Biallelic variants in ribonuclease inhibitor (RNH1), an inflammasome modulator, are associated with a distinctive subtype of acute, necrotizing encephalopathy.

PURPOSE: Mendelian etiologies for acute encephalopathies in previously healthy children are poorly understood, with the exception of RAN binding protein 2 (RANBP2)-associated acute necrotizing encephalopathy subtype 1 (ANE1). We provide clinical, genetic, and neuroradiological evidence that biallelic variants in ribonuclease inhibitor (RNH1) confer susceptibility to a distinctive ANE subtype. METHODS: This study aimed to evaluate clinical data, neuroradiological studies, genomic sequencing, and protein immunoblotting results in 8 children from 4 families who experienced acute febrile encephalopathy. RESULTS: All 8 healthy children became acutely encephalopathic during a viral/febrile illness and received a variety of immune modulation treatments. Long-term outcomes varied from death to severe neurologic deficits to normal outcomes. The neuroradiological findings overlapped with ANE but had distinguishing features. All affected children had biallelic predicted damaging variants in RNH1: a subset that was studied had undetectable RNH1 protein. Incomplete penetrance of the RNH1 variants was evident in 1 family. CONCLUSION: Biallelic variants in RNH1 confer susceptibility to a subtype of ANE (ANE2) in previously healthy children. Intensive immunological treatments may alter outcomes. Genomic sequencing in children with unexplained acute febrile encephalopathy can detect underlying genetic etiologies, such as RNH1, and improve outcomes in the probands and at-risk siblings.

Epigenetics and autism spectrum disorder: A report of an autism case with mutation in H1 linker histone HIST1H1E and literature review.

Genetic mutations in genes encoding proteins involved in epigenetic machinery have been reported in individuals with autism spectrum disorder (ASD), intellectual disability, congenital heart disease, and other disorders. H1 histone linker protein, the basic component in nucleosome packaging and chromatin organization, has not been implicated in human disease until recently. We report a de novo deleterious mutation of histone cluster 1 H1 family member e (HIST1H1E; c.435dupC; p.Thr146Hisfs*50), encoding H1 histone linker protein H1.4, in a 10-year-old boy with autism and intellectual disability diagnosed through clinical whole exome sequencing. The c.435dupC at the 3' end of the mRNA leads to a frameshift and truncation of the positive charge in the carboxy-terminus of the protein. An expression study demonstrates the mutation leads to reduced protein expression, supporting haploinsufficiency of HIST1H1E protein and loss of function as an underlying mechanism of dysfunction in the brain. Taken together with other recent cases with mutations of HIST1H1E in intellectual disability, the evidence supporting the link to causality in disease is strong. Our finding implicates the deficiency of H1 linker histone protein in autism. The systematic review of candidate genes implicated in ASD revealed that 42 of 215 (19.5%) genes are directly involved in epigenetic regulations and the majority of these genes belong to histone writers, readers, and erasers. While the mechanism of how haploinsufficiency of HIST1H1E causes autism is entirely unknown, our report underscores the importance of further study of the function of this protein and other histone linker proteins in brain development.

Skipping the Line: Inequality in Access to Developmental-Behavioral Care.

CASE: The mother of an 18-month-old boy contacted the developmental and behavioral pediatrics clinic to request an evaluation because of concerns that her son is not using any words and only recently began walking. The child's mother became upset when she was notified that the clinic policy requires receipt of a formal request for evaluation from the primary care physician and that the first available appointment was in 9 months. Later that day, the child's grandmother contacted the clinic and reported that she is a member of the Donor Society affiliated with the university/medical system. Membership in the Donor Society is granted to individuals who have met specific philanthropic thresholds benefiting the university. One benefit to members of the Donor Society is the ability to access subspecialty medical services for themselves and their family members, across all disciplines, within 5 business days of their request.After confirming the details of the Donor Society promise with the philanthropic department of the hospital, a small committee of professionals within the clinic gathered to discuss the implications of this promised benefit to Donor Society members. This clinic is the only source for specialized, multidisciplinary developmental-behavioral health care that accepts public insurance within a 200-mile radius. The current waitlist for evaluation is 9 to 15 months depending on the reason for referral, and approximately 75% of patients on the waitlist receive some form of public assistance and/or live in a rural or underserved area. During the discussion, it was noted that there are 2 developmental-behavioral pediatric clinicians who practice within a cash-based private practice setting in the community. The waitlist for that practice was recently reported to be 3 to 6 months depending on the reason for evaluation, but that practice also requires a referral from the primary care physician before scheduling an initial evaluation.How would you recommend that the clinicians in the developmental and behavioral pediatrics clinic respond to the request to fulfill the promises made by the university to members of the Donor Society? How does a promise such as this one made to the Donor Society affect structural inequalities within the health care system and what strategies could be used to mitigate further inequalities that may result?

