The clinical and genetic spectrum of inherited glycosylphosphatidylinositol deficiency disorders.

Inherited glycosylphosphatidylinositol deficiency disorders (IGDs) are a group of rare multisystem disorders arising from pathogenic variants in glycosylphosphatidylinositol anchor pathway (GPI-AP) genes. Despite associating 24 of at least 31 GPI-AP genes with human neurogenetic disease, prior reports are limited to single genes without consideration of the GPI-AP as a whole and with limited natural history data. In this multinational retrospective observational study, we systematically analyse the molecular spectrum, phenotypic characteristics, and natural history of 83 individuals from 75 unique families with IGDs, including 70 newly reported individuals: the largest single cohort to date. Core clinical features were developmental delay or intellectual disability (DD/ID, 90%), seizures (83%), hypotonia (72%), and motor symptoms (64%). Prognostic and biologically significant neuroimaging features included cerebral atrophy (75%), cerebellar atrophy (60%), callosal anomalies (57%), and symmetric restricted diffusion of the central tegmental tracts (60%). Sixty-one individuals had multisystem involvement including gastrointestinal (66%), cardiac (19%), and renal (14%) anomalies. Though dysmorphic features were appreciated in 82%, no single dysmorphic feature had a prevalence >30%, indicating substantial phenotypic heterogeneity. Follow-up data were available for all individuals, 15 of whom were deceased at the time of writing. Median age at seizure onset was 6 months. Individuals with variants in synthesis stage genes of the GPI-AP exhibited a significantly shorter time to seizure onset than individuals with variants in transamidase and remodelling stage genes of the GPI-AP (P=0.046). Forty individuals had intractable epilepsy. The majority of individuals experienced delayed or absent speech (95%); motor delay with non-ambulance (64%); and severe-to-profound DD/ID (59%). Individuals with a developmental epileptic encephalopathy (51%) were at greater risk of intractable epilepsy (P=0.003), non-ambulance (P=0.035), ongoing enteral feeds (P<0.001), and cortical visual impairment (P=0.007). Serial neuroimaging showed progressive cerebral volume loss in 87.5% and progressive cerebellar atrophy in 70.8%, indicating a neurodegenerative process. Genetic analyses identified 93 unique variants (106 total), including 22 novel variants. Exploratory analyses of genotype-phenotype correlations using unsupervised hierarchical clustering identified novel genotypic predictors of clinical phenotype and long-term outcome with meaningful implications for management. In summary, we expand both the mild and severe phenotypic extremities of the IGDs; provide insights into their neurological basis; and, vitally, enable meaningful genetic counselling for affected individuals and their families.

International Consensus Statement on the Radiological Evaluation of Dysraphic Malformations of the Spine and Spinal Cord.

Dysraphic malformations of the spine and spinal cord (DMSSC) represent a spectrum of common congenital anomalies typically (though not exclusively) affecting the lower spinal segments. These may be responsible for varying degrees of neurologic, orthopedic, and urologic morbidity. With advances in neuroimaging, it is now possible to better diagnose and evaluate these disorders both prenatally and postnatally. Neuroimaging, performed at the right time and with technique optimization, is integral in guiding clinical management. However, the terminology used to describe these lesions has become increasingly confusing, and there is a lack of consensus regarding the essential radiologic features and their clinical weighting. This variability in radiologic practice risks unstructured decision making and increases the likelihood of suboptimal, less informed clinical management. In this manuscript, the first of a series of consensus statements, we outline a standardized international consensus statement for the radiologic evaluation of children with suspected DMSSC derived from a critical review of the literature, and the collective clinical experience of a multinational group of experts. We provide recommendations for plain radiography, sonography, CT, and MR imaging in the evaluation of DMSSC with an emphasis on technique of imaging and imaging protocols.

International Consensus Statement on the Radiological Screening of Contact Children in the Context of Suspected Child Physical Abuse.

