Clustered mutations in the GRIK2 kainate receptor subunit gene underlie diverse neurodevelopmental disorders.

Kainate receptors (KARs) are glutamate-gated cation channels with diverse roles in the central nervous system. Bi-allelic loss of function of the KAR-encoding gene GRIK2 causes a nonsyndromic neurodevelopmental disorder (NDD) with intellectual disability and developmental delay as core features. The extent to which mono-allelic variants in GRIK2 also underlie NDDs is less understood because only a single individual has been reported previously. Here, we describe an additional eleven individuals with heterozygous de novo variants in GRIK2 causative for neurodevelopmental deficits that include intellectual disability. Five children harbored recurrent de novo variants (three encoding p.Thr660Lys and two p.Thr660Arg), and four children and one adult were homozygous for a previously reported variant (c.1969G>A [p.Ala657Thr]). Individuals with shared variants had some overlapping behavioral and neurological dysfunction, suggesting that the GRIK2 variants are likely pathogenic. Analogous mutations introduced into recombinant GluK2 KAR subunits at sites within the M3 transmembrane domain (encoding p.Ala657Thr, p.Thr660Lys, and p.Thr660Arg) and the M3-S2 linker domain (encoding p.Ile668Thr) had complex effects on functional properties and membrane localization of homomeric and heteromeric KARs. Both p.Thr660Lys and p.Thr660Arg mutant KARs exhibited markedly slowed gating kinetics, similar to p.Ala657Thr-containing receptors. Moreover, we observed emerging genotype-phenotype correlations, including the presence of severe epilepsy in individuals with the p.Thr660Lys variant and hypomyelination in individuals with either the p.Thr660Lys or p.Thr660Arg variant. Collectively, these results demonstrate that human GRIK2 variants predicted to alter channel function are causative for early childhood development disorders and further emphasize the importance of clarifying the role of KARs in early nervous system development.

Pediatric cervical spine injuries on CT: difference in accuracy of interpretations by pediatric versus non-pediatric radiologists.

PURPOSE: To retrospectively compare the accuracy of interpretation of initial cervical computerized tomography (CCT) by a non-pediatric radiologist (NPR) versus a pediatric radiologist (PR). METHODS: IRB approval and consent waiver were granted to review all injured children from 2010 to 2014 in the trauma registry with CT and magnetic resonance imaging (MRI) of the cervical spine. Patients with negative CCT who subsequently had positive MRI from a single institution comprised the study group. Patients with negative CCT and MRI, matched by age, gender, and severity scores, comprised the control group. The CCTs from both groups were initially interpreted at the time of service by a NPR. Subsequently, a single PR with 20 years of experience blinded to clinical/imaging data reinterpreted these CCT examinations. CT interpretations were then compared with MRI results and evaluated for statistical significance using SSPS software. The data analysis utilized summary statistics, two-tailed binomial test, and univariate χ2 test. Significance for all comparisons was assessed at P < 0.05. RESULTS: The study group was comprised of the 21 patients with negative CCT and positive MRI. Of the cohort included, 76% (16) were male and 24% (5) were female. The age range was 1 month-17 years, with a mean age of 9.7 years. CCT interpretation by NPR had a specificity of 91.7% (sensitivity 71.2%, positive predictive value 81.3%, and negative predictive value 86.3%) compared with results of MRI. Six of the 21 negative CCTs were interpreted by the PR as positive, mainly craniocervical junction injuries, and confirmed by MRI (28.6%, P < .001 compared with the NPR); no control CCT was interpreted by the PR as positive (sensitivity 100%, positive predictive value 100%, and negative predictive value 58.3%). CONCLUSION: In our retrospective study, a pediatric radiologist has improved recognition of pediatric cervical spine injuries on CT compared with non-pediatric radiologist.

The Perils of Perfectionism.

