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Background: Dominant negative STAT3 loss-of-function is the most common genetic cause of hyper-IgE syndrome (HIES). Patients may present with a host of both immune and non-immune manifestations, including connective tissue abnormalities, recurrent infections, malignant predisposition, and biochemical evidence of elevated serum IgE or eosinophilia. Aim: To describe a novel splice-site variant in STAT3 resulting in HIES. Methods: Case report of two family members with HIES. Results: A proband and his son presented with neonatal-onset pustular rash, recurrent skin and sinopulmonary infections and elevated serum IgE and were diagnosed with AD-HIES. They were identified to harbor a novel splice-site variant in the DNA-binding domain (DBD) of STAT3: c.1110-3C>G, predicted to result in defective splicing in exon 12. Interestingly, a number of other patients with AD-HIES have mutations affecting the same splice-site, suggesting this may be a hot-spot for mutagenesis. Conclusion: Splice-site mutations in the DBD of STAT3 are increasingly identified as a cause of AD-HIES. Future work is required to delineate whether patients with splice-site mutations have unique clinical characteristics, supporting efforts for genotype-phenotype correlation in this disease. Statement of Novelty: We present a novel splice-site mutation in the DNA-binding domain of STAT3 leading to autosomal dominant hyper-IgE syndrome.

Background: Since the onset of the COVID-19 pandemic, a main challenge for clinicians and public health decision-makers has revolved around risk stratification in vulnerable populations, in particular individuals with inborn errors of immunity (IEI). However, available reports of the clinical course of COVID-19 in patients with IEI show wide variability, from a complete lack of symptoms to severe and complicated disease. Objective: To present the clinical features and outcomes of SARS-CoV-2 infection in adult patients with IEI. Methods: We performed a retrospective chart review documenting patient characteristics and clinical course of SARS-CoV-2 infection between December 2021 and July 2022. Results: Ten adult patients with IEI followed in our center were diagnosed with COVID-19, as determined by RT-PCR or rapid antigen testing. IEI in this cohort included those with humoral and combined immunodeficiencies, as well as phagocytic defects. An underlying lung comorbidity was identified in 3 patients. Symptoms were mostly mild and self-limiting, and no severe outcomes, complications, or mortality were noted in this study. Conclusions: We suggest that patients affected by a wide range of both humoral and combined IEI may demonstrate resilience, while highlighting the possible protective effects of vaccination and immunoglobulin replacement in this population. Statement of Novelty: We report on the mild COVID-19 clinical course of 10 adults with IEI.

MECP2 duplication syndrome (MDS) is a neurodevelopmental disorder caused by tandem duplication of theMECP2locus and its surrounding genes, includingIRAK1. Current MDS mouse models involve transgenic expression ofMECP2only, limiting their applicability to the study of the disease. Herein, we show that an efficient and precise CRISPR/Cas9 fusion proximity-based approach can be utilized to generate anIrak1-Mecp2tandem duplication mouse model. TheMecp2 Dupmodel displays a neurological phenotype in keeping with MDS and demonstrates an abnormal immune response to infection not previously observed in other mouse models, possibly stemming from concurrentIrak1overexpression. TheMecp2 Dupmouse line thus provides an innovative tool to investigate disease mechanisms and potential therapeutic development.