Let Me Spell It Out: The Impact of Microaggression on the Health Care Professional.

CASE: Rachel is a 10-year-old White girl with attention-deficit/hyperactivity disorder and a history of trauma who presented for evaluation by Dr. Narayanaswamy, a developmental-behavioral pediatrician. A pediatric resident observed the visit with permission from Rachel's parents.During the visit, Dr. Narayanaswamy spoke to Rachel's case manager over the phone to advocate for a trauma-based day treatment program at her school. At the end of the call, the case manager asked the physician for her full name. Dr. Narayanaswamy responded with her name and asked the case manager, "Would you like me to spell it?" At that time, Rachel's father began to laugh, shook his head, and incredulously remarked, "Ugh, yeah you need to spell it." Dr. Narayanaswamy ignored the comment and completed the phone call.After the visit, Dr. Narayanaswamy explained to the resident that the father's derisive laughter was a microaggression. The resident appreciated the observation and, after a pause, asked why she chose not to defend herself when the microaggression occurred. Dr. Narayanaswamy reflected that she had refrained from responding to Rachel's father over concern that he would retaliate by providing low ratings on the postvisit patient satisfaction survey sent to all patients who received care at the institution. The granular survey results, comprising ratings in each survey subheading category for each clinician, are made public to members of her division each quarter, and low ratings are scrutinized by the leadership. Dr. Narayanaswamy thought it unfortunate that she felt inhibited in her response because this deprived the resident of observing ways to address microaggressions during an encounter, deprived herself the opportunity to respond directly to Rachel's father, and deprived Rachel from an instructive moment about racial empathy.Dr. Narayanaswamy wrote a letter about the incident to the chief of clinical affairs to inquire what recourse clinicians had in these situations and whether certain patient encounters could be flagged to prevent the postvisit patient survey from being automatically sent. The chief responded that the incident was unfortunate and praised Dr. Narayanaswamy's restraint and professionalism but denied her request to have postvisit surveys blocked for certain encounters. He shared that if a clinician were to be dissatisfied with a visit satisfaction rating, the clinician could petition for a review, and a committee would subsequently determine whether the review could be removed.How can health care professionals respond to microaggressions while maintaining a therapeutic alliance with the patient/family members and how can institutions support health care professionals in this endeavor?

Media content and externalizing behaviors in Latino toddlers.

OBJECTIVE: There has been limited study of the association between media exposure and behavior in children younger than age 3 years. We sought to study this association in toddlers and determine whether the association varied depending on media content. METHODS: We carried out a secondary analysis of a cohort of Latino mother-infant dyads followed from birth to 33 months. We assessed media exposure at 21 and 33 months with a 24-hour recall diary that included information about the duration and content of each program watched. Behavior was assessed at 33 months by the Child Behavior Checklist. RESULTS: This analysis included 99 dyads. Results from multiple logistic regression analyses indicated associations of child behavior outcomes with 21-month total media exposure and both 21-month and 33-month exposure to noneducational young child media such as cartoons, after adjusting for maternal education, country of origin, and depressive symptoms, participation in a parenting program, and difficult child temperament. Media exposure has most consistent associations with aggressive behavior and externalizing problems. CONCLUSIONS: Media exposure was associated with externalizing behavior in Latino toddlers, with the strongest association for media oriented toward young children but without educational content. This finding has importance for both parents of young children and pediatricians as they provide anticipatory guidance.

