Long-term weight gain in children with craniopharyngioma.

OBJECTIVE: Adamantinomatous craniopharyngioma mainly affects children. Excessive weight gain is a major long-term complication. The primary objective of this study was to assess long-term weight changes in children treated for craniopharyngioma. The secondary objectives were to identify risk factors for excessive weight gain and to look for associations with hypothalamic damage by the tumour or treatment. DESIGN: Single-centre retrospective cohort study. METHOD: Children managed for craniopharyngioma at our centre between 1990 and 2019 were included. The body mass index (BMI) standard deviation scores (SDS) at baseline and at last follow-up were compared. Univariate and multivariate analyses were performed in order to identify variables associated with the long-term BMI-SDS variation. RESULTS: The 108 patients had a mean follow-up of 10.4 years. The mean BMI-SDS increase over time was 2.11 (P < .001) overall, 1.21 (P < .001) in the group without hypothalamic involvement by the tumour, and 1.95 (P < .001) in the group managed using intended hypothalamus-sparing surgery. The absence of hypothalamic involvement by the tumour or treatment was significantly associated with less weight gain (P = .046 and P < .01, respectively). After adjustment, factors associated with a BMI-SDS change greater than 2 were female sex (P = .023), tumour involving the hypothalamus (P = .04), and higher baseline BMI (P < .001). CONCLUSION: Clinically significant weight gain occurred in nearly all children treated for craniopharyngioma, including those whose hypothalamus was spared by the tumour and intentionally by treatment. However, hypothalamus integrity was associated with less weight gain. Despite hypothalamus-sparing strategies, hypothalamic obesity remains a major concern, indicating a need for novel treatment approaches.

CNS tumors with PLAGL1-fusion: beyond ZFTA and YAP1 in the genetic spectrum of supratentorial ependymomas.

A novel methylation class, "neuroepithelial tumor, with PLAGL1 fusion" (NET-PLAGL1), has recently been described, based on epigenetic features, as a supratentorial pediatric brain tumor with recurrent histopathological features suggesting an ependymal differentiation. Because of the recent identification of this neoplastic entity, few histopathological, radiological and clinical data are available. Herein, we present a detailed series of nine cases of PLAGL1-fused supratentorial tumors, reclassified from a series of supratentorial ependymomas, non-ZFTA/non-YAP1 fusion-positive and subependymomas of the young. This study included extensive clinical, radiological, histopathological, ultrastructural, immunohistochemical, genetic and epigenetic (DNA methylation profiling) data for characterization. An important aim of this work was to evaluate the sensitivity and specificity of a novel fluorescent in situ hybridization (FISH) targeting the PLAGL1 gene. Using histopathology, immunohistochemistry and electron microscopy, we confirmed the ependymal differentiation of this new neoplastic entity. Indeed, the cases histopathologically presented as "mixed subependymomas-ependymomas" with well-circumscribed tumors exhibiting a diffuse immunoreactivity for GFAP, without expression of Olig2 or SOX10. Ultrastructurally, they also harbored features reminiscent of ependymal differentiation, such as cilia. Different gene partners were fused with PLAGL1: FOXO1, EWSR1 and for the first time MAML2. The PLAGL1 FISH presented a 100% sensitivity and specificity according to RNA sequencing and DNA methylation profiling results. This cohort of supratentorial PLAGL1-fused tumors highlights: 1/ the ependymal cell origin of this new neoplastic entity; 2/ benefit of looking for a PLAGL1 fusion in supratentorial cases of non-ZFTA/non-YAP1 ependymomas; and 3/ the usefulness of PLAGL1 FISH.

A comprehensive histomolecular characterization of meningioangiomatosis: Further evidence for a precursor neoplastic lesion.

