Search

OBJECTIVE The objective of this study was to describe the clinical and neuroradiological characteristics of a cohort of preterm infants who had undergone external ventricular drain insertion as a temporary measure to treat posthemorrhagic ventricular dilatation. In addition, the authors investigated the factors predicting permanent shunt dependency. METHODS The authors retrospectively reviewed the medical records of a cohort of preterm infants who had undergone external ventricular drain insertion at Gaslini Children’s Hospital (Genoa, Italy) between March 2012 and February 2018. They also analyzed clinical characteristics and magnetic resonance imaging data, including diffusion- and susceptibility-weighted imaging studies, which were obtained before both catheter insertion and removal. RESULTS Twenty-eight infants were included in the study. The mean gestational age was 28.2 ± 2.7 weeks, and the mean birth weight was 1209 ± 476 g. A permanent ventriculoperitoneal shunt was inserted in 15/28 (53.6%) infants because of the failure of external ventricular drainage as a temporary treatment option. Compared with the shunt-free group, the shunt-dependent group had a significantly lower gestational age (29.3 ± 2.3 vs 27.2 ± 2.7 weeks, p = 0.035) and tended toward a lower birth weight (p = 0.056). None of the clinical and neuroradiological characteristics significantly differed between the shunt-free and shunt-dependent groups at the time of catheter insertion. As expected, ventricular parameters as well as the intraventricular extension of intracerebral hemorrhage, as assessed using the intraventricular hemorrhage score, were reportedly higher in the shunt-dependent group than in the shunt-free group before catheter removal. CONCLUSIONS External ventricular drainage is a reliable first-line treatment for posthemorrhagic hydrocephalus. However, predicting its efficacy as a unique treatment remains challenging. A lower gestational age is associated with a higher risk of posthemorrhagic hydrocephalus progression, suggesting that the more undeveloped the mechanisms for the clearance of blood degradation products, the greater the risk of requiring permanent cerebrospinal fluid diversion, although sophisticated MRI investigations are currently unable to corroborate this hypothesis.

Background Coronavirus disease-2019 (COVID-19) pandemic had a great impact over all elective neurosurgical activity and important implications in management of neurosurgical urgencies. During the pandemic, some pediatric hospitals reported their experiences. After the emergency phase of the COVID-19 pandemic, the health care system needs to be reorganized to again manage all nonurgent activities, while ensuring safety of both patients and health care workers. Methods We developed preventive measures to limit any possibility of COVID-19 spread, according to the principles of epidemiologic prevention and suggestions from recent literature. To evaluate the efficacy of these measures, we retrospectively reviewed the neurosurgical activity at our institution from May 4 to July 15, 2020. Results One hundred nineteen patients were admitted to the neurosurgical ward, and 80 surgical procedures were performed. Furthermore, 130 outpatient clinics were scheduled. A total of 258 nasopharyngeal swabs and 249 specific interviews were performed. In our series, no cases of positivity for severe acute respiratory syndrome coronavirus-2 infection were found, and no surgical cases were postponed. Discussion We present the management of the neurosurgical activity after the emergency phase at the Neurosurgical Department of Giannina Gaslini Children's Hospital in Genoa, Italy. Conclusions The Italian health care system is undertaking a process of reorganization of resources, in an attempt to restore all nonurgent activities while ensuring safety. After the emergency phase, we are learning to live together with COVID-19 and, although epidemiologic data are encouraging, we must be prepared for an eventual second peak.

Purpose: The craniometrics of head circumference (HC) and ventricular size are part of the clinical assessment of infants with hydrocephalus and are often utilized in conjunction with other clinical and radiological parameters to determine the success of treatment. We aimed to assess the effect of endoscopic third ventriculostomy (ETV) and shunting on craniometric measurements during the follow-up of a cohort of infants with symptomatic triventricular hydrocephalus secondary to aqueductal stenosis. Methods: We performed a post hoc analysis of data from the International Infant Hydrocephalus Study (IIHS)-a prospective, multicenter study of infants (< 24 months old) with hydrocephalus from aqueductal stenosis who were treated with either an ETV or shunt. During various stages of a 5-year follow-up period, the following craniometrics were measured: HC, HC centile, HC z-score, and frontal-occipital horn ratio (FOR). Data were compared in an analysis of covariance, adjusting for baseline variables including age at surgery and sex. Results: Of 158 enrolled patients, 115 underwent an ETV, while 43 received a shunt. Both procedures led to improvements in the mean HC centile position and z-score, a trend which continued until the 5-year assessment point. A similar trend was noted for FOR which was measured at 12 months and 3 years following initial treatment. Although the values were consistently higher for ETV compared with shunt, the differences in HC value, centile, and z-score were not significant. ETV was associated with a significantly higher FOR compared with shunting at 12 months (0.52 vs 0.44; p = 0.002) and 3 years (0.46 vs 0.38; p = 0.03) of follow-up. Conclusion: ETV and shunting led to improvements in HC centile, z-score, and FOR measurements during long-term follow-up of infants with hydrocephalus secondary to aqueductal stenosis. Head size did not significantly differ between the treatment groups during follow-up, however ventricle size was greater in those undergoing ETV when measured at 1 and 3 years following treatment.