Introduction: The phosphoinositide 3-kinase (PI3K) pathway plays critical roles in diverse cellular processes, including differentiation, proliferation, motility, survival, and growth. PI3Kδ, comprised of the catalytic subunit p110δ and regulatory subunit p85α, is essential for normal lymphocyte and myeloid development and function. Gain-of-function mutations in PIK3CD (encoding p110δ) cause a combined immunodeficiency known as activated PI3Kδ syndrome (APDS), in which patients frequently present with recurrent respiratory infections, severe recurrent (or persistent) infections with herpes family viruses, and lymphadenopathy. Aim: To describe the clinical presentation, immune evaluation, and genetic work-up of 2 patients (daughter and mother) with recurrent sinopulmonary, soft tissue, and skin infections. Results: Both daughter and mother presented with recurrent sinopulmonary and soft tissue infections. Immune evaluation of the daughter revealed intermittent hypogammaglobulinemia and abnormal specific vaccine responses, while immune parameters of her mother were normal. Whole exome sequencing identified a novel mutation in PIK3CD (NM_005026), c.C719T, resulting in p.T240M. Western blot analysis of downstream AKT levels revealed increased basal phosphorylation, in line with gain-of-function mutations of PIK3CD. Conclusion: The novel missense mutation in PIK3CD occurs in the region encoding the Ras-binding domain (RBD) of p110δ, and likely alters the structural configuration of the domain. To date, pathogenic mutations targeting the RBD of p110δ have not yet been described. Our results expand on the genotypic spectrum of APDS. Statement of Novelty: We describe a novel mutation in the Ras-binding domain of PIK3CD leading to a presentation of recurrent sinopulmonary and soft tissue infections in the context of APDS.

In more than one-third of primary immunodeficiency (PID) patients, extensive genetic analysis including whole-exome sequencing (WES) fails to identify the genetic defect. Whole-genome sequencing (WGS) is able to detect variants missed by other genomics platforms, enabling the molecular diagnosis of otherwise unresolved cases. Here, we report two siblings, offspring of consanguineous parents, who experienced similar severe events encompassing early onset of colitis, lymphoproliferation, and hypogammaglobulinemia, typical of lipopolysaccharide-responsive and beige-like anchor (LRBA) or cytotoxic T lymphocyte antigen 4 (CTLA4) deficiencies. Gene-panel sequencing, comparative genomic hybridization (CGH) array, and WES failed to reveal a genetic aberration in relevant genes. WGS of these patients detected a 12.3 kb homozygous tandem duplication that was absent in control cohorts and is predicted to disrupt the reading frame of the LRBA gene. The variant was validated by PCR and Sanger sequencing, demonstrating the presence of the junction between the reference and the tandem-duplicated sequence. Droplet digital PCR (ddPCR) further confirmed the copy number in the unaffected parents (CN = 3, heterozygous) and affected siblings (CN = 4, homozygous), confirming the expected segregation pattern. In cases of suspected inherited immunodeficiency, WGS may reveal a mutation when other methods such as microarray and WES analysis failed to detect an aberration.

Background: Chronic mucocutaneous Candidiasis (CMCC) is characterized by recurrent or persistent fungal infections of the skin, nails, and oral and genital mucosae. There are several underlying genetic causes for CMCC, with mutations in Signal Transducer and Activator of Transcription-1 (STAT1) accounting for the majority of cases. Aim: To broaden the genotypic spectrum of CMCC caused by STAT1 mutations. Methods: We evaluated a young patient and her family with CMCC. Immune workup and targeted gene sequencing were performed. Results: The proband presented at 7 years of age with persistent oral thrush. Immune evaluation revealed her cellular and humoral immunity to be within normal range. Given that her family history was significant for oral lesions in father, siblings, and paternal family members, STAT1 gene sequencing was performed. A novel heterozygous missense c.G799A, predicting a p. Ala267Thr amino acid change within the coiled-coil domain, was identified in our patient and 3 of her family members. Conclusion: Gain-of-function mutations in STAT1 have been associated with a variety of phenotypes, ranging from isolated CMCC to severe fatal combined immunodeficiency, mycobacterial infections, autoimmune disorders, as well as malignancy and aneurysms. Here, we describe a novel STAT1 mutation, c.G799A, resulting in a very mild phenotype of isolated CMCC in 4 members of one kindred. Statement of novelty: We describe 4 patients with a mild phenotype of CMCC caused by a novel STAT1 heterozygous mutation.

