than 30 years. It is considered to be the result of complex interactions between centrally located fat, insulin resistance, subclinical inflammation, and other factors in genetically predisposed individuals. MetS diagnosis in adults has been linked to increased risk for cardiovascular disease (CVD) and type 2 diabetes mellitus (T2D). However, MetS in children and adolescents remains a controversial issue despite the extensive research in the field. It is still uncertain which definition should be used for its diagnosis in this age group, what is the clinical significance of such a diagnosis, and how reliably it can predict the future risk of developing CVD and T2D. Even if a child is diagnosed with MetS, management includes addressing each of the syndrome's components individually with weight loss and lifestyle modifications as the basic approach. Co-morbid conditions, such as nonalcoholic fatty liver disease, obstructive sleep apnea, and polycystic ovary syndrome should also be considered. It seems that MetS in children and adolescents should be used clinically as a conceptual framework for the identification of risk factors clustered around obesity and insulin resistance rather than a syndrome that needs to be diagnosed by measuring absolute "all-or-none" criteria. [ABSTRACT FROM AUTHOR]

Background: Contrast-enhanced harmonic voiding urosonography has been introduced as a sensitive, radiation-free imaging method for the diagnosis of vesicoureteric reflux. Objective: To evaluate the occurrence/severity of vesicoureteric reflux in infants with mild prenatal hydronephrosis comparing voiding cystourethrography and voiding urosonography. Materials and methods: Sixty infants with prenatal hydronephrosis were studied (anteriοposterior pelvic diameter 5–9 mm on ultrasound [US] at gestational weeks 21–30). Postnatal US was performed within the first month of life, as well as voiding cystourethrography and contrast-enhanced voiding urosonography at 1.5–2.5 months at the same session. Results: Vesicoureteric reflux was diagnosed on at least one modality in 19/60 (32%) infants, and more often on contrast-enhanced voiding urosonography (18/60, 30%) than on voiding cystourethrography (8/60, 13%), P=0.046. Among girls, reflux was more often seen on contrast-enhanced voiding urosonography (6/16, 38%) than on voiding cystourethrography (1/16, 6%), P=0.03. Vesicoureteric reflux missed by voiding cystourethrography was more severe (Grades I, II and III in one, nine and four kidney-ureter-units, respectively), compared with a single case missed by contrast-enhanced voiding urosonography (Grade I in one kidney-ureter-unit). Conclusion: In the absence of a reference standard, our results imply that voiding cystourethrography might underdiagnose reflux, and/or contrast-enhanced voiding urosonography may overdiagnose reflux. [ABSTRACT FROM AUTHOR]

Purpose/Aim of the Study: Osteoprotegerin (OPG) is an α tumor necrosis factor receptor superfamily glucoprotein that acts as a decoy receptor for the receptor activator of nuclear factor kappa B ligand (RANKL), exerting an antiresoptive bone effect. It was recently shown that OPG/RANKL axis is activated during vascular calcification, contributing to atherosclerotic lesions formation. Additionally, OPG levels are charachterized as an independent risk factor for overall vascular mortality in obese adults. We aimed to investigate OPG levels in children/adolescents with obesity and explore possible relations with obesity-related insulin resistance (IR). Material and Methods: A total of 160 participants (85 obese) were enrolled. Participants with obesity underwent an oral glucose tolerance test. IR was evaluated according to the homeostasis model assessment-insulin resistance index. Serum OPG levels were determined. Results: OPG levels did not differ significantly between obese subjects and controls in the total sample (p = 0.133). However, in the adolescents' subgroup, serum OPG levels were significantly increased in obesity (p = 0.019). After stratifying participants according to their IR status, only subjects with both obesity and IR exhibited increased OPG levels compared to controls (p < 0.001). Factor analysis further associated OPG levels variation to insulin levels variation and to IR. Conclusions: Obese individuals demonstrate increased serum OPG levels during puberty. Obesity per se is not the potent factor for this increase; indeed, IR accompanying obesity seems to exert a fundamental role in OPG upregulation. [ABSTRACT FROM AUTHOR]