Is exposure to media intended for preschool children associated with less parent-child shared reading aloud and teaching activities?

OBJECTIVE: To determine whether electronic media exposure is associated with decreased parental reading and teaching activities in the homes of preschool children. METHODS: A convenience sample presenting for well-child care to an urban hospital pediatric clinic was enrolled. Inclusion criteria were: child's age 3 to 5 years and not yet in kindergarten. Electronic media exposure (TV, movies/video, computer/video games) was assessed with a 24-hour recall diary and characterized on the basis of industry ratings. Reading aloud and teaching activities were assessed with the StimQ-Preschool READ and PIDA (Parental Involvement in Developmental Advance) subscales, respectively. RESULTS: A total of 77 families were assessed. Children were exposed to a mean (SD) of 200.8 (128.9) minutes per day of media, including 78.2 (63.7) minutes of educational young child-oriented, 62.0 (65.6) minutes of noneducational young child-oriented, 14.8 (41.4) minutes of school age/teen-oriented, and 29.2 (56.6) minutes of adult-oriented media, as well as to 16.6 (47.5) minutes of media of unknown type. A total of 79.2% watched 2 or more hours per day. Noneducational young child-oriented exposure was associated with fewer reading (semipartial correlation coefficient [SR] = -0.24, P = .02) and teaching (SR = -0.27, P = .01) activities; similar relationships were not found for other media categories. Children exposed to 2 or more hours of total electronic media per day had 1.6 (95% confidence interval, 0.4-2.9) fewer days per week of reading than children exposed to less than 2 hours (SR = -0.27, P = .01). CONCLUSIONS: This study found an association between increased exposure to noneducational young child-oriented media and decreased teaching and reading activities in the home. This association represents a mechanism by which media exposure could adversely affect development.

Use of videotaped interactions during pediatric well-child care: impact at 33 months on parenting and on child development.

OBJECTIVE: We performed a randomized, controlled trial to assess the impact of the Video Interaction Project (VIP), a program based in pediatric primary care in which videotaped interactions are used by child development specialists to promote early child development. METHOD: Ninety-nine Latino children (52 VIP, 47 controls) at risk of developmental delay based on poverty and low maternal education were assessed at age 33 months. VIP was associated with improved parenting practices including increased teaching behaviors. RESULTS: VIP was associated with lower levels of parenting stress. VIP children were more likely to have normal cognitive development and less likely to have developmental delays. CONCLUSION: This study provides evidence that a pediatric primary care-based intervention program can have an impact on the developmental trajectories of at-risk young preschool children.

Loss-of-function variants of SCN8A in intellectual disability without seizures.

OBJECTIVE: To determine the functional effect of SCN8A missense mutations in 2 children with intellectual disability and developmental delay but no seizures. METHODS: Genomic DNA was analyzed by next-generation sequencing. SCN8A variants were introduced into the Nav1.6 complementary DNA by site-directed mutagenesis. Channel activity was measured electrophysiologically in transfected ND7/23 cells. The stability of the mutant channels was assessed by Western blot. RESULTS: Both children were heterozygous for novel missense variants that altered conserved residues in transmembrane segments of Nav1.6, p.Gly964Arg in D2S6 and p.Glu1218Lys in D3S1. Both altered amino acids are evolutionarily conserved in vertebrate and invertebrate channels and are predicted to be deleterious. Neither was observed in the general population. Both variants completely prevented the generation of sodium currents in transfected cells. The abundance of Nav1.6 protein was reduced by the Glu1218Lys substitution. CONCLUSIONS: Haploinsufficiency of SCN8A is associated with cognitive impairment. These observations extend the phenotypic spectrum of SCN8A mutations beyond their established role in epileptic encephalopathy (OMIM#614558) and other seizure disorders. SCN8A should be considered as a candidate gene for intellectual disability, regardless of seizure status.