An Ultra-Rare Mixed Phenotype with Combined AP-4 and ERF Mutations: The First Report in a Pediatric Patient and a Literature Review.

The adaptor protein 4 (AP-4) constitutes a conserved hetero-tetrameric complex within the family of adaptor protein (AP) complex, crucial for the signal-mediated trafficking of integral membrane proteins. Mutations affecting all subunits of the AP-4 complex have been linked to autosomal-recessive cerebral palsy and a complex hereditary spastic paraparesis (HSP) phenotype. Our report details the case of a 14-year-old boy born to consanguineous parents, presenting psychomotor delay, severe intellectual disability, microcephaly, and trigonocephaly. Despite a history of febrile seizures, subsequent years were devoid of seizures, with normal EEG. Exome sequencing revealed pathogenic variants in both the AP4B1 and ERF genes. Significantly, the patient exhibited features associated with AP4B1 mutations, including distinctive traits such as cranial malformations. The ERF gene variant, linked to craniosynostosis, likely contributes to the observed trigonocephaly. This case represents the initial documentation of a concurrent mutation in the AP4B1 and ERF genes, underscoring the critical role of exome analysis in unraveling complex phenotypes. Understanding these complex genotypes offers valuable insights into broader syndromic conditions, facilitating comprehensive patient management.

The Influence of Ketogenic Diet on Gut Microbiota: Potential Benefits, Risks and Indications.

The ketogenic diet (KD) restricts carbohydrate consumption, leading to an increase in ketone bodies, such as acetoacetate, ß-hydroxybutyrate, and acetone, which are utilized as energy substrates. This dietary approach impacts several biochemical processes, resulting in improved clinical management of various disorders, particularly in childhood. However, the exact mechanisms underlying the efficacy of KD remain unclear. Interestingly, KD may also impact the gut microbiota, which plays a pivotal role in metabolism, nutrition, and the development of the immune and nervous systems. KD has gained popularity for its potential benefits in weight loss, blood sugar control, and certain neurological conditions. This narrative review sums up KD-related studies published over 30 years. While short-term studies have provided valuable insights into the effects of KD on the gut microbiota, persistent uncertainties surround its long-term efficacy and potential for inducing dysbiosis. The significant influence of KD on epigenetic mechanisms, intracellular pathways, and gut microbial composition underscores its potential as a therapeutic choice. However, a judicious consideration of the potential risks associated with the strict adherence to a low-carbohydrate, high-fat, and high-protein regimen over prolonged periods is imperative. As KDs gain popularity among the adolescent and young adult demographic for weight management, it becomes imperative to undertake additional research to comprehensively assess their impact on nutritional status and gut microbiota, ensuring a holistic and sustainable approach to medical nutrition.

Uptake of Vaccinations among Children with Chronic Diseases Is Affected by Knowledge Gaps and Implementation Challenges in Italy.

(1) Background: Children with chronic medical conditions may be at increased risk for severe complications related to vaccine-preventable infections. Therefore, additional booster doses or supplementary vaccines are recommended, over and above the routine immunization schedule for healthy children. The aim of this study was to investigate attitude, knowledge, and practices toward additional vaccinations for children affected by chronic conditions among pediatricians and parents. (2) Methods: This study is based on two surveys: (i) a national cross-sectional survey, targeting pediatrician working in hospitals or in the primary health sector; (ii) a local cross-sectional survey, targeting parents of children with a previous diagnosis of chronic disease. (3) Results: Despite the fact that most of the health professionals and parents interviewed had an overall positive vaccine attitude, most pediatricians did not show an adequate knowledge of additional vaccinations for children affected by chronic diseases. Moreover, the coverage of additional recommended vaccinations in chronic pediatric patients was low. (4) Conclusions: This research highlighted important existing challenges hampering optimal vaccination coverage among pediatric chronic patients, including knowledge gaps on tailored vaccination schedules among pediatricians and organizational issues. The ongoing review of the Italian national immunization plan is a not-to-be-missed-opportunity to include evidence-based, detailed, and comprehensive recommendations on vaccinations for children affected by chronic conditions.

