Increased prevalence of negative pregnancy and fetal outcomes in women with primary adrenal insufficiency. A systematic review and meta-analysis.

Maternal primary adrenal insufficiency (PAI) during pregnancy, due to either Addison disease (AD) or congenital adrenal hyperplasia (CAH), is rare. Only few studies have examined the subsequent important outcomes of maternal glucocorticoid and mineralocorticoid deficiencies during pregnancy upon the fetus and the neonate. Therefore, this systematic review and meta-analysis evaluated the impact of these deficiencies, with data from PubMed/Medline, Cochrane/CENTRAL, and Google Scholar. A total of 31 studies were included for qualitative analysis and 11 for quantitative analysis. Studies examining the prevalence of spontaneous abortion, preterm birth, the occurrence of small for gestational age (SGA) neonates, as well as the neonatal birth weight were included. The systematic review revealed a substantial number of spontaneous abortions, preterm births and SGA neonates in pregnant women with PAI. The meta-analysis showed a mean spontaneous abortion prevalence of 18%, 18% and 17% in women with PAI, AD or CAH, respectively. The mean preterm birth prevalence was 11% when women with AD or CAH were analyzed together, and 13% and 9% in women with AD or CAH, respectively, when these women were analyzed separately. The mean prevalence of SGA neonates was 8% when women with AD or CAH were analyzed together, and 5% and 10% in women with AD or CAH, respectively, when these women were analyzed separately. The mean fetal birth weight was within normalcy in all women with PAI, as well as in women with AD or CAH. In conclusion the executed systematic review of 31 studies followed by a meta-analysis of 11 studies in pregnant women with PAI has shown a greater prevalence of pregnancies with negative outcome (spontaneous abortion, preterm birth) and of negative fetal outcome (SGA) in women with either AD or CAH, as compared to control pregnant women.

The Role of Secreted Frizzled-Related Protein 5 (Sfrp5) in Overweight and Obesity in Childhood and Adolescence.

Background/Objective: Secreted frizzled-related protein 5 (Sfrp5) is an anti-inflammatory adipokine that has been implicated in the pathophysiology of obesity and its metabolic complications. Despite the fact that numerous studies have been carried out in adults, limited data on Sfrp5 exist for youth, especially in relation to overweight and obesity. Methods: In our study, we assessed the concentrations of Sfrp5, total oxidative (TOS) and antioxidative (TAS) status, high-sensitivity C-reactive protein (hs-CRP), and several cytokines (IL-1α, IL-1ß, IL-2, IL-6, IL-8, IL-12, TNF-α) in 120 children and adolescents (mean age ± SE: 11.48 ± 0.25 years; 48 prepubertal, 72 pubertal; 74 males and 46 females) before and 1 year after the implementation of a personalized, structured, lifestyle intervention program of healthy diet, sleep, and physical exercise. Results: Based on the body mass index (BMI), participants were categorized as having morbid obesity (n = 63, 52.5%), obesity (n = 21, 17.5%), overweight (n = 22, 18.33%), or normal BMIs (n = 14, 11.67%), based on the International Obesity Task Force (IOTF) cut-off points. Following the 1-year lifestyle intervention program, a significant improvement in anthropometric measurements (BMI, BMI-z score, diastolic blood pressure, WHR, and WHtR), body-composition parameters, hepatic enzymes, lipid profile, inflammation markers, and the insulin-sensitivity profile (HbA1C, HOMA index) was observed in all subjects. Sfrp5 decreased in subjects with obesity (p < 0.01); however, it increased significantly (p < 0.05) in patients with morbid obesity. Linear regression analysis indicates that TNF-α and systolic blood pressure were the best positive predictors and hs-CRP was the best negative predictor for Sfpr5 concentration at initial assessment and glucose concentration for ΔSfrp5, while TNF-α and TAS were the best positive predictors for Sfpr5 concentration at annual assessment. Conclusions: These results indicate that Sfrp5 is associated with severe obesity and is increased following weight loss in children and adolescents with morbid obesity. It is also related to metabolic homeostasis, as well as inflammation and oxidative status.