Background: The Forkhead box protein N1 (FOXN1) is a key regulator of thymic epithelial development, and its complete deficiency leads to a nude-severe combined immunodeficiency (SCID) phenotype. More recently, heterozygous mutations in FOXN1 have been linked with a syndrome of congenital lymphopenia and a wide clinical spectrum, with most cases being caused by missense mutations. Aim: To broaden the genotypic and phenotypic spectrum of heterozygous FOXN1 deficiency. Methods: Case report of a patient with FOXN1 haploinsufficiency due to a novel splice-site mutation. Results: Our patient was identified at 3 weeks of life given an abnormal newborn screen (NBS) for SCID, and was found to have congenital lymphopenia preferentially affecting CD8+ T-cells. Her cellular and humoral function were both excellent, and she has remained entirely asymptomatic and thriving for the first 3 years of her life. The patient was found on whole exome sequencing to carry a heterozygous splice-site mutation in the FOXN1 gene, affecting the Forkhead domain. The mutation was also identified in her asymptomatic mother. Conclusion: Heterozygous FOXN1 mutations are an increasingly-recognized cause of congenital lymphopenia. Our experience suggests most patients remain clinically well, with main manifestation including T-lymphopenia, mostly affecting CD8+ cells. Identification of the same variant in an asymptomatic parent suggests age-dependent improvement in T-cell counts and an overall benign course, while provides impetus for diligent conservative management with regular follow-up. Statement of novelty: Heterozygous FOXN1 deficiency is a relatively new entity, attributed in most cases to missense mutations in FOXN1. To further expand the knowledge basis regarding this emerging disorder, as well as its genotypic repertoire, we herein report a case of heterozygous FOXN1 deficiency caused by a splice site mutation.

Background: Ataxia telangiectasia typically presents in early pre-school years with progressive cerebellar ataxia and oculocutaneous telangiectasias. Referral to Immunology is often made after diagnosis has been established, as patients are prone to both humoral and cellular immune abnormalities. Case presentation: We herein report a 10-year old boy, previously undiagnosed, who presented with recurrent pneumonias. On history, frequent falls and speech difficulty were reported, with no telangiectasias on exam. Screening with alpha-fetoprotein was abnormal, followed by ATM gene sequencing, showing a homozygous intronic mutation. Over the next 3 years the patient deteriorated neurologically, and developed appreciable telangiectasias. Conclusion: A review of the literature demonstrates that intronic/splicing mutations may result in atypical ataxia telangiectasia phenotypes and delayed presentations. We advise immunologists to have a high index of suspicion for ataxia telangiectasia when assessing a patient with immunodeficiency and neurologic regression, regardless of age, and even in the absence of telangiectasias. Statement of novelty: We present a case of phenotypically atypical (“leaky”) ataxia telangiectasia resulting from a novel homozygous splice-site mutation in the ATM gene. Given high reported prevalence of intronic and splice-site mutations in ATM, we recommend full gene sequencing in patients suspected to have ataxia telangiectasia, especially in those with late onset or unusual manifestations.

BACKGROUND STAT1 gain-of-function (GOF) is an immune dysregulatory disorder with poorly studied genotype-phenotype correlation, impeding prognostication and early intervention. Given previous mechanistic studies, as well as anecdotal clinical reports, we sought to systematically determine whether DNA-binding domain (DBD) mutations in STAT1 result in a different phenotype than mutations in other gene domains. METHODS Negative prognostic features previously identified by the International STAT1 GOF Study Group (invasive infections, intracranial aneurysms, and malignancy), as well as other clinical features and mortality, were compared within a cohort of 30 patients with STAT1 GOF diagnosed at our center, consisting of 9 patients with DBD mutations and 21 patients with non-DBD mutations. We subsequently re-analyzed mortality data from a large, previously-published 274-patient cohort by the International STAT1 GOF Study Group. RESULTS While no differences were noted with respect to malignancy or symptomatic aneurysms, invasive /opportunistic infections were substantially more common among DBD patients, as were sinopulmonary infections, bronchiectasis, enteropathy, endocrinopathies, lymphoproliferative manifestations, and recurrent fevers/HLH. DBD patients also had a lower probability of survival and younger age of mortality compared with non-DBD patients. Our re-evaluation of the published data from the International STAT1 GOF Study Group revealed a similar finding of earlier mortality among patients harboring DBD mutations. CONCLUSION We report that STAT1 GOF patients with DBD mutations may be regarded as a unique subgroup, impacted more by early-onset profound combined immunodeficiency and with earlier mortality. These findings may impact clinical decision making with respect to early intervention, and in particular hematopoietic stem cell transplant considerations, in such patients.