Importance: Physical abuse is a common but preventable cause of long-term childhood morbidity and mortality. Despite the strong association between abuse in an index child and abuse in contact children, there is no guidance outlining how to screen the latter, significantly more vulnerable group, for abusive injuries. Consequently, the radiological assessment of contact children is often omitted, or variably performed, allowing occult injuries to go undetected and increasing the risk of further abuse. Objective: To report an evidence-based and consensus-derived set of best practices for the radiological screening of contact children in the context of suspected child physical abuse. Evidence Review: This consensus statement is supported by a systematic review of the literature and the clinical opinion of an internationally recognized group of 26 experts. The modified Delphi consensus process comprised 3 meetings of the International Consensus Group on Contact Screening in Suspected Child Physical Abuse held between February and June 2021. Findings: Contacts are defined as the asymptomatic siblings, cohabiting children, or children under the same care as an index child with suspected child physical abuse. All contact children should undergo a thorough physical examination and a history elicited prior to imaging. Contact children younger than 12 months should have neuroimaging, the preferred modality for which is magnetic resonance imaging, and skeletal survey. Contact children aged 12 to 24 months should undergo skeletal survey. No routine imaging is indicated in asymptomatic children older than 24 months. Follow-up skeletal survey with limited views should be performed if abnormal or equivocal at presentation. Contacts with positive findings should be investigated as an index child. Conclusions and Relevance: This Special Communication reports consensus recommendations for the radiological screening of contact children in the context of suspected child physical abuse, establishing a recognized baseline for the stringent evaluation of these at-risk children and providing clinicians with a more resilient platform from which to advocate for them.

Thromboembolic toxicity observed with concurrent trametinib and lenalidomide therapy.

The event-free survival of pediatric low-grade gliomas is poor, and patients often require multiple treatment strategies. While MEK and RAF inhibitors are efficacious in early-phase trials, not all patients respond, and many experience progression following completion of therapy. Evaluating combination therapies that may enhance efficacy or prolong disease stabilization is warranted. We report our institutional experience using concurrent trametinib and lenalidomide in the treatment of primary pediatric central and peripheral nervous system tumors. Two of four patients using this combination therapy experienced severe thromboembolic events, necessitating discontinuation of therapy. This combination requires further investigation, and we urge caution if used.

Response assessment in pediatric craniopharyngioma: recommendations from the Response Assessment in Pediatric Neuro-Oncology (RAPNO) Working Group.

BACKGROUND: Craniopharyngioma is a histologically benign tumor of the suprasellar region for which survival is excellent but quality of life is often poor secondary to functional deficits from tumor and treatment. Standard therapy consists of maximal safe resection with or without radiation therapy. Few prospective trials have been performed, and response assessment has not been standardized. METHODS: The Response Assessment in Pediatric Neuro-Oncology (RAPNO) committee devised consensus guidelines to assess craniopharyngioma response prospectively. RESULTS: Magnetic resonance imaging is the recommended radiologic modality for baseline and follow-up assessments. Radiologic response is defined by 2-dimensional measurements of both solid and cystic tumor components. In certain clinical contexts, response to solid and cystic disease may be differentially considered based on their unique natural histories and responses to treatment. Importantly, the committee incorporated functional endpoints related to neuro-endocrine and visual assessments into craniopharyngioma response definitions. In most circumstances, the cystic disease should be considered progressive only if growth is associated with acute, new-onset or progressive functional impairment. CONCLUSIONS: Craniopharyngioma is a common pediatric central nervous system tumor for which standardized response parameters have not been defined. A RAPNO committee devised guidelines for craniopharyngioma assessment to uniformly define response in future prospective trials.

Early outcomes of a myofascial repair technique for fetal myelomeningocele.

PURPOSE: Fetal repair of myelomeningocele (MMC) and myeloschisis leads to improved neurologic outcomes compared to postnatal repair, but the effects of modifications in closure techniques have not been extensively studied. Previous work has suggested that a watertight repair is requisite for improvement in hindbrain herniation (HBH) and to decrease postnatal hydrocephalus (HCP). Our institution adopted the myofascial closure technique for open fetal MMC repair in July 2019, which we hypothesized would result in decreased need for patch closure, improved HBH, and decreased rate of surgically-treated HCP. METHODS: A single-center retrospective study of patients who underwent fetal MMC or myeloschisis repair between March 2013 and February 2022 was performed. Outcomes were evaluated (n = 70 prior to July 2019, n = 34 after July 2019). Statistical significance was determined by Fisher's exact and Chi square tests (p < 0.05 significant). RESULTS: Patients who underwent myofascial closure were less likely to require a patch for skin closure (14.7% vs 58.6%, p < 0.0001). Myofascial closure was also associated with an increased rate of HBH improvement on two-week postoperative fetal MRI (93.9% vs 65.7%, p = 0.002). Surgically-treated HCP at one year was lower in the myofascial closure group (n = 21), however this did not reach statistical significance (23.8% vs 41.9%, p = 0.19). CONCLUSIONS: We conclude that the myofascial closure technique for repair of fetal MMC and myeloschisis is associated with significantly decreased need for patch closure and improvement in hindbrain herniation compared to our previous skin closure technique. These results support a surgical approach that employs a multilayer watertight closure.