The Impact of Thyroid Hormones on Cardiometabolic Risk in Children and Adolescents with Obesity, Overweight and Normal Body Mass Index (BMI): A One-Year Intervention Study.

Thyroid hormones regulate metabolism and have a major impact in maintaining cardiovascular homeostasis. The purpose of our study was to examine the relation of thyrotropin (TSH) and thyroid hormones with cardiometabolic parameters in children and adolescents with obesity, overweight, and normal body mass index (BMI) before and after the implementation of a comprehensive, multidisciplinary, personalized, lifestyle intervention program for 1 year. One thousand three hundred and eleven (n = 1311) children and adolescents aged 2 to 18 years (mean age ± SD: 10.10 ± 2.92 years) were studied prospectively. Patients were categorized as having obesity (n = 727, 55.45%), overweight (n = 384, 29.29%) or normal BMI (n = 200, 15.26%) according to the International Obesity Task Force (IOTF) cutoff points. All patients received personalized guidance on diet, sleep, and physical activity at regular intervals throughout the 1-year period. Detailed clinical evaluation and hematologic, biochemical and endocrinologic investigations were performed at the beginning and the end of the study. Subjects with obesity had a more adverse cardiometabolic risk profile than subjects with overweight and normal BMI on both assessments. At initial evaluation, total T3 concentrations were positively associated with uric acid and HbA1C, and free T4 concentrations were negatively associated with insulin concentrations, while there was no association between TSH concentrations and cardiometabolic risk parameters. Following the 1 year of the multidisciplinary, lifestyle intervention program, the concentrations of lipids, HbA1C, ALT, and γGT improved significantly in all subjects. Changes in TSH concentrations were positively associated with changes in systolic blood pressure (SBP), glucose, triglycerides, and cholesterol concentrations. Changes in free T4 concentrations were negatively associated with changes in cholesterol and insulin concentrations. Furthermore, changes in T3 concentrations were positively associated with changes in HbA1C, glucose, uric acid, and triglyceride concentrations. These findings indicate that in children and adolescents with overweight and obesity, thyroid hormones are associated with indices conferring cardiometabolic risk.

Challenges in the management of patients with HNF1B MODY and multisystem manifestations: the cases of two adolescent boys.

INTRODUCTION: Hepatocyte nuclear factor-1 beta (HNF1B) encodes a homeodomain-containing transcription factor, which is expressed early in embryogenesis and is involved in the development of multiple tissues and organs. HNF1B mutations cause complex multisystem disorders, with renal developmental disease and maturity onset diabetes of the young (HNF1B MODY), a rare cause of diabetes mellitus, being representative features. METHODS: We present two adolescent boys from different socioeconomic backgrounds who were diagnosed with genetically confirmed HNF1B MODY following hospitalization for diabetic ketoacidosis in the first case and after diagnostic work-up due to impaired glucose tolerance in the second case. Multisystem manifestations, including pancreatic hypoplasia and early-onset diabetes mellitus (DM), renal cysts, hypomagnesemia, hyperuricemia, liver and biliary impairment, genital tract malformations, and primary hyperparathyroidism were also present, strongly suggesting HNF1B MODY. RESULTS: The first patient was treated with subcutaneous insulin but was lost to follow-up due to social reasons. Conversely, early diagnosis in the second patient allowed the management of multisystem defects by a multidisciplinary team of experts. Moreover, manifestation of HNF1B MODY in the form of diabetic ketoacidosis was prevented and a structured diabetes training program has proven successful in regulating glycemic control, postponing the necessity for insulin treatment. CONCLUSION: Early genetic work-up of patients with dysglycemia associated with a specific phenotype suggestive of HNF1B MODY is extremely important in the care of children and adolescents with diabetes since it ensures that early and optimal management is initiated, thereby preventing the onset of life-threatening diabetic ketoacidosis and other multisystem complications and/or comorbidities.

A toddler with severe vitamin D-dependent rickets type 1 A (VDDR1A), hungry bone syndrome, and severe RSV infection: presentation and therapeutic challenges.

