Serum Lipocalin-2 Levels as a Biomarker in Pre- and Post-Pubertal Klinefelter Syndrome Patients: A Pilot Study.

Klinefelter syndrome (KS) is a male genetic disease caused by the presence of an extra X chromosome, causing endocrine disorders mainly responsible for a high rate of infertility and metabolic disorders in adulthood. Scientific research is interested in identifying new biomarkers that can be predictive or prognostic of alterations strictly connected to KS. Lipocalin-2 (LCN-2, also known as NGAL) is a small protein initially identified within neutrophils as a protein related to innate immunity. Serum LCN-2 estimation seems to be a useful tool in predicting the metabolic complications caused by several pathological conditions. However, little is known about its potential role in infertility conditions. The present pilot study aims to investigate the presence of LCN-2 in the serum of a group of pre-pubertal and post-pubertal children affected by KS, compared to healthy controls. We demonstrated for the first time the presence of elevated levels of LCN-2 in the serum of KS patients, compared to controls. This increase was accompanied, in pre-pubertal KS patients, by the loss of correlation with LH and HDL, which instead was present in the healthy individuals. Moreover, in all KS individuals, a positive correlation between LCN-2 and inhibin B serum concentration was found. Despite the limited size of the sample analyzed, our preliminary data encourage further studies to confirm the findings and to extend the study to KS adult patients, to verify the predictive/prognostic value of LCN-2 as new biomarker for metabolic diseases and infertility associated with the pathology.

Neuroinflammation and Oxidative Stress in Individuals Affected by DiGeorge Syndrome.

DiGeorge syndrome (DGS) is a rare genetic disease caused by microdeletions of the 22q11.2 region (DGS1). A haploinsufficiency at 10p level has been proposed also as a DGS cause (DGS2). Clinical manifestations are variable. The most frequent features are thymic hypoplasia or aplasia with consequent immune deficiency, cardiac malformations, hypoparathyroidism, facial and palatine abnormalities, variable degrees of cognitive impairment and psychiatric disorders. The specific aim of this descriptive report is to discuss the correlation between oxidative stress and neuroinflammation in DGS patients with microdeletions of the 22q11.2 region. The deleted chromosomic region maps various genes involved in mitochondrial metabolisms, such as DGCR8 and TXNRD2, that could lead to reactive oxygen species (ROS) increased production and antioxidant depletion. Furthermore, increased levels of ROS in mitochondria would lead to the destruction of the projection neurons in the cerebral cortex with consequent neurocognitive impairment. Finally, the increase in modified protein belonging to the family of sulfoxide compounds and hexoses, acting as inhibitors of the IV and V mitochondria complex, could result in direct ROS overproduction. Neuroinflammation in DGS individuals could be directly related to the development of the syndrome's characteristic psychiatric and cognitive disorders. In patients with psychotic disorders, the most frequent psychiatric manifestation in DGS, Th-17, Th-1 and Th-2 cells are increased with consequent elevation of proinflammatory cytokine IL-6 and IL1ß. In patients with anxiety disorders, both CD3 and CD4 are increased. Some patients with autism spectrum disorders (ASDs) have an augmented level of proinflammatory cytokines IL-12, IL-6 and IL-1ß, while IFNγ and the anti-inflammatory cytokine IL-10 seem to be reduced. Other data proposed that altered synaptic plasticity could be directly involved in DGS cognitive disorders. In conclusion, the use of antioxidants for restoring mitochondrial functionality in DGS could be a useful tool to protect cortical connectivity and cognitive behavior.

Malignant and Benign Head and Neck Tumors of the Pediatric Age: A Narrative Review.

Malignant tumors of the head and neck are rare in children, but it is important to know these lesions and identify them early in order to have a good outcome for these patients. Benign lesions of the head and neck are much more frequent and have an excellent prognosis. For this reason, it is necessary to recognize the warning signs and symptoms and understand when to refer the patient to a reference center for the treatment of these pathologies. The clinical presentation of both benign and malignant lesions in children may be similar as usually, both categories have compressive effects. This confirms the fact that the clinical diagnosis is not sufficient and always requires instrumental investigations and biopsies. In this narrative review, we analyzed both malignant lesions such as lymphoma, rhabdomyosarcoma, thyroid tumors, salivary gland tumors, neuroblastoma, and nasopharyngeal carcinoma, and benign ones such as cystic dermoid teratoma, hemangioma, juvenile angiofibroma and fibrosis dysplasia. Indeed, we set out to discuss the most common lesions of this site by evaluating their characteristics to highlight the differentiation of malignant tumors from benign lesions and their correct clinical-therapeutic management. A literature search was carried out in the PubMed and Google Scholar databases to identify all narrative reviews addressing malignant and benign head and neck tumors of the pediatric age. In conclusion, the care of children affected by head and neck benign lesions and malignancy must be combined and multidisciplinary. It is essential to recognize the diseases early in order to differentiate and intervene as soon as possible for the correct clinical-therapeutic management.