Prevalence of cerebral sinovenous thrombosis in abusive head trauma.

BACKGROUND: Cerebral sinovenous thrombosis (CSVT) has been proposed in legal settings to be an atraumatic mimic of abusive head trauma (AHT). OBJECTIVE: The objective of this study was to determine the prevalence of CSVT and subdural hemorrhage (SDH) in a large AHT population. MATERIALS AND METHODS: This retrospective cohort study measured the prevalence of CSVT and SDH on magnetic resonance venograms in 243 patients diagnosed with AHT at a single center. We also reported additional intra- and extracranial injuries, head injury severity and length of hospital stay. RESULTS: Among 243 patients diagnosed with AHT, 7% (16/243) had CSVT. SDH was present in 94% (15/16) of the CSVT cases. Cytotoxic edema and subarachnoid hemorrhage were in 88% (14/16) and 69% (11/16) of the CSVT cases, respectively. Extracranial signs of abuse were also in 100% (16/16) of the patients with CSVT. Critical to maximal head injury severity (abbreviated injury scale >=5) was in 75% (12/16) of the CSVT population vs. 33% (82/243) in the total AHT population. Length of hospital and pediatric intensive care unit stay was greater in those with CSVT (10 vs. 21.9 and 3.5 vs. 7.3 days). CONCLUSION: These findings suggest that CSVT is uncommon in AHT and is associated with additional traumatic injuries and greater injury severity.

ACR Appropriateness Criteria® Ataxia-Child.

Childhood ataxia may be due to multifactorial causes of impairment in the coordination of movement and balance. Acutely presenting ataxia in children may be due to infectious, inflammatory, toxic, ischemic, or traumatic etiology. Intermittent or episodic ataxia in children may be manifestations of migraine, benign positional vertigo, or intermittent metabolic disorders. Nonprogressive childhood ataxia suggests a congenital brain malformation or early prenatal or perinatal brain injury, and progressive childhood ataxia indicates inherited causes or acquired posterior fossa lesions that result in gradual cerebellar dysfunction. CT and MRI of the central nervous system are the usual modalities used in imaging children presenting with ataxia, based on the clinical presentation. This document provides initial imaging guidelines for a child presenting with acute ataxia with or without a history of recent trauma, recurrent ataxia with interval normal neurological examination, chronic progressive ataxia, and chronic nonprogressive ataxia. The ACR Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision process support the systematic analysis of the medical literature from peer reviewed journals. Established methodology principles such as Grading of Recommendations Assessment, Development, and Evaluation or GRADE are adapted to evaluate the evidence. The RAND/UCLA Appropriateness Method User Manual provides the methodology to determine the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances in which peer reviewed literature is lacking or equivocal, experts may be the primary evidentiary source available to formulate a recommendation.

Perinatal Ischemic Stroke: Etiology and Imaging.

Perinatal ischemic stroke is a common cause of lifelong disability.

Imaging of Macrocephaly.

Macrocephaly is a common diagnosis in the pediatric population, particularly in the infantile time period. There is a wide range of causes of macrocephaly, from benign to malignant, for which imaging plays a key role in the diagnosis and clinical guidance. Our aim is to review the distinct and prevalent neuroimaging findings in the evaluation of the macrocephalic infant.

Torcular Dural Sinus Malformation: Fetal and Postnatal Imaging Findings and Their Associations With Clinical Outcomes.

