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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.

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.

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.

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.

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.

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.

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.