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.

Two-Center Review of Posterior Vault Expansion following a Staged or Expectant Treatment of Crouzon and Apert Craniosynostosis.

BACKGROUND: The timing of posterior cranial expansion for the management of intracranial pressure can be "staged" by age and dysmorphology or "expectant" by pressure monitoring. The authors report shared outcome measures from one center performing posterior vault remodeling (PCVR) or distraction (PVDO) following a staged approach and another performing spring-assisted expansion (SAPVE) following an expectant protocol. METHODS: Apert or Crouzon syndrome patients who underwent posterior expansion younger than 2 years were included. Perioperative outcomes and subsequent cranial operations were recorded up to last follow-up and intracranial volume changes measured and adjusted using growth curves. RESULTS: Thirty-eight patients were included. Following the expectant protocol, Apert patients underwent SAPVE at a younger age (8 months) than Crouzon patients (16 months). The initial surgery time was shorter but total operative time, including device removal, was longer for PVDO (3 hours 52 minutes) and SAPVE (4 hours 34 minutes) than for PCVR (3 hours 24 minutes). Growth-adjusted volume increase was significant and comparable. Fourteen percent of PCVR, 33% of PVDO, and 11% of SAPVE cases had complications, but without long-term deficits. Following the staged approach, 5% underwent only PVDO, 85% had a staged posterior followed by anterior surgery, and 10% required a third expansion. Following the expectant approach, 42% of patients had only posterior expansion at last follow-up, 32% had a secondary cranial surgery, and 26% had a third cranial expansion. CONCLUSION: Two approaches involving posterior vault expansion in young syndromic patients using three techniques resulted in comparable early volume expansion and complication profiles. CLINICAL QUESTION/LEVEL OF EVIDENCE: Therapeutic, III.

An algorithmic clinicoradiological approach to paediatric cranial vault lesions: distinguishing normal variants from pathologies.

Lesions of the paediatric cranial vault are diverse both in their presentation and aetiology. As such, they pose a diagnostic challenge to the paediatric neurosurgeon and neuroradiologist. In this article, we delineate the spectrum of paediatric calvarial pathology into four distinct groups: (1) lytic lesion(s); (2) focal sclerotic lesion(s); (3) diffuse cranial vault sclerosis; and (4) abnormal shape of the cranial vault. It is our aim that this more pragmatic, algorithmic approach may mitigate diagnostic uncertainty and aid the more accurate diagnosis of paediatric calvarial lesions.

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.

Diagnostic accuracy of qualitative MRI in 550 paediatric brain tumours: evaluating current practice in the computational era.

BACKGROUND: To investigate the accuracy of qualitative reporting of conventional magnetic resonance imaging (MRI) in the classification of paediatric brain tumours. METHODS: Preoperative MRI reports of 608 children prior to resection or biopsy of an intracranial lesion were retrospectively reviewed. A total of 550 children had complete radiological and histopathological notes, thereby reaching our inclusion criteria. Concordance between MRI report and final histopathological diagnosis was assessed using an established lexicon derived from the WHO 2016 classification of CNS tumours. Levels of agreement based on cellular origin, tumour type, and tumour grade were evaluated. Diagnostic accuracy, sensitivity, specificity, confidence intervals, and positive and negative predictive values were calculated. RESULTS: Diagnostic accuracy differed significantly between tumour types and tumour grades. Sensitivities were highest for ependymomas and sellar, pituitary, pineal, and cranial and/or paraspinal nerve tumours (range 80.65-100%). Sensitivity was slightly lower for astrocytic gliomas, oligodendrogliomas, and choroid plexus, neuronal, mixed neuronal-glial, embryonal, and histiocytic tumours (range 63.33-79.59%). Low sensitivities were noted for meningiomas and mesenchymal non-meningothelial, melanocytic, and germ cell tumours (range 0-56.25%). The most correct tumour type predictions were made in the posterior fossa whilst the most incorrect predictions were made in the lobar regions, pineal/tectal plate area, and the supratentorial ventricles. CONCLUSIONS: This is the largest published series investigating the predictive accuracy of MRI in paediatric brain tumours. We show that diagnostic accuracy varies greatly by tumour type and location. Looking forward, we should develop and leverage computational methods to improve accuracy in the tumour types and anatomical locations where qualitative diagnostic accuracy is lower.

Spring-assisted posterior vault expansion-a single-centre experience of 200 cases.