Meningioangiomatosis (MAM) remains a poorly understood lesion responsible for epileptic disease. In the past, MAM was primarily described in the context of neurofibromatosis type 2 before being mainly reported sporadically. Moreover, the malformative or tumoral nature is still debated. Because a subset of MAM are associated with meningiomas, some authors argue that MAM corresponds to an infiltration pattern of these tumors. For these reasons, MAM has not been added to the World Health Organization (WHO) Classification of Central Nervous System Tumors as a specific entity. In the present study, we characterized a series of pure MAM (n = 7) and MAM associated with meningiomas (n = 4) using histopathology, immunohistochemistry, genetic (fluorescent in situ and DNA sequencing analyses), and epigenetic (DNA-methylation profiling) data. We evidenced two distinct morphological patterns: MAM with a fibroblastic-like pattern having few lesional cells, and MAM with a more cellular pattern. A subset was associated with the genetic alterations previously reported in meningiomas (such as a KMT2C mutation and a hemizygous deletion of chromosome 22q including the NF2 gene). The DNA-methylation profile, using a t-distributed stochastic neighbor embedding analysis, evidenced that MAM (pure or associated with meningiomas) clustered in a separate group from pediatric meningiomas. The present results seem to suggest that MAM represents a neoplastic lesion and encourage the further study of similar additional series so that it may be included in a future WHO classification.

Clinical, Neuroimaging, and Metabolic Footprint of the Neurodevelopmental Disorder Caused by Monoallelic HK1 Variants.

Background and Objectives: Hexokinase 1 (encoded by HK1) catalyzes the first step of glycolysis, the adenosine triphosphate-dependent phosphorylation of glucose to glucose-6-phosphate. Monoallelic HK1 variants causing a neurodevelopmental disorder (NDD) have been reported in 12 individuals. Methods: We investigated clinical phenotypes, brain MRIs, and the CSF of 15 previously unpublished individuals with monoallelic HK1 variants and an NDD phenotype. Results: All individuals had recurrent variants likely causing gain-of-function, representing mutational hot spots. Eight individuals (c.1370C>T) had a developmental and epileptic encephalopathy with infantile onset and virtually no development. Of the other 7 individuals (n = 6: c.1334C>T; n = 1: c.1240G>A), 3 adults showed a biphasic course of disease with a mild static encephalopathy since early childhood and an unanticipated progressive deterioration with, e.g., movement disorder, psychiatric disease, and stroke-like episodes, epilepsy, starting in adulthood. Individuals who clinically presented in the first months of life had (near)-normal initial neuroimaging and severe cerebral atrophy during follow-up. In older children and adults, we noted progressive involvement of basal ganglia including Leigh-like MRI patterns and cerebellar atrophy, with remarkable intraindividual variability. The CSF glucose and the CSF/blood glucose ratio were below the 5th percentile of normal in almost all CSF samples, while blood glucose was unremarkable. This biomarker profile resembles glucose transporter type 1 deficiency syndrome; however, in HK1-related NDD, CSF lactate was significantly increased in all patients resulting in a substantially different biomarker profile. Discussion: Genotype-phenotype correlations appear to exist for HK1 variants and can aid in counseling. A CSF biomarker profile with low glucose, low CSF/blood glucose, and high CSF lactate may point toward monoallelic HK1 variants causing an NDD. This can help in variant interpretation and may aid in understanding the pathomechanism. We hypothesize that progressive intoxication and/or ongoing energy deficiency lead to the clinical phenotypes and progressive neuroimaging findings.

"Hemispheric pilocytic astrocytoma" revisited: A comprehensive clinicopathological and molecular series emphasizing their overlap with other glioneuronal tumors.

Pilocytic astrocytomas (PA) typically exhibit distinct clinical, radiological, histopathological, and genetic features. DNA-methylation profiling distinguishes PA according to their location (infratentorial, midline, hemispheric, or spinal). In the hemispheric location, distinguishing PA from glioneuronal tumors remains a common diagnostic challenge for neuropathologists. Furthermore, the current version of the DKFZ classifier seems to have difficulty separating them from gangliogliomas. In this study, after central radiological review, we identified a histopathologically defined set of PA (histPA, n = 11) and a cohort of DNA-methylation defined PA (mcPA, n = 11). Nine out of the 11 histPA matched the methylation class of hemispheric PA, whereas 2 cases were classified at the end of the study as dysembryoplastic neuroepithelial tumors. Similarly, the mcPA cohort contained tumors mainly classified as PA (7/11), but 4 cases were classified as glioneuronal. The analysis of the 16 tumors with an integrated diagnosis of PA revealed that they affect mainly children with a wide spectrum of radiological, histopathological (i.e. a predominantly diffuse growth pattern), and genetic characteristics (large range of mitogen-activated protein kinase alterations). Based on these results, we consider hemispheric PA to be different from their counterparts in other locations and to overlap with other glioneuronal tumors, reinforcing the necessity of interpreting all data to obtain an accurate diagnosis.