Signal transducer and activator of transcription 1 (STAT1) gain-of-function (GOF) is an autosomal dominant immune disorder marked by wide infectious predisposition, autoimmunity, vascular disease, and malignancy. Its molecular hallmark, elevated phospho-STAT1 (pSTAT1) following interferon (IFN) stimulation, is seen consistently in all patients and may not fully account for the broad phenotypic spectrum associated with this disorder. While over 100 mutations have been implicated in STAT1 GOF, genotype–phenotype correlation remains limited, and current overexpression models may be of limited use in gene expression studies. We generated heterozygous mutants in diploid HAP1 cells using CRISPR/Cas9 base-editing, targeting the endogenous STAT1 gene. Our models recapitulated the molecular phenotype of elevated pSTAT1, and were used to characterize the expression of five IFN-stimulated genes under a number of conditions. At baseline, transcriptional polarization was evident among mutants compared with wild type, and this was maintained following prolonged serum starvation. This suggests a possible role for unphosphorylated STAT1 in the pathogenesis of STAT1 GOF. Following stimulation with IFNα or IFNγ, differential patterns of gene expression emerged among mutants, including both gain and loss of transcriptional function. This work highlights the importance of modeling heterozygous conditions, and in particular transcription factor-related disorders, in a manner which accurately reflects patient genotype and molecular signature. Furthermore, we propose a complex and multifactorial transcriptional profile associated with various STAT1 mutations, adding to global efforts in establishing STAT1 GOF genotype–phenotype correlation and enhancing our understanding of disease pathogenesis.

Pediatric Longitudinal Experience with Residents (PedLER) is a unique program at the University of Toronto, designed to foster formal mentorship between pediatric residents and first-year medical students.

Nuclear factor κ-light-chain-enhancer of activated B cells (NF-κB) signaling pathways play a key role in various cell processes related to host immunity. The last few years have seen an explosion of disorders associated with NF-κB components from core members of the canonical and noncanonical cascades to adaptor protein and ubiquitination-related enzymes. Disease phenotypes have extended beyond susceptibility to infections and include autoimmunity, lymphoproliferation, atopy, and inflammation. Concurrently, studies are unveiling a tightly regulated system marked by extensive cross-talk between the canonical and noncanonical pathways, as well as among the NF-κB and other signaling pathways. As the rate of discovery in the realm of NF-κB defects accelerates, this review presents a timely summary of major known defects causing human disease, as well as diagnostic, therapeutic, and research challenges and opportunities.

Fever of unknown origin is an important diagnostic challenge in pediatrics that requires a thoughtful approach. The differential diagnosis is broad and includes infectious, autoimmune, oncologic, neurologic, genetic, and iatrogenic causes. Infection remains the most common etiology, and uncommon presentations of infections are still more likely than classic presentations of rare conditions. We report a case of a retropharyngeal abscess in a toddler whose presentation is marked by a prolonged fever (>3 weeks). This case highlights the importance of close follow-up with serially repeated history and physical examinations to guide the evaluation of a patient with fever of unknown origin.

