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Contains fulltext : 243955.pdf (Publisher’s version ) (Open Access) PURPOSE: Pathogenic variants in SETD1B have been associated with a syndromic neurodevelopmental disorder including intellectual disability, language delay, and seizures. To date, clinical features have been described for 11 patients with (likely) pathogenic SETD1B sequence variants. This study aims to further delineate the spectrum of the SETD1B-related syndrome based on characterizing an expanded patient cohort. METHODS: We perform an in-depth clinical characterization of a cohort of 36 unpublished individuals with SETD1B sequence variants, describing their molecular and phenotypic spectrum. Selected variants were functionally tested using in vitro and genome-wide methylation assays. RESULTS: Our data present evidence for a loss-of-function mechanism of SETD1B variants, resulting in a core clinical phenotype of global developmental delay, language delay including regression, intellectual disability, autism and other behavioral issues, and variable epilepsy phenotypes. Developmental delay appeared to precede seizure onset, suggesting SETD1B dysfunction impacts physiological neurodevelopment even in the absence of epileptic activity. Males are significantly overrepresented and more severely affected, and we speculate that sex-linked traits could affect susceptibility to penetrance and the clinical spectrum of SETD1B variants. CONCLUSION: Insights from this extensive cohort will facilitate the counseling regarding the molecular and phenotypic landscape of newly diagnosed patients with the SETD1B-related syndrome.

IntroductionProspective comparative effectiveness research in chronic nonbacterial osteomyelitis (CNO) is lacking.ObjectivesStudy objectives were to: 1) determine the use and safety of each consensus treatment plan (CTP) regimen for CNO, 2) the feasibility of usingchronic nonbacterialosteomyelitis international registry (CHOIR) data for comparative effectiveness research, and 3) develop and validate a CNO clinical disease activity score (CDAS) using CHOIR.MethodsConsenting children or young adults with CNO were enrolled into CHOIR. Demographic, clinical, and imaging data were prospectively collected. The CNO CDAS was developed through a Delphi survey and nominal group technique. External validation surveys were administered to CHOIR participants.Results140 (76%) CHOIR participants enrolled between August 2018 and September 2020 received at least one CTP regimen. Baseline characteristics from the three groups were well matched. Patient pain, patient global assessment, and clinical CNO lesion count were key variables included in the CNO CDAS. The CDAS showed a strong correlation with patient/parent report of difficulty using a limb, back, or jaw and patient/parent report of disease severity, but a weak correlation with patient/parent report of fatigue, sadness, and worry. The change in CDAS was significant in patients reporting disease worsening or improvement. The CDAS significantly decreased after initiating second-line treatments from median 12 (8-15.5) to 5 (3-12). While second-line treatments were well tolerated, psoriasis was the most common adverse event.ConclusionThe CNO CDAS was developed and validated for disease monitoring and assessment of treatment effectiveness. CHOIR provided a comprehensive framework for future comparative effectiveness research.Key messagesThechronic nonbacterialosteomyelitis international registry (CHOIR) provides comprehensive prospective data for comparison of treatment effectivenessThe clinical disease activity score (CDAS) has content and construct validity to assess CNO

ObjectiveTo standardize and improve the accuracy of detection of arthritis by thermal imaging.MethodsChildren with clinically active arthritis in the knee or ankle, as well as healthy controls, were enrolled to the development cohort; another group of children with knee symptoms was enrolled to the validation cohort. Ultrasound was performed in the arthritis subgroup for the development cohort. Joint exam by certified rheumatologists was used as a reference for the validation cohort. Infrared thermal data were analyzed using custom software. Temperature after within-limb calibration (TAWiC) was defined as the temperature differences between joint and ipsilateral mid-tibia. TAWiC of knees and ankles was evaluated using ANOVA across subgroups. Optimal thresholds were determined by receiver-operating characteristic analysis using Youden index.ResultsThere were significant differences in mean and 95th TAWiC of knee in anterior, medial, lateral views, and of ankles in anterior view, between inflamed and uninflamed counterparts (P < 0.05). The area under the curve was higher by 30% when using TAWiCknee than that when using absolute temperature. Within the validation cohort, the sensitivity of accurate detection of arthritis in the knees using both mean and 95th TAWiC from individual views or all 3 views combined ranged from 0.60 to 0.70, and the specificity was > 0.90 in all views.ConclusionChildren with active arthritis or tenosynovitis in knees or ankles exhibited higher TAWiC than healthy joints. Our validation cohort study showed promise for the clinical utility of infrared thermal imaging for arthritis detection.

