Cerebral cavernous malformations (CCMs) are hamartomatous vascular malformations characterized by abnormally enlarged capillary cavities without intervening brain parenchyma. They cause seizures and cerebral hemorrhages, which can result in focal neurological deficits. Three CCM loci have been mapped, and loss-of-function mutations were identified in the KRIT1 (CCM1) and MGC4607 (CCM2) genes. We report herein the identification of PDCD10 (programmed cell death 10) as the CCM3 gene. The CCM3 locus has been previously mapped to 3q26-27 within a 22-cM interval that is bracketed by D3S1763 and D3S1262. We hypothesized that genomic deletions might occur at the CCM3 locus, as reported previously to occur at the CCM2 locus. Through high-density microsatellite genotyping of 20 families, we identified, in one family, null alleles that resulted from a deletion within a 4-Mb interval flanked by markers D3S3668 and D3S1614. This de novo deletion encompassed D3S1763, which strongly suggests that the CCM3 gene lies within a 970-kb region bracketed by D3S1763 and D3S1614. Six additional distinct deleterious mutations within PDCD10, one of the five known genes mapped within this interval, were identified in seven families. Three of these mutations were nonsense mutations, and two led to an aberrant splicing of exon 9, with a frameshift and a longer open reading frame within exon 10. The last of the six mutations led to an aberrant splicing of exon 5, without frameshift. Three of these mutations occurred de novo. All of them cosegregated with the disease in the families and were not observed in 200 control chromosomes. PDCD10, also called "TFAR15," had been initially identified through a screening for genes differentially expressed during the induction of apoptosis in the TF-1 premyeloid cell line. It is highly conserved in both vertebrates and invertebrates. Its implication in cerebral cavernous malformations strongly suggests that it is a new player in vascular morphogenesis and/or remodeling.

Object Although endoscopic third ventriculostomy (ETV) has been accepted as a procedure of choice for the treatment of obstructive hydrocephalus, the outcome of this treatment remains controversial with regard to age, cause, and long-term follow-up results. The goal of this study was to assess the risk of failure associated with these factors in a retrospective cohort study. Methods Between 1999 and 2007, 368 ETVs were performed in 350 patients (165 patients < 18 years of age) with hydrocephalus at the University Hospital of Toulouse. Failure of ETV was defined as cases requiring any subsequent surgical procedure for CSF diversion or death related to hydrocephalus management. Results Tumors (53%), primary aqueductal stenosis (18%), and intracranial hemorrhage (13%) were the most common causes of hydrocephalus. The median follow-up period was 47 months (range 6–106 months), and the overall success rate was 68.5% (252 of the 368 procedures). Patients < 6 months of age had a 5-fold increased risk of ETV failure than older patients (adjusted hazard ratio [HRa] 5.0; 95% CI 2.4–10.4; p < 0.001). Hemorrhage-related (HRa 4.0; 95% CI 1.9–8.5; p < 0.001) and idiopathic chronic hydrocephalus (HRa 6.3, 95% CI 2.5–15.0, p < 0.001) had a higher risk of failure than other causes. Most failures (97%) occurred within 2 months of the initial procedure. The overall morbidity rate was 10%, although most complications were minor. Finally, the introduction of ETV in the authors' department reduced the number of shunt insertions and hospital admissions for shunt failures by half and was a source of cost savings. Conclusions Endoscopic third ventriculostomy is a safe procedure and an effective treatment option for hydrocephalus. Factors indicating potential poor ETV outcome seem to be very young children and hemorrhage-related and chronic hydrocephalus in adults.

Symptoms of Gerstmann syndrome can be found during direct brain mapping in the angular gyrus region. In this series of patients, sites producing interferences in writing, calculating, and finger recognition were demonstrated in the angular gyrus, which may or may not have been associated with object-naming, color-naming, or reading sites.

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We investigated the challenging diagnostic case of a ventricular cystic glioneuronal tumor with papillary features, by RNA sequencing using the Illumina TruSight RNA Fusion panel. We did not retrieve the SLC44A1-PRKCA fusion gene specific for papillary glioneuronal tumor, but an EWSR1-PATZ1 fusion transcript. RT-PCR followed by Sanger sequencing confirmed the EWSR1-PATZ1 fusion. It matched with canonic EWSR1 fusion oncogene, juxtaposing the entire N-terminal transcriptional activation domain of EWSR1 gene and the C-terminal DNA binding domain of a transcription factor gene, PATZ1. PATZ1 protein belongs to the BTB-ZF (broad-complex, tramtrack and bric-à-brac -zinc finger) family. It directly regulates Pou5f1 and Nanog and is essential to maintaining stemness by inhibiting neural differentiation. EWSR1-PATZ1 fusion is a rare event in tumors: it was only reported in six round cell sarcomas and in three gliomas of three exclusively molecular studies. The first reported glioma was a BRAF negative ganglioglioma, the second a BRAF negative glioneuronal tumor, not otherwise specified and the third, very recently reported, a high grade glioma, not otherwise specified. In our study, forty BRAF negative gangliogliomas were screened by FISH using EWSR1 break-apart probes. We performed methylation profiling for the index case and for seven out of the ten FISH positive cases. The index case clustered apart from other pediatric low grade glioneuronal entities, and specifically from the well-defined ganglioglioma methylation group. An additional pediatric intraventricular ganglioglioma clustered slightly more closely with ganglioglioma, but showed differences from the main ganglioglioma group and similarities with the index case. Both cases harbored copy number variations at the PATZ1 locus. EWSR1-PATZ1 gene fusion might define a new type of glioneuronal tumors, distinct from gangliogliomas.