Molecular Mechanisms of Fetal and Neonatal Lupus: A Narrative Review of an Autoimmune Disease Transferal across the Placenta.

This study, conducted by searching keywords such as "maternal lupus", "neonatal lupus", and "congenital heart block" in databases including PubMed and Scopus, provides a detailed narrative review on fetal and neonatal lupus. Autoantibodies like anti-Ro/SSA and anti-La/SSB may cross the placenta and cause complications in neonates, such as congenital heart block (CHB). Management options involve hydroxychloroquine, which is able to counteract some of the adverse events, although the drug needs to be used carefully because of its impact on the QTc interval. Advanced pacing strategies for neonates with CHB, especially in severe forms like hydrops, are also assessed. This review emphasizes the need for interdisciplinary care by rheumatologists, obstetricians, and pediatricians in order to achieve the best maternal and neonatal health in lupus pregnancies. This multidisciplinary approach seeks to improve the outcomes and management of the disease, decreasing the burden on mothers and their infants.

Rare genetic forms of obesity in childhood and adolescence: A narrative review of the main treatment options with a focus on innovative pharmacological therapies.

The prevalence of obesity in children and adolescents is increasing, and it is recognised as a complex disorder that often begins in early childhood and persists throughout life. Both polygenic and monogenic obesity are influenced by a combination of genetic predisposition and environmental factors. Rare genetic obesity forms are caused by specific pathogenic variants in single genes that have a significant impact on weight regulation, particularly genes involved in the leptin-melanocortin pathway. Genetic testing is recommended for patients who exhibit rapid weight gain in infancy and show additional clinical features suggestive of monogenic obesity as an early identification allows for appropriate treatment, preventing the development of obesity-related complications, avoiding the failure of traditional treatment approaches. In the past, the primary recommendations for managing obesity in children and teenagers have been focused on making multiple lifestyle changes that address diet, physical activity, and behaviour, with the goal of maintaining these changes long-term. However, achieving substantial and lasting weight loss and improvements in body mass index (BMI) through lifestyle interventions alone is rare. Recently the progress made in genetic analysis has paved the way for innovative pharmacological treatments for different forms of genetic obesity. By understanding the molecular pathways that contribute to the development of obesity, it is now feasible to identify specific patients who can benefit from targeted treatments based on their unique genetic mechanisms.  Conclusion: However, additional preclinical research and studies in the paediatric population are required, both to develop more personalised prevention and therapeutic programs, particularly for the early implementation of innovative and beneficial management options, and to enable the translation of these novel therapy approaches into clinical practice. What is Known: • The prevalence of obesity in the paediatric population is increasing, and it is considered as a multifaceted condition that often begins in early childhood and persists in the adult life. Particularly, rare genetic forms of obesity are influenced by a combination of genetic predisposition and environmental factors and are caused by specific pathogenic variants in single genes showing a remarkable impact on weight regulation, particularly genes involved in the leptin-melanocortin pathway. • Patients who present with rapid weight gain in infancy and show additional clinical characteristics indicative of monogenic obesity should undergo genetic testing, which, by enabling a correct diagnosis, can prevent the development of obesity-related consequences through the identification for appropriate treatment. What is New: • In recent years, advances made in genetic analysis has made it possible to develop innovative pharmacological treatments for various forms of genetic obesity. In fact, it is now achievable to identify specific patients who can benefit from targeted treatments based on their unique genetic mechanisms by understanding the molecular pathways involved in the development of obesity. • As demonstrated over the last years, two drugs, setmelanotide and metreleptin, have been identified as potentially effective interventions in the treatment of certain rare forms of monogenic obesity caused by loss-of-function mutations in genes involved in the leptin-melanocortin pathway. Recent advancements have led to the development of novel treatments, including liraglutide, semaglutide and retatrutide, that have the potential to prevent the progression of metabolic abnormalities and improve the prognosis of individuals with these rare and severe forms of obesity. However, extensive preclinical research and, specifically, additional studies in the paediatric population are necessary to facilitate the translation of these innovative treatment techniques into clinical practice.

Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections (PANDAS): Myth or Reality? The State of the Art on a Controversial Disease.

Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections (PANDAS) syndrome is one of the most controversial diseases in pediatric rheumatology. Despite first being described more than 25 years ago as the sudden and rapid onset of obsessive-compulsive disorder (OCD) and/or tic disorder symptoms as complications of a Group A beta-hemolytic Streptococcus (GAS) infection, precise epidemiological data are still lacking, and there are no strong recommendations for its treatment. Recent advances in the comprehension of PANDAS pathophysiology are largely attributable to animal model studies and the understanding of the roles of Ca++/calmodulin-dependent protein kinase (CaM kinase) II, disrupted dopamine release in the basal ganglia, and striatal cholinergic interneurons. The diagnosis of PANDAS should be made after an exclusion process and should include prepubescent children with a sudden onset of OCD and/or a tic disorder, with a relapsing/remitting disease course, a clear temporal association between GAS infection and onset or exacerbation of symptoms, and the association with other neurological abnormalities such as motoric hyperactivity and choreiform movements. Antibiotic medications are the primary therapeutic modality. Nonetheless, there is a paucity of randomized studies and validated data, resulting in a scarcity of solid recommendations.

Graves' disease after COVID mRNA vaccination for the first time diagnosed in adolescence-case report. Cause and effect relationship or simple coincidence?

OBJECTIVES: Over the past 3 years, coronavirus disease 2019 with its worldwide spread has profoundly marked public health, therefore anti-COVID-19 vaccinations have been developed to prevent the dissemination of the disease. To date, 71 cases of Graves' disease (GD) after vaccination against SARS-Cov-2 were described in the adult population. Our goal is to present the first case in the paediatric population. CASE PRESENTATION: We present the first case of a 16-year-old adolescent girl who developed GD 6-7 weeks after the second dose anti-COVID-19 mRNA vaccine. Therapy with methimazole and propranolol was started, achieving normal thyroid function and negativity of thyroid autoantibodies at the time of therapy discontinuation after 8 months. CONCLUSIONS: This case shows that the development of GD after COVID-19 mRNA vaccination can occur also in the adolescent population. Nevertheless, the small number of cases of GD described so far, after many millions of vaccinations, makes it impossible to determine whether this is simple a coincidence or a cause. Further epidemiological data on the incidence of GD in the vaccination period compared to the previous period will be able to clearly define this question.

Rare genetic forms of obesity in childhood and adolescence, a comprehensive review of their molecular mechanisms and diagnostic approach.

Obesity represents a major health problem in the pediatric population with an increasing prevalence worldwide, associated with cardiovascular and metabolic disorders, and due to both genetic and environmental factors. Rare forms of obesity are mostly monogenic, and less frequently due to polygenic influence. Polygenic form of obesity is usually the common obesity with single gene variations exerting smaller impact on weight and is commonly non-syndromic.Non-syndromic monogenic obesity is associated with variants in single genes typically related to the hypothalamic leptin-melanocortin signalling pathway, which plays a key role in hunger and satiety regulation, thus body weight control. Patients with these genetic defects usually present with hyperphagia and early-onset severe obesity. Significant progress in genetic diagnostic testing has recently made for early identification of patients with genetic obesity, which guarantees prompt intervention in terms of therapeutic management of the disease. What is Known: • Obesity represents a major health problem among children and adolescents, with an increasing prevalence worldwide, associated with cardiovascular disease and metabolic abnormalities, and it can be due to both genetic and environmental factors. • Non-syndromic monogenic obesity is linked to modifications in single genes usually involved in the hypothalamic leptin-melanocortin signalling pathway, which plays a key role in hunger and satiety regulation. What is New: • The increasing understanding of rare forms of monogenic obesity has provided significant insights into the genetic causes of pediatric obesity, and our current knowledge of the various genes associated with childhood obesity is rapidly expanding. • A useful diagnostic algorithm for early identification of genetic obesity has been proposed, which can ensure a prompt intervention in terms of therapeutic management of the disease and an early prevention of the development of associated metabolic conditions.

Hyperlipidemia and Cardiovascular Risk in Children and Adolescents.

Atherosclerotic cardiovascular disease (ASCVD) represents the major cause of morbidity and mortality worldwide. The onset of the atherosclerosis process occurs during childhood and adolescence, subsequently leading to the onset of cardiovascular disease as young adults. Several cardiovascular risk factors can be identified in children and adolescents; however, hyperlipidemia, in conjunction with the global obesity epidemic, has emerged as the most prevalent, playing a key role in the development of ASCVD. Therefore, screening for hyperlipidemia is strongly recommended to detect high-risk children presenting with these disorders, as these patients deserve more intensive investigation and intervention. Treatment should be initiated as early as possible in order to reduce the risk of future ASCVD. In this review, we will discuss lipid metabolism and hyperlipidemia, focusing on correlations with cardiovascular risk and screening and therapeutic management to reduce or almost completely avoid the development of ASCVD.

Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections (PANDAS) Syndrome: A 10-Year Retrospective Cohort Study in an Italian Centre of Pediatric Rheumatology.

BACKGROUND: Pediatric Autoimmune Neuropsychiatric Disorders Associated with Streptococcal Infections (PANDAS) syndrome is a rare pediatric disorder consisting of a sudden onset of obsessive-compulsive disorder (OCD) and/or tics after a group A Streptococcus (GAS) infection. METHODS: In the period between 2013 and 2023, 61 children presented to our Pediatric Rheumatology unit with a suspicion of PANDAS syndrome. Among these, a retrospective analysis was conducted, and 19 fulfilled the current classification criteria and were included in this study. RESULTS: The male-to-female ratio was 14:5, the median age at onset was 7.0 (2.0-9.5) years, and the median age at diagnosis was 8.0 (3.0-10.4) years. The median follow-up period was 16.0 (6.0-72.0) months. Family and personal history were relevant in 7/19 and 6/19 patients. Tics were present in all patients. Details for motor tics were retrospectively available in 18/19 patients, with the eyes (11/18) and neck/head (10/18) being most often involved. Vocal tics were documented in 8/19, behavioral changes in 10/19, and OCD in 2/19. Regarding the therapeutic response, all patients responded to amoxicillin, 12/13 to benzathine benzylpenicillin, and 7/9 to azithromycin. CONCLUSIONS: Our findings partially overlap with previous reports. Larger prospective studies are needed to improve treatment strategies and classification criteria.

Cardiovascular Risk in Childhood Cancer Survivors.

Cancer is a prominent cause of death worldwide in the pediatric population. Since childhood cancer is not possible to prevent, it is essential to focus on a prompt and correct diagnosis followed by effective, evidence-based therapy with individualized supportive care. Given the enhancement of childhood cancer management over the past decades, survival rate has significantly improved, thus leading to the progression of several late effects, including metabolic derangements. These metabolic imbalances are associated with the underlying disease and the cancer treatments. As a result, the metabolic state may contribute to a high risk of cardiovascular morbidity and premature mortality among childhood cancer survivors. This review aims to summarize the potential pathophysiological mechanisms linked to the risk of diabetes and metabolic syndrome and screening recommendations. Further investigations are needed to clarify the underlying mechanisms of such metabolic abnormalities and to improve long-term cardiometabolic survival among these patients.

Insulin resistance in children.

PURPOSE OF REVIEW: Insulin resistance (IR) is a clinical condition due to the decline in the efficiency of insulin promoting glucose uptake and utilization. The aim of this review is to provide an overview of the current knowledge on IR in children, focusing on its physiopathology, the most appropriate methods of measurement of IR, the assessment of risk factors, the effects of IR in children, and finally giving indications on screening and treatment. RECENT FINDINGS: IR has evolved more and more to be a global public health problem associated with several chronic metabolic diseases. SUMMARY: Detecting a correct measurement method and specific risk predictors, in order to reduce the incidence of IR, represents a challenging goal.

Hypertension in Patients with Insulin Resistance: Etiopathogenesis and Management in Children.

Insulin resistance (IR) is a key component in the etiopathogenesis of hypertension (HS) in patients with diabetes mellitus (DM). Several pathways have been found to be involved in this mechanism in recent literature. For the above-mentioned reasons, treatment of HS should be specifically addressed in patients affected by DM. Two relevant recently published guidelines have stressed this concept, giving specific advice in the treatment of HS in children belonging to this group: the European Society of HS guidelines for the management of high blood pressure in children and adolescents and the American Academy of Pediatrics Clinical Practice Guideline for Screening and Management of High Blood Pressure in Children and Adolescents. Our aim is to summarize the main pathophysiological mechanisms through which IR causes HS and to highlight the specific principles of treatment of HS for children with DM.

Recent Advances on Familial Hypercholesterolemia in Children and Adolescents.