BACKGROUND: Torcular dural sinus malformations (tDSMs) are rare vascular malformations that present in fetuses and infants. Existing data on prognostic imaging features, as well as the associated morbidity and mortality, are limited and variable. We therefore reviewed cases of tDSMs diagnosed on fetal magnetic resonance imaging (MRI) at our referral center to identify pre- and postnatal MRI imaging features associated with long-term outcomes. METHODS: We searched our imaging database for fetal and postnatal MRI reports of tDSM cases. The electronic medical record was then reviewed for pre- and postnatal clinical data, including follow-up imaging. Neurological outcomes were characterized using the previously reported scale based on the Bicêtre Score. Imaging features association with outcome scores were compared using the Fisher exact test. RESULTS: Sixteen cases of tDMS diagnosed by fetal MRI with postnatal clinical follow-up were identified, 11 of whom underwent postnatal MRI. The majority of cases of tDSM (73%) decreased in size or resolved on postnatal follow-up study without treatment. Restricted diffusion and parenchymal hemorrhage on fetal MRI were the only imaging features identified significantly associated with unfavorable neurological outcome or death, present in two patients with poor outcomes (two of two) and only one with a normal outcome (one of 14) (P = 0.025). CONCLUSIONS: Findings of tDSM on fetal MRI most often regress and/or resolve with normal or mild neurological outcomes, with the most significant predictor of poor outcome being the presence of parenchymal injury on fetal MRI. In addition, a subset will present with venolymphatic malformations.

Visualization of the Anal Dimple by Fetal MRI: Is It Feasible?

INTRODUCTION: The aim of this study was to determine the feasibility of fetal MRI in identifying the normal anal dimple (AD) and compare it with prenatal ultrasound (US). METHODS: Retrospective review of 130 patients with both fetal MRI and US. The gestational age (GA) was stratified into four groups: (1) 16 to 21 weeks-6 days; (2) 22 to 27 weeks-6 days; (3) 28 to 33 weeks-6 days; and (4) 34 weeks and beyond. Steady-state free precession (SSFP) and single shot fast spin echo (SSFSE) axial T2 MRI and transverse US images of the fetal perineum were analyzed, and visualization of the AD was determined. Clinical indication, gender, single versus multiple gestation, best MRI sequence where it was seen, and postnatal AD information were recorded. RESULTS: The AD was visualized in 125/130 fetal MRIs, and visualization was independent of GA (p 0.230). US visualized the AD in 67/130 cases, and the best GA for visualization was in group 3 (p < 0.001). There was no difference in AD visualization between SSFSE and SSFP sequences (p 0.167). CONCLUSION: Prenatal visualization of the AD by MRI is feasible and superior to US, independent of GA. Adding AD visualization to routine screening prenatal US and MRI may increase recognition of anorectal malformation.

Response assessment in paediatric intracranial ependymoma: recommendations from the Response Assessment in Pediatric Neuro-Oncology (RAPNO) working group.

Response criteria for paediatric intracranial ependymoma vary historically and across different international cooperative groups. The Response Assessment in the Pediatric Neuro-Oncology (RAPNO) working group, consisting of an international panel of paediatric and adult neuro-oncologists, neuro-radiologists, radiation oncologists, and neurosurgeons, was established to address both the issues and the unique challenges in assessing the response in children with CNS tumours. We established a subcommittee to develop response assessment criteria for paediatric ependymoma. Current practice and literature were reviewed to identify major challenges in assessing the response of paediatric ependymoma to clinical trial therapy. For areas in which data were scarce or unavailable, consensus was reached through an iterative process. RAPNO response assessment recommendations include assessing disease response on the basis of changes in tumour volume, and using event-free survival as a study endpoint for patients entering clinical trials without bulky disease. Our recommendations for response assessment include the use of brain and spine MRI, cerebral spinal fluid cytology, neurological examination, and steroid use. Baseline postoperative imaging to assess for residual tumour should be obtained 24-48 h after surgery. Our consensus recommendations and response definitions should be prospectively validated in clinical trials.

Isolated lesions of the suprasternal notch in pediatric patients.