CNS erythroblastic sarcoma: a potential emerging pediatric tumor type characterized by NFIA::RUNX1T1/3 fusions.

Erythroblastic sarcoma (ES) (previously called chloroma or granulocytic sarcoma) are rare hematological neoplams characterized by the proliferation of myeloid blasts at extramedullary sites, and primarily involve the skin and soft tissue of middle-aged adults. ES may be concomitant with or secondary to myeloid neoplasms (mostly acute myeloid leukemia (AML)) or in isolated cases (de novo) without infiltration of the bone marrow by blasts. ES share cytogenetic and molecular abnormalities with AML, including RUNX1T1 fusions. Some of these alterations seem to be correlated with particular sites of involvement. Herein, we report an isolated erythroblastic sarcoma with NFIA::RUNX1T1 located in the central nervous system (CNS) of a 3-year-old boy. Recently, two pediatric cases of CNS MS with complete molecular characterization have been documented. Like the current case, they concerned infants (2 and 3 years-old) presenting a brain tumor (pineal involvement) with leptomeningeal dissemination. Both cases also harbored a NFIA::RUNX1T3 fusion. ES constitutes a diagnostic challenge for neuropathologists because it does not express differentiation markers such as CD45, and may express CD99 which could be confused with CNS Ewing sarcoma. CD43 is the earliest pan-hematopoietic marker and CD45 is not expressed by erythroid lineage cells. E-cadherin (also a marker of erythroid precursors) and CD117 (expressed on the surface of erythroid lineage cells) constitute other immunhistochemical hallmarks of ES. The prognosis of patients with ES is similar to that of other patients with AML but de novo forms seem to have a poorer prognosis, like the current case. To conclude, pediatric ES with NFIA::RUNX1T1/3 fusions seem to have a tropism for the CNS and thus constitute a potential pitfall for neuropathologists. Due to the absence of circulating blasts and a DNA-methylation signature, the diagnosis must currently be made by highlighting the translocation and expression of erythroid markers.

Fluid suppression in amide proton transfer-weighted (APTw) CEST imaging: New theoretical insights and clinical benefits.

PURPOSE: Amide proton transfer-weighted (APTw) MRI at 3T provides a unique contrast for brain tumor imaging. However, APTw imaging suffers from hyperintensities in liquid compartments such as cystic or necrotic structures and provides a distorted APTw signal intensity. Recently, it has been shown that heuristically motivated fluid suppression can remove such artifacts and significantly improve the readability of APTw imaging. THEORY AND METHODS: In this work, we show that the fluid suppression can actually be understood by the known concept of spillover dilution, which itself can be derived from the Bloch-McConnell equations in comparison to the heuristic approach. Therefore, we derive a novel post-processing formula that efficiently removes fluid artifact, and explains previous approaches. We demonstrate the utility of this APTw assessment in silico, in vitro, and in vivo in brain tumor patients acquired at MR scanners from different vendors. RESULTS: Our results show a reduction of the CEST signals from fluid environments while keeping the APTw-CEST signal intensity almost unchanged for semi-solid tissue structures such as the contralateral normal appearing white matter. This further allows us to use the same color bar settings as for conventional APTw imaging. CONCLUSION: Fluid suppression has considerable value in improving the readability of APTw maps in the neuro-oncological field. In this work, we derive a novel post-processing formula from the underlying Bloch-McConnell equations that efficiently removes fluid artifact, and explains previous approaches which justify the derivation of this metric from a theoretical point of view, to reassure the scientific and medical field about its use.

Performance of Non-EPI DW MRI for Pediatric Cholesteatoma Follow-Up.