Phenomenon: The call component of clerkship presents students with unique opportunities and challenges. Clerkship programs employ various call modalities, including traditional call, night float, and evening call. The impact of these call models on the student experience has not been explored in depth. Approach: Focus groups were conducted with 4th-year medical students, exploring their multidimensional experiences with various call modalities during clerkship. Transcripts were analyzed using thematic analysis. Findings: Thirty-nine students participated in 6 focus groups. Four overarching themes were identified: (a) educational value conferred by clinical exposure and teaching, (b) maintaining quality of life and developing features of burnout, (c) formation of professional identity via relationships with team members, and (d) perceived quality of patient care provided. Students associated evening call with burnout and poor educational value but also better patient continuity of care. Night float and traditional call contributed to a sense of team bonding and had enhanced perceived educational value while on call but resulted in loss of formal academic teaching time. Insights: Call modality impacts student learning, well-being, professional identity formation, and patient care; however, trade-off among these elements exists across all call models. Enhancing the value of student call experience may be achieved by implementation of various purposeful changes. These may include creating consistency between student and resident call schedules, maximizing recovery time between call shifts, and avoiding scheduling of students for call prior to academic sessions.

The nuclear factor kappa-light-chain-enhancer of activated B-cells (NFκB) family of transcription factors plays an instrumental role in human immunity and lymphoid organ development. Inherited defects affecting these factors or their regulation are associated with increased susceptibility to infections, as well as non-immune abnormalities. Hematopoietic stem cell transplantations (HSCT) have been shown to correct the immune abnormalities in a few patients with NFκB pathway defects. Here we review the pre-HSCT characteristics, as well as the HSCT and outcome of 35 patients who received HSCT for NFκB defects. Twenty-three patients (65.7%) were reported to have survived HSCT. Survival was higher among patients with X-linked ectodermal dysplasia and immunodeficiency (XL-EDA-ID), and those with CARD11-BCL10-MALT1 (CBM) complex defects, in comparison to patients with autosomal dominant ectodermal dysplasia and immunodeficiency (AD-EDA-ID) and IKBKB defects. Survival following myeloablative conditioning was simi...

Aim Autistic regression is a unique variant within the autism spectrum disorders (ASDs), with recent reports raising the possibility of immune aetiology. This study explores clinical clues for an association between autistic regression and autoimmunity. Method Single-centre charts of children diagnosed with ASD in 2014 were reviewed. We compared the rates of: (1) familial autoimmunity in first-degree and second-degree relatives; (2) febrile illness preceding initial parental concern, as a potential precipitant of immune activation; and (3) possible non-immune precipitants such as pregnancy and postnatal complications. Results The charts of 206 children with ASD and 33 diagnosed with autistic regression variant were reviewed. The incidence of febrile illness in the 6 months prior to initial parental concern was significantly higher in the children with autistic regression compared with those with ASD (30% vs 0%; p

Purpose: Inherited defects in the adenosine deaminase (ADA) enzyme can cause severe combined immune deficiency (SCID) and systemic abnormalities. Management options for ADA-deficient patients include enzyme replacement therapy (ERT), hematopoietic stem cell transplantation (HSCT), and gene therapy (GT). Here, we describe the long-term benefits of these treatments. Methods: Survival, infections, systemic sequelae, and laboratory assessments were recorded for all ADA-deficient SCID patients, managed at a single center since 1985, who survived 5 or more years following treatment. Results: Of 20 ADA-deficient patients, the 8 (40%) who survived 5 or more years (range 6–29.5years, median 14years) were included in the study. Among the long-term survivors, two patients were treated exclusively with ERT, five underwent HSCT (three from HLA-matched sibling donors, two from HLA-mismatched related donors), and one received GT. The long-term survivors often suffered from recurrent respiratory infections; however, opportunistic infections occurred in only one patient. Systemic sequelae included lung disease such as bronchiectasis and asthma (four patients), neurologic abnormalities (six patients), metabolic disturbances (two patients), allergy and autoimmunity (six patients), and neoplasms (three patients). Normal CD4+ T cell numbers and function, as well as antibody production, were usually observed after HSCT and GT, but not after ERT. Late deaths occurred in two patients at 15 and 25years after HSCT, respectively, and were attributed to respiratory failure. Conclusions: ADA-deficient patients commonly suffer from long-term complications, emphasizing the need for improved management and for multi-disciplinary follow-up.