BACKGROUND: Vitamin D-dependent rickets type 1 A (VDDR1A) is an autosomal recessive disorder due to mutations in the CYP27B1 gene which result in inability to generate 1,25(OH)2D. CASE PRESENTATION: An 18-month-old boy with VDDR1A presented with hypotonia and respiratory distress. He had been diagnosed 2 months earlier, having been evaluated for stunted growth, hypotonia, and delayed developmental milestones. He was stabilized with oxygen and bronchodilators for his bronchiolitis and high doses of alfacalcidol, calcium, and phosphate supplements for his hungry bone syndrome. Of note, the patient sustained upper limb fractures after a fall from his bed during admission. Overall, he had a protracted disease course; however, his bone profile gradually improved and he steadily recovered. CONCLUSION: VDDR1A causes failure to thrive, hypotonia, and increased fracture risk and may complicate the clinical course of lower respiratory tract infections. Furthermore, management of hungry bone syndrome requires supraphysiologic doses of vitamin D metabolites and calcium.

Cephalometric Evaluation of Children with Short Stature of Genetic Etiology: A Review.

Introduction: A plethora of biological molecules regulate chondrogenesis in the epiphyseal growth plate. Disruptions of the quantity and function of these molecules can manifest clinically as stature abnormalities of various etiologies. Traditionally, the growth hormone/insulin-like growth factor 1 (IGF1) axis represents the etiological centre of final stature attainment. Of note, little is known about the molecular events that dominate the growth of the craniofacial complex and its correlation with somatic stature. Aim: Given the paucity of relevant data, this review discusses available information regarding potential applications of lateral cephalometric radiography as a potential clinical indicator of genetic short stature in children. Materials and Methods: A literature search was conducted in the PubMed electronic database using the keywords: cephalometric analysis and short stature; cephalometric analysis and achondroplasia; cephalometric analysis and hypochondroplasia; cephalometric analysis and skeletal abnormalities; cephalometr* and SHOX; cephalometr* and CNP; cephalometr* and ACAN; cephalometr* and CNVs; cephalometr* and IHH; cephalometr* and FGFR3; cephalometr* and Noonan syndrome; cephalometr* and "Turner syndrome"; cephalometr* and achondroplasia. Results: In individuals with genetic syndromes causing short stature, linear growth of the craniofacial complex is confined, following the pattern of somatic short stature regardless of its aetiology. The angular and linear cephalometric measurements differ from the measurements of the average normal individuals and are suggestive of a posterior placement of the jaws and a vertical growth pattern of the face. Conclusions: The greater part of the existing literature regarding cephalometric measurements in short-statured children with genetic syndromes provides qualitative data. Furthermore, cephalometric data for individuals affected with specific rare genetic conditions causing short stature should be the focus of future studies. These quantitative data are required to potentially establish cut-off values for reference for genetic testing based on craniofacial phenotypes.

Childhood Obesity, Hypothalamic Inflammation, and the Onset of Puberty: A Narrative Review.

The onset of puberty, which is under the control of the hypothalamic-pituitary-gonadal (HPG) axis, is influenced by various factors, including obesity, which has been associated with the earlier onset of puberty. Obesity-induced hypothalamic inflammation may cause premature activation of gonadotropin-releasing hormone (GnRH) neurons, resulting in the development of precocious or early puberty. Mechanisms involving phoenixin action and hypothalamic microglial cells are implicated. Furthermore, obesity induces structural and cellular brain alterations, disrupting metabolic regulation. Imaging studies reveal neuroinflammatory changes in obese individuals, impacting pubertal timing. Magnetic resonance spectroscopy enables the assessment of the brain's neurochemical composition by measuring key metabolites, highlighting potential pathways involved in neurological changes associated with obesity. In this article, we present evidence indicating a potential association among obesity, hypothalamic inflammation, and precocious puberty.

Functional MRI Techniques Suggesting that the Stress System Interacts with Three Large Scale Core Brain Networks to Help Coordinate the Adaptive Response: A Systematic Review.