OBJECTIVE. The purposes of this article are to describe the perfectionism that occurs among radiologists and to propose methods of assuaging it. CONCLUSION. Perfectionism can take a great toll on radiologists and those they work with. Only by setting realistic expectations and learning from failure is genuine professional fulfillment possible.

Incidence of pulmonary emboli on chest computed tomography angiography based upon referral patterns.

Pulmonary embolism (PE) is a potentially lethal condition, and the diagnosis of PE can be difficult. The purpose of this study is to evaluate the incidence of PE on chest computed tomography angiography (CTA) studies ordered in the inpatient, outpatient, and emergency department (ED) settings and further segregated based on the adult and pediatric populations, and by the ordering clinician (attending physicians, resident physicians, or physician extenders). A retrospective review of chest CTA examinations performed between July 1,2009 and June 30, 2010 was performed. Of 5848 adult CTA studies, PE was diagnosed in 594 (10.1 %). Of these positive studies, 315 (53 %) were inpatient, 234 (39.4 %) were ED patients, and 45 (7.6 %) were outpatient. Four hundred sixty-four of 4445 (10.4 %) CTA examinations ordered by attending physicians were positive for PE. Seventy-four of the 801 (9.2 %) CTA examinations ordered by resident physicians were positive for PE. Fifty-six of the 608 CTA examinations ordered by physician extenders were positive for PE. Thirty-three pediatric CTA studies for PE met criteria and none of them indicated PE. There is no significant difference in the incidence of PE in chest CTA based on setting or ordering clinician.

Using a rhabdomyosarcoma patient-derived xenograft to examine precision medicine approaches and model acquired resistance.

BACKGROUND: Precision (Personalized) medicine has the potential to revolutionize patient health care especially for many cancers where the fundamental disease etiology remains either elusive or has no available therapy. Here we outline a study in alveolar rhabdomyosarcoma, in which we use gene expression profiling and a series of drug prediction algorithms combined with a matched patient-derived xenograft (PDX) model to test bioinformatically predicted therapies. PROCEDURE: A PDX model was developed from a patient biopsy and a number of drugs identified using gene expression analysis in combination with drug prediction algorithms. Drugs chosen from each of the predictive methodologies, along with the patient's standard-of-care therapy (ICE-T), were tested in vivo in the PDX tumor. A second study was initiated using the tumors that re-grew following the ICE-T treatment. Further expression analysis identified additional therapies with potential anti-tumor efficacy. RESULTS: A number of the predicted therapies were found to be active against the tumors in particular BGJ398 (FGFR2) and ICE-T. Re-transplanted ICE-T treated tumorgrafts demonstrated a decreased response to ICE-T recapitulating the patient's refractory disease. Gene expression profiling of the ICE-T treated tumorgrafts identified cytarabine (SLC29A1) as a potential therapy, which was shown, along with BGJ398, to be highly active in vivo. CONCLUSIONS: This study illustrates that PDX models are suitable surrogates for testing potential therapeutic strategies based on gene expression analysis, modeling clinical drug resistance and hold the potential to assist in guiding prospective patient care.

Pediatric thoracic spine injuries: a single-institution experience.

OBJECTIVE: The objective of our study was to determine the incidence of various fractures of the thoracic spine in pediatric patients. CONCLUSION: Simple compression and process-only fractures were the most common types of fractures and all other fracture types were infrequent. Distraction injury was unexpectedly more common in the nonjunctional thoracic spine than in the junctional thoracic spine.

Segmental Agenesis of the Corpus Callosum With Pituitary Hypoplasia.

We report a 3-year-old male with findings of segmental agenesis of the corpus callosum, pituitary hypoplasia, and Chiari I malformation. The patient was born at 33 weeks and spent five weeks in the NICU for hypoglycemia, hypotension, and dyspnea. In infancy, the patient passed an adrenocorticotropic hormone stimulation test, while cortisol, growth hormone, and insulin-like growth factor levels were within reference range. Following height and weight percentile regression the patient underwent arginine and clonidine stimulation testing at 3 years of age, prompting pituitary evaluation via MRI. The results provided exemplary neuroimaging of segmental callosal agenesis, in which the genu and splenium form despite the absence of the callosal body. This finding adds support to a newer theory of embryological callosal development where progression does not occur linearly in the rosto-caudal direction.