Anti N-methyl-d-aspartate (NMDA) receptor encephalitis in children is associated with psychiatric changes, seizures, and dyskinesias. We present the first report of autistic regression in a toddler caused by this entity. A 33-month-old boy presented with decreased appetite, irritability, and insomnia following an upper respiratory tract infection. Over the next few weeks he lost language and social skills, and abnormal movements of his hand developed. Within a month, this patient came to fit the diagnostic criteria for autistic spectrum disorder. Upon investigation, anti-NMDA receptor antibodies were found in the boy's cerebrospinal fluid. He was treated with intravenous immunoglobulins and steroids, resulting in reacquisition of language and social skills and resolution of movements. Our case emphasizes the significance of suspecting anti-NMDA receptor encephalitis as the cause of autistic regression, even in an age group where the diagnosis of autistic spectrum disorder is typically made, and especially when presentation follows a febrile illness.

Basal ganglia injury, accompanied by extrapyramidal signs, has been described in the setting of chronic tuberculous meningitis; however, such injury rarely occurs in acute bacterial meningitis and has never been reported with meningococcal meningitis. We report the case of a boy who developed tongue bradykinesia and dysarthria 1 week following presentation with meningococcal meningitis. Magnetic resonance imaging revealed bilateral basal ganglia lesions, suspected to result from cytotoxic edema secondary to infection. The patient subsequently developed general bradykinesia, choreoathetosis, and ataxia, which had improved but not completely subsided by the time of discharge, 8 weeks following initial presentation. The purpose of this report is to present basal ganglia injury with extrapyramidal signs as a possible complication of meningococcal meningitis. Furthermore, we emphasize the importance of suspecting parkinsonian signs as early indicators of basal ganglia involvement in the setting of meningitis, which may later develop into a full-blown movement disorder.

Some cruciferous plants may serve as preventive treatments for several medical conditions; our objective was to systematically investigate their safety in humans. Four electronic databases were searched, and, of 10,831 references identified, 50 were included. Data were extracted by two independent reviewers, whereafter the association between interventions and adverse events was assessed. Adverse events in 53 subjects were identified through clinical trials; of these, altered drug metabolism was rated as certainly/likely caused by cruciferous plants. Adverse events in 1247 subjects were identified through observational studies, of which none received high causality ratings. Adverse events in 35 subjects were identified through case reports, of which allergies and warfarin resistance were rated as certainly/likely caused by cruciferous plants. We conclude that cruciferous plants are safe in humans, with the exception of allergies. Individuals treated with warfarin should consult their physician. Further investigation of uses of cruciferous plants in preventative medicine is warranted.

Studies in animal models have established that intra-uterine vitamin A deficiency can hinder hindbrain formation; however, reports of such a phenomenon in humans had not been published until recently, when our group presented the case of an infant diagnosed with pontocerebellar hypoplasia and vitamin A deficiency. We currently report the cases of 3 infants with cerebellar hypoplasia and hypovitaminosis A, whose vitamin A consumption was determined to be adequate, and whose mothers had no such deficiency. We suggest a possible pathophysiology whereby a mutation in the gene coding for cytoplasmic retinol-binding protein II, which is expressed both in the placenta and the yolk sac (during fetal development) and in the absorptive intestinal cells, can cause vitamin A deficiency, forming hindbrain anomalies. Validation of our hypothesis will require further research, including fetal vitamin A measurements and hindbrain examination in cytoplasmic retinol-binding protein II knockout animals.

