Perinatal outcome in anti-NMDAr encephalitis during pregnancy-a systematic review with individual patients' data analysis.

INTRODUCTION: Anti-N-methyl-D-aspartate receptor (NMDAr) antibody encephalitis is an autoimmune disorder characterized by synaptic NMDAr current disruption and receptor hypofunction, often affecting women during pregnancy. Clinical manifestations associated with anti-NMDAr encephalitis can occur both in the mother and fetus. METHODS: We generated a systematic search of the literature to identify epidemiological, clinical, and serological data related to pregnant women with anti-NMDAr encephalitis and their children, analyzing the fetal outcomes. We examined the age and neurologic symptoms of the mothers, the presence of an underlying tumor, immunotherapies used during pregnancy, duration of the pregnancy, and type of delivery. RESULTS: Data from 41 patients were extrapolated from the included studies. Spontaneous interruption of pregnancy, premature birth, and cesarean section were reported in pregnant women with NMDAr encephalitis. Several fetal and neonatal symptoms (e.g., movement disorders, spina bifida, poor sucking, respiratory distress, cardiac arrhythmias, infections, icterus, hypoglycemia, and low birth weight) depending on the mother's serum anti-NR1 concentration were also reported. CONCLUSIONS: We characterized the outcomes of children born from mothers with anti-NMDAr encephalitis, analyzing the pivotal risk factors related to pregnancy and maternal disorder. Neuropsychiatric involvement seems strictly related to pathogenic NMDAr antibodies detected in maternal and/or neonatal serum. These findings clarify a complex condition to manage, outlining the risks associated with pregnant women with anti-NMDAr encephalitis and also providing a concrete guide for therapeutic strategies to prevent potential harm to the fetus and the child's neurodevelopment.

Allelic heterogeneity and abnormal vesicle recycling in PLAA-related neurodevelopmental disorders.

The human PLAA gene encodes Phospholipase-A2-Activating-Protein (PLAA) involved in trafficking of membrane proteins. Through its PUL domain (PLAP, Ufd3p, and Lub1p), PLAA interacts with p97/VCP modulating synaptic vesicles recycling. Although few families carrying biallelic PLAA variants were reported with progressive neurodegeneration, consequences of monoallelic PLAA variants have not been elucidated. Using exome or genome sequencing we identified PLAA de-novo missense variants, affecting conserved residues within the PUL domain, in children affected with neurodevelopmental disorders (NDDs), including psychomotor regression, intellectual disability (ID) and autism spectrum disorders (ASDs). Computational and in-vitro studies of the identified variants revealed abnormal chain arrangements at C-terminal and reduced PLAA-p97/VCP interaction, respectively. These findings expand both allelic and phenotypic heterogeneity associated to PLAA-related neurological disorders, highlighting perturbed vesicle recycling as a potential disease mechanism in NDDs due to genetic defects of PLAA.

Quality and Characteristics of Pediatric Rheumatology Content on Social Media: Toward a New Era of Education for Patients and Caregivers?

Social media platforms are an extremely common form of online interaction, with more than 4.5 billion users worldwide in 2022. According to Statista.com, there is a significant expectation that this usage will exceed 6 billion by the year 2027.

GH therapy in children with juvenile idiopathic arthritis: a four-decade review.

Chronic inflammatory conditions, such as juvenile idiopathic arthritis, are associated with growth failure. Growth failure appears to be correlated with both the effects of inflammation and negative effects of glucocorticoids (used as therapeutic option) on the growth hormone axis and locally on the growth plate and bone metabolism. In the last decade, the introduction of biologics has changed the disease course regarding consequences and outcomes. Anyway in some cases, treatment with biologics has failed in restoring normal growth in patients with juvenile idiopathic arthritis; in contrast, several studies have reported improved height velocity and growth rate in patients with juvenile idiopathic arthritis treated with growth hormone. This study aimed to evaluate the impact of growth hormone treatment on the growth and pubertal development in juvenile idiopathic arthritis patients through a narrative review of the literature over the last four decades.

Kidney manifestations of pediatric Sjögren's syndrome.

Approximately 1% of all patients with Sjögren's syndrome (SS) are children. Unlike the adult form, in which sicca syndrome is the main presentation, in children, the most common clinical finding is recurrent enlargement of the salivary glands. In pediatric SS, extraglandular manifestations represent a significant feature and, among these, kidney manifestations are relevant. Kidney involvement is observed in 5-20.5% of children with SS, most frequently tubulointerstitial nephritis. This injury can lead to serious phenotypes, including distal kidney tubular acidosis with the development of severe hypokalemia, which can lead to ECG abnormalities, weakness, and hypokalemic periodic paralysis. Kidney implications in pediatric SS also include nephrolithiasis, nephrocalcinosis, and various types of glomerular damage, which often require immunosuppressive therapies. Laboratory findings are usually comparable to adults, including hyperglobulinemia and high rates of antinuclear antibodies (ANA, 63.6-96.2%), and anti-Ro/SSA (36.4-84.6%). The current classification criteria for SS are inaccurate for the pediatric population, and more specific criteria are needed to improve the diagnostic rate. Due to the rarity of the disease, strong recommendations for treatment are lacking, and several therapeutic strategies have been reported, mostly based on glucocorticoids and disease-modifying antirheumatic drugs, with different outcomes. The aim of this paper is to provide an overview of the kidney implications of pediatric SS based on the latest evidence of the medical literature.