BACKGROUND: Palpable masses of the head and neck are a common indication for imaging in the pediatric population. Midline lesions of the infrahyoid neck, particularly lesions isolated to the suprasternal notch, are not well studied. OBJECTIVE: To delineate the histopathological and imaging spectrum of masses that occur within and isolated to the suprasternal notch. MATERIALS AND METHODS: A retrospective study was performed to identify patients with an isolated lesion of the suprasternal notch that had available pathological diagnoses. Available imaging was reviewed and characterized by fellowship-trained pediatric radiologists and compared by descriptive statistics to the final pathological diagnoses. RESULTS: Eighteen masses isolated to the suprasternal notch with available pathological diagnoses were identified. Of these, congenital epithelial inclusion cysts were diagnosed in 14 patients (77.8%) with dermoid cysts comprising 11 of those (61.1%) and epidermoid cysts accounting for 3 (16.7%). The most common imaging appearance was a cystic or pseudosolid appearance without vascularity. CONCLUSIONS: Isolated resected lesions of the suprasternal notch in pediatric patients are most frequently dermoid/epidermoid cysts, with a differential diagnosis including other less common entities.

Improved prediction of postoperative pediatric cerebellar mutism syndrome using an artificial neural network.

BACKGROUND: Postoperative pediatric cerebellar mutism syndrome (pCMS) is a common but severe complication that may arise following the resection of posterior fossa tumors in children. Two previous studies have aimed to preoperatively predict pCMS, with varying results. In this work, we examine the generalization of these models and determine if pCMS can be predicted more accurately using an artificial neural network (ANN). METHODS: An overview of reviews was performed to identify risk factors for pCMS, and a retrospective dataset was collected as per these defined risk factors from children undergoing resection of primary posterior fossa tumors. The ANN was trained on this dataset and its performance was evaluated in comparison to logistic regression and other predictive indices via analysis of receiver operator characteristic curves. The area under the curve (AUC) and accuracy were calculated and compared using a Wilcoxon signed-rank test, with P < .05 considered statistically significant. RESULTS: Two hundred and four children were included, of whom 80 developed pCMS. The performance of the ANN (AUC 0.949; accuracy 90.9%) exceeded that of logistic regression (P < .05) and both external models (P < .001). CONCLUSION: Using an ANN, we show improved prediction of pCMS in comparison to previous models and conventional methods.

Novel clinical algorithm for hypothalamic obesity in youth with brain tumours and factors associated with excess weight gain.

BACKGROUND: A standardized approach for identifying and treating hypothalamic obesity (HO) in children with hypothalamic tumours is lacking. OBJECTIVES: To describe children with hypothalamic tumours at risk for obesity, assess outcomes of a novel HO clinical algorithm, and identify factors associated with weight gain. METHODS: Retrospective analysis of youth with hypothalamic and suprasellar tumours, seen at a paediatric tertiary care centre from 2010 to 2020. RESULTS: The study cohort (n = 130, 50% female, median age at diagnosis 5 [range 0-17]y) had a median duration of follow up of 5 (0.03-17)y. At last recorded body mass index (BMI) measurement, 34% had obesity, including 17% with severe obesity. Median onset of overweight and obesity after diagnosis was 6.2 (0.3-134) and 8.9 (0.7-65) months, respectively. After algorithm implementation (n = 13), the proportion that had an early dietitian visit (within 6 months) increased from 36% to 54%, (p = 0.498) and weight management referrals increased from 51% to 83% (p = 0.286). Higher BMI z-score at diagnosis was associated with overweight and obesity development (p < 0.001). CONCLUSION: Patients with hypothalamic tumours commonly develop obesity. Use of a clinical algorithm may expedite recognition of HO. Further research is needed to identify predictors of weight gain and to develop effective treatment.

Methionine synthase deficiency: Variable clinical presentation and benefit of early diagnosis and treatment.

Methionine synthase deficiency (cblG complementation group) is a rare inborn error of metabolism affecting the homocysteine re-methylation pathway. It leads to a biochemical phenotype of hyperhomocysteinemia and hypomethioninemia. The clinical presentation of cblG is variable, ranging from seizures, encephalopathy, macrocytic anemia, hypotonia, and feeding difficulties in the neonatal period to onset of psychiatric symptoms or acute neurologic changes in adolescence or adulthood. Given the variable and nonspecific symptoms seen in cblG, the diagnosis of affected patients is often delayed. Medical management of cblG includes the use of hydroxocobalamin, betaine, folinic acid, and in some cases methionine supplementation. Treatment has been shown to lead to improvement in the biochemical profile of affected patients, with lowering of total homocysteine levels and increasing methionine levels. However, the published literature contains differing conclusions on whether treatment is effective in changing the natural history of the disease. Herein, we present five patients with cblG who have shown substantial clinical benefit from treatment with objective improvement in their neurologic outcomes. We demonstrate more favorable outcomes in our patients who were treated early in life, especially those who were treated before neurologic symptoms manifested. Given improved outcomes from treatment of presymptomatic patients, cblG warrants inclusion in newborn screening.