Summary: Context: Adults with plasma glucose levels at one hour (1h‐GL) ≥8.6 mmol/L during an oral glucose tolerance test (OGTT) are at increased risk for type 2 diabetes mellitus and present an unfavourable cardiometabolic and inflammatory profile, but relevant data on children are scarce. Objective: To investigate if elevated 1h‐GL during OGTT in obese children and adolescents is associated with insulin resistance and specific pro‐inflammatory biomarkers. Research Design and Methods: The study group comprised 88 obese children who attended the Outpatient Pediatric Clinic of our Hospital between January and December 2016. Children were divided into two groups according to 1h‐GL during an OGTT: group 1 (n = 57) consisted of those with 1h‐GL <8.6 mmol/L and group 2 (n = 31) of those with 1h‐GL ≥8.6 mmol/L. Arterial blood pressure, body mass index (BMI) and waist circumference (WC) z‐scores were measured in all participants. Specific insulin resistance (IR) indices, that is HOMA‐IR, Matsuda index and Cederholm insulin sensitivity index (ISI) were calculated. Further, pro‐inflammatory biomarkers that have been correlated with obesity complications, namely adiponectin, leptin, visfatin and interleukin (IL)‐6 together with lipid levels were measured in all participants. Logistic regression analysis was used. Results: Children in group 2 had higher insulin (15.5 ± 6.4 vs 10.9 ± 4.8 μU/mL), HOMA‐IR (3.41 ± 1.4 vs 2.34 ± 1.05) and lower Matsuda index [4.7 (3.1) vs 18.4 (17) median plus IQR] and Cederholm ISI (38 ± 6 vs 56 ± 11), than children in group 1 (all P < 0.001). They also had higher visfatin (15.4 ± 5.2 vs 10.1 ± 7 ng/mL), and IL‐6 [12.5 (6.7) vs 4.8 (4.4) pg/mL], and lower adiponectin (5.9 ± 3.4 vs 11.8 ± 4.7 μg/mL) than children in group 1 (all P < 0.001). Logistic regression showed that these differences between the two groups were independent of age, sex, Tanner stage, BMI and WC z‐scores. Conclusions: In obese children, 1h‐GL ≥8.6 mmol/L during an OGTT is correlated with worsened IR, and an unfavourable metabolic and inflammatory profile. Thus, 1h‐GL could be used as an additional marker to identify obese children and adolescents at increased risk of developing obesity complications. [ABSTRACT FROM AUTHOR]

DNA methylation of cytosine-guanine sites (CpGs) is associated with type 1 diabetes (T1D). The sequence of methylated and non-methylated sites in a specific genetic region constitutes its methyl-haplotype. The aim of the present study was to identify insulin gene promoter (IGP) methyl-haplotypes among children and adolescents with T1D and suggest a predictive model for the discrimination of cases and controls according to methyl-haplotypes. A total of 40 individuals (20 T1D) participated. The IGP region from peripheral whole blood DNA of 40 participants (20 T1D) was sequenced using next-generation sequencing, sequences were read using FASTQ files and methylation status was calculated by python-based pipeline for targeted deep bisulfite sequenced amplicons (ampliMethProfiler). Methylation profile at 10 CpG sites proximal to transcription start site of the IGP was recorded and coded as 0 for unmethylation or 1 for methylation. A single read could result in '1111111111' methyl-haplotype (all methylated), '000000000' methyl-haplotype (all unmethylated) or any other combination. Principal component analysis was applied to the generated methyl-haplotypes for dimensionality reduction, and the first three principal components were employed as features with five different classifiers (random forest, decision tree, logistic regression, Naive Bayes, support vector machine). Naive Bayes was the best-performing classifier, with 0.9 accuracy. Predictive models were evaluated using receiver operating characteristics (AUC 0.96). Methyl-haplotypes '1111111111', '1111111011', '1110111111', '1111101111' and '1110101111' were revealed to be the most significantly associated with T1D according to the dimensionality reduction method. Methylation-based biomarkers such as IGP methyl-haplotypes could serve to identify individuals at high risk for T1D. [ABSTRACT FROM AUTHOR]