Klinefelter Syndrome: A Genetic Disorder Leading to Neuroendocrine Modifications and Psychopathological Vulnerabilities in Children-A Literature Review and Case Report.

Klinefelter syndrome (KS), characterized by an additional X-chromosome in males, manifests in a wide range of neuroendocrine and psychiatric symptoms. Individuals with KS often face increased risks of hormonal dysfunction, leading to depression and anxiety, although extended research during pediatric and adolescent age is still limited. This critical phase, decisive for KS children, is influenced by a combination of genetic, environmental and familial factors, which impact brain plasticity. In this report, we reviewed, in a narrative form, the crucial KS psychopathological hallmarks in children. To better describe neuroendocrine and neuropsychiatric outcomes in children with KS, we presented the case of an 11-year-old prepubertal child with mosaic KS who was referred to our Center of Developmental Psychopathology due to a decline in his academic performance, excessive daytime fatigue and increased distractibility over the past few months. Family history revealed psychiatric conditions among first- and second-degree relatives, including recently divorced parents and a 15-year-old sister. Early-onset persistent depressive disorder and anxious traits were diagnosed. Timely identification of susceptible children, with thorough examination of familial psychiatric history, environmental influences and neurocognitive profile, alongside targeted interventions, could potentially mitigate lifelong psychopathology-related disabilities in pediatric and adolescent KS cases, including those with mosaic KS.

Italian Guidelines for the diagnosis and treatment of Fetal Alcohol Spectrum Disorders: international diagnostic criteria - differences and similarities

The umbrella term Fetal Alcohol Spectrum Disorders (FASD) brings together under its definition a heterogeneous continuum of disabilities linked by a common etiology and pathogenesis: exposure to alcohol during intrauterine life. Despite extensive research, definitive toxic thresholds remain elusive, underscoring the recommendation for complete alcohol abstinence during pregnancy and lactation. FASD poses diagnostic challenges due to its varied presentations and heterogeneous phenotype. Consequently, no singular diagnostic guideline exists, with multiple expert-driven diagnostic systems globally available. This review aims to synthesize recent and notable guidelines facilitating FASD diagnosis. While efforts were made to include the latest diagnostic systems, determining which scheme is best applied to each individual patient population necessitates clinician discretion. In Italy, the guidelines proposed by Hoyme, revised in 2016, are commonly utilized, yet comparative analysis among guidelines offers valuable insights into their historical context and diagnostic utility. Our discussion explores both similarities and discrepancies among systems for diagnosing FASD, shedding light on their evolution and practical application. The objective of our work was to compare in a practical and precise manner the various existing guidelines used globally regarding the diagnosis of FAS. Our review therefore proposes the diagnostic criteria used by the various working groups and compares them, trying to create a practical comparison between the various guidelines, identifying differences and similarities.

Italian Guidelines for the diagnosis and treatment of Fetal Alcohol Spectrum Disorders: clinical hallmarks.

Fetal Alcohol Spectrum Disorders (FASD) are a condition that arises when a person is exposed to alcohol during pregnancy. The main clinical manifestations include craniofacial anomalies, growth retardation, birth defects and change in brain structure and function. These alterations can result in deficits across various domains such as cognition, executive function, memory, vision, hearing, motor skills, behavior, and social adaptation. The effects of alcohol extend beyond the brain, affecting other systems including sensory organs, heart, and kidneys. Given that diagnosing FASD involves excluding other conditions, it is crucial for physicians to be familiar with its main characteristics to facilitate early identification and implement appropriate health strategies for the patient. Moreover, there is a pressing need for primary prevention strategies centered around raising awareness about the risks associated with alcohol consumption during pregnancy. The articles for this report aimed to analyze and evaluate studies focusing on the clinical features observed in FASD children were sourced from online databases such as Medline, Medline Complete and PubMed, covering literature published between 1981 and 2024, written in English, using search terms such as fetal alcohol spectrum disorders, fetal alcohol syndrome, prenatal alcohol exposure, and alcohol-related birth defects. The evidence gathered underscores that prenatal alcohol exposure primarily affects the brain and its functions, resulting in severe impacts. Furthermore, abnormalities in other vital organs such as the sensory, cardiovascular, and renal systems are frequently observed.