ACR Appropriateness Criteria® Seizures-Child.

In children, seizures represent an extremely heterogeneous group of medical conditions ranging from benign cases, such as a simple febrile seizure, to life-threatening situations, such as status epilepticus. Underlying causes of seizures also represent a wide range of pathologies from idiopathic cases, usually genetic, to a variety of acute and chronic intracranial or systemic abnormalities. This document discusses appropriate utilization of neuroimaging tests in a child with seizures. The clinical scenarios in this document take into consideration different circumstances at the time of a child's presentation including the patient's age, precipitating event (if any), and clinical and electroencephalogram findings and include neonatal seizures, simple and complex febrile seizures, post-traumatic seizures, focal seizures, primary generalized seizures in a neurologically normal child, and generalized seizures in neurologically abnormal child. This practical approach aims to guide clinicians in clinical decision-making and to help identify efficient and appropriate imaging workup. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision include an extensive analysis of current medical literature from peer reviewed journals and the application of well-established methodologies (RAND/UCLA Appropriateness Method and Grading of Recommendations Assessment, Development, and Evaluation or GRADE) to rate the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where evidence is lacking or equivocal, expert opinion may supplement the available evidence to recommend imaging or treatment.

Neuroimaging of retinal hemorrhage utilizing adjunct orbital susceptibility-weighted imaging.

Retinal hemorrhages are an integral part of the evaluation of abusive head trauma (AHT). Timely detection of retinal hemorrhage not only facilitates the diagnosis of AHT, but has the potential to prevent further abuse to the child and the siblings and to identify the abuser. The gold standard for diagnosing retinal hemorrhage is a dilated fundoscopy exam, which requires pharmacological dilation. As such, there is a small percentage of patients for whom the dilated fundoscopy exam might be delayed. Evolving literature suggests that MRI, specifically susceptibility-weighted imaging (SWI), of the orbits might provide an alternative diagnostic tool for noninvasively detecting retinal hemorrhages, particularly when there is a delay in administering the dilated fundoscopy exam. In this paper we review the utility of SWI for detecting retinal hemorrhages in abusive head trauma, including discussion of diagnostic limitations and future research.

Visualization of the fetal anus by prenatal ultrasound for the diagnosis of anorectal malformations: is it feasible?

PURPOSE: The goal of this study was to determine the feasibility of identifying the anal dimple (AD) on routine prenatal ultrasound. Using the presence, absence, appearance, and location of the anal dimple as an indirect sign for possible underlying anorectal malformations (ARM), we hypothesize that evaluation of the anal dimple as part of the fetal anatomic survey may increase the sensitivity in detecting less severe ARMs. METHODS: In a prospective longitudinal observational study, pregnant women who underwent prenatal ultrasound (US) at the Colorado Fetal Care Center between January 2019 and 2020 were enrolled. The variables recorded included gestational age, singleton versus multiple pregnancy, gender of the fetus, visualization of the AD, and reason for non-visualization of the AD. RESULTS: A total of 900 ultrasounds were performed, evaluating 1044 fetuses, in 372 different pregnant women. Gestational ages ranged from 16 to 38 weeks. The AD was visualized in 612 fetuses (58.6%) and not seen in 432 (41.4%). The two most common reasons for non-visualization were extremes in gestational age (n = 155; 36%) and fetal position (n = 152; 35.3%). The optimal gestational age range for AD visualization was 28-33 weeks + 6 days, with 78.1% visualization rate. CONCLUSION: Visualization of the anal dimple by ultrasound is feasible and may aid in the detection of less severe ARMs, ultimately impacting pregnancy management and family counseling. The optimal timing for anal dimple visualization is late second and third trimester.