Probiotics as Adjuvants in Vaccine Strategy: Is There More Room for Improvement?

BACKGROUND: It has been recognized that microbiota plays a key role in shaping immune system maturation and activity. Since probiotic administration influences the microbiota composition and acts as a biological response modifier, the efficacy of an adjuvant for boosting vaccine-specific immunity is investigated. METHODS: A review of the literature was performed, starting from the mechanisms to laboratory and clinical evidence. RESULTS: The mechanisms, and in vitro and animal models provide biological plausibility for microbiota use. Probiotics have been investigated as adjuvants in farm conditions and as models to understand their potential in human vaccinations with promising results. In human studies, although probiotics were effective in ameliorating seroconversion to vaccines for influenza, rotavirus and other micro-organisms, the results for clinical use are still controversial, especially in particular settings, such as during the last trimester of pregnancy. CONCLUSION: Although this topic remains controversial, the use of probiotics as adjuvant factors in vaccination represents a strategic key for different applications. The available data are deeply influenced by heterogeneity among studies in terms of strains, timing and duration of administration, and patients. Although these do not allow us to draw definitive conclusions, probiotics as adjuvants in vaccination should be considered in future studies, especially in the elderly and in children, where vaccine effectiveness and duration of immunization really matter.

The clinical impact of maternal weight on offspring health: lights and shadows in breast milk metabolome.

INTRODUCTION: Pre-pregnancy overweight and obesity, depending on maternal nutrition and metabolic state, can influence fetal, neonatal, and long-term offspring health, regarding cardio-metabolic, respiratory, immunological, and cognitive outcomes. Thus, maternal weight can act, through mechanisms not fully understood, on the physiology and metabolism of some fetal organs and tissues, to adapt themselves to the intrauterine environment and nutritional reserves. These effects can occur by modulating gene expression, neonatal microbiome, and through breastfeeding. AREAS COVERED: In this paper, we investigated the potential effects of metabolites found altered in breast milk (BM) of overweight/obese mothers, through an extensive review of metabolomics studies, and the potential short and long-term clinical effects in the offspring, especially overweight, glucose homeostasis, insulin resistance, oxidative stress, infections, immune processes, neurodevelopment. EXPERT OPINION: Metabolomics seems the ideal tool to investigate BM variation depending on maternal or fetal/neonatal factors. In particular, BM metabolome alterations according to maternal conditions were recently pointed out in cases of gestational diabetes, preeclampsia, intrauterine growth restriction and maternal overweight/obesity. In our opinion, even if BM is the food of choice in neonatal nutrition, the deepest comprehension of its composition in overweight/obese mothers could allow targeted supplementation, to improve offspring health and metabolic homeostasis.

Raising Children on a Vegan Diet: Parents' Opinion on Problems in Everyday Life.

A growing number of Italian families are adopting a vegan diet (VD) for their offspring from infancy for various reasons, with health benefits and ethics being the most common reasons. Barriers to effective communication with primary care pediatricians (PCPs) are perceived by many parents and, depending on the actors involved and the environment, a VD may affect social interactions in everyday life. A national cross-sectional survey was conducted between July and September 2020. Parents of children following a VD completed an online questionnaire. Data from 176 Italian parents were collected. About 72% (71.8%) of the children included in this study had been on a VD since weaning. Parents did not inform their primary care pediatricians (PCP) about the VD in 36.2% of the cases. In 70.8% of the cases, PCPs were perceived as skeptical or against a VD. About 70% (71.2%) of the parents relied on medical dietitians, and 28.2% on nutritionists/dietitians for dietary counseling. Parents administered an individual B12 supplement in 87.2% of the cases. To the best of our knowledge, this survey is the first which explores the relationship between vegan parents and their PCPs, the parental management of their children's diet and problems regarding the implementation of a VD in everyday life.

Breastfeeding and Allergic Diseases: What's New?