Italian Guidelines for the diagnosis and treatment of Fetal Alcohol Spectrum Disorders: international diagnostic criteria - differences and similarities.

The umbrella term Fetal Alcohol Spectrum Disorders (FASD) brings together under its definition a heterogeneous continuum of disabilities linked by a common etiology and pathogenesis: exposure to alcohol during intrauterine life. Despite extensive research, definitive toxic thresholds remain elusive, underscoring the recommendation for complete alcohol abstinence during pregnancy and lactation. FASD poses diagnostic challenges due to its varied presentations and heterogeneous phenotype. Consequently, no singular diagnostic guideline exists, with multiple expert-driven diagnostic systems globally available. This review aims to synthesize recent and notable guidelines facilitating FASD diagnosis. While efforts were made to include the latest diagnostic systems, determining which scheme is best applied to each individual patient population necessitates clinician discretion. In Italy, the guidelines proposed by Hoyme, revised in 2016, are commonly utilized, yet comparative analysis among guidelines offers valuable insights into their historical context and diagnostic utility. Our discussion explores both similarities and discrepancies among systems for diagnosing FASD, shedding light on their evolution and practical application. The objective of our work was to compare in a practical and precise manner the various existing guidelines used globally regarding the diagnosis of FAS. Our review therefore proposes the diagnostic criteria used by the various working groups and compares them, trying to create a practical comparison between the various guidelines, identifying differences and similarities.

Delay in the fine-tuning of locomotion in infants with meconium positive to biomarkers of alcohol exposure: a pilot study.

INTRODUCTION: Prenatal alcohol exposure causes a variety of impairments to the fetus called Fetal Alcohol Spectrum Disorders (FASD). Since it is very difficult to identify women that consume alcohol during pregnancy, different methods have been studied to evaluate alcohol exposure. Ethyl Glucuronide (EtG) and Fatty Acid Ethyl Esters (FAEEs) are commonly used to measure alcohol consumption in individuals at-risk for alcohol abuse, including pregnant women. MATERIALS AND METHODS: We conducted a study of two cohorts of 1.5 year-old infants (of mothers without a history of alcohol abuse) with or without meconium samples positive to both EtG and FAEEs and we evaluated their cognitive-behavioral development by the Griffiths Mental Developmental Scale (GMDS) method. Our protocol included 8 infants with meconium positive to alcohol metabolites (EtG and FAEEs) and 7 with meconium negative to alcohol metabolites. RESULTS: None of the 8 alcohol metabolites positive meconium infants exhibited distinctive facial features and growth retardation of severe FASD, showing that other factors may contribute to the FASD onset but elevations in EtG and FAEEs in the meconium were significantly associated with disrupted neurodevelopment and adaptive functions within the first year and a half of life. Indeed, we found out that infants with meconium positive for both EtG and FAEEs, although without displaying any FASD morphological features, had a delay in the fine regulation of their own locomotory capabilities. CONCLUSIONS: Further analyses and larger studies are needed to estimate the right link between prenatal alcohol exposure and the different range of disorders connected but this study provides an additional step in the field of FASD in order to suggest early treatments for at-risk newborns and infants.

Autoimmune Polyendocrine Syndromes in the Pediatric Age.

Autoimmune polyendocrine syndromes (APSs) encompass a heterogeneous group of rare diseases characterized by autoimmune activity against two or more endocrine or non-endocrine organs. Three types of APSs are reported, including both monogenic and multifactorial, heterogeneous disorders. The aim of this manuscript is to present the main clinical and epidemiological characteristics of APS-1, APS-2, and IPEX syndrome in the pediatric age, describing the mechanisms of autoimmunity and the currently available treatments for these rare conditions.

Clinical Management and Therapy of Precocious Puberty in the Sapienza University Pediatrics Hospital of Rome, Italy.