Clinical and molecular heterogeneity of VPS13D-related neurodevelopmental and movement disorders.

BACKGROUND: The VPS13 family of proteins has been implicated in lipid transport and trafficking between endoplasmic reticulum and organelles, to maintain homeostasis of subcellular membranes. Recently, pathogenic variants in each human VPS13S gene, have been linked to distinct human neurodevelopmental or neurodegenerative disorders. Within the VPS13 family of genes, VPS13D is known to be implicated in mitochondria homeostasis and function. METHODS: We investigated a Pakistani sibship affected with neurodevelopmental impairment and severe hyperkinetic (choreoathetoid) movements. Whole exome sequencing (WES) and Sanger sequencing were performed to identify potential candidate variants segregating in the family. We described clinical phenotypes and natural history of the disease during a 3-year clinical follow-up and summarized literature data related to previously identified patients with VPS13D-related neurological disorders. RESULTS: We identified by WES an homozygous non-synonymous variant in VPS13D (c.5723 T > C; p.Ile1908Thr) as the potential underlying cause of the disease in our family. Two young siblings developed an early-onset neurological impairment characterized by global developmental delay, with impaired speech and motor milestones, associated to hyperkinetic movement disorders as well as progressive and non-progressive neurological abnormalities. CONCLUSION: In this study we delineated the heterogeneity of VPS13D-related clinical phenotypes and described a novel VPS13D homozygous variant associated with severe neurological impairment. Further studies will be pivotal to understand the exact VPS13D function and its impact on mitochondria homeostasis, brain development and regulation of movements, to further clarify genotype-phenotype correlations and provide crucial prognostic information and potential therapeutic implications.

The therapeutic effects of physical treatment for patients with hereditary spastic paraplegia: a narrative review.

Background: Hereditary spastic paraplegia (HSP) encompass a variety of neurodegenerative disorders that are characterized by progressive deterioration of walking ability and a high risk for long-term disability. The management of problems associated with HSP, such as stiffness, deformity, muscle contractures, and cramping, requires strict adherence to recommended physiotherapy activity regimes. The aim of this paper is to conduct a critical narrative review of the available evidence focusing exclusively to the therapeutic advantages associated with various forms of physical therapy (PT) in the context of HSP, emphasizing the specific benefit of every distinct approach in relation to muscle relaxation, muscle strength, spasticity reduction, improvement of weakness, enhancement of balance, posture, walking ability, and overall quality of life. Methods: To conduct a literature review, the databases PubMed, Scopus, and DOAJ (last access in June 2023) were searched. Results: The PubMed search returned a total of 230 articles, Scopus returned 218, and DOAJ returned no results. After screening, the final list included 7 papers on PT treatment for HSP patients. Conclusion: Electrostimulation, magnetotherapy, hydrotherapy, PT, robot-assisted gait training, and balance rehabilitation have the potential to increase lower extremity strength and decrease spasticity in HSP patients.

NUP85 as a Neurodevelopmental Gene: From Podocyte to Neuron.

Pathogenic gene variants encoding nuclear pore complex (NPC) proteins were previously implicated in the pathogenesis of steroid-resistant nephrotic syndrome (SRNS). The NUP85 gene, encoding nucleoporin, is related to a very rare form of SRNS with limited genotype-phenotype information. We identified an Italian boy affected with an SRNS associated with severe neurodevelopmental impairment characterized by microcephaly, axial hypotonia, lack of achievement of motor milestones, and refractory seizures with an associated hypsarrhythmic pattern on electroencephalography. Brain magnetic resonance imaging (MRI) showed hypoplasia of the corpus callosum and a simplified gyration of the cerebral cortex. Since the age of 3 years, the boy was followed up at our Pediatric Nephrology Department for an SRNS, with a focal segmental glomerulosclerosis at renal biopsy. The boy died 32 months after SRNS onset, and a Whole-Exome Sequencing analysis revealed a novel compound heterozygous variant in NUP85 (NM_024844.5): 611T>A (p.Val204Glu), c.1904T>G (p.Leu635Arg), inherited from the father and mother, respectively. We delineated the clinical phenotypes of NUP85-related disorders, reviewed the affected individuals so far reported in the literature, and overall expanded both the phenotypic and the molecular spectrum associated with this ultra-rare genetic condition. Our study suggests a potential occurrence of severe neurological phenotypes as part of the NUP85-related clinical spectrum and highlights an important involvement of nucleoporin in brain developmental processes and neurological function.