OBJECTIVE: To evaluate the accuracy, sensitivity, and specificity of nonecho planar (non-EPI) diffusion-weighted (DW) magnetic resonance imaging (MRI) to detect residual cholesteatoma in children. STUDY DESIGN: Retrospective study. SETTING: Tertiary comprehensive hospital. METHODS: Children operated on for a first-stage cholesteatoma procedure from 2010 to 2019 were included. MRIs were performed with non-EPI DW sequences. Initial reports were collected, indicating the presence or absence of hyperintensity suggestive of cholesteatoma. Three hundred twenty-three MRIs were correlated with the subsequent surgery (66%) or year-later MRI (21%), or were considered accurate if performed 5 years or more after the last surgery (13%). The sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of each imaging procedure for the detection of cholesteatoma were calculated. RESULTS: Two hundred twenty-four children with mean age of 9 ± 4 years old presented with cholesteatoma. MRIs were performed 27 ± 24 months after surgery. Residual cholesteatoma was diagnosed in 35%. The sensitivity, specificity, PPV, and NPV of MRI were 62%, 86%, 74%, and 78%, respectively. Accuracy, sensitivity, and specificity increased significantly over time (multivariate analysis). The mean delay after last surgery was of 30 ± 2.0 months for accurate MRI (true positive or negative) versus 17 ± 2.0 months for nonaccurate (false positive or negative) MRIs (p < .001). CONCLUSION: However, long the delay after the last surgery, the sensitivity of non-EPI diffusion sequence MRI in children has limitations for the detection of residual cholesteatoma. Surveillance for residual cholesteatoma should incorporate findings at primary surgery, surgeon experience, a low threshold for second-look procedures, and routine imaging.

Diffuse midline glioma invasion and metastasis rely on cell-autonomous signaling.

BACKGROUND: Diffuse midline gliomas (DMG) are pediatric tumors with negligible 2-year survival after diagnosis characterized by their ability to infiltrate the central nervous system. In the hope of controlling the local growth and slowing the disease, all patients receive radiotherapy. However, distant progression occurs frequently in DMG patients. Current clues as to what causes tumor infiltration circle mainly around the tumor microenvironment, but there are currently no known determinants to predict the degree of invasiveness. METHODS: In this study, we use patient-derived glioma stem cells (GSCs) to create patient-specific 3D avatars to model interindividual invasion and elucidate the cellular supporting mechanisms. RESULTS: We show that GSC models in 3D mirror the invasive behavior of the parental tumors, thus proving the ability of DMG to infiltrate as an autonomous characteristic of tumor cells. Furthermore, we distinguished 2 modes of migration, mesenchymal and ameboid-like, and associated the ameboid-like modality with GSCs derived from the most invasive tumors. Using transcriptomics of both organoids and primary tumors, we further characterized the invasive ameboid-like tumors as oligodendrocyte progenitor-like, with highly contractile cytoskeleton and reduced adhesion ability driven by crucial over-expression of bone morphogenetic pathway 7 (BMP7). Finally, we deciphered MEK, ERK, and Rho/ROCK kinases activated downstream of the BMP7 stimulation as actionable targets controlling tumor cell motility. CONCLUSIONS: Our findings identify 2 new therapeutic avenues. First, patient-derived GSCs represent a predictive tool for patient stratification in order to adapt irradiation strategies. Second, autocrine and short-range BMP7-related signaling becomes a druggable target to prevent DMG spread and metastasis.

Imaging features to distinguish posterior fossa ependymoma subgroups.