X-linked adrenal hypoplasia congenita (AHC) is a rare disorder that usually presents clinically as adrenal insufficiency in early infancy. It is caused by mutations in the NR0B1 gene which is located on the short arm of chromosome X (Xp21). The NR0B1 gene plays an important role in normal development and function of both the adrenal and gonadal axes and some patients with the disease can present in adolescence with hypogonadotropic hypogonadism. Testicular microlithiasis is an ultrasonographic finding of unknown etiology that has been associated with several benign conditions such as cryptorchidism, congenital adrenal hyperplasia, varicoceles, and testicular malignancy. We report the case of an 11-year-old boy who was diagnosed at the age of 8 months with X-linked AHC due to adrenal failure and presented testicular microlithiasis during follow-up. To the best of our knowledge, this is the first case of an X-linked AHC patient diagnosed with testicular microlithiasis in follow-up. [ABSTRACT FROM AUTHOR]

17-beta hydroxysteroid dehydrogenase type 3 (17ßHSD-3) enzyme catalyzes the conversion of androstenedione (Δ4) to testosterone (T) in the testes of the developing fetus, thus playing a crucial role in the differentiation of the gonads and in establishing the male sex phenotype. Any mutation in the encoding gene (HSD17B3) can lead to varying degrees of undervirilization of the affected male, ranging from completely undervirilized external female genitalia to predominantly male with micropenis and hypospadias. We present here an infant who was referred to our clinic because of ambiguous genitalia at birth. Gonads were palpable in the inguinal canal bilaterally and no Müllerian structures were identified on pelvic ultrasound. Because of a low T/Δ4 ratio after a human chorionic gonadotropin stimulation test,a tentative diagnosis of 17ßHSD-3 deficiency was made which was confirmed after genetic analysis of the HSD17B3 gene of the patient. The molecular analysis identified compound heterozygosity of two previously described mutations and could offer some further validation for the idea of a founder effect for 655-1;G→A mutation in the Greek population [ABSTRACT FROM AUTHOR]

Food allergy in children is associated with Vitamin D deficiency: A case-control study Keywords: food allergy; vitamin D binding protein; vitamin D deficiency EN food allergy vitamin D binding protein vitamin D deficiency 644 645 2 02/24/22 20220301 NES 220301 The association between food allergy (FA), vitamin D deficiency (VDD) and vitamin D binding protein (VDBP) is of special interest.1 A previous study has shown that low serum vitamin D levels were associated with food allergy, particularly amongst infants with specific I VDBP i gene polymorphisms.2 In addition, infants of Australian-born parents with inadequate vitamin D levels were more likely to be food allergic than were those with adequate vitamin D levels.3 In the United States, a significant association between VDD and the sensitisation to food allergens was detected.1 On the contrary, a recent systematic review could not detect any difference in vitamin D levels in children with or without FA, indicating that the relationship between FA and vitamin D remains controversial.4 In this study, we aimed to evaluate the association of FA with VDD and the association of FA with vitamin D, after controlling for VDBP levels, parental smoking, breastfeeding and family history of atopy. We conducted a case-control study in the Paediatric Allergy Department of the University Hospital of Ioannina, between 7/2018 and 1/2020, including children with definite IgE-mediated FA, and age and gender-matched controls with no history of food allergy. [Extracted from the article]

Background: Atypical hemolytic uremic syndrome (aHUS) is frequently associated with gene mutations in complement-regulatory proteins and activators. Different complement C3 gene mutations have been associated with different outcomes in aHUS. Case-Diagnosis/Treatment: We report the case of a 21-year-old male with a C3 heterozygous gene mutation (p.Ile1157Thr) who developed aHUS at the age of 10 months and had six relapses, the last at the age of 14.5 years. Each relapse was characterized by an apparent predominance of hematological manifestations with milder renal involvement and was followed by complete recovery, with creatinine values and hematological parameters usually recovering after the 3rd to 6th day of hospitalization. The patient was treated with plasma infusion, apart from the initial and the last episode, when dialysis was needed. Twenty years after the onset, he retains normal renal function, with no proteinuria or hypertension. One similar case of highly recurrent aHUS carrying the same C3 mutation as our patient with recovery of renal function has been previously reported. Conclusions: We further support that aHUS associated with the p.Ile1157Thr C3 mutation may be highly recurrent, but with recovered renal function. The prevalent p.Ile1157Thr C3 gene mutation has variable disease manifestations and both severe and milder renal phenotypes have been found. [ABSTRACT FROM AUTHOR]