BACKGROUND Post-haemorrhagic ventricular dilatation (PHVD) still represents an important cause of brain injury in premature infants. Intervention for PHVD is recommended once Ventricular Index (VI) crosses the 97th percentile + 4 mm line according to Levene. OBJECTIVES We aimed to compare PHVD severity, timing of intervention, and outcome between outborn infants transferred to a level IV NICU in order to be treated for PHVD and a control population of inborn infants. METHODS Preterm infants with PHVD requiring treatment were divided into: outborn infants (transferred to our NICU in order to be treated for PHVD) and inborn infants (PHVD diagnosed at our NICU). Age at intervention, difference between VI and the 97th percentile according to postmenstrual age (VI-p97), permanent shunt rate, and developmental delay rate were compared between the two groups. Neurodevelopmental outcome was assessed using the Vineland Adaptive Behavior Scales II (VABS-II), a parental questionnaire investigating four domains of adaptive behaviour and overall adaptive functioning. Developmental delay was defined as a score

Cerebellar tonsil herniation comprises a spectrum of disorders sharing a common neuroimaging finding consisting of downward displacement of the cerebellar tonsils through the foramen magnum and into the upper cervical spinal canal. This not uncommon condition may result from a large host of congenital or acquired causes, and confusion regarding its classification and pathogenesis still exists. Terminology also remains heterogeneous, including inconsistencies in the usage of the "Chiari 1" monicker. In this paper, the hypothesized mechanisms of development of tonsillar herniation are reviewed and strategies of management are discussed, with particular attention to surgical options adapted to the underlying etiology. A focus will be placed on acquired causes of tonsillar herniation.

Background Nontraumatic atlantoaxial subluxation, also known as Grisel syndrome, is a rare disease that usually affects children. The typical presentation is torticollis in patients with a history of surgical operations or airway infections. Methods We describe 5 patients with Grisel syndrome, referring to medical care for a torticollis, a few weeks after an airway infection, with no trauma associated. Radiologic confirmation of the diagnosis, with computed tomography and magnetic resonance imaging studies, was carried out. Results The patients were treated with external immobilization for 3 months, followed by surgical fixation in the case of recurrence after collar removal or inveterate subluxation. We performed a review of the literature to define the best management of this disease. Conclusions Management of Grisel syndrome depends on the degree of subluxation basing on the Fielding and Hawkins classification. The initial nonsurgical management consists of close reduction and immobilization. Surgical fixation is indicated in cases of conservative treatment failure.

Hemispheric surgery is an effective and cost-effective option for hemispheric epilepsy. Data specifically focusing on very early infancy are scant. In our study, we report the results of hemispheric surgery in children under three years of age, along with clinical, neuroradiological and EEG features, from two Italian epilepsy surgery centres. After reviewing our epilepsy surgery databases (2008-2018), we identified 14 patients (seven males) submitted to hemispheric surgery, under three years (range: 2-29 months), with a follow-up of at least 12 months. No deaths occurred, and surgical complications were observed in 3/17 procedures. At final follow-up visit (mean: 30.8 months; range: 12-90), 10/14 patients (71.4%) achieved Engel Class I (eight Class 1A, one Class 1B, and one Class 1C). Antiepileptic drugs were completely discontinued in three and reduced in eight, thus a significant decrease in drug regimen after surgery was achieved in 11/14 patients (78.6%). Before surgery, severe developmental delay was present in 10 patients, moderate in two and mild in two. At the last follow-up visit, the degree of developmental delay changed from severe to moderate in five patients, remained unchanged in six cases (four severe and two moderate), and changed from mild to moderate in two following surgery. In many cases, hemispheric surgery in children under three years is effective in achieving seizure freedom or reducing seizure frequency, with the possibility of simplifying complex drug regimens. Moreover, it appears to be a safe and well tolerated procedure, leading to improvement in cognition and posture.

Background Various strategies have been proposed for the treatment of gelastic seizures due to hypothalamic hamartomas (HH), advancing from surgical removal techniques toward functional disconnection strategies. One of the most recent procedure is the Magnetic Resonance guided Laser Interstitial Thermal Therapy (MRg-LITT), which has progressively proved to be a safe and effective technique for hamartomas ablation. In this paper, the authors' preliminary experience with the first two patients treated with this technique in Italy is presented, in order to underline the feasibility of a pure non robotized frameless technique (FS MRg-LITT) while confirming the procedure effectiveness on seizure control. Methods Patients undergoing FS MRg-LITT for the treatment of HH related gelastic seizures since January 2020 were included. A two steps procedure was performed by using the neuronavigation system to define the entry point, the trajectories and to assess the accuracy. Visualase Laser Ablation System was then used for the MR guided ablation of the HH. A multidisciplinary (neurosurgeons, epileptologist, neuroradiologist) institutional board evaluated the patients both in the perioperative period and during follow up. Results A total number of 2 pediatric patients were described. The mean operative time resulted to be 6 hours while the mean accuracy was 0.4 mm. No peri-operative complications were reported. The mean length of stay was 4 days. Lastly, at 1-year follow up both patients resulted to be seizure free and endocrinological functions were preserved. Conclusions FS MRg-LITT for the treatment of HH-related epilepsy could represent an effective technique, being able to guarantee adequate level of accuracy and potentially extending the accessibility of MRg-LITT by lowering its costs and simplifying the overall procedure.