Asthma and other allergic disorders, such as atopic dermatitis and food allergies, are common chronic health problems in childhood. The rapid rise in the prevalence of these conditions registered over the last few decades has stressed the need to identify the modifiable risk factors associated with the development of these diseases. Breast milk, recognized as the gold standard for healthy growth and development of the newborn, is one of the major factors associated with a lower incidence of allergic and infectious diseases in childhood and young adulthood. Although the underlying mechanisms for these effects are not well understood, breastfeeding leads to immune system maturation. In this narrative review, we summarize existing evidence on breastfeeding and human milk composition in relation to allergic disease prevention or development.

When a Neonate Is Born, So Is a Microbiota.

In recent years, the role of human microbiota as a short- and long-term health promoter and modulator has been affirmed and progressively strengthened. In the course of one's life, each subject is colonized by a great number of bacteria, which constitute its specific and individual microbiota. Human bacterial colonization starts during fetal life, in opposition to the previous paradigm of the "sterile womb". Placenta, amniotic fluid, cord blood and fetal tissues each have their own specific microbiota, influenced by maternal health and habits and having a decisive influence on pregnancy outcome and offspring outcome. The maternal microbiota, especially that colonizing the genital system, starts to influence the outcome of pregnancy already before conception, modulating fertility and the success rate of fertilization, even in the case of assisted reproduction techniques. During the perinatal period, neonatal microbiota seems influenced by delivery mode, drug administration and many other conditions. Special attention must be reserved for early neonatal nutrition, because breastfeeding allows the transmission of a specific and unique lactobiome able to modulate and positively affect the neonatal gut microbiota. Our narrative review aims to investigate the currently identified pre- and peri-natal factors influencing neonatal microbiota, before conception, during pregnancy, pre- and post-delivery, since the early microbiota influences the whole life of each subject.

Application of exhaled nitric oxide (FeNO) in pediatric asthma.

PURPOSE OF REVIEW: Fractional concentration of Nitric Oxide in the exhaled air (FeNO) is a moderately good biomarker of type-2 airway inflammation, and its measurement is feasible also in children. The available evidence is still not enough to support the routine use of FeNO to diagnose or manage asthma in every patient in clinical practice. However, its role in identifying asthma with eosinophilic inflammation is of particular interest in the management of severe asthma. RECENT FINDINGS: In healthy subjects, FeNO levels increase with age and height, particularly in males, and are also influenced by ethnicity. FeNO measurement can support asthma diagnosis and help in predicting asthma development later in life in young children with recurrent wheezing. FeNO-guided asthma management is effective in reducing asthma exacerbations but may result in a higher daily dose of inhaled corticosteroids. FeNO can also be used as a marker to evaluate adherence to asthma treatment and predict response to different biologicals, especially Omalizumab and Dupilumab. SUMMARY: This review outlines recent data on the application of FeNO in childhood-onset asthma diagnosis and management, as well as in phenotyping subjects with severe asthma who may benefit from monoclonal antibodies administration.

The extra-lymphoid compartment of breast milk: Not a simple transfer of passive immunization.

Discussion on how breast milk shows similarity to the immune gut micro-environment, creating a sort of immune "extended gut" between mother and child; helps advance the newborn's immune endowment by further tuning mucosal immunity and CD8 memory cells in the early life intestine.

The Human Breast Milk Metabolome in Overweight and Obese Mothers.

Pre-pregnancy body mass index (BMI) is a major relevance factor, since maternal overweight and obesity can impair the pregnancy outcome and represent risk factors for several neonatal, childhood, and adult conditions, including excessive weight gain, cardiovascular disease, diabetes mellitus, and even behavioral disorders. Currently, breast milk (BM) composition in such category of mothers was not completely defined. In this field, metabolomics represents the ideal technology, able to detect the whole profile of low molecular weight molecules in BM. Limited information is available on human BM metabolites differences in overweight or obese compared to lean mothers. Analyzing all the metabolomics studies published on Medline in English language, this review evaluated the effects that 8 specific types of metabolites found altered by maternal overweight and obesity (nucleotide derivatives, 5-methylthioadenosine, sugar-alcohols, acylcarnitine and amino acids, polyamines, mono-and oligosaccharides, lipids) can exert on the risk of offspring obesity development and other potentially associated health outcomes and complications. However, metabolites variations in samples collected from overweight and obese mothers and the potentially correlated effects highlighted below still need further investigations and should be confirmed in future metabolomics studies on larger samples. Finally, the positive or negative influence of maternal overweight and obesity on the offspring, potentially exerted by breastfeeding, should be analyzed in close correlation with maternal age, genetic and environmental factors, including diet, and taking into account the interactions occurring between BM metabolites and lactobiome. The evaluation of all the factors affecting BM metabolites in overweight and obese mothers can lead to the comprehensive description of such biofluid and the related effects on breastfed subjects, potentially highlighting personalized needs of BM supplementation or short- and long-term prevention strategies to optimize offspring health.