Near-pair patch generative adversarial network for data augmentation of focal pathology object detection models.

Purpose: The limited volume of medical training data remains one of the leading challenges for machine learning for diagnostic applications. Object detectors that identify and localize pathologies require training with a large volume of labeled images, which are often expensive and time-consuming to curate. To reduce this challenge, we present a method to support distant supervision of object detectors through generation of synthetic pathology-present labeled images. Approach: Our method employs the previously proposed cyclic generative adversarial network (cycleGAN) with two key innovations: (1) use of "near-pair" pathology-present regions and pathology-absent regions from similar locations in the same subject for training and (2) the addition of a realism metric (Fréchet inception distance) to the generator loss term. We trained and tested this method with 2800 fracture-present and 2800 fracture-absent image patches from 704 unique pediatric chest radiographs. The trained model was then used to generate synthetic pathology-present images with exact knowledge of location (labels) of the pathology. These synthetic images provided an augmented training set for an object detector. Results: In an observer study, four pediatric radiologists used a five-point Likert scale indicating the likelihood of a real fracture (1 = definitely not a fracture and 5 = definitely a fracture) to grade a set of real fracture-absent, real fracture-present, and synthetic fracture-present images. The real fracture-absent images scored 1.7±1.0, real fracture-present images 4.1±1.2, and synthetic fracture-present images 2.5±1.2. An object detector model (YOLOv5) trained on a mix of 500 real and 500 synthetic radiographs performed with a recall of 0.57±0.05 and an F2 score of 0.59±0.05. In comparison, when trained on only 500 real radiographs, the recall and F2 score were 0.49±0.06 and 0.53±0.06, respectively. Conclusions: Our proposed method generates visually realistic pathology and that provided improved object detector performance for the task of rib fracture detection.

High sensitivity methods for automated rib fracture detection in pediatric radiographs.

Rib fractures are highly predictive of non-accidental trauma in children under 3 years old. Rib fracture detection in pediatric radiographs is challenging because fractures can be obliquely oriented to the imaging detector, obfuscated by other structures, incomplete, and non-displaced. Prior studies have shown up to two-thirds of rib fractures may be missed during initial interpretation. In this paper, we implemented methods for improving the sensitivity (i.e. recall) performance for detecting and localizing rib fractures in pediatric chest radiographs to help augment performance of radiology interpretation. These methods adapted two convolutional neural network (CNN) architectures, RetinaNet and YOLOv5, and our previously proposed decision scheme, "avalanche decision", that dynamically reduces the acceptance threshold for proposed regions in each image. Additionally, we present contributions of using multiple image pre-processing and model ensembling techniques. Using a custom dataset of 1109 pediatric chest radiographs manually labeled by seven pediatric radiologists, we performed 10-fold cross-validation and reported detection performance using several metrics, including F2 score which summarizes precision and recall for high-sensitivity tasks. Our best performing model used three ensembled YOLOv5 models with varied input processing and an avalanche decision scheme, achieving an F2 score of 0.725 ± 0.012. Expert inter-reader performance yielded an F2 score of 0.732. Results demonstrate that our combination of sensitivity-driving methods provides object detector performance approaching the capabilities of expert human readers, suggesting that these methods may provide a viable approach to identify all rib fractures.

Molecular-guided therapy for the treatment of patients with relapsed and refractory childhood cancers: a Beat Childhood Cancer Research Consortium trial.