We describe a rare case of functioning gonadotropins-producing pediatric adenoma immunostaining positively for FSH and focally for TSH causing central precocious puberty associated to central hypothyroidism in a 6 year-old girl.Clinical evaluation revealed precocious puberty, as confirmed by hormonal determination with elevated FSH and estradiol, while central hypothyroidism was biochemically diagnosed by a low fT4 and normal TSH. Head MRI showed the presence of a hyperintense pituitary lesion. The patient successfully underwent transsphenoidal endoscopic resection of the pituitary macroadenoma.Pathologic evaluation of the tissue resected at surgery confirmed the diagnosis of pituitary adenoma with positive immunohistochemistry for FSH and focally for TSH in a mixed pattern. Ten months after surgery, there were no neurological signs and symptoms. Postoperative head MRI showed no abnormalities and no evidence of tumor regrowth.Early and accurate diagnosis, multidisciplinary approach and close follow up are crucial factors for the favorable outcome.

Brain tumors are the most common solid tumors in childhood. There is the need for biomarkers of residual disease, therapy response and recurrence. Cerebrospinal fluid (CSF) is a source of brain tumor biomarkers. We analyzed the proteome of waste CSF from extraventricular drainage (EVD) from 29 children bearing different brain tumors and 17 controls needing EVD insertion for unrelated causes. 1598 and 1526 proteins were identified by liquid chromatography-coupled tandem mass spectrometry proteomics in CSF control and brain tumor patients, respectively, 263 and 191 proteins being exclusive of either condition. Bioinformatic analysis revealed promising protein biomarkers for the discrimination between control and tumor (TATA-binding protein-associated factor 15 and S100 protein B). Moreover, Thymosin beta-4 (TMSB4X) and CD109, and 14.3.3 and HSP90 alpha could discriminate among other brain tumors and low-grade gliomas plus glyoneuronal tumors/pilocytic astrocytoma, or embryonal tumors/medulloblastoma. Biomarkers were validated by ELISA assay. Our method was able to distinguish among brain tumor vs non-tumor/hemorrhagic conditions (controls) and to differentiate two large classes of brain tumors. Further prospective studies may assess whether the biomarkers proposed by our discovery approach can be identified in other bodily fluids, therefore less invasively, and are useful to guide therapy and predict recurrences.

Moyamoya vasculopathy is a rare chronic cerebrovascular disorder characterized by the stenosis of the terminal branches of the internal carotid arteries and the proximal tracts of anterior and middle cerebral arteries. Although surgical revascularization does not significantly change the underlying pathogenic mechanisms, it plays a pivotal role in the management of affected individuals, allowing to decrease the risk of ischemic and hemorrhagic complications. Surgical approaches may be direct (extracranial-intracranial bypass), indirect, or a combination of the two. Several indirect techniques classifiable according to the tissue (muscle, periosteum, galea, dura mater, and extracranial tissues) or vessel (artery) used as a source of blood supply are currently available. In this study, we reviewed the pertinent literature and analyzed the advantages, disadvantages, and pitfalls of the most relevant indirect revascularization techniques. We discussed the technical aspects and the therapeutical implications of each procedure, providing a current state-of-the-art overview on the limits and pitfalls of indirect revascularization in the treatment of moyamoya vasculopathy.

Background Moyamoya disease (MMD) is a chronic, occlusive cerebrovascular disease characterized by bilateral steno-occlusive changes at the terminal portion of the internal carotid arteries and an abnormal vascular network at the base of the brain determining stroke in children. Patients with a similar vasculopathy and associated conditions are affected by the moyamoya syndrome (MMS). Most of the studies focused on MMD were carried out on East-Asian population. Ring Finger 213 (RNF213) has been identified as the strongest susceptibility gene for MMD in East-Asian people. Overall, 74.5% of the East-Asian patients carry the founder variant p.Arg4810Lys of RNF213 never reported in Caucasians. A different genetic landscape among the diverse ethnic populations seems to exist. Methods We sequenced the coding sequence region of RNF213, TGFB1 and PDGFRB in 21 ethnically homogeneous Italian children with moyamoya; comprehensive sequencing data are available from parents of eight of them. The analyses were carried out by NGS on Thermo-fisher PGM platform. We also performed a comprehensive review of the literature about the variations of these three genes in Caucasian patients. Results Several new variants of RNF213 gene were detected, in particular, two new pathogenic mutations on RNF213 (p.Trp4677Leu and p.Cys4017Ser) were identified in one MMS case and in one MMD case, respectively. Moreover, in a MMS case a new probably causing disease mutation p.Pro1063Thr of PDGFRB was detected. Conclusions The genetic susceptibility of Asian moyamoya vasculopathy seems to differ from the Caucasian disease. No additional differences seem to exist between MMD and MMS.