Human Breast Milk: Bioactive Components, from Stem Cells to Health Outcomes.

PURPOSE OF REVIEW: Breast milk (BM) is a peculiar fluid owing unique properties and resulting the ideal food during early neonatal period. As widely known, it can improve the outcome of both neonate and lactating mother, influencing their whole life. BM is characterized by several beneficial components; among these, a great role is played by BM own and specific microbiome, deeply investigated in many studies. Moreover, the use of metabolomics in BM analysis allowed a better characterization of its metabolic pathways that vary according to lactation stage and neonatal gestational age. The aim of this review is to describe growth factors, cytokines, immunity mediators, and stem cells (SCs) contained in BM and investigate their functions and effects on neonatal outcome, especially focusing on immuno- and neurodevelopment. RECENT FINDINGS: We evaluated recent and updated literature on this field. The article that we analyzed to write this review have been found in MEDLINE using breast milk-derived stem cells, biofactors, growth factors, breastfeeding-related outcomes, neurodevelopment, and neonatal immunological system as keywords. Discovering and characterizing BM components could result very useful to clarify the pathophysiology of their influence on neonatal growth and even to improve artificial formulations' composition. Moreover, since SCs abilities and their involvement in the development of several diseases, they could help to discover specific targets for new therapies. It could be useful to characterize BM-derived SC markers, properties, and variations during lactation stages, to understand their potential role in therapeutic applications, since they could be noninvasively isolated from BM. More studies will help to describe more in detail the characteristics of mother-to-child communication through breastfeeding and its potential role in the next future.

Mothers and fathers of children with epilepsy: gender differences in post-traumatic stress symptoms and correlations with mood spectrum symptoms.

BACKGROUND: Post-traumatic stress disorder (PTSD) and post-traumatic stress spectrum have been recently applied to understand the impact of life-threatening disease or injury in one's child; nevertheless, scant data are available on a particular chronic illness such as epilepsy whose phenotypic expression is seizures, which are acute, sudden, and unpredictable manifestations. Subjects with bipolar disorders or with mood spectrum symptoms demonstrated to be more vulnerable to develop PTSD in the aftermath of a trauma. OBJECTIVES: The main aim of this study was to evaluate post-traumatic symptoms among 134 parents of children with a diagnosis of epilepsy, followed at the outpatient neurologic unit of Department of Pediatrics in Santa Chiara Hospital in Pisa, as well as gender differences. The second aim of this study was to estimate the impact of lifetime mood spectrum on post-traumatic stress symptoms in the same study sample after fulfillment of the Trauma and Loss Spectrum-Self Report (TALS-SR) and the Mood Spectrum-Self Report (MOODS-SR) lifetime version. RESULTS: Results showed 10.4% and 37.3% of PTSD full and partial, respectively. Demographic characteristics and clinical features of the study sample did not show any impact on stress symptomatology. Mothers presented higher rates at all Diagnostic and Statistical Manual of Mental Disorders (DSM)-5 PTSD symptoms' clusters except avoidance. Nevertheless, noteworthy correlations between post-traumatic symptomatology and mood spectrum symptoms detected with the self-report tools, emerged only in the subgroup of the fathers. CONCLUSION: These findings corroborate the need to provide assistance to caregivers of pediatric patients and confirm the hypothesis that lifetime mood spectrum may have an impact on reaction to traumas.

Baby-led weaning: what a systematic review of the literature adds on.