BACKGROUND: Children with relapsed central nervous system (CNS tumors), neuroblastoma, sarcomas, and other rare solid tumors face poor outcomes. This prospective clinical trial examined the feasibility of combining genomic and transcriptomic profiling of tumor samples with a molecular tumor board (MTB) approach to make real­time treatment decisions for children with relapsed/refractory solid tumors. METHODS: Subjects were divided into three strata: stratum 1-relapsed/refractory neuroblastoma; stratum 2-relapsed/refractory CNS tumors; and stratum 3-relapsed/refractory rare solid tumors. Tumor samples were sent for tumor/normal whole-exome (WES) and tumor whole-transcriptome (WTS) sequencing, and the genomic data were used in a multi-institutional MTB to make real­time treatment decisions. The MTB recommended plan allowed for a combination of up to 4 agents. Feasibility was measured by time to completion of genomic sequencing, MTB review and initiation of treatment. Response was assessed after every two cycles using Response Evaluation Criteria in Solid Tumors (RECIST). Patient clinical benefit was calculated by the sum of the CR, PR, SD, and NED subjects divided by the sum of complete response (CR), partial response (PR), stable disease (SD), no evidence of disease (NED), and progressive disease (PD) subjects. Grade 3 and higher related and unexpected adverse events (AEs) were tabulated for safety evaluation. RESULTS: A total of 186 eligible patients were enrolled with 144 evaluable for safety and 124 evaluable for response. The average number of days from biopsy to initiation of the MTB-recommended combination therapy was 38 days. Patient benefit was exhibited in 65% of all subjects, 67% of neuroblastoma subjects, 73% of CNS tumor subjects, and 60% of rare tumor subjects. There was little associated toxicity above that expected for the MGT drugs used during this trial, suggestive of the safety of utilizing this method of selecting combination targeted therapy. CONCLUSIONS: This trial demonstrated the feasibility, safety, and efficacy of a comprehensive sequencing model to guide personalized therapy for patients with any relapsed/refractory solid malignancy. Personalized therapy was well tolerated, and the clinical benefit rate of 65% in these heavily pretreated populations suggests that this treatment strategy could be an effective option for relapsed and refractory pediatric cancers. TRIAL REGISTRATION: ClinicalTrials.gov, NCT02162732. Prospectively registered on June 11, 2014.

Rate of and factors affecting sonographic visualization of the appendix in asymptomatic children.

Reported sonographic visualization rates of the appendix in children are variable. Visualization rates may be affected by patient's age and various patients' physical characteristics. The purpose of this study is to determine the frequency of sonographic visualization of the appendix by pediatric sonographers, to assess factors that may affect visualization of the appendix, and to define the characteristics of the appendix and periappendiceal region in asymptomatic children. Asymptomatic children between the ages of 2 and 18 were prospectively enrolled and evaluated for 15 min by pediatric sonographers. Of the 123 patients, the entire appendix was seen in 68 patients (55.2 %) and at least partially visualized in an additional 14 for a total of 82 patients (66.7 %). Visualization rate was not affected by body mass index, age, or gender. Appendiceal characteristics and periappendiceal findings were similar to previously published data. The average time required to initially detect the appendix was 275.2 + 211.3 s.

Association of Abnormal Findings on Neonatal Cranial Ultrasound With Neurobehavior at Neonatal Intensive Care Unit Discharge in Infants Born Before 30 Weeks' Gestation.