Arachnoid cysts may present with symptoms deriving from cyst rupture, usually causing intracystic hemorrhage and subdural hematoma or hygroma. Rupture is usually caused by minor trauma, spontaneous rupture is an exceptional event, and 57 cases have been described in literature. We here present and discuss the largest series of spontaneously ruptured middle fossa arachnoid cysts in order to investigate clinical presentation and best treatment available. We report a retrospective series of 17 pediatric patients surgically treated for middle fossa arachnoid cyst with signs of cyst rupture without a history of trauma in the previous 90 days. We describe clinical presentation, treatment, and outcome at follow-up discussing our results with a literature review including all reported cases of spontaneous rupture of middle fossa arachnoid cysts. In our experience patients most frequently presented with subdural hygroma, in literature, a chronic hematoma was most frequently reported. Headache is the most reported symptom at presentation. Neurological deficits and consciousness alterations are rare. Surgical treatment may resolve brain compression only or reduce rupture recurrence risk. Conservative treatment has also been proposed. Different treatments are reported and discussed focusing on indications, contraindications, risks, and expected benefits. We propose, when safely possible, microsurgical cyst fenestration in skull base cisterns as the treatment of choice for these patients as long as it addresses both immediate decompression and risk of rupture recurrence. We report good outcomes and low incidence of complications from our series with a mean postoperative follow-up of 30 months.

Since external ventricular drainage (EVD) related infections are usually due to skin flora, an extradural intra/extra-cranial accessory device, developed for pediatric patients under three years of age undergoing EVD positioning, is described. The aim of this paper is to provide technical description of this device, underlining the possibility to reduce infective risk and to prevent EVD dislocation.Patients undergoing A-D device EVD placement between 1990 and 2017 at authors' institution were retrospectively considered. The device was made of a fully MRI-compatible inert material (Ketron-Peek-1000), composed of two pieces securely fixable to the skull, bridging the catheter directly from the epidural space to the extracranial space without letting it come in contact with the skin.A total number of 350 patients were considered. The mean age was 1.4 years, being the youngest patient a newborn of 25 weeks of gestational age. Mean time of EVD maintenance was 45 days, ranging from 21 to 81 days. 2 cases (0.6%) of EVD related infections were reported, while, pull-out of the ventricular catheter occurred in 3 cases (0.9%). No cases of bone fractures related to the clamp effect provided by A-D device were reported in the series CONCLUSIONS: This device could represent a safe and feasible option to reduce EVD related infections and catheter pull-out in pediatric patients. The encouraging results could strength the aim of the device to allow safer and longer length of CSF drainage. Moreover, the fully MRI-compatible nature and its non-magnetic properties allow to use it with neuronavigation systems.

Introduction: Moyamoya disease is a steno-occlusive cerebrovascular disease of unknown etiology involving the terminal portion of the internal carotid artery and the proximal portions of the anterior and middle cerebral arteries with associated collateral vascular network. When the vascular pattern is associated with a particular condition (e.g., Type 1 neurofibromatosis, Down syndrome), it is defined as moyamoya syndrome (MMS) (or quasi-moyamoya). Among different indirect bypass techniques used to prevent ischemic injury by increasing collateral blood flow to hypoperfused areas of the cortex, multiple burr holes technique is an easy and diffuse indirect revascularization approach in the treatment of moyamoya. Discussion: While the effectiveness in patients with moyamoya disease was demonstrated, its role in MMS remains uncertain. In this study, we describe surgical and diagnostic implications in three pediatric cases of moyamoya sydrome unsuccessfully treated with multiple cranial burr hole technique. A critical review of the literature about the use of the surgical indirect revascularization techniques in pediatric patients was also reported.

BACKGROUND AND PURPOSE: Indirect revascularization surgery is an effective treatment in children with Moyamoya vasculopathy. In the present study, we hypothesized that DSC-PWI may reliably assess the evolution of CBF-related parameters after revascularization surgery, monitoring the outcome of surgical pediatric patients with Moyamoya vasculopathy. Thus, we aimed to evaluate differences in DSC-PWI parameters, including the hemodynamic stress distribution, in surgical and nonsurgical children with Moyamoya vasculopathy and to correlate them with long-term postoperative outcome. MATERIALS AND METHODS: Pre- and postoperative DSC parameters of 28 patients (16 females; mean age, 5.5 ± 4.8 years) treated with indirect revascularization were compared with those obtained at 2 time points in 10 nonsurgical patients (6 females; mean age, 6.9 ± 4.7 years). We calculated 4 normalized CBF-related parameters and their percentage variance: mean normalized CBF of the MCA territory, mean normalized CBF of the proximal MCA territory, mean normalized CBF of cortical the MCA territory, and hemodynamic stress distribution. The relationship between perfusion parameters and postoperative outcomes (poor, fair, good, excellent) was explored using 1-way analysis of covariance (P < .05). RESULTS: A significant decrease of the mean normalized CBF of the proximal MCA territory and hemodynamic stress distribution and an increase of the mean normalized CBF of the cortical MCA territory were observed after revascularization surgery (P < .001). No variations were observed in nonsurgical children. Postoperative hemodynamic stress distribution and its percentage change were significantly different in outcome groups (P < .001). CONCLUSIONS: DSC-PWI indices show postoperative hemodynamic changes that correlate with clinical outcome after revascularization surgery in children with Moyamoya disease.

We studied the intellectual profiles of 13 Italian children diagnosed with spina bifida myelomeningocele and shunted hydrocephalus (MMC HC) against a control group of children. The results showed that MMC HC group had lower performance in all subtests, four indices, and the FSIQ of the Wechsler Intelligence Scale for Children, forth-edition. The MMC HC group showed flat cognitive profiles between subtests within each index and between four core indices. However, the cognitive abilities that were mostly impaired seemed to be related to visual selective and focused attention, to visual acuity, to visuo-perceptive organization and visuomotor integration and to visual short-term memory.