To determine the impact of physical activity on temperature after within-limb calibration (TAWiC) measures and their reproducibility. To determine if thermal imaging from a smartphone attached thermal camera is comparable to thermal imaging using a handheld thermal camera for detection of arthritis in children.Children without symptoms were enrolled to the "asymptomatic exercise cohort", and received infrared imaging, using a standard handheld camera, after initial resting period, after activity, and after second resting period. Children seen in the rheumatology clinic with knee pain were enrolled into the "symptomatic knee pain cohort" and received imaging with both the smartphone-attached and handheld cameras before a routine clinical exam. TAWiC was defined as the temperature differences between joint and ipsilateral mid-tibia as the main readout for arthritis detection.The asymptomatic exercise cohort demonstrated notable changes in absolute and TAWiC temperatures collected by thermal imaging after physical activity, and temperatures did not consistently return to pre-activity levels after a second period of rest. The 95th TAWiC from anterior view were, resting one -0.1 C (0.5), activity -0.7 C (0.5), resting two -0.2 C (0.6) (resting 1 vs resting 2, p-value = 0.13). In the symptomatic knee pain cohort, the smartphone attached and handheld thermal cameras performed similarly in regards to detection of joint inflammation and evaluation of joint temperature using the TAWiC algorithm, with high sensitivity of 80% (55.2-100.0%) and specificity of 84.2% (76.0-92.4%) in the anterior knee view when compared with the gold standard joint exam performed by a pediatric rheumatologist. The mean 95th TAWiC temperature difference between the two cameras was -0.1 C (-0.1 to 0.0) (p = 0.0004).This study showed continued validity of the TAWiC algorithm across two distinct thermal camera platforms and demonstrates promise for improved accessibility and utility of this technology for arthritis detection.

ObjectiveChronic nonbacterial osteomyelitis (CNO) is a rare autoinflammatory bone disease that is gaining recognition from clinicians and researchers. We aim to publish data from our cohort of patients with CNO living in the northwestern United States to increase the awareness of specific demographics, characteristics, and presentation of this rare disease.MethodsA retrospective chart review was performed of our electronic medical records. Patients with complete chart records who met criteria for a diagnosis of CNO from 2005 to 2019 were included. Extracted data including patient demographics, bone biopsy results, and lesion locations on advanced imaging were analyzed. King County census data were used to calculate the annual new case rate within our center.ResultsA total of 215 CNO cases were diagnosed at our large tertiary pediatric hospital. The majority of cases were of White race residing in Washington’s most populous county, King County. Most cases were diagnosed in 2016 to 2019, showing a significant increase in the annual case rate from 8 to 23 per million children in King County, though there did not appear to be a seasonal predilection. Biopsy rate decreased from 75% to 52%. One hundred fifty-two (71%) children had family history of autoimmunity. With increasing use of whole-body magnetic resonance imaging (WB-MRI), results showed 68% had multiple lesions.ConclusionCNO has been diagnosed at an increased rate in recent years. WB-MRI may assist in identifying other lesions that may be asymptomatic on presentation. Bone biopsy is still required in some children at the time of diagnosis.