OBJECTIVE: Synthesis of functional MRI (fMRI) and functional connectivity (FC) analysis data on human stress system (SS) function, as it relates to the dynamic function of the Salience (SN), Default Mode (DMN) and Central Executive (CEN) networks. METHODS: Systematic search of Medline, Scopus, Clinical Trials.gov, and Google Scholar databases of studies published prior to September 2022 resulted in 28 full-text articles included for qualitative synthesis. RESULTS: Acute stress changes the states of intra-/inter- neural network FCs and activities from those of resting, low arousal state in the SN, DMN and CEN, during which intra- and inter-network FCs and activities of all three networks are low. SS activation is positively linked to the activity of the SN and negatively to that of the DMN, while, in parallel, it is associated with an initial decrease and a subsequent increase of the intra- network FC and activity of the CEN. The FC between the DMN and the CEN increases, while those between the SN and the CEN decrease, allowing time for frontal lobe strategy input and "proper" CEN activity and task decision. SN activation is linked to sensory hypersensitivity, "impaired" memory, and a switch from serial to parallel processing, while trait mindfulness is associated with FC changes promoting CEN activity and producing a "task-ready state". CONCLUSION: SS activation is tightly connected to that of the SN, with stress hormones likely potentiating the intra-network FC of the latter, attenuating that of the DMN, and causing a biphasic suppression- to-activation response of the CEN, all adaptive changes favoring proper decisions and survival.

Non-Traditional Cardiovascular Risk Factors in Adolescents with Obesity and Metabolic Syndrome May Predict Future Cardiovascular Disease.

Obesity in adolescence is associated with significant morbidity and predisposes adolescents to the development of cardiovascular disease (CVD). Although a number of traditional CVD risk factors have been identified in youth, limited data exist regarding non-traditional CVD risk factors. In 89 adolescents with metabolic syndrome (MetS), with 60 age-, gender-, and BMI-matched controls, we determined the non-traditional CVD risk factors (hs-CRP, TG/HDL ratio, ApoB/ApoA1 ratio, NAFLD) in order to investigate whether they may be used as biomarkers for predicting future CVD, and we evaluated their response to the implementation of a multidisciplinary, personalized, lifestyle intervention program for 1 year. We demonstrated that the TG/HDL ratio, IL-2, IL-6, IL-17A, and INF-γ were significantly increased in subjects with MetS than in controls, and may be used as biomarkers to predict future CVD. Subjects with MetS had an increased mean carotid intima-media thickness (cIMT) and prevalence of NAFLD than the controls, while the prevalence of NAFLD correlated strongly with cIMT and IL-6 concentrations. Most of the non-traditional cardiovascular risk factors improved following the implementation of a lifestyle intervention program. These findings indicate that adolescents with MetS may have a greater risk for developing atherosclerosis early in life, while early lifestyle intervention is crucial for preventing the arteriosclerotic process in youth.

Key features of puberty onset and progression can help distinguish self-limited delayed puberty from congenital hypogonadotrophic hypogonadism.

Introduction: Delayed puberty (DP) is a frequent concern for adolescents. The most common underlying aetiology is self-limited DP (SLDP). However, this can be difficult to differentiate from the more severe condition congenital hypogonadotrophic hypogonadism (HH), especially on first presentation of an adolescent patient with DP. This study sought to elucidate phenotypic differences between the two diagnoses, in order to optimise patient management and pubertal development. Methods: This was a study of a UK DP cohort managed 2015-2023, identified through the NIHR clinical research network. Patients were followed longitudinally until adulthood, with a definite diagnosis made: SLDP if they had spontaneously completed puberty by age 18 years; HH if they had not commenced (complete, cHH), or had commenced but not completed puberty (partial, pHH), by this stage. Phenotypic data pertaining to auxology, Tanner staging, biochemistry, bone age and hormonal treatment at presentation and during puberty were retrospectively analysed. Results: 78 patients were included. 52 (66.7%) patients had SLDP and 26 (33.3%) patients had HH, comprising 17 (65.4%) pHH and 9 (34.6%) cHH patients. Probands were predominantly male (90.4%). Male SLDP patients presented with significantly lower height and weight standard deviation scores than HH patients (height p=0.004, weight p=0.021). 15.4% of SLDP compared to 38.5% of HH patients had classical associated features of HH (micropenis, cryptorchidism, anosmia, etc. p=0.023). 73.1% of patients with SLDP and 43.3% with HH had a family history of DP (p=0.007). Mean first recorded luteinizing hormone (LH) and inhibin B were lower in male patients with HH, particularly in cHH patients, but not discriminatory. There were no significant differences identified in blood concentrations of FSH, testosterone or AMH at presentation, or in bone age delay. Discussion: Key clinical markers of auxology, associated signs including micropenis, and serum inhibin B may help distinguish between SLDP and HH in patients presenting with pubertal delay, and can be incorporated into clinical assessment to improve diagnostic accuracy for adolescents. However, the distinction between HH, particularly partial HH, and SLDP remains problematic. Further research into an integrated framework or scoring system would be useful in aiding clinician decision-making and optimization of treatment. .