Objective Vein of Galen aneurysmal malformation (VGAM) is a rare fetal anomaly, the neurological outcome of which can be good with appropriate perinatal management. However, most fetal series are too small to allow reliable statistical assessment of potential prognostic indicators. Our aim was to assess, in a two-center series of 49 cases, the prognostic value of several prenatal variables, in order to identify possible prenatal indicators of poor outcome, in terms of mortality and cerebral disability. Methods This was a retrospective study involving 49 cases of VGAM diagnosed prenatally and managed at two centers over a 17-year period (1999–2015). All cases had undergone detailed prenatal cerebral and cardiac assessment by grayscale ultrasound, color and pulsed-wave Doppler and magnetic resonance imaging (MRI). Ultrasound and MRI examination reports and images were reviewed and outcome information was obtained from medical reports. Volume of the VGAM (on ultrasound and MRI) was calculated and development of straight-sinus dilatation, ventriculomegaly and other major brain abnormalities was noted. Cardiothoracic ratio, tricuspid regurgitation and reversed blood flow across the aortic isthmus were evaluated on fetal echocardiography. Major brain lesions were considered by definition to be associated with poor outcome in all cases. Pregnancy and fetoneonatal outcome were known in all cases. Fetoneonatal outcome and brain damage were considered as dependent variables in the statistical evaluation. Poor outcome was defined as death, late termination of pregnancy due to association with related severe brain anomalies or severe neurological impairment. Results At a mean follow-up time of 20 (range, 0–72) months, 36.7% of the whole series and 52.9% of the cases which did not undergo late termination were alive and free of adverse sequelae. Five (10.2%) cases showed progression of the lesion between diagnosis and delivery. On univariate analysis, dilatation of the straight sinus, VGAM volume ≥ 20 000 mm3 and tricuspid regurgitation were all significantly related to poor outcome. However, on logistic regression analysis, the only variables associated significantly with poor outcome were tricuspid regurgitation and, to a lesser extent, VGAM volume ≥ 20 000 mm3. The former was also the only variable associated with brain damage. Conclusions Major brain lesions, tricuspid regurgitation and, to a lesser extent, VGAM volume ≥ 20 000 mm3 are the only prenatal variables associated with poor outcome in fetal VGAM. Prenatal multidisciplinary counseling should be based on these variables. Copyright © 2016 ISUOG. Published by John Wiley & Sons Ltd.

// Giovanni Morana 1, * , Cesar Augusto Alves 1, 2, * , Domenico Tortora 1 , Mariasavina Severino 1 , Paolo Nozza 3 , Armando Cama 4 , Marcello Ravegnani 4 , Gabriella D’Apolito 5 , Alessandro Raso 4 , Claudia Milanaccio 6 , Claudia da Costa Leite 2 , Maria Luisa Garre 6 and Andrea Rossi 1 1 Neuroradiology Unit, Istituto Giannina Gaslini, Genova, Italy 2 Radiology Institute, Hospital das Clinicas, Sao Paulo, Brazil 3 Pathology Unit, Istituto Giannina Gaslini, Genova, Italy 4 Neurosurgery Unit, Istituto Giannina Gaslini, Genova, Italy 5 Neuroradiology Unit, Ospedale M. Bufalini, Cesena, Italy 6 Neuro-Oncology Unit, Istituto Giannina Gaslini, Genova, Italy * co-first authorship Correspondence to: Giovanni Morana, email: giovannimorana@gaslini.org Keywords: DWI, CNS embryonal tumors, medulloblastoma, ATRT, relapse Received: February 17, 2017 Accepted: June 16, 2017 Published: July 25, 2017 ABSTRACT Diffusion weighted imaging (DWI) has an established role in primary CNS embryonal tumor (ET) characterization; however, its diagnostic utility in detecting relapse has never been determined. We aimed to compare DWI and conventional MRI sensitivity in CNS ET recurrence detection, and to evaluate the DWI properties of contrast-enhancing radiation induced lesions (RIL). Fifty-six patients with CNS ET (25 with disease relapse, 6 with RIL and 25 with neither disease relapse nor RIL) were retrospectively evaluated with DWI, conventional MRI (including both T2/FLAIR and post-contrast images), or contrast-enhanced MR imaging (CE-MRI) alone. MRI studies were independently reviewed by two neuroradiologists for detection and localization of potential brain relapses. Sensitivity for focal relapse detection was calculated for each image set on a lesion-by-lesion basis. A descriptive per subject analysis was also performed. Evaluation of follow-up MRI studies served as standard of reference. Focal recurrence detection sensitivity of DWI (96%) was significantly higher than conventional MRI (77%) and CE-MRI alone (51%) (p=0.0003 and p