Importance: Cranial ultrasound (CUS) findings are routinely used to identify preterm infants at risk for impaired neurodevelopment, and neurobehavioral examinations provide information about early brain function. The associations of abnormal findings on early and late CUS with neurobehavior at neonatal intensive care unit (NICU) discharge have not been reported. Objective: To examine the associations between early and late CUS findings and infant neurobehavior at NICU discharge. Design, Setting, and Participants: This prospective cohort study included infants enrolled in the Neonatal Neurobehavior and Outcomes in Very Preterm Infants Study between April 2014 and June 2016. Infants born before 30 weeks' gestational age were included. Exclusion criteria were maternal age younger than 18 years, maternal cognitive impairment, maternal inability to read or speak English or Spanish, maternal death, and major congenital anomalies. Overall, 704 infants were enrolled. The study was conducted at 9 university-affiliated NICUs in Providence, Rhode Island; Grand Rapids, Michigan; Kansas City, Missouri; Honolulu, Hawaii; Winston-Salem, North Carolina; and Torrance and Long Beach, California. Data were analyzed from September 2019 to September 2021. Exposures: Early CUS was performed at 3 to 14 days after birth and late CUS at 36 weeks' postmenstrual age or NICU discharge. Abnormal findings were identified by consensus of standardized radiologists' readings. Main Outcomes and Measures: Neurobehavioral examination was performed using the NICU Network Neurobehavioral Scale (NNNS). Results: Among the 704 infants enrolled, 675 had both CUS and NNNS data (135 [20.0%] Black; 368 [54.5%] minority race or ethnicity; 339 [50.2%] White; 376 [55.7%] male; mean [SD] postmenstrual age, 27.0 [1.9] weeks). After covariate adjustment, lower attention (adjusted mean difference, -0.346; 95% CI, -0.609 to -0.083), hypotonicity (mean difference, 0.358; 95% CI, 0.055 to 0.662), and poorer quality of movement (mean difference, -0.344; 95% CI, -0.572 to -0.116) were observed in infants with white matter damage (WMD). Lower attention (mean difference, -0.233; 95% CI, -0.423 to -0.044) and hypotonicity (mean difference, 0.240; 95% CI, 0.014 to 0.465) were observed in infants with early CUS lesions. Conclusions and Relevance: In this cohort study of preterm infants, certain early CUS lesions were associated with hypotonicity and lower attention around term-equivalent age. WMD was associated with poor attention, hypotonicity, and poor quality of movement. Infants with these CUS lesions might benefit from targeted interventions to improve neurobehavioral outcomes during their NICU hospitalization.

Pediatric craniocervical junction injuries.

OBJECTIVE: The purpose of this article is to review pediatric craniocervical junction injuries in the context of embryology, developmental anatomy, and biomechanics. CONCLUSION: The craniocervical junction is functionally and developmentally distinct from the rest of the spine, and mechanistic models often fail to explain these injuries. Various developmental features and complex anatomy likely contribute to injury in this region in children. Some of the injury patterns at the craniocervical junction in children are similar to adults, but many are unique.

Ossification patterns of the atlas vertebra.

OBJECTIVE: The objective of this study was to characterize ossification patterns of the C1 (atlas) vertebra in children, to better differentiate normal variants from traumatic injury. MATERIALS AND METHODS: A retrospective review of all sinus and temporal bone CT examinations was performed for the period of 2002-2009. Patients 96 months old or younger for whom C1 level was at least partially imaged were included. Patients with a history of trauma or genetic disorder-associated spinal abnormalities were excluded. RESULTS: A total of 1270 CT examinations were reviewed. The anterior arch of C1 was completely imaged in 841 patients (66%), and the posterior arch was completely imaged in 378 patients (30%). Multiple anterior arch ossification centers were observed in 179 of 841 patients (21%), and posterior arch variants were present in nine of 378 patients (2%). At least partial ossification of the anterior arch was seen in 113 of 147 children (77%) younger than 25 months, whereas only 14 of the remaining 694 children (2%) older than 24 months failed to show any ossification. Incomplete ossification of the anterior arch was noted in 47 of 103 patients (46%) in the 85-96-month-old category. The posterior arches were at least partially ossified in all children. Incomplete fusion of the posterior synchondrosis was seen in 17 of 108 patients (16%) older than 60 months. CONCLUSION: C1 ossification patterns and timing of synchondrosis fusion are variable. Knowledge of these patterns is important to better differentiate a normal variant from traumatic injury.

Pediatric lateral atlantodental interval: how much asymmetry is normal?