Backgrounds and Objectives: Fibroblast growth factor 21 (FGF-21) is a complex hormone, sharing common sites of action with thyroid hormones. We investigated the association among FGF-21 levels, resting metabolic rate (RMR), and l-thyroxin (LT4) treatment in children and adolescents with Hashimoto's thyroiditis. Materials and Methods: A total of 60 youngsters with chronic autoimmune thyroiditis (AIT) (30 with subclinical hypothyroidism, 30 with euthyroidism) and 30 age and sex-matched healthy participants (5–18 years old) were enrolled in the study. Anthropometric, biochemical parameters, and RMR levels were assessed in all participants; serum FGF-21 levels were measured in the control group and the group with subclinical hypothyroidism before and six months after medication with LT4. Results: FGF-21 levels were lower in the treatment group compared with the healthy ones, but this difference was not statistically significant (p > 0.05); despite the increase in FGF-21 levels after six months of LT4 treatment, this difference was not statistically significant (p > 0.05). Free thyroxin (FT4) levels correlated well with FGF-21 levels (r = 0.399, p < 0.01), but further analysis revealed no interaction between these two variables. Both patient groups presented elevated triglyceride (TG) levels compared to controls (p < 0.05). LT4 treatment had no impact on RMR and lipid or liver or glycaemic parameters. An increase in fat mass and fat-free mass were reported, independently of FGF-21 levels. Conclusions: In youngsters with subclinical hypothyroidism due to Hashimoto's thyroiditis, the serum FGF-21 levels are not significantly lower than in healthy individuals and increase after treatment with LT4 without a statistical significance. Further studies with a large number of young patients and severe hypothyroidism are recommended to confirm our results. [ABSTRACT FROM AUTHOR]

Henoch-Schönlein purpura (HSP)-associated stenosing ureteritis represents a rare complication of the disease, typically presenting with severe manifestations. This article reports on a 3.5-year-old boy with HSP and severe nephritis who developed a unilateral stenosing ureteritis with atypical manifestations, resulting in a nonfunctional kidney and consequent nephrectomy. The urinary tract ultrasound was normal in the first week of illness, and the diagnosis was made during follow-up 8 months after onset. The predominance of nephritic manifestations may have masked any signs of ureteritis, leading to the delay in diagnosis. To clarify the clinical spectrum of this complication, an extensive review of the literature was performed. We emphasize the necessity of repeated urinary tract ultrasound both early and later in the course of HSP, especially in cases with renal involvement, so that an early diagnosis of this complication can prevent a potentially serious renal outcome. [ABSTRACT FROM AUTHOR]

The insulin (INS) gene is the one of the most important genes involved in the pathogenesis of Type 1 Diabetes (T1D) after the Major Histocompatibility Complex genes. Studies addressing the issue of hyper- or hypo-methylation status of the INS gene promoter have reported inconsistent results. The majority of studies showed hypomethylation; however a few studies have shown hypermethylation at specific cytosine-guanosine (CpG) sites in the promoter region of the INS gene. The aim of the present study was to analyze the methylation status of the promoter region of the INS gene in Greek children and adolescents with T1D. A total of 20 T1D participants (mean diabetes duration of 6.15±4.12 years) and 20 age- and sex-matched controls were enrolled in the present study. DNA was isolated from whole blood samples, modified using sodium bisulfite and analyzed using PCR and electrophoresis. DNA was then pooled with highly reactive supermagnetic beads at similar molar quantities, submitted for library construction and finally sequenced using next-generation sequencing. The methylation profile at 10 CpG sites around the transcription start site (TSS) of the INS promoter was analysed and expressed as the mean ± standard deviation. The overall mean methylation in patients with T1D did not differ compared with the healthy controls. There was a statistically significant difference between the two groups in hypermethylation at position -345 (P=0.02), while a trend (P=0.06) at position -102 was observed. According to the results of the present study, increased methylation in the INS gene promoter at specific CpG sites around the TSS were already present in childhood T1D. These data may possibly serve as a guide towards the identification of a methylation pattern for detection of development of T1D in genetically predisposed children. [ABSTRACT FROM AUTHOR]