Background Over the last decades, significant advancements have been achieved in the treatment of pediatric brain tumors as a result of radiation therapy (RT). With the increasing diffusion of this treatment, iatrogenic damage to cerebrovascular tissues contouring the radiation target volume has become the subject of debate, especially radiation-induced moyamoya syndrome (RIMS). Methods A systematic literature search was performed on the association between moyamoya vasculopathy and cranial irradiation in children. Large case series of patients with moyamoya were analyzed and clinicoradiologic data were collected reviewing pediatric patients treated with RT for primary brain tumors at our institution. Results The risk of developing RIMS is higher in younger children, in patients with optic pathway glioma, and in those receiving higher radiation doses. Headache is the most common presenting symptom and cerebral infarction is frequent. The preferred surgical techniques were pial synangiosis and encephaloduroarteriosynangiosis. In our case series, surgical revascularization led to neovascularization, with clinical improvement or stability in all patients. Medical therapy did not significantly affect the clinical course. Conclusions Pediatric patients receiving involved field RT for the treatment of brain tumors have an increased risk of developing RIMS. Prompt diagnosis and early surgical revascularization play a pivotal role in decreasing the clinical impact of this complication. The use of new techniques, such as the intensity-modulated RT, and the increasing dose saving for the organs at risk, are essential to prevent iatrogenic vasculopathy. The combination of appropriate medical therapy and surgery will improve patient management and clinical outcome.

Chiari malformation type I (CMI), a rare disorder of the craniocerebral junction with an estimated incidence of 1 in 1280, is characterized by the downward herniation of the cerebellar tonsils of at least 5 mm through the foramen magnum, resulting in significant neurologic morbidity. Classical CMI is thought to be caused by an underdeveloped occipital bone, resulting in a posterior cranial fossa which is too small to accommodate the normal-sized cerebellum. In this review, we dissect the lines of evidence supporting a genetic contribution for this disorder. We present the results of two types of approaches: animal models and human studies encompassing different study designs such as whole genome linkage analysis, case-control association studies, and expression studies. The update of the literature also includes the most recent findings emerged by whole exome sequencing strategy. Despite evidence for a genetic component, no major genes have been identified and the genetics of CMI is still very much unknown. One major challenge is the variability of clinical presentation within CMI patient population that reflects an underlying genetic heterogeneity. The identification of the genes that contribute to the etiology of CMI will provide an important step to the understanding of the underlying pathology. The finding of a predisposing gene may lead to the development of simple and accurate diagnostic tests for better prognosis, counseling, and clinical management of patients and their relatives.

Describe presentation and management of Chiari type 1 malformation. We report our surgical case series proposing a decision making scheme for helping surgeons decide which surgical procedure to perform and when. We retrospectively examined a series of surgically treated patients with Chiari type 1 malformation. Treatment of associated anomalies, surgical complications, and need for reintervention for insufficient decompression at first surgery are discussed. A total of 172 patients have been surgically treated for Chiari type 1 malformation at the Neurosurgery Unit of IRCCS Giannina Gaslini Children Hospital of Genoa, Italy, in a period between 2006 and 2017. The first treatment addressing Chiari type 1 malformation was bone and ligamentous decompression alone in 104 patients (65%), associated with dural delamination in 3 patients (1.9%) and associated with duraplasty with autologous graft in 53 patients (33.1%). Postoperative complications occurred in 5 patients (2.9%). Reintervention for insufficient decompression at follow-up was needed in 6 patients (3.5%). Surgical decompression of the posterior cranial fossa (PCF) is indicated in symptomatic patients while asymptomatic patients must be followed in a wait and see fashion. Different types of surgical decompression of different invasiveness have been proposed from only bone and ligamentous decompression to coagulation of cerebellar tonsils. Intraoperative ultrasonography is a useful tool to define when a decompression is sufficient. We did not find correlation between the need for reintervention for insufficient decompression and different invasiveness of the techniques. We believe that this finding suggests that our proposed scheme leads to the best tailored treatment for the single patient.

Background In the last years, numerous studies evaluated different tools for the diagnosis of positional plagiocephaly (PP). The purpose of this study was to evaluate ultrasonography (US) as a first line screening test of lambdoid sutural patency in child with PP and to compare our results with the literature. Materials and methods All consecutive patients who referred to our Institute from January 2016 to October 2017 with the suspicion of PP, were included in the study and performed US examination of the lambdoid sutures. A 3-6 month clinical follow up was performed by a paediatric neurosurgeon or a paediatrician to confirm the diagnosis of PP. Results Thirty-five children performed US examination and in all cases the diagnosis of PP was confirmed. No cases of anticipated suture fusion were examined during this period. The concordance between US findings and clinical exam follow-up was 100%. Conclusions Ultrasonography of the lambdoid sutures represents an ideal first-line screening test and reliable alternative to other diagnostic techniques for lambdoid sutural patency in child with PP, being radiation free, fast and cheap.

Background Bilateral lambdoid and posterior sagittal synostosis is a rarely encountered multisutural craniosynostosis accounting for 0.3%−0.7% of all craniosynostoses. It has been named “Mercedes−Benz Syndrome” (MBS) because of the bone ridges that resemble the Mercedes−Benz logo. The typical head shape is usually described as anterior turricephaly combined with mild brachycephaly. We describe a case of pure MBS without involvement of other sutures. Since we believe that MBS is a different pathology when other sutures are involved, we will discuss our case with a review of the literature, including all reported cases of bilateral lambdoid and posterior sagittal synostosis with no other sutures involved but sagittal and bilateral lambdoid. Case Description A 3-month-old female baby came to our attention because of a turrycephalic appearance of the head. Findings of the neurologic examination were unremarkable. Computed tomography scan showed premature fusion of posterior third of sagittal suture and bilateral lambdoid suture. Magnetic resonance imaging did not show relevant intracranial abnormalities. She underwent sagittal decompression extended posteriorly below the lambdoid suture combined with biparietal decompression to obtain expansion of both parieto-frontal bones and posterior fossa. Post-operative course was uneventful. Follow-up at 3 months showed a good aesthetic result, and results of the neurologic examination were unremarkable. Conclusions Pure MBS is a rare condition that unlike other multisutural complex craniosynostosis is rarely associated with genetic syndromes, has a low rate of associated intracranial anomalies, and has less need for more skull-remodeling surgery. The choice of the most suitable surgical procedure must be tailored on the patient, considering preoperative head appearance and eventually associated anomalies.