The Cardiofaciocutaneous Syndrome: From Genetics to Prognostic-Therapeutic Implications.

Cardiofaciocutaneous (CFC) syndrome is one of the rarest RASopathies characterized by multiple congenital ectodermal, cardiac and craniofacial abnormalities with a mild to severe ocular, gastrointestinal and neurological involvement. It is an autosomal dominant syndrome, with complete penetrance, caused by heterozygous pathogenic variants in the genes BRAF, MAP2K1/MEK1, MAP2K2/MEK2, KRAS or, rarely, YWHAZ, all part of the RAS-MAPK pathway. This pathway is a signal transduction cascade that plays a crucial role in normal cellular processes such as cell growth, proliferation, differentiation, survival, metabolism and migration. CFC syndrome overlaps with Noonan syndrome, Costello syndrome, neurofibromatosis type 1 and Legius syndrome, therefore making the diagnosis challenging. Neurological involvement in CFC is more severe than in other RASopathies. Phenotypic variability in CFC patients is related to the specific gene affected, without a recognized genotype-phenotype correlation for distinct pathogenic variants. Currently, there is no specific treatment for CFC syndrome. Encouraging zebrafish model system studies suggested that, in the future, MEK inhibitors could be a suitable treatment of progressive phenotypes of CFC in children. A multidisciplinary care is necessary for appropriate medical management.

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.

Pain Evaluation and Treatment in Children: A Practical Approach.

Pain is the most common complaint reported by children who access the emergency departments, but despite its frequency and the availability of many international guidelines, it often remains underreported and undertreated. Recently, the American Academy of Pediatrics and the American Pain Society have reiterated the importance of a multidisciplinary approach in order to eliminate pain in children. In all pediatric settings, an adequate assessment is the initial stage in a proper clinical approach to pain, especially in the emergency departments; therefore, an increasing number of age-related tools have been validated. A wide range of analgesic agents are currently available for pain management, and they should be tailored according to the patient's age, the drug's pharmacokinetics and the intensity of pain. In order to facilitate the choice of the appropriate drug, a treatment algorithm based on a ladder approach can be used. Moreover, non-pharmacological techniques should be considered to alleviate anxiety and distress in pediatric age. This review aims to offer a simple but intuitive description of the best strategies for pain relief in children, starting with the prompt recognition and quantification of pain through adequate assessment scales, and following with the identification of the most appropriate therapeutic choice among the ones available for pediatric age.

The benefits of physical therapy in juvenile idiopathic arthritis.

Juvenile idiopathic arthritis (JIA) is the most common chronic rheumatic disease in children and an important cause of short-term and long-term disability. Recommended physiotherapy activity programs are essential for controlling JIA associated complications such as stiffness, deformity, muscle contractures, and cramps. It is uncertain if physiotherapy (PT) can significantly enhance prognosis and quality of life (QOL). In this review we focused on the specific effects of various PT on JIA manifestations. To conduct a literature review, the databases PubMed, Scopus, and DOAJ (last access in June 2023) were searched. The PubMed search returned a total of 952 articles, Scopus returned 108, and DOAJ returned no results. After screening, the final list included 18 papers on PT treatment for JIA patients. In children with JIA, targeted PT exercise may have the ability to improve strength, posture, aerobic conditioning, gait, functional mobility, and reduce pain.

Renal involvement in monogenic autoinflammatory diseases: A narrative review.

Autoinflammatory diseases (AIDs) are mostly caused by dysfunctions in single genes encoding for proteins with a prominent role in the regulation of innate immunity, such as complement factors, inflammasome components, tumour necrosis factor (TNF)-α, and proteins belonging to type I-interferon (IFN) signalling pathways. Due to the deposition of amyloid A (AA) fibrils in the glomeruli, unprovoked inflammation in AIDs frequently affects renal health. In fact, secondary AA amyloidosis is the most common form of amyloidosis in children. It is caused by the extracellular deposition of fibrillar low-molecular weight protein subunits resulting from the degradation and accumulation of serum amyloid A (SAA) in numerous tissues and organs, primarily the kidneys. The molecular mechanisms underlying AA amyloidosis in AIDs are the elevated levels of SAA, produced by the liver in response to pro-inflammatory cytokines, and a genetic predisposition due to specific SAA isoforms. Despite the prevalence of amyloid kidney disease, non-amyloid kidney diseases may also be responsible for chronic renal damage in children with AIDs, albeit with distinct characteristics. Glomerular damage can result in various forms of glomerulonephritis with distinct histologic characteristics and a different underlying pathophysiology. This review aims to describe the potential renal implications in patients with inflammasomopathies, type-I interferonopathies, and other rare AIDs in an effort to improve the clinical course and quality of life in paediatric patients with renal involvement.