Familial hypercholesterolemia is a common autosomal hereditary disorder characterized by elevated concentrations of low-density lipoprotein cholesterol and the development of premature atherosclerosis and cardiovascular disease. Early diagnosis, as well as prompt and aggressive treatment, are fundamental steps to prevent cardiovascular complications and a high rate of premature mortality in children and adolescents. Clinics and genetics are the two main aspects on which diagnosis is based. Widespread screening programs are a respectable option for the early detection of familial hypercholesterolemia. Different types of screening have been proposed so far; however, the optimal screening program has not yet been found. The treatment approach for both heterozygous and homozygous familial hypercholesterolemia in the pediatric population is multidisciplinary, including lifestyle modifications, standard lipid-lowering medications, and novel pharmacological agents. The latter show promising results, especially for patients who experience intolerance to other treatment or present with more severe conditions. Our purpose is to focus on the importance of the early detection of familial hypercholesterolemia, and to highlight the best therapeutic strategies, including the recent approaches based on current clinical evidence, that need to be adopted from the earliest stages of life.

Treatment Options for Lipodystrophy in Children.

Lipodystrophy includes a heterogeneous group of rare diseases characterized by different amounts of adipose tissue loss and several metabolic complications, including hypertriglyceridemia, steatohepatitis and particularly insulin resistance, that may lead to severe morbidity and, sometimes, mortality. Therefore, therapy for lipodystrophy primarily consists of a conventional approach that involves standard treatments of metabolic abnormalities. Given the evidence of leptin deficiency in lipodystrophy syndromes, leptin replacement therapy has been considered as a treatment option. Long-term studies on the use of therapy with a methionylated analog of human leptin, metreleptin, first on animals and subsequently on human patients, demonstrated enormous improvements of patients' clinical features and metabolic conditions. Recently, metreleptin was approved by Food and Drug Administration (FDA) for the treatment of generalized lipodystrophy and by European Medicines Agency (EMA) for the treatment of both generalized and partial lipodystrophy. However, further research is being conducted for new and different therapeutic agents, especially helpful for the treatment of patients with partial lipodystrophy, as some of them do not have access to metreleptin therapy or show poor response.

Lipodystrophies in Children.

BACKGROUND: Lipodystrophy includes a wide group of diseases characterized by reduction, absence, or altered distribution of adipose tissue. Lipodystrophies are classified into generalized or partial, according to the fat distribution, and congenital or acquired, considering the etiology. SUMMARY: Impaired glucose and lipid metabolism are typically present, thus severe insulin resistance, diabetes mellitus, dyslipidemia, and hepatic steatosis are frequent complications. Because of the rarity and the diversification of lipodystrophies, diagnosis might be challenging, typically for partial forms that cannot be easily recognized, leading to progression of the several metabolic abnormalities associated. First management of lipodystrophy is diet and lifestyle changes, followed by the treatment of metabolic complications. Replacement therapy with metreleptin, currently available in the USA and Europe, has shown improvement of metabolic profile in a great number of patients with lipodystrophy. KEY MESSAGES: The purpose of this review was to describe the phenotypic characteristics of all the known lipodystrophic types and to present specific steps for obtaining an early diagnosis and assessing the best treatment of lipodystrophy.

Early Insulin Resistance, Type 2 Diabetes, and Treatment Options in Childhood.

BACKGROUND: Type 2 diabetes (T2D) represents just the tip of the iceberg of the complex metabolic alterations associated with obesity and other clinical conditions associated to impaired adipose tissue storage. SUMMARY: Available data have suggested the presence of a continuous spectrum of metabolic alterations developed in the progression from insulin resistance (IR) to T2D, most of which are likely preventable through the early characterization of all the multiple risk factors involved. Therefore, the complete characterization of the natural history of the disease and the major modifiable factors represents a milestone in the daily care of young subject at risk for the development of impaired glucose metabolism early in life. This review will focus on the main components defining the risk of IR and T2D in childhood with a specific focus on the main aspects of treatment options available in children and adolescents. KEY MESSAGES: Impaired adipose tissue storage documented in obesity results in a continuous spectrum of metabolic alterations ranging from IR to T2DM. These metabolic alterations are mostly likely preventable through the early characterization of all the multiple risk factors involved. The complete characterization of the disease and of the major modifiable factors represent a milestone in the daily care of young subject at risk for the development of impaired glucose metabolism early in life.