Molecular heterogeneity and CXorf67 alterations in posterior fossa group A (PFA) ependymomas

Of nine ependymoma molecular groups detected by DNA methylation profiling, the posterior fossa type A (PFA) is most prevalent. We used DNA methylation profiling to look for further molecular heterogeneity among 675 PFA ependymomas. Two major subgroups, PFA-1 and PFA-2, and nine minor subtypes were discovered. Transcriptome profiling suggested a distinct histogenesis for PFA-1 and PFA-2, but their clinical parameters were similar. In contrast, PFA subtypes differed with respect to age at diagnosis, gender ratio, outcome, and frequencies of genetic alterations. One subtype, PFA-1c, was enriched for 1q gain and had a relatively poor outcome, while patients with PFA-2c ependymomas showed an overall survival at 5 years of > 90%. Unlike other ependymomas, PFA-2c tumors express high levels of OTX2, a potential biomarker for this ependymoma subtype with a good prognosis. We also discovered recurrent mutations among PFA ependymomas. H3 K27M mutations were present in 4.2%, occurring only in PFA-1 tumors, and missense mutations in an uncharacterized gene, CXorf67, were found in 9.4% of PFA ependymomas, but not in other groups. We detected high levels of wildtype or mutant CXorf67 expression in all PFA subtypes except PFA-1f, which is enriched for H3 K27M mutations. PFA ependymomas are characterized by lack of H3 K27 trimethylation (H3 K27-me3), and we tested the hypothesis that CXorf67 binds to PRC2 and can modulate levels of H3 K27-me3. Immunoprecipitation/mass spectrometry detected EZH2, SUZ12, and EED, core components of the PRC2 complex, bound to CXorf67 in the Daoy cell line, which shows high levels of CXorf67 and no expression of H3 K27-me3. Enforced reduction of CXorf67 in Daoy cells restored H3 K27-me3 levels, while enforced expression of CXorf67 in HEK293T and neural stem cells reduced H3 K27-me3 levels. Our data suggest that heterogeneity among PFA ependymomas could have clinicopathologic utility and that CXorf67 may have a functional role in these tumors

Failure of human rhombic lip differentiation underlies medulloblastoma formation

Medulloblastoma (MB) comprises a group of heterogeneous paediatric embryonal neoplasms of the hindbrain with strong links to early development of the hindbrain 1–4. Mutations that activate Sonic hedgehog signalling lead to Sonic hedgehog MB in the upper rhombic lip (RL) granule cell lineage 5–8. By contrast, mutations that activate WNT signalling lead to WNT MB in the lower RL 9,10. However, little is known about the more commonly occurring group 4 (G4) MB, which is thought to arise in the unipolar brush cell lineage 3,4. Here we demonstrate that somatic mutations that cause G4 MB converge on the core binding factor alpha (CBFA) complex and mutually exclusive alterations that affect CBFA2T2, CBFA2T3, PRDM6, UTX and OTX2. CBFA2T2 is expressed early in the progenitor cells of the cerebellar RL subventricular zone in Homo sapiens, and G4 MB transcriptionally resembles these progenitors but are stalled in developmental time. Knockdown of OTX2 in model systems relieves this differentiation blockade, which allows MB cells to spontaneously proceed along normal developmental differentiation trajectories. The specific nature of the split human RL, which is destined to generate most of the neurons in the human brain, and its high level of susceptible EOMES +KI67 + unipolar brush cell progenitor cells probably predisposes our species to the development of G4 MB

Microencephaloceles: Another dual pathology of intractable temporal lobe epilepsy in childhood

Temporal lobe encephaloceles can be associated with temporal lobe epilepsy. The authors report on the case of an adolescent with multiple microencephaloceles, in the anterolateral middle fossa floor, identified at surgery (temporal lobectomy) for intractable partial-onset seizures of temporal origin. Magnetic resonance imaging revealed only hippocampal atrophy. Subdural electrodes demonstrated ictal activity arising primarily from the anterior and lateral temporal lobe, close to the microencephaloceles, spreading to the anterior and posterior mesial structures. Pathological examination revealed diffuse temporal gliosis involving the hippocampus, together with microdysgenesis of the amygdala. The literature on epilepsy secondary to encephaloceles is reviewed and the contribution of the microencephaloceles to the seizure disorder in this patient is discussed

Diffusion characteristics of pediatric pineal tumors.