Objective Given the lack of significant responses to many queries regarding behavior, treatment options, and possible prevention of iatrogenic intraspinal inclusion tumors (IITs), we think that further clinical, radiologic, and follow-up data are mandatory to better characterize this entity. We retrospectively reviewed a series of 14 consecutive patients with IIT occurring after myelomeningocele repair. The long follow-up is a mainstay of this series and may help a better understanding of the history of this slow-growing disease. To date, this is the largest series of IITs after myelomeningocele repair reported in the literature. Methods A retrospective chart review was performed to identify all cases of surgically repaired myelomeningocele at the Department of Neurosurgery of G. Gaslini Children’s Hospital in Genoa, from January 1993 to January 2018. Among them, data regarding patients in whom an IIT developed were recovered. The medical records of these patients and their clinical history, neurologic examination, and diagnostic workup were reviewed. Results From January 1993 to January 2018, 160 cases of myelomeningocele were surgically treated. Among them, 14 cases of IIT developed. The mean time between myelomeningocele repair and IIT diagnosis was 94.7 months. The mean follow-up time was 60.1 months. Conclusions It is well established that IITs may be discovered in patients who have previously undergone myelomeningocele repair. In our series, with a long follow-up time, we describe the possible range of behavior of such lesions and the utility of surgical treatment of primary therapy. Our series confirms that residual IITs showed marked stability during our long follow-up.

// Samantha Mascelli 1 , Paolo Nozza 2 , David T.W. Jones 3 , Carole Colin 4 , Angela Pistorio 5 , Claudia Milanaccio 1 , Marcello Ravegnani 1 , Alessandro Consales 1 , Olaf Witt 6 , Giovanni Morana 7 , Armando Cama 1 , Valeria Capra 1 , Roberto Biassoni 8 , Stefan M. Pfister 3, 6 , Dominique Figarella-Branger 4, 9 , Maria Luisa Garre 10 , Alessandro Raso 1 1 Dipartimento Testa, Collo e Neuroscienze, Istituto Giannina Gaslini, 16147 Genoa, Italy 2 UOC Anatomia Patologica, Istituto Giannina Gaslini, 16147 Genoa, Italy 3 Division of Paediatric Neurooncology, German Cancer Research Center (DKFZ), Heidelberg 69120, Germany 4 CRO2 UMR_S911, Inserm, Aix-Marseille Universite, 13385 Marseille, France 5 Epidemiologia, Biostatistica e Comitati, Istituto Giannina Gaslini, 16147 Genoa, Italy 6 Department of Paediatric Oncology, Haematology and Immunology, University of Heidelberg, Heidelberg, 69120 Heidelberg, Germany 7 Neuroradiologia Istituto Giannina Gaslini, 16147 Genoa, Italy 8 Laboratory Molecular Medicine, Translational Medicine Department, Istituto Giannina Gaslini, 16147 Genoa, Italy 9 APHM, Hopital de la Timone, Service d’Anatomie Pathologique et de Neuropathologie, 13385 Marseille, France 10 Centro di Neuro-Oncologia, Istituto Giannina Gaslini, 16147 Genoa, Italy Correspondence to: Samantha Mascelli, email: SamanthaMascelli@gaslini.org Keywords: low-grade gliomas, polymorphism, pilocytic astrocytoma, paediatric, TP53 Received: March 25, 2016 Accepted: May 10, 2016 Published: June 25, 2016 ABSTRACT Pilocytic astrocytoma and ganglioglioma may occur in inaccessible or surgically difficult areas. In case of incomplete resection, the availability of biological predictors of tumour progression could be particularly important. To this end, an analysis of p53 codon 72 polymorphism and assessment of its role as prognostic marker were performed. The status of the p53 Arg72Pro polymorphism was evaluated by pyrosequencing method in a multicenter cohort of 170 paediatric patients. Genotype/phenotype associations were investigated either by means of bivariate or multivariate analyses. In the partially resected pilocytic astrocytomas, the Arg/Arg variant predicts early tumour progression (median survival time: 23.1 months) and is associated with poor event-free survival ( p value = 0.0009). This finding remains true also in case of adjuvant therapies, with a 5-year event-free survival of 30.6% for cases with Arg/Arg variant vs. 78.7% for those with other genotypes. There is no association between ganglioglioma and the polymorphism. The assessment of Arg/Arg variant could improve the management of pilocytic astrocytoma. TP53 codon 72 analysis could distinguish low-risk cases, in which surgery could be conservative, from high-risk cases needing an aggressive surgery plan.