Lifestyle and Pharmacological Interventions and Treatment Indications for the Management of Obesity in Children and Adolescents.

Obesity is a multifactorial chronic impairment that further decreases quality of life and life expectancy. Worldwide, childhood obesity has become a pandemic health issue causing several comorbidities that frequently present already in childhood, including cardiovascular (hypertension, dyslipidemia), metabolic (Type 2 diabetes mellitus, fatty liver disease, metabolic syndrome), respiratory, gastrointestinal and musculoskeletal disorders. In addition, obese children frequently experience stress and psychosocial symptoms, including mood disorders, anxiety, prejudice and low self-esteem. Given that cardiovascular risk factors and pediatric obesity have the tendency to pertain into adulthood, obesity management, including weight control and physical activity, should start before the late teens and certainly before the first signs of atherosclerosis can be detected. This review aims to concisely present options for childhood obesity management, including lifestyle modification strategies and pharmacological treatment, as well as the respective treatment indications for the general practitioner.

The impact of physical activity, quality of life and eating habits on cardiometabolic profile and adipokines in youth with T1D.

PURPOSE: Individuals with Type-1-Diabetes (T1D) are at higher risk of having premature cardiovascular-disease (CVD). Physical activity and healthy lifestyle are major components in the prevention of diabetes' related comorbidities and complications. The aim of this study was to investigate the impact of physical activity, eating habits and quality of life in children and adolescents with T1D on diabetic control, cardiovascular and biochemical profile, infection indices, and adipokine levels. METHODS: This cross-sectional study involved 80 participants (36 boys/44 girls) with T1D, aged (mean ± SD) 14.9 ± 3.4 years, who attended the Diabetes and Metabolism Clinic of a University Children's Hospital, using anthropometric studies, lipid profile, high-sensitivity-C-Reactive-Protein(hs-CRP), Interleukin-6(IL6), leptin and adiponectin levels. Physical activity was assessed with pedometers (total-steps/week) and questionnaire. RESULTS: In 20(25%) children the level of exercise was >75th percentile, in 20(25%) <25th percentile and in 40(50%) children ranged between 25-75th percentile, respectively. Higher levels of physical activity were associated with weight (beta = -0.053, p < 0.001), waist circumference (beta = -0.077, p < 0.001), BMI (beta = -0.167, p = 0.009), muscle mass (beta = -0.0619, p = 0.001) and HDL-C (beta = 0.039, p = 0.033). Quality of life was positively related to weight (beta = 5.49511, p = 0.002), waist circumference (beta = 6.593345, p = 0.012), muscle mass (beta = 7.324088, p < 0.001) and T1D duration (beta = 19.22442, p = 0.005). Lipid profile was positively associated with sweets and chocolate consumption (beta = 0.348, p < 0.05), while vegetable (beta = -0.245, p < 0.05) and white milk consumption (beta = -0.2295, p < 0.05) were negatively associated with waist/height ratio. CONCLUSIONS: In the present study, higher levels of physical activity were associated with improved lipid profile (HDL-C, triglycerides) and body composition [waist circumference, Body-Mass-Index (BMI] of children and adolescents with T1D. Higher scoring in quality-of-life questionnaires were related to older children with longer diabetes duration. Unhealthy eating habits unfavorably affected lipid profile and body composition in T1D youth.