OBJECTIVES: Posterior fossa ependymoma group A (EPN_PFA) and group B (EPN_PFB) can be distinguished by their DNA methylation and give rise to different prognoses. We compared the MRI characteristics of EPN_PFA and EPN_PFB at presentation. METHODS: Preoperative imaging of 68 patients with posterior fossa ependymoma from two centers was reviewed by three independent readers, blinded for histomolecular grouping. Location, tumor extension, tumor volume, hydrocephalus, calcifications, tissue component, enhancement or diffusion signal, and histopathological data (cellular density, calcifications, necrosis, mitoses, vascularization, and microvascular proliferation) were compared between the groups. Categorical data were compared between groups using Fisher's exact tests, and quantitative data using Mann-Whitney tests. We performed a Benjamini-Hochberg correction of the p values to account for multiple tests. RESULTS: Fifty-six patients were categorized as EPN_PFA and 12 as EPN_PFB, with median ages of 2 and 20 years, respectively (p = 0.0008). The median EPN_PFA tumoral volume was larger (57 vs 29 cm3, p = 0.003), with more pronounced hydrocephalus (p = 0.002). EPN_PFA showed an exclusive central position within the 4th ventricle in 61% of patients vs 92% for EPN_PFB (p = 0.01). Intratumor calcifications were found in 93% of EPN_PFA vs 40% of EPN_PFB (p = 0.001). Invasion of the posterior fossa foramina was mostly found for EPN_PFA, particularly the foramina of Luschka (p = 0.0008). EPN_PFA showed whole and homogeneous tumor enhancement in 5% vs 75% of EPN_PFB (p = 0.0008). All mainly cystic tumors were EPN_PFB (p = 0.002). The minimal and maximal relative ADC was slightly lower in EPN_PFA (p = 0.02 and p = 0.01, respectively). CONCLUSION: Morphological characteristics from imaging differ between posterior fossa ependymoma subtypes and may help to distinguish them preoperatively. CLINICAL RELEVANCE STATEMENT: This study provides a tool to differentiate between group A and group B ependymomas, which will ultimately allow the therapeutic strategy to be adapted in the early stages of patient management. KEY POINTS: • Posterior fossa ependymoma subtypes often have different imaging characteristics. • Posterior fossa ependymomas group A are commonly median or lateral tissular calcified masses, with incomplete enhancement, affecting young children and responsible for pronounced hydrocephalus and invasion of the posterior fossa foramina. • Posterior fossa ependymomas group B are commonly median non-calcified masses of adolescents and adults, predominantly cystic, and minimally invasive, with total and homogeneous enhancement.

Interhemispheric Vertical Hemispherotomy: Technique, Outcome, and Pitfalls-A Bicentric Retrospective Case Series of 39 Cases.

BACKGROUND AND OBJECTIVES: When seizure onset affects a whole hemisphere, hemispheric disconnections are efficient and safe procedures. However, both lateral peri-insular hemispherotomy and vertical paramedian hemispherotomy approaches report a failure rate around 20%, which can be explained by residual connections giving rise to persistent seizures. In this study, we present the interhemispheric vertical hemispherotomy (IVH), a technical variation of the vertical paramedian hemispherotomy approach, that aims to increase seizure control avoiding residual connections while exposing the corpus callosum. METHODS: This is a retrospective study of IVH in two centers, with analysis of clinical and MRI data and outcomes. A detailed description of the technique is provided with a video. RESULTS: IVH was performed in 39 children. The mean age at surgery was 7.2 years, and etiologies were as follows: malformations of cortical development (n = 14), Rasmussen's encephalitis (n = 10), stroke (n = 10), post-traumatic (3), and Sturge-Weber Syndrome (2). Hemispheric disconnection was complete on postoperative MRI in 34 cases. There was no mortality, hydrocephalus occurred in one case, and subdural collection occurred in four cases. A second surgery was performed in four cases because of seizure relapse (n = 3) and/or incomplete disconnection on MRI (n = 4). With a mean follow-up of 3.2 years, International League Against Epilepsy class I epilepsy outcome was obtained for 37/39 patients. CONCLUSION: IVH is a safe and effective variation of the vertical approaches for hemispheric disconnection. It allows a good exposure and anatomic control of the corpus callosum, which is a frequent site of incomplete disconnection. IVH may be limited by the thalamic volume and the ventricular size, notably in hemimegalencephaly cases.

Evidence of spinal stiffening following fusionless bipolar fixation for neuromuscular scoliosis: a shear wave elastography assessment of lumbar annulus fibrosus.