Given the involvement of cilia in midline neurodevelopment, we set to determine whether children with midline neuroanatomical defects have increased prevalence of ciliary dysfunction, using nasal nitric oxide measurement, a screening test for primary ciliary dyskinesia.We measured the nasal nitric oxide levels of 26 children ages 6-17, with congenital midline central nervous system defects, who are otherwise healthy. We evaluated the effect of variables including: age, gender, and anomaly (brain, spinal cord, or combined) on our measurements. We compared our results with the previously established normal range (153.6-509.9 nL/min) and to the cutoff for children with primary ciliary dyskinesia (77 nL/min).The overall range for nasal nitric oxide in our cohort was 56.5-334.7 nL/min, with age, gender, and anomaly not having a significant effect. The overall mean, 217.7 nL/min, was significantly lower than the preestablished mean in normal children, 314.51 nL/min (P0.01). Four patients (15.4%) had nitric oxide levels below the lower end of normal, with two (7.7%) having values below the cutoff for primary ciliary dyskinesia.This is the first study to report a possible association between ciliary dysfunction and isolated congenital midline neuroanatomical defects, not in the context of any known syndrome. We suggest that genes known to cause isolated central nervous system defects may also be involved in the function of cilia. Longitudinal studies are required to investigate whether, in children with abnormal measurements, nasal nitric oxide levels normalize over time, and whether these children suffer from any respiratory sequelae.

Chronic placental insufficiency and subsequent intrauterine growth restriction (IUGR) increase the risk of hypoxic-ischemic encephalopathy in the newborn by 40 fold. The latter, in turn, increases the risk of cerebral palsy and developmental disabilities. This study seeks to determine the effectiveness of broccoli sprouts (BrSp), a rich source of the isothiocyanate sulforaphane, as a neuroprotectant in a rat model of chronic placental insufficiency and IUGR. Placental insufficiency and IUGR was induced by bilateral uterine artery ligation (BUAL) on day E20 of gestation. Dams were fed standard chow or chow supplemented with 200 mg of dried BrSp from E15 – postnatal day 14 (PD14). Controls received Sham surgery and the same dietary regime. Pups underwent neurologic reflex testing and open field testing, following which they were euthanized and their brains frozen for neuropathologic assessment. Compared to Sham, IUGR pups were delayed in attaining early reflexes and performed worse in the open field, both of which were significantly improved by maternal supplementation of BrSp (p < 0.05). Neuropathology revealed diminished white matter, ventricular dilation, astrogliosis and reduction in hippocampal neurons in IUGR animals compared to Sham, whereas broccoli sprout supplementation improved outcome in all histological assessments (p < 0.05). Maternal dietary supplementation with BrSp prevented the detrimental neurocognitive and neuropathologic effects of chronic intrauterine ischemia. These findings suggest a novel approach for prevention of cerebral palsy and/or developmental disabilities associated with placental insufficiency.

We compared the social communication deficits of children with moderate to severe acquired brain injury or autism spectrum disorder, while accounting for the role of attention-deficit hyperactivity disorder (ADHD) symptoms. Parents of 20 children aged 6 to 10 years (10 acquired brain injury; 10 autism spectrum disorder) completed the Social Communication Questionnaire, and Conners 3 Parent Short. A multivariate analysis of covariance revealed significant differences between groups in Social Communication Questionnaire restricted repetitive behavior scores, but not reciprocal social interaction or social communication. Multiple linear regressions indicated diagnosis did not predict reciprocal social interaction or social communication scores and that Conners 3 Parent Short Form hyperactivity scores were the strongest predictor of Social Communication Questionnaire reciprocal social interaction scores after accounting for age and Intelligence Quotient. The lack of difference in social communication deficits between groups may help in understanding the pathophysiology underlying the behavioral consequences of acquired brain injury. The link between hyperactivity and reciprocal interaction suggests that targeting hyperactivity may improve social outcomes in children following acquired brain injury.

SOX6, a member of the SOX gene family, plays a key role in the development of several mammalian tissues and organs, including the central nervous system. Specifically, this gene modulates the differentiation and proliferation of interneurons in the medial ganglionic eminence, as well as oligodendrocytes in the spinal cord. We describe the case of a 4-year-old girl with global developmental delay and a spinal cord syrinx who presented with recurrent episodes of parkinsonian symptoms subsequent to febrile illnesses. The symptoms included gait instability, tremor, and dysarthria, with a progressive relapsing-remitting course over the span of 2 years. The patient was later found to have a large deletion-type mutation in the SOX6 gene. This case is the first report in humans implying a role for SOX6 in basal ganglia function, as well as spinal cord development.