The Genetic Basis of Childhood Obesity: A Systematic Review.

Overweight and obesity in childhood and adolescence represents one of the most challenging public health problems of our century owing to its epidemic proportions and the associated significant morbidity, mortality, and increase in public health costs. The pathogenesis of polygenic obesity is multifactorial and is due to the interaction among genetic, epigenetic, and environmental factors. More than 1100 independent genetic loci associated with obesity traits have been currently identified, and there is great interest in the decoding of their biological functions and the gene-environment interaction. The present study aimed to systematically review the scientific evidence and to explore the relation of single-nucleotide polymorphisms (SNPs) and copy number variants (CNVs) with changes in body mass index (BMI) and other measures of body composition in children and adolescents with obesity, as well as their response to lifestyle interventions. Twenty-seven studies were included in the qualitative synthesis, which consisted of 7928 overweight/obese children and adolescents at different stages of pubertal development who underwent multidisciplinary management. The effect of polymorphisms in 92 different genes was assessed and revealed SNPs in 24 genetic loci significantly associated with BMI and/or body composition change, which contribute to the complex metabolic imbalance of obesity, including the regulation of appetite and energy balance, the homeostasis of glucose, lipid, and adipose tissue, as well as their interactions. The decoding of the genetic and molecular/cellular pathophysiology of obesity and the gene-environment interactions, alongside with the individual genotype, will enable us to design targeted and personalized preventive and management interventions for obesity early in life.

The Role of SNPs in the Pathogenesis of Idiopathic Central Precocious Puberty in Girls.

The initiation of puberty is a crucial timepoint of development, with its disruptions being associated with multiple physical and psychological complications. Idiopathic Central Precocious Puberty (iCPP) has been correlated with Single-Nucleotide Polymorphisms (SNPs) of certain genes that are implicated in various steps of the process of pubertal onset. The aim of this review was to gather current knowledge on SNPs of genes associated with iCPP. We searched articles published on the PubMed, EMBASE and Google Scholar platforms and gathered current literature. KISS1, KISS1R, PLCB1, PRKCA, ITPR1, MKRN3, HPG axis genes, NPVF/NPFFR1, DLK1, KCNK9Q, LIN28B, PROK2R, IGF-1, IGF2, IGF-1R, IGF-2R, IGFBP-3, insulin, IRS-1, LEP/LEPR, PPARγ2, TAC3, TACR3, Estrogen receptors, CYP3A4 and CYP19A1 were studied for implication in the development of precocious puberty. SNPs discovered in genes KISS1, KISS1R, PLCB1, MKRN3, NPVF, LIN28B, PROK2R, IRS-1 TAC3, and CYP3A4 were significantly correlated with CPP, triggering or protecting from CPP. Haplotype (TTTA)13 in CYP19A1 was a significant contributor to CPP. Further investigation of the mechanisms implicated in the pathogenesis of CPP is required to broaden the understanding of these genes' roles in CPP and possibly initiate targeted therapies.

Leukocyte Telomere Length in Children With Congenital Adrenal Hyperplasia.

CONTEXT: Exposure to chronic stress and hypercortisolism is associated with decreased leukocyte telomere length (LTL), a marker for biological aging and cardiovascular disease. Children with congenital adrenal hyperplasia (CAH) are treated with glucocorticoids. OBJECTIVE: To investigate LTL in children with CAH. METHODS: In this prospective observational cohort study, conducted at 4 academic pediatric endocrinology outpatient clinics, children with genetically confirmed CAH were assessed at 2 follow-up visits (mean 4.1 ± 0.7 months apart). At each visit, LTL was determined by quantitative real-time PCR. All subjects underwent detailed clinical and endocrinologic evaluation and were classified as undertreated, optimally treated, or overtreated, accordingly. The influence of clinical factors on LTL was investigated using linear mixed models adjusted for age, sex, and BMI-z. RESULTS: We studied 76 patients, of whom 31 (41%) were girls, 63 (83%) had classic CAH, 67 (88%) received hydrocortisone, and 8 (11%) prednisolone. Median age at first visit was 12.0 years (IQR, 6.3-15.1), and median BMI-z was 0.51 (IQR, -0.12 to 1.43). LTL was shorter in patients with classic vs nonclassic CAH (-0.29, P = 0.012), in overtreated than in optimally treated patients (-0.07, P = 0.002), and patients receiving prednisolone compared with hydrocortisone (-0.34, P < 0.001). LTL was not associated with undertreatment or daily hydrocortisone-equivalent dose (P > 0.05). CONCLUSION: LTL is shorter in patients with classic than nonclassic CAH, and in those who are overtreated with hydrocortisone or treated with long-acting glucocorticoids. These findings may be attributed to chronic exposure to supraphysiologic glucocorticoid concentrations and indicate that LTL may be used as a biomarker for monitoring glucocorticoid treatment.