OBJECTIVES: There are no established criteria for stiffness after fusionless surgery for neuromuscular scoliosis (NMS). As a result, there is no consensus regarding the surgical strategy to propose at long-term follow-up. This study reports the first use of shear wave elastography for assessing the mechanical response of lumbar intervertebral discs (IVDs) after fusionless bipolar fixation (FBF) for NMS and compares them with healthy controls. The aim was to acquire evidence from the stiffness of the spine following FBF. PATIENTS AND METHODS: Nineteen NMS operated on with FBF (18 ± 2y at last follow-up, 6 ± 1 y after surgery) were included prospectively. Preoperative Cobb was 89 ± 20° and 35 ± 1° at latest follow-up. All patients had reached skeletal maturity. Eighteen healthy patients (20 ± 4 y) were also included. Shear wave speed (SWS) was measured in the annulus fibrosus of L3L4, L4L5 and L5S1 IVDs and compared between the two groups. A measurement reliability was performed. RESULTS: In healthy subjects, average SWS (all disc levels pooled) was 7.5 ± 2.6 m/s. In NMS patients, SWS was significantly higher at 9.9 ± 1.4 m/s (p < 0.05). Differences were significant between L3L4 (9.3 ± 1.8 m/s vs. 7.0 ± 2.5 m/s, p = 0.004) and L4L5 (10.3 ± 2.3 m/s vs. 7.1 ± 1.1 m/s, p = 0.0006). No difference was observed for L5S1 (p = 0.2). No correlation was found with age at surgery, Cobb angle correction and age at the SWE measurement. CONCLUSIONS: This study shows a significant increase in disc stiffness at the end of growth for NMS patients treated by FBF. These findings are a useful adjunct to CT-scan in assessing stiffness of the spine allowing the avoidance of surgical final fusion at skeletal maturity.

The pontine diffuse midline glioma, EGFR-subtype with ependymal features: Yet another face of diffuse midline glioma, H3K27-altered.

Diffuse midline glioma with two components: classical glial and ependymal.

A new subtype of diffuse midline glioma, H3 K27 and BRAF/FGFR1 co-altered: a clinico-radiological and histomolecular characterisation.

Diffuse midline gliomas (DMG) H3 K27-altered are incurable grade 4 gliomas and represent a major challenge in neuro-oncology. This tumour type is now classified in four subtypes by the 2021 edition of the WHO Classification of the Central Nervous System (CNS) tumours. However, the H3.3-K27M subgroup still appears clinically and molecularly heterogeneous. Recent publications reported that rare patients presenting a co-occurrence of H3.3K27M with BRAF or FGFR1 alterations tended to have a better prognosis. To better study the role of these co-driver alterations, we assembled a large paediatric and adult cohort of 29 tumours H3K27-altered with co-occurring activating mutation in BRAF or FGFR1 as well as 31 previous cases from the literature. We performed a comprehensive histological, radiological, genomic, transcriptomic and DNA methylation analysis. Interestingly, unsupervised t-distributed Stochastic Neighbour Embedding (tSNE) analysis of DNA methylation profiles regrouped BRAFV600E and all but one FGFR1MUT DMG in a unique methylation cluster, distinct from the other DMG subgroups and also from ganglioglioma (GG) or high-grade astrocytoma with piloid features (HGAP). This new DMG subtype harbours atypical radiological and histopathological profiles with calcification and/or a solid tumour component both for BRAFV600E and FGFR1MUT cases. The analyses of a H3.3-K27M BRAFV600E tumour at diagnosis and corresponding in vitro cellular model showed that mutation in H3-3A was the first event in the oncogenesis. Contrary to other DMG, these tumours occur more frequently in the thalamus (70% for BRAFV600E and 58% for FGFR1MUT) and patients have a longer overall survival with a median above three years. In conclusion, DMG, H3 K27 and BRAF/FGFR1 co-altered represent a new subtype of DMG with distinct genotype/phenotype characteristics, which deserve further attention with respect to trial interpretation and patient management.

Laser interstitial thermal therapy is effective and safe for the treatment of brain tumors in NF1 patients after cerebral revascularization for moyamoya angiopathy: a report on two cases.

Background: The co-occurrence of moyamoya vasculopathy and extra-optic pathway tumors is rare in neurofibromatosis type 1 (NF1), with only four cases described in the literature. Brain surgery in these patients may be challenging because of the risk of brain infarction after skin and dural incision. Given its percutaneous and minimally invasive nature, laser interstitial thermal therapy (LITT) is an ideal option for the treatment of brain tumors in these patients. Here, we report on two patients with NF1 and moyamoya syndrome (MMS) treated for a brain glioma with LITT, after cerebral revascularization. Cases: The first patient, with familial NF1, underwent bilateral indirect revascularization with multiple burr holes (MBH) for symptomatic MMS. Two years later, she was diagnosed with a left temporal tumor, with evidence of radiologic progression over 10 months. The second patient, also with familial NF1, developed unilateral MMS when he was 6 years old and was treated with MBH. At the age of 15 years, MRI showed a right cingular lesion, growing on serial MRIs. Both patients underwent LITT with no perioperative complications; they are progression free at 10 and 12 months, respectively, and the tumors have decreased in volume. Discussion: While the association of extra-optic neoplasm and moyamoya angiopathy is seldom reported in NF1, tumor treatment is challenging in terms of both avoiding stroke and achieving oncological control. Here, we show in 2 cases, that LITT could be a safe and effective option in these rare conditions.