PURPOSE: Children affected by premature fusion of the cranial sutures due to craniosynostosis can present with raised intracranial pressure and (turri)brachycephalic head shapes that require surgical treatment. Spring-assisted posterior vault expansion (SA-PVE) is the surgical technique of choice at Great Ormond Street Hospital for Children (GOSH), London, UK. This study aims to report the SA-PVE clinical experience of GOSH to date. METHODS: A retrospective review was carried out including all SA-PVE cases performed at GOSH between 2008 and 2020. Demographic and clinical data were recorded including genetic diagnosis, craniofacial surgical history, surgical indication and assessment, age at time of surgery (spring insertion and removal), operative time, in-patient stay, blood transfusion requirements, additional/secondary (cranio)facial procedures, and complications. RESULTS: Between 2008 and 2020, 200 SA-PVEs were undertaken in 184 patients (61% male). The study population consisted of patients affected by syndromic (65%) and non-syndromic disorders. Concerns regarding raised intracranial pressure were the surgical driver in 75% of the cases, with the remainder operated for shape correction. Median age for SA-PVE was 19 months (range, 2-131). Average operative time for first SA-PVE was 150 min and 87 for spring removal. Median in-patient stay was 3 nights, and 88 patients received a mean of 204.4 ml of blood transfusion at time of spring insertion. A single SA-PVE sufficed in 156 patients (85%) to date (26 springs still in situ at time of this analysis); 16 patients underwent repeat SA-PVE, whilst 12 underwent rigid redo. A second SA-PVE was needed in significantly more cases when the first SA-PVE was performed before age 1 year. Complications occurred in 26 patients with a total of 32 events, including one death. Forty-one patients underwent fronto-orbital remodelling at spring removal and 22 required additional cranio(maxillo)facial procedures. CONCLUSIONS: Spring-assisted posterior vault expansion is a safe, efficient, and effective procedure based on our 12-year experience. Those that are treated early in life might require a repeat SA-PVE. Long-term follow-up is recommended as some would require additional craniomaxillofacial correction later in life.

Sibling screening in suspected abusive head trauma: a proposed guideline.

Abusive head trauma (AHT) is the leading cause of death from child abuse in children younger than 5 years. It is well documented that the infant contacts of children presenting with suspected AHT are at an increased risk of abuse when compared to the general infant population. Despite this association, a paucity of literature stratifies this risk and translates it to the clinic such that this high-risk group is stringently screened for abusive injuries. In this light, the authors propose a standardised screening method for all contact children of the index case and call for further consensus on the subject.

Abusive head trauma: neuroimaging mimics and diagnostic complexities.

Traumatic brain injury is responsible for approximately half of all childhood deaths from infancy to puberty, the majority of which are attributable to abusive head trauma (AHT). Due to the broad way patients present and the lack of a clear mechanism of injury in some cases, neuroimaging plays an integral role in the diagnostic pathway of these children. However, this nonspecific nature also presages the existence of numerous conditions that mimic both the clinical and neuroimaging findings seen in AHT. This propensity for misdiagnosis is compounded by the lack of pathognomonic patterns and clear diagnostic criteria. The repercussions of this are severe and have a profound stigmatic effect. The authors present an exhaustive review of the literature complemented by illustrative cases from their institutions with the aim of providing a framework with which to approach the neuroimaging and diagnosis of AHT.

Parenchymal brain injuries in abusive head trauma.

The consequences of abusive head trauma (AHT) can be devastating for both the individual child and for wider society. Death is undoubtedly a very real possibility, but even for those children who survive, there is often very significant morbidity with the potential for gross motor and cognitive impairment, behavioural problems, blindness and epilepsy, which can greatly affect their quality of life. Caring for such children places a vast financial and infrastructural burden on society that frequently extends well into adulthood. While few struggle to have any sympathy for the perpetrator, frequently the infant's father, it should be noted that a single solitary and momentary loss of complete control can have horrific and unforeseen consequences. A number of papers within this edition describe features of AHT and include descriptions of skull fractures and extra-axial haemorrhage, along with mimics of such phenomena. However, in this review we concentrate our attention on the myriad of parenchymal findings that can occur. Such parenchymal injuries include hypoxic-ischaemic damage, clefts, contusion and focal haemorrhage. We offer our perspectives on current thinking on these entities and put them in the context of the immensely important question - how do we recognise abusive head trauma?

Skull fractures in abusive head trauma: a single centre experience and review of the literature.

PURPOSE: The authors provide a comprehensive framework with which to approach paediatric calvarial injury sustained as a result of suspected abusive head trauma (AHT). This is achieved through the presentation of a case series set in the context of the unique morphology of the infant skull and the possible diagnostic pitfalls which may arise due to the presence of variant anatomy or other mimicking conditions. METHODS: A retrospective analysis of sixty-three patients referred to our institution with suspected AHT was carried out. Seventeen patients with skull fractures were identified and their fractures were described in terms of anatomical location, type and course. Our data was then interpreted in the light of known anatomical fracture mimics and the available literature on the subject. RESULTS: Forty-two skull fractures were identified and described in our cohort, most of which were simple linear fractures of the parietal bones (33%). There were also a substantial number of complex stellate fractures, namely of the parietal (29%) and occipital (10%) bones. Eleven fracture mimics including accessory sutures and wormian bones were also identified in this cohort. CONCLUSIONS: Our study supports and builds on the existing literature, thereby offering a more complete view of the spectrum of calvarial damage sustained as a result of AHT in the context of its diagnostic pitfalls.