Chronic Stress and Steatosis of Muscles, Bones, Liver, and Pancreas: A Review.

BACKGROUND: Chronic stress is a recognized risk factor for poor health, body composition disequilibrium, impaired mental health, and deterioration of quality of life. Chronic stress-related cortisol oversecretion and circadian dysregulation and associated systemic low grade, injurious inflammation ("para-inflammation") contribute to steatosis in various metabolically active solid organs, affecting both their structure and function. The aim of this review was to summarize current knowledge on the impact of chronic stress and associated para-inflammation on skeletal muscle, bone, liver, and pancreas, leading to their steatosis. Current management of these maladaptive conditions is also included and underscored in this review. SUMMARY: Steatosis of metabolically active solid organs is involved in various metabolic processes and considered a risk factor for chronic noncommunicable diseases, yet its role in chronic stress physiology and pathophysiology has been overlooked. KEY MESSAGES: Chronic stress-associated steatosis of several solid organs is generally disregarded in current clinical practice. Physicians should be alert for these steatoses and should address them adequately so as to provide appropriate medical care. New guidelines generated by learned societies are needed, along with large observational studies, to offer novel solutions to this old problem.

The Effect of a Comprehensive Life-Style Intervention Program of Diet and Exercise on Four Bone-Derived Proteins, FGF-23, Osteopontin, NGAL and Sclerostin, in Overweight or Obese Children and Adolescents.

The adipose and bone tissues demonstrate considerable interconnected endocrine function. In the present study, we determined the concentrations of fibroblast growth factor-23 (FGF-23), osteopontin, neutrophil gelatinase-associated lipocalin (NGAL) and sclerostin in 345 children and adolescents who were overweight or obese (mean age ± SD mean: 10.36 ± 0.16 years; 172 males, 173 females; 181 prepubertal; and 164 pubertal) before and after their participation in a comprehensive life-style intervention program of diet and exercise for one year. Following the one-year life-style interventions, there was a significant decrease in BMI (p < 0.01), FGF-23 (p < 0.05), osteopontin (p < 0.01) and NGAL (p < 0.01), and an increase in sclerostin (p < 0.01) concentrations. BMI z-score (b = 0.242, p < 0.05) and fat mass (b = 0.431, p < 0.05) were the best positive predictors and waist-to-height ratio (WHtR) (b = −0.344, p < 0.05) was the best negative predictor of the change of osteopontin. NGAL concentrations correlated positively with HbA1C (b = 0.326, p < 0.05), WHtR (b = 0.439, p < 0.05) and HOMA-IR (b = 0.401, p < 0.05), while BMI (b = 0.264, p < 0.05), fat mass (b = 1.207, p < 0.05), HDL (b = 0.359, p < 0.05) and waist circumference (b = 0.263, p < 0.05) were the best positive predictors of NGAL. These results indicate that FGF-23, osteopontin, NGAL and sclerostin are associated with being overweight or obese and are altered in relation to alterations in BMI. They also indicate a crosstalk between adipose tissue and bone tissue and may play a role as potential biomarkers of glucose metabolism. Further studies are required to delineate the physiological mechanisms underlying this association in children and adolescents.

Familial Aggregation of a Novel Missense Variant of COL2A1 Gene Associated with Short Extremities: Case Report and Review of the Literature.