Background: Ciliary mutations cause multi-system disorders, often involving the CNS. We set to evaluate the prevalence of ciliary dysfunction in children with isolated neuroanatomical defects, by measuring nasal nitric oxide (nNO), a screening test for Primary Ciliary Dyskinesia (PCD). Study design: We measured nNO levels of 26 children with congenital midline CNS defects. We evaluated the effect of age, gender, and anomaly (brain, spinal cord, or combined) on measurements. We compared our results to the previously established normal range (153.6-509.9 nL/min), and to the cutoff for PCD (77 nL/min). Results: The range for nNO in our cohort was 56.5-334.7 nL/min, with age, gender, and anomaly not having a significant effect. The overall mean, 217.7 nL/min, was significantly lower than that of normal children, 314.51 nL/min (pConclusions: We report an association between ciliary dysfunction and isolated midline neuroanatomical defects, not in context of any known syndrome. This suggests that genes causing isolated CNS defects, may be implied in the function of cilia. Longitudinal studies are required to investigate whether children with abnormal measurements suffer from any respiratory sequelae.

Background: Autistic regression (AR) accounts for 20-40% of patients with Autism Spectrum Disorder (ASD) .1 Literature demonstrates specific immune changes in AR patients,2 as well as association between AR and autoimmune thyroiditis.3 Our study explores the clinical association between AR and autoimmunity, focusing on possible precipitants and familial autoimmunity, in comparison with patients with infantile autism (IA). Methods: charts of children diagnosed with ASD in 2014 were reviewed, and patients were classified as either AR or IA based on Autism Diagnostic Interview (ADI-R) criteria.4 Information regarding pregnancy, perinatal complications, febrile illness preceding the diagnosis, and family history of autoimmune conditions was collected. Results: 206 children had IA and 33 had AR. No difference was found in prevalence of pregnancy or perinatal complications. The incidence of febrile illness in the 6 months prior to diagnosis and the prevalence of familial autoimmunity, were significantly higher in the AR group (pConclusions: the association between AR and preceding febrile illness, as well as familial autoimmunity, supports the notion of AR as a separate entity within ASD, possibly mediated by autoimmune changes.

The efficacy of modafinil in comparison with methylphenidate in treatment of pediatric attention-deficit hyperactivity disorder (ADHD) has not been thoroughly investigated. This study compared the effect of modafinil versus methylphenidate on continuous attention task in children with ADHD, using the Test of Variables of Attention. Twenty-eight participants completed a baseline test followed by administration of a single dose of either methylphenidate or modafinil, after which the test was repeated. The test was performed a third time, after each subject received a dose of the medication not previously administered. Comparison of scores showed mean baseline, postmethylphenidate, and postmodafinil scores of –2.04, 0.017, and 0.09, respectively. No difference was found between improvements observed with either medication ( P < .05). Adverse events for both agents were mild and self-limited, including abdominal pain, diarrhea, and hyposomnia. The authors conclude that modafinil is as effective as methylphenidate; however, a larger scale long-term study is required to confirm these results.

Prenatal alcohol exposure is a cause of congenital brain malformations such as hydrocephalus; however, a complete mechanism accounting for this phenomenon has yet to be discovered. We report a case of a newborn who was exposed to alcohol throughout pregnancy and presented with low serum vitamin A and hydrocephalus. To our knowledge, the connection between prenatal ethanol exposure, vitamin A deficiency, and a developmental brain anomaly has never been described in humans before. A possible mechanism may be mediated by disruption of the homeostasis of vitamin A, an important morphogen in the developing nervous system. This, in turn, compromises the activity of the floor plate, a structure in charge of polarization and midline formation in the neural tube. We conclude that vitamin A screening and supplementation might be recommended for newborns of mothers who ingested ethanol during pregnancy.