Imaging of the cervical spine is commonly performed in the pediatric patient population, typically after trauma, as well as for a variety of nontraumatic reasons. There are many challenges in the interpretation of these studies, particularly at the level of the atlantoaxial joint. We recognized a particular problem with assessing the lateral atlantodental interval in our emergency radiology department. Mild lateral atlantodental interval asymmetry in relatively asymptomatic patients was being interpreted as indicative of atlantoaxial rotatory fixation, which leads to the recommendation for dynamic computed tomographic examinations. The goal of this study was to define the reference range of the lateral atlantodental interval in pediatric patients to help avoid misinterpretation of radiographic findings and resultant excessive imaging.

Relationship between the clinical characteristics of osteomyelitis and the finding of extraosseous fat on MRI in pediatric patients.

BACKGROUND: MRI is frequently utilized to evaluate patients for osteomyelitis. The findings of intramedullary and extramedullary fat globules as well as extramedullary fat-fluid levels can help improve the specificity of MRI for this diagnosis. OBJECTIVE: To correlate these MRI findings with the clinical characteristics in children with osteomyelitis. MATERIALS AND METHODS: A retrospective electronic medical record search for pediatric patient charts from March 2004 to November 2009 that contained the word "osteomyelitis" in the "principal diagnosis" portion of the international classification of disease (ICD) billing code. Each electronic chart was reviewed. MRI examinations of selected children were reviewed by a pediatric radiologist, a general radiologist and a transitional year resident. RESULTS: A total of 10 patients/11 MRI studies were included. Five of the 11 had the MRI finding of extramedullary globular fat signal. There was a significantly increased likelihood of seeing this finding in children of pubertal or postpubertal age compared to those of prepubertal age (p < 0.05). CONCLUSION: This study provides evidence that the MRI finding of extramedullary fat globules in children with acute osteomyelitis is associated with the clinical characteristic of being within or above the age range for puberty.

Repurposing eflornithine to treat a patient with a rare ODC1 gain-of-function variant disease.

Background: Polyamine levels are intricately controlled by biosynthetic, catabolic enzymes and antizymes. The complexity suggests that minute alterations in levels lead to profound abnormalities. We described the therapeutic course for a rare syndrome diagnosed by whole exome sequencing caused by gain-of-function variants in the C-terminus of ornithine decarboxylase (ODC), characterized by neurological deficits and alopecia. Methods: N-acetylputrescine levels with other metabolites were measured using ultra-performance liquid chromatography paired with mass spectrometry and Z-scores established against a reference cohort of 866 children. Results: From previous studies and metabolic profiles, eflornithine was identified as potentially beneficial with therapy initiated on FDA approval. Eflornithine normalized polyamine levels without disrupting other pathways. She demonstrated remarkable improvement in both neurological symptoms and cortical architecture. She gained fine motor skills with the capacity to feed herself and sit with support. Conclusions: This work highlights the strategy of repurposing drugs to treat a rare disease. Funding: No external funding was received for this work.

Rate and associations of epididymal cysts on pediatric scrotal ultrasound.

PURPOSE: We established the baseline occurrence of epididymal cysts, and the correlation between epididymal cysts and testicular size. MATERIALS AND METHODS: We retrospectively reviewed all pediatric scrotal ultrasounds done at our institution in 8 years. We analyzed the proportion of cysts by patient age and compared testicular size in boys with vs without epididymal cysts. RESULTS: Of all patients 14.4% had epididymal cysts. The cyst incidence increased with age, ie 35.3% of boys older than 15 years had cysts. Boys with epididymal cysts had larger testes than boys without cysts regardless of side or age (p <0.001). CONCLUSIONS: Epididymal cysts are more common in older boys. Boys with epididymal cysts had larger testes than boys without cysts.

Cervical spine injuries in pediatrics: are children small adults or not?

Diagnosis of cervical spine injuries is crucial whether in children or adults. It is necessary to understand the injuries unique to the developing spine. Equally important is an insight to similarities in injury patterns between adults and children.