We present two cases of family members (first cousins) with short extremities caused by a novel variant of COL2A1 gene (NM_001844.5). Case 1 description: A 29-year-old woman presented in her first pregnancy for a second trimester anomaly scan at 23 weeks of gestation. Fetal long bones were measured below the third centile for gestational age. Follow-up scans revealed fetal long bone growth deceleration. Initial genetic work-up was negative and the rest of the maternal follow-up was unremarkable. A male baby weighing 3180 g was delivered at 39 weeks and 4 days of gestation. Case 2 description: A 33-year-old pregnant woman presented for a routine second trimester anomaly scan at 20 weeks and 4 days of gestation. All fetal measurements were appropriate for the gestational age. The routine growth scan performed at 32 weeks showed fetal long bone measurements below the third centile for gestational age, while the follow-up growth scan at 36 weeks and 4 days of gestation revealed consistent, below the third centile, fetal long bone growth. Given that the fetuses of these two cases were related (first cousins), whole exome sequencing (WES) was performed on Case 2. WES revealed a novel heterozygous missense variant c.1132G>A (p. Gly378Ser) of COL2A1 gene (NM_001844.5). Subsequently, targeted genetic sequencing for the variant was performed on Case 1 and the same novel variant was found. Targeted sequencing revealed the same variant in the mother of Case 1 and the father of Case 2 (siblings). A female baby weighing 3200 g was delivered at 40 weeks and 4 days of gestation.

Markedly elevated troponin and NT-proBNP and myocardial dysfunction in an adolescent with severe diabetic ketoacidosis: A case report.

Severe diabetic ketoacidosis (DKA), rarely, may be associated with elevated troponin and proBNP levels in adults with a history of diabetes. However, few cases have reported this association in children with severe and complicated DKA. We describe a case of severe DKA (pH: 6.89, HCO3: 6.5) in a 14-yr-old female adolescent in which the symptoms of DKA were presented days before the diagnosis. The patient was under the effect of acidosis (Kussmaul respiration) for 12 h before admission to our hospital, where she was admitted in a critical clinical condition. After successful treatment with DKA with intensive intravenous fluid and regular insulin, the patient presented with abnormal cardiac rhythm, disturbance of interventricular septum motility, a mild decrease in left ventricular systolic function, negative T waves in leads III and aVF, and a marked increase in troponin and brain natriuretic peptide (NT-proBNP) levels. All abnormal findings completely resolved within 8 days after the initiation of DKA treatment. The phenomenon in our case was transient, and the patient had a good long-term outcome. However, it represents a challenge for clinicians; therefore, emphasis should be given to cardiac monitoring during the course of severe and prolonged DKA in children and adolescents.

Could COVID-19's Aftermath on Children's Health Be Felt into the 22nd Century?

The COVID-19 pandemic has massively affected people's health, societies, and the global economy. Our lives are no longer as they were before COVID-19, and, most likely, will never be the same again. We hypothesize that the effect of the COVID-19 pandemic on population health and the economy will last for a very long time and will still be felt in the 22nd century. Our hypothesis is based on evidence from the 1918-1919 influenza pandemic, the Dutch famine during the Second World War, and the 2007-2008 economic crisis, as well as from the rationally predicted impact of COVID-19 on human development. We expect that the COVID-19 pandemic, including the mitigation measures taken against it, will affect children's development in multiple ways, including obesity, both while in utero and during critical and sensitive windows of development, including the early childhood years and those of puberty and adolescence. The psychosocial and biological impact of this effect will be considerable and unequally distributed. The implications will last at least a lifetime, and, through inter-generational transmission, will likely take us to future generations, into the 22nd century. We argue for the urgent need of designing and initiating comprehensive longitudinal cohort studies to closely monitor the long-term effects of COVID-19 on children conceived, born, and raised during the pandemic. Such an approach requires a close and effective collaboration between scientists, healthcare providers, policymakers, and the younger generations, and it will hopefully uncover evidence necessary to understand and mitigate the impact of the pandemic on people's lives in the 21st and 22nd centuries.