The term weaning describes the time period in which a progressive reduction of breastfeeding or the feeding of infant-formula takes place while the infant is gradually introduced to solid foods. It is a crucial time in an infant's life as not only does it involve with a great deal of rapid change for the child, but it is also associated with the development of food preferences, eating behaviours and body weight in childhood and also in adolescence and adulthood.Therefore, how a child is weaned may have an influence later, on the individual's entire life. Babies are traditionally first introduced to solid foods using spoon-feeding, in most countries.Beside to traditional approach, an alternative method, promoting infant self-feeding from six months of age, called baby-led weaning or "auto-weaning", has grown in popularity. This approach causes concern to healthy professionals and parents themselves as data from observational studies pointed out to a potential risk of iron and energy inadequacy as well as choking risk. Aim of this systematic review was to critically examine the current evidence about baby-led weaning approach and to explore the need for future research.A systematic search was conducted in Cochrane library databases and DARE (Database of Abstract of Reviews of Effects), EMBASE and MEDLINE in the period 2000-2018 (up to March 1st) to address some key questions on baby-led weaning. Prisma guidelines for systematic reviews has been followed.After the inclusion/exclusion process, we included for analysis of evidence 12 articles, 10 observational cross-sectional studies and 2 randomized controlled trials. Pooling of results from very different outcomes in the studies included was not possible. Both randomized trials have potential bias; therefore, the quality of the evidence is low.There are still major unresolved issues about baby-led weaning that require answers from research and that should be considered when advices are requested from health professionals by parents willing to approach this method.

Impact of delivery mode on the colostrum microbiota composition.

BACKGROUND: Breast milk is a rich nutrient with a temporally dynamic nature. In particular, numerous alterations in the nutritional, immunological and microbiological content occur during the transition from colostrum to mature milk. The objective of our study was to evaluate the potential impact of delivery mode on the microbiota of colostrum, at both the quantitative and qualitative levels (bacterial abundance and microbiota network). METHODS: Twenty-nine Italian mothers (15 vaginal deliveries vs 14 Cesarean sections) were enrolled in the study. The microbiota of colostrum samples was analyzed by next generation sequencing (Ion Torrent Personal Genome Machine). The colostrum microbiota network associated with Cesarean section and vaginal delivery was evaluated by means of the Auto Contractive Map (AutoCM), a mathematical methodology based on Artificial Neural Network (ANN) architecture. RESULTS: Numerous differences between Cesarean section and vaginal delivery colostrum were observed. Vaginal delivery colostrum had a significant lower abundance of Pseudomonas spp., Staphylococcus spp. and Prevotella spp. when compared to Cesarean section colostrum samples. Furthermore, the mode of delivery had a strong influence on the microbiota network, as Cesarean section colostrum showed a higher number of bacterial hubs if compared to vaginal delivery, sharing only 5 hubs. Interestingly, the colostrum of mothers who had a Cesarean section was richer in environmental bacteria than mothers who underwent vaginal delivery. Finally, both Cesarean section and vaginal delivery colostrum contained a greater number of anaerobic bacteria genera. CONCLUSIONS: The mode of delivery had a large impact on the microbiota composition of colostrum. Further studies are needed to better define the meaning of the differences we observed between Cesarean section and vaginal delivery colostrum microbiota.

A history of recurrent wheezing can delay the diagnosis of foreign body aspiration in a paediatric emergency department.

Foreign body aspiration (FBA) into the airways is a potentially life-threatening event, and more frequent in children younger than 3 years of age; it can mimic other diseases by its frequently non-specific clinical and radiological presentation. The commonest misdiagnoses in children are asthma and recurrent respiratory tract infections with wheezing. This often makes it particularly difficult for a timely and proper diagnosis, especially when there is a silent history of FBA (not a rare occurrence in the age group at highest risk). We report a case of a 2-year-old boy who arrived at the emergency department at the Hospital of Ferrara, with dyspnoea, fever and wheezing, which had started 12 h after aspiration of a pistachio. The asymptomatic period after the pistachio aspiration, a history of recurrent wheezing during respiratory infections and the non-specificity of clinical and radiological findings, delayed the right diagnosis of FBA.