Pediatric and perinatal stroke can present as an early symptom in undiagnosed syndromes characterized by simple Mendelian inheritance. In order to diagnose those patients affected with a monogenic disorder in which an arterial cerebrovascular event or arteriopathy may have preceded any other specific symptom, we aimed to establish and validate a targeted gene panel, and to determine its diagnostic yield and clinical utility. To this end, thirty-eight patients were selected with heterogeneous cryptogenic stroke phenotypes, mostly including multiple and recurrent ischemic or hemorrhagic arterial strokes and porencephalies, variably associated with calcifications, intracranial or systemic steno-occlusive arteriopathies, positive family history, and syndromic conditions. Clinical and neuroradiological data were collected for every patient enrolled in the study, and DNA samples were tested by means of a customized gene panel including 15 genes associated with known genetic diseases related to pediatric stroke. In four patients (10.5%) the analyses unraveled pathogenetic variants in ABCC6 and COL4A1 genes, leading to a definite genetic diagnosis with a great beneficial impact on patients management, while results were null in the remaining patients. These findings suggest a high complexity and variability of the included stroke phenotypes, that could not be fully accounted for by the genes tested in the present study. A wider gene panel or an unbiased genomic approach may be better suited and advisable to explain a greater proportion of pediatric and perinatal stroke events.

Background Dermoid and epidermoid cysts are among the most frequent lesions of the scalp in the pediatric population. Optimal management of a suspected dermoid or epidermoid cyst in children is debated: Some authors advocate conservative management on the basis of the benign histology of these entities, while others prefer surgical excision. Objective Our objective is to demonstrate that excision of dermoid and epidermoid cysts is a safe procedure and that early surgery is effective in preventing potential complications related to cyst growth. Methods We retrospectively collected data on patients who underwent surgery for excision of proven dermoid or epidermoid cysts between January 2006 and October 2017. Results In 234 patients, 237 cysts were excised. Mean age at presentation was 26.99 ± 32.7 months; 48.7% of patients were operated on between 1 and 3 years of age, and 32.9% were younger than 1 year of age. Cysts were more frequently located in the frontal bone than in occipital and supraorbital regions. In 36.28% of cases there was no significant cranial impingement, while 21.94% of the cysts eroded through a partial thickness of the cranium, 12.23% were in the full thickness of the skull, and 0.84% had epidural extension. We identified 22 intradiploic cysts. Statistical analysis demonstrated significant association between frontal and pterional localization and bone erosion. Neither major complications nor cyst recurrence were observed. Conclusions Excision of dermoid and epidermoid cysts is a safe procedure for neurosurgeons dealing with this disease, even in young patients. Early resection is recommended due to the potential adverse effects that may occur if these cysts are left untreated.

Objective The aim of this article is to introduce a new skin and fascia opening for intrathecal baclofen pump implantation in the abdomen, with the purpose of reducing complications related to wound breakdown. Methods We introduce a novel way of cutaneous and fascial opening that leads two opposed “L shaped” incisions. Results This method entails numerous advantages. The first advantage is avoiding the direct alignment of overlapped sutures, which creates a locus minoris resistentiae that can weaken and break under the push of the pump. Another advantage consists of an increased obstruction against deep extension of infective processes from cutaneous origin. The wide opening of the subfascial pocket permits the implantation of any type of pump available, and it reduces complexities in reopening the pouch for pump replacement. It also permits the fastening of all anchoring systems usually present in pumps. Another advantage is the improved possibility of careful muscle cauterization thanks to the wide fascia opening, with reduced risk of postsurgical hematoma. Our results showed a reduction of wound complications with this method. Conclusions This method could contribute to reducing the rate of wound complications and patient discomfort.

Chiari malformation type I (CMI) is a congenital abnormality of the cranio-cerebral junction with an estimated incidence of 1 in 1280. CMI is characterized by underdevelopment of the occipital bone and posterior fossa (PF) and consequent cerebellar tonsil herniation. The presence for a genetic basis to CMI is supported by many lines of evidence. The cellular and molecular mechanisms leading to CM1 are poorly understood. The occipital bone formation is dependent on complex interactions between genes and molecules with pathologies resulting from disruption of this delicate process. Whole-exome sequencing of affected and not affected individuals from two Italian families with non-isolated CMI was undertaken. Single-nucleotide and short insertion-deletion variants were prioritized using KGGSeq knowledge-based platform. We identified three heterozygous missense variants: DKK1 c.121G>A (p.(A41T)) in the first family, and the LRP4 c.2552C>G (p.(T851R)) and BMP1 c.941G>A (p.(R314H)) in the second family. The variants were located at highly conserved residues, segregated with the disease, but they were not observed in 100 unaffected in-house controls. DKK1 encodes for a potent soluble WNT inhibitor that binds to LRP5 and LRP6, and is itself regulated by bone morphogenetic proteins (BMPs). DKK1 is required for embryonic head development and patterning. LRP4 is a novel osteoblast expressed receptor for DKK1 and a WNT and BMP 4 pathways integrator. Screening of DKK1 in a cohort of 65 CMI sporadic patients identified another missense variant, the c.359G>T (p.(R120L)), in two unrelated patients. These findings implicated the WNT signaling in the correct development of the cranial mesenchyme originating the PF.