Contains fulltext : 218267.pdf (Publisher’s version ) (Closed access) PURPOSE: Intellectual disability (ID) and autism spectrum disorder (ASD) are genetically heterogeneous neurodevelopmental disorders. We sought to delineate the clinical, molecular, and neuroimaging spectrum of a novel neurodevelopmental disorder caused by variants in the zinc finger protein 292 gene (ZNF292). METHODS: We ascertained a cohort of 28 families with ID due to putatively pathogenic ZNF292 variants that were identified via targeted and exome sequencing. Available data were analyzed to characterize the canonical phenotype and examine genotype-phenotype relationships. RESULTS: Probands presented with ID as well as a spectrum of neurodevelopmental features including ASD, among others. All ZNF292 variants were de novo, except in one family with dominant inheritance. ZNF292 encodes a highly conserved zinc finger protein that acts as a transcription factor and is highly expressed in the developing human brain supporting its critical role in neurodevelopment. CONCLUSION: De novo and dominantly inherited variants in ZNF292 are associated with a range of neurodevelopmental features including ID and ASD. The clinical spectrum is broad, and most individuals present with mild to moderate ID with or without other syndromic features. Our results suggest that variants in ZNF292 are likely a recurrent cause of a neurodevelopmental disorder manifesting as ID with or without ASD.

Pathogenic variants in SETD1B have been associated with a syndromic neurodevelopmental disorder including intellectual disability, language delay and seizures. To date, clinical features have been described for eleven patients with (likely) pathogenic SETD1B sequence variants. We perform an in-depth clinical characterization of a cohort of 36 unpublished individuals with SETD1B sequence variants, describing their molecular and phenotypic spectrum. Selected variants were functionally tested using in vitro and genome-wide methylation assays. Our data present evidence for a loss-of-function mechanism of SETD1B variants, resulting in a core clinical phenotype of global developmental delay, language delay including regression, intellectual disability, autism and other behavioral issues, and variable epilepsy phenotypes. Developmental delay appeared to precede seizure onset, suggesting SETD1B dysfunction impacts physiological neurodevelopment even in the absence of epileptic activity. Interestingly, males are significantly overrepresented and more severely affected, and we speculate that sex-linked traits could affect susceptibility to penetrance and the clinical spectrum of SETD1B variants. Finally, despite the possibility of non-redundant contributions of SETD1B and its paralogue SETD1A to epigenetic control, the clinical phenotypes of the related disorders share many similarities, indicating that elucidating shared and divergent downstream targets of both genes will help to understand the mechanism leading to the neurobehavioral phenotypes. Insights from this extensive cohort will facilitate the counseling regarding the molecular and phenotypic landscape of newly diagnosed patients with the SETD1B-related syndrome.

Objective Mutations in phosphatidylinositol-4,5-bisphosphate 3-kinase (PI3K) complex have been associated with a broad spectrum of brain and organ overgrowth syndromes. For example, mutations in phosphatidylinositol-3-kinase regulatory subunit 2 (PIK3R2) have been identified in human patients with megalencephaly polymicrogyria polydactyly hydrocephalus (MPPH) syndrome, which includes brain overgrowth. To better understand the pathogenesis of PIK3R2-related mutations, we have developed and characterized a murine model. Methods We generated a knock-in mouse model for the most common human PIK3R2 mutation, p.G373R (p.G367R in mice) using CRISPR/Cas9. The mouse phenotypes, including brain size, seizure activity, cortical lamination, cell proliferation/size/density, interneuron migration, and PI3K pathway activation, were analyzed using standard methodologies. For human patients with PIK3R2 mutations, clinical data (occipitofrontal circumference [OFC] and epilepsy) were retrospectively obtained from our clinical records (published / unpublished). Results The PI3K-AKT pathway was hyperactivated in these mice, confirming the p.G367R mutation is an activating mutation in vivo. Similar to human patients with PIK3R2 mutations, these mice have enlarged brains. We found cell size to be increased but not cell numbers. The embryonic brain showed mild defects in cortical lamination, although not observed in the mature brain. Furthermore, electroencephalogram (EEG) recordings from mutant mice showed background slowing and rare seizures, again similar to our observations in human patients. Interpretation We have generated a PIK3R2 mouse model that exhibits megalencephaly and EEG changes, both of which overlap with human patients. Our data provide novel insight into the pathogenesis of the human disease caused by PIK3R2 p.G373R mutation. We anticipate this model will be valuable in testing therapeutic options for human patients with MPPH. ANN NEUROL 2020;88:1077-1094.