BACKGROUND: Diffusion weighted imaging (DWI) has been shown to be helpful in characterizing tumor cellularity, and predicting histology. Several works have evaluated this technique for pineal tumors; however studies to date have not focused on pediatric pineal tumors. OBJECTIVE: We evaluated the diffusion characteristics of pediatric pineal tumors to confirm if patterns seen in studies using mixed pediatric and adult populations remain valid. MATERIALS AND METHODS: This retrospective study was performed after Institutional Review Board approval. We retrospectively evaluated all patients 18 years of age and younger with pineal tumors from a single institution where preoperative diffusion weighted imaging as well as histologic characterization was available. RESULTS: Twenty patients (13 male, 7 female) with pineal tumors were identified: seven with pineoblastoma, four with Primitive Neuroectodermal Tumor (PNET), two with other pineal tumors, and seven with germ cell tumors including two germinomas, three teratomas, and one mixed germinoma-teratoma. The mean apparent diffusion coefficient (ADC) values in pineoblastoma (544 ± 65 × 10(–6) mm(2)/s) and pineoblastoma/PNET (595 ± 144 × 10(–6) mm(2)/s) was lower than that of the germ cell tumors (1284 ± 334 × 10(–6) mm(2)/s; p < 0.0001 vs pineoblastoma). One highly cellular germinoma had an ADC value of 694 × 10(–6) mm(2)/s. CONCLUSION: ADC values can aid in differentiation of pineoblastoma/PNET from germ cell tumors in a population of children with pineal masses

Pediatric extratemporal epilepsy presenting with a complex auditory aura

INTRODUCTION: Ear plugging (placing fingers in or covering the ears) is a clinical seizure semiology that has been described as a response to an unformed, auditory hallucination localized to the superior temporal neocortex. The localizing value of ear plugging in more complex auditory hallucinations may have more involved circuitry. We report on one child, whose aura was a more complex auditory phenomenon, consisting of a door opening and closing, getting louder as the ictus persisted. METHODS: This child presented, at four years of age, with brief episodes of ear plugging followed by an acute emotional change that persisted until surgical resection of a left mesial frontal lesion at 11 years of age. Scalp video-EEG, magnetic resource imaging, magnetoencephalography, and invasive video-EEG monitoring were carried out. RESULTS: The scalp EEG changes always started after clinical onset. These were not localizing, and encompassed a wide field over the bi-frontal head regions, the left side predominant over the right. Intracranial video-EEG monitoring with subdural electrodes over both frontal and temporal regions localized the seizure-onset to the left mesial frontal lesion. The patient has remained seizure-free since the resection on June 28, 2006, approximately one and a half years ago. CONCLUSION: Ear plugging in response to simple auditory auras localize to the superior temporal gyrus. If the patient has more complex, formed auditory auras, not only may the secondary auditory areas in the temporal lobe be involved, but one has to entertain the possibility of ictal-onset from the frontal cortex

Diffusion tensor imaging to evaluate commissural disconnection after corpus callosotomy

Abstract Introduction Corpus callosum transection can prevent propagation of epileptic discharges. If seizures persist after surgery, assessment of the efficacy of the transection requires knowledge that the commissural fibers have been disrupted. We evaluated whether diffusion tensor imaging (DTI) and diffusion tensor fiber tracking can assess the degree of callosal transection and determine which white matter pathways remain intact. Methods This HIPAA-compliant retrospective study was performed after Institutional Review Board approval. Patients who underwent corpus callosotomy with postoperative magnetic resonance imaging (MRI) that included DTI were identified. Axial DTI was performed with either 15 or 25 noncollinear directions of encoding. MRI and DTI were reviewed by two board-certified neuroradiologists to evaluate commissural disconnection. Results One hundred eleven patients underwent corpus callosotomy with postoperative MRI, of which 32 had postoperative DTI. Of these 32, there were 16 males and 16 females, with a mean age of 12.2±6.3 years (range 0.24 to 32.8 years, median 12.3). Eighteen patients had undergone complete callosal transection and 14 patients had partial callosal transection. Seventeen of 18 patients undergoing complete callosal transection had structural and diffusion tensor fiber tracking (DT-FT) evidence of complete transection. The forceps major was intact in all patients undergoing partial transection. At least some commissural fibers originating from the precuneus, postcentral gyrus, and posterior cingulate were intact in all six partial transections which spared the callosal isthmus. Conclusion DTI and DT-FT aid in the postoperative characterization in patients with callosal transection for seizure control. This can confirm whether the intended fibers have been disconnected, helping in the planning for possible further surgical intervention versus other therapies

Angiocentric glioma-induced seizures in a 2-year-old child

A 2-year-old child presented with medically refractory seizures and was found to have a right frontoparietal parasagittal angiocentric glioma. Depth electrodes were used to document ictal onset from within the tumor rather than from the surrounding tissues. Ictal activity then spread to a wide area on the cortical surface, including the region around the tumor and hand motor cortex. Lesionectomy permitted sparing of adjacent areas of eloquent cortex, and the child is now seizure-free on monotherapy