Association between acute complications in PMM2-CDG patients and haemostasis anomalies: Data from a multicentric study and suggestions for acute management.

OBJECTIVES: Patients with PMM2-CDG develop acute events (stroke-like episodes (SLEs), thromboses, haemorrhages, seizures, migraines) associated with both clotting factors (factor XI) and coagulation inhibitors (antithrombin, protein C and protein S) deficiencies. The aim of the study was to correlate acute events to haemostasis and propose practical guidelines. METHODS: In this multicentric retrospective study, we evaluated clinical, radiological, haemostasis and electroencephalography data for PMM2-CDG patients hospitalized for acute events. Cerebral events were classified as thrombosis, haemorrhage, SLE, or "stroke mimic" (SM: normal brain imaging or evoking a migraine). RESULTS: Thirteen patients had a total of 31 acute episodes: 27 cerebral events with 7 SLEs, 4 venous thromboses, 4 haemorrhages (3 associated with thrombosis), 15 SMs at a mean age of 7.7 years; 4 non-cerebral thromboses, one of which included bleeding. A trigger was frequently involved (infection, head trauma). Although sometimes normal at baseline state, factor XI, antithrombin and protein C levels decreased during these episodes. No correlation between haemostasis anomalies and type of acute event was found. DISCUSSION: Acute events in PMM2-CDG are not negligible and are associated with haemostasis anomalies. An emergency protocol is proposed for their prevention and treatment (https://www.filiere-g2m.fr/urgences). For cerebral events, brain Magnetic Resonance Imaging with perfusion weight imaging and diffusion sequences, electroencephalogram and haemostasis protein levels guide the treatment: anticoagulation, antithrombin or fresh frozen plasma supplementation, antiepileptic therapy. Preventing bleeding and thrombosis is required in cases of surgery, prolonged immobilization, hormone replacement therapy. CONCLUSION: Acute events in PMM2-CDG are associated with abnormal haemostasis, requiring practical guidance.

Monoallelic variation in DHX9, the gene encoding the DExH-box helicase DHX9, underlies neurodevelopment disorders and Charcot-Marie-Tooth disease.

DExD/H-box RNA helicases (DDX/DHX) are encoded by a large paralogous gene family; in a subset of these human helicase genes, pathogenic variation causes neurodevelopmental disorder (NDD) traits and cancer. DHX9 encodes a BRCA1-interacting nuclear helicase regulating transcription, R-loops, and homologous recombination and exhibits the highest mutational constraint of all DDX/DHX paralogs but remains unassociated with disease traits in OMIM. Using exome sequencing and family-based rare-variant analyses, we identified 20 individuals with de novo, ultra-rare, heterozygous missense or loss-of-function (LoF) DHX9 variant alleles. Phenotypes ranged from NDDs to the distal symmetric polyneuropathy axonal Charcot-Marie-Tooth disease (CMT2). Quantitative Human Phenotype Ontology (HPO) analysis demonstrated genotype-phenotype correlations with LoF variants causing mild NDD phenotypes and nuclear localization signal (NLS) missense variants causing severe NDD. We investigated DHX9 variant-associated cellular phenotypes in human cell lines. Whereas wild-type DHX9 was restricted to the nucleus, NLS missense variants abnormally accumulated in the cytoplasm. Fibroblasts from an individual with an NLS variant also showed abnormal cytoplasmic DHX9 accumulation. CMT2-associated missense variants caused aberrant nucleolar DHX9 accumulation, a phenomenon previously associated with cellular stress. Two NDD-associated variants, p.Gly411Glu and p.Arg761Gln, altered DHX9 ATPase activity. The severe NDD-associated variant p.Arg141Gln did not affect DHX9 localization but instead increased R-loop levels and double-stranded DNA breaks. Dhx9-/- mice exhibited hypoactivity in novel environments, tremor, and sensorineural hearing loss. All together, these results establish DHX9 as a critical regulator of mammalian neurodevelopment and neuronal homeostasis.

Fast-track virtual reality software to facilitate 3-dimensional reconstruction in congenital heart disease.

OBJECTIVES: Two limitations of the clinical use of 3-dimensional (3D) reconstruction and virtual reality systems are the relatively high cost and the amount of experience required to use hardware and software to effectively explore medical images. We have tried to simplify the process and validate a new tool developed for this purpose with a novel software package. METHODS: Five patients with right partial anomalous pulmonary venous return with adequate preoperative images acquired with magnetic resonance imaging were enrolled. Five volunteers with no previous experience in the field of 3D reconstruction were instructed to use the software after viewing a short video tutorial. Users were then asked to create a 3D model of each patient's heart using DIVA software. Their results were compared quantitatively and qualitatively with a benchmark reconstruction performed by an experienced user. RESULTS: All our participants recreated 3D models in a relatively short time, maintaining a good overall quality (average quality score ≥ 3 on a scale of 1-5). The overall trend of all the parameters analysed showed a statistical improvement between case 1 and case 5, as users became more and more experienced. CONCLUSIONS: DIVA is a simple software program that allows accurate 3D reconstruction in a relatively short time ("fast-track" virtual reality). In this study, we demonstrated the potential use of DIVA by inexperienced users, with a significant improvement in quality and time after a few cases were performed. Further studies are needed to confirm the potential application of this technology on a larger scale.

A comprehensive analysis of infantile central nervous system tumors to improve distinctive criteria for infant-type hemispheric glioma versus desmoplastic infantile ganglioglioma/astrocytoma.

Recent epigenomic analyses have revealed the existence of a new DNA methylation class (MC) of infant-type hemispheric glioma (IHG). Like desmoplastic infantile ganglioglioma/astrocytoma (DIG/DIA), these tumors mainly affect infants and are supratentorial. While DIG/DIA is characterized by BRAF or RAF1 alterations, IHG has been shown to have receptor tyrosine kinase (RTK) gene fusions (ALK, ROS1, NTRK1/2/3, and MET). However, in this rapidly evolving field, a more comprehensive analysis of infantile glial/glioneuronal tumors including clinical, radiological, histopathological, and molecular data is needed. Here, we retrospectively investigated data from 30 infantile glial/glioneuronal tumors, consecutively compiled from our center. They were analyzed by two experienced pediatric neuroradiologists in consensus, without former knowledge of the molecular data. We also performed a comprehensive clinical, and histopathological examination (including molecular evaluation by next-generation sequencing, RNA sequencing, and fluorescence in situ hybridization [FISH] analyses), as well as DNA methylation profiling for the samples having sufficient material available. The integrative histopathological, genetic, and epigenetic analyses, including t-distributed stochastic neighbor embedding (t-SNE) analyses segregated tumors into 10 DIG/DIA (33.3%), six IHG (20.0%), three gangliogliomas (10.0%), two pleomorphic xanthoastrocytomas (6.7%), two pilocytic astrocytomas (6.7%), two supratentorial ependymomas, ZFTA fusion-positive (6.7%), two supratentorial ependymomas, YAP1 fusion-positive (6.7%), two embryonal tumors with PLAGL2-family amplification (6.7%), and one diffuse low-grade glioma, MAPK-pathway altered. This study highlights the significant differential features, in terms of histopathology (leptomeningeal infiltration, intense desmoplasia and ganglion cells in DIG/DIA and necrosis, microvascular proliferation, and siderophages in IHG), and radiology between DIG/DIA and IHG. Moreover, these results are consistent with the literature data concerning the molecular dichotomy (BRAF/RAF1 alterations vs. RTK genes' fusions) between DIG/DIA and IHG. This study characterized histopathologically and radiologically two additional cases of the novel embryonal tumor characterized by PLAGL2 gene amplification.