Genetic Background and Molecular Mechanisms of Juvenile Idiopathic Arthritis.

Juvenile idiopathic arthritis (JIA) is the most common chronic rheumatic disease in the paediatric population. JIA comprises a heterogeneous group of disorders with different onset patterns and clinical presentations with the only element in common being chronic joint inflammation. This review sought to evaluate the most relevant and up-to-date evidence on current knowledge regarding the pathogenesis of JIA subtypes to provide a better understanding of these disorders. Despite significant improvements over the past decade, the aetiology and molecular mechanisms of JIA remain unclear. It has been suggested that the immunopathogenesis is characterised by complex interactions between genetic background and environmental factors that may differ between JIA subtypes. Human leukocyte antigen (HLA) haplotypes and non-HLA genes play a crucial role in the abnormal activation of both innate and adaptive immune cells that cooperate in causing the inflammatory process. This results in the involvement of proinflammatory cytokines, including tumour necrosis factor (TNF)α, interleukin (IL)-1, IL-6, IL-10, IL-17, IL-21, IL-23, and others. These mediators, interacting with the surrounding tissue, cause cartilage stress and bone damage, including irreversible erosions. The purpose of this review is to provide a comprehensive overview of the genetic background and molecular mechanisms of JIA.

The pyrin inflammasome, a leading actor in pediatric autoinflammatory diseases.

The activation of the pyrin inflammasome represents a highly intriguing mechanism employed by the innate immune system to effectively counteract pathogenic agents. Despite its key role in innate immunity, pyrin has also garnered significant attention due to its association with a range of autoinflammatory diseases (AIDs) including familial Mediterranean fever caused by disruption of the MEFV gene, or in other genes involved in its complex regulation mechanisms. Pyrin activation is strictly dependent on homeostasis-altering molecular processes, mostly consisting of the disruption of the small Ras Homolog Family Member A (RhoA) GTPases by pathogen toxins. The downstream pathways are regulated by the phosphorylation of specific pyrin residues by the kinases PKN1/2 and the binding of the chaperone 14-3-3. Furthermore, a key role in pyrin activation is played by the cytoskeleton and gasdermin D, which is responsible for membrane pores in the context of pyroptosis. In addition, recent evidence has highlighted the role of steroid hormone catabolites and alarmins S100A8/A9 and S100A12 in pyrin-dependent inflammation. The aim of this article is to offer a comprehensive overview of the most recent evidence on the pyrin inflammasome and its molecular pathways to better understand the pathogenesis behind the significant group of pyrin-related AIDs.

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.

Lutein levels in arterial cord blood correlate with neurotrophic calcium binding S100B protein in healthy preterm and term newborns.

BACKGROUND: S100B is an established biomarker of brain development and damage. Lutein (LT) is a naturally occurring xanthophyll carotenoid mainly concentrated in the central nervous system (CNS), but its neurotrophic role is still debated. We investigated whether LT cord blood concentrations correlate with S100B in a cohort of preterm and term healthy newborns. METHODS: We conducted a prospective study on the distribution of LT and S100B in arterial cord blood of healthy preterm (n = 50) and term (n = 50) newborns. RESULTS: S100B and LT showed a pattern of concentration characterized by higher levels (P < 0.01, for all) at 33-36 weeks gestation (GA) followed by a progressive decrease (P < 0.01, for all) from 37 onwards with a dip at term. Both S100B and LT were gender-dependent with significantly (P < 0.01, for all) higher levels in females in preterm and term groups. S100B (R = 0.68; P < 0.001) and LT (R = 0.40; P = 0.005) correlated with GA at sampling. A positive significant correlation (R = 0.87; P < 0.001) between S100B and LT was found. CONCLUSIONS: The present data showing a correlation between S100B and LT supports the notion of a LT trophic role in the CNS. Further investigations in high-risk infants are needed to elucidate LT involvement in the pathophysiological cascade of events leading to CNS development and damage.

A 5-Year-Old Child with a Deep Neck Abscess Complicated by Laryngeal Obstruction.

Deep neck space infections (DNSI) are defined as infections in the potential spaces and fascial planes of the neck. We show the clinical case of a retro and para-pharyngeal abscess in a healthy 5-year-old child complicated by compression and dislocation of the larynx with marked airway caliber reduction and potentially fatal extension up to the mediastinal aditus. DNSI can occur at any age and, due to its rapid progression, requires immediate treatment in children. In healthy children, concurrent abscesses in separate neck spaces are rare. DNSI recurrence should alert the physician to the possibility of a congenital problem, and if imaging fails, laryngoscopy may be the best diagnostic technique.