Puberty identifies the transition from childhood to adulthood. Precocious puberty is the onset of signs of pubertal development before age eight in girls and before age nine in boys, it has an incidence of 1/5000-1/10,000 with an F:M ratio ranging from 3:1 to 20:1. Precocious puberty can be divided into central, also known as gonadotropin-dependent precocious puberty or true precocious puberty, and peripheral, also recognized as gonadotropin-independent precocious puberty or precocious pseudopuberty. Thus, the main aim of this narrative report is to describe the standard clinical management and therapy of precocious puberty according to the experience and expertise of pediatricians and pediatric endocrinologists at Policlinico Umberto I, Sapienza University of Rome, Italy. In the suspicion of early sexual maturation, it is important to collect information regarding the age of onset, the speed of maturation of secondary sexual features, exposure to exogenous sex steroids and the presence of neurological symptoms. The objective examination, in addition to the evaluation of secondary sexual characteristics, must also include the evaluation of auxological parameters. Initial laboratory investigations should include serum gonadotropin levels (LH and FSH) and serum levels of the sex steroids. Brain MRI should be performed as indicated by the 2009 Consensus Statement in all boys regardless of chronological age and in all girls with onset of pubertal signs before 6 years of age. The gold standard in the treatment of central precocious puberty is represented by GnRH analogs, whereas, as far as peripheral forms are concerned, the triggering cause must be identified and treated. At the moment there are no reliable data establishing the criteria for discontinuation of GnRH analog therapy. However, numerous pieces of evidence suggest that the therapy should be suspended at the physiological age at which puberty occurs.

The role of the pediatrician in the management of the child and adolescent with gender dysphoria.

Gender dysphoria is a clinical condition characterized by significant distress due to the discordance between biological sex and gender identity. Currently, gender dysphoria is also found more frequently in children and adolescents, thanks to greater social sensibleness and new therapeutic possibilities. In fact, it is estimated that the prevalence of gender dysphoria in pediatric age is between 0.5% and 2% based on the statistics of the various countries. Therefore, the pediatrician cannot fail to update himself on these issues and above all should be the reference figure in the management of these patients. Even if the patient must be directed to a referral center and be followed up by a multidisciplinary team, the treating pediatrician will care to coordinate the clinical and therapeutic framework. The aim of the present report is therefore to integrate literature data with our clinical experience to propose a new clinical approach in which the pediatrician should be the reference in the care of these patients, directing them towards the best therapeutic approach and staying in contact with the specialists of the referral center.

COVID-19 Affects Serum Brain-Derived Neurotrophic Factor and Neurofilament Light Chain in Aged Men: Implications for Morbidity and Mortality.

BACKGROUND AND METHODS: Severe COVID-19 is known to induce neurological damage (NeuroCOVID), mostly in aged individuals, by affecting brain-derived neurotrophic factor (BDNF), matrix metalloproteinases (MMP) 2 and 9 and the neurofilament light chain (NFL) pathways. Thus, the aim of this pilot study was to investigate BDNF, MMP-2, MMP-9, and NFL in the serum of aged men affected by COVID-19 at the beginning of the hospitalization period and characterized by different outcomes, i.e., attending a hospital ward or an intensive care unit (ICU) or with a fatal outcome. As a control group, we used a novelty of the study, unexposed age-matched men. We also correlated these findings with the routine blood parameters of the recruited individuals. RESULTS: We found in COVID-19 individuals with severe or lethal outcomes disrupted serum BDNF, NFL, and MMP-2 presence and gross changes in ALT, GGT, LDH, IL-6, ferritin, and CRP. We also confirmed and extended previous data, using ROC analyses, showing that the ratio MMPs (2 and 9) versus BDNF and NFL might be a useful tool to predict a fatal COVID-19 outcome. CONCLUSIONS: Serum BDNF and NFL and/or their ratios with MMP-2 and MMP-9 could represent early predictors of NeuroCOVID in aged men.

The Impact of Oxidative Stress on Pediatrics Syndromes.

Oxidative stress is a condition determined by an imbalance between antioxidant and oxidative factors. Oxidative stress can have serious consequences on our organism. Indeed, it causes both necrosis and cell apoptosis, determining cellular aging, increased carcinogenesis, vascular stiffening, increased autoimmune diseases, and muscle decay. In the context of pediatric syndromes, oxidative stress could play a role in the first order. In fact, our review of the literature showed that in some pathologies, such as fetal alcohol spectrum disorders, oxidative stress related to the intake of ethanol during pregnancy is a main etiological factor determining the associated clinical syndrome. On the contrary, in Williams syndrome, Down syndrome, Marfan syndrome, Gaucher syndrome, ataxia-telangiectasia, autistic spectrum disorder, Fanconi's anemia, and primitive immunodeficiencies, the increase in oxidative stress is directly associated with the genetic alterations that cause the same pathologies. Although further studies are needed to better understand the relationship between oxidative stress and pediatric diseases, a better knowledge of this crucial issue encourages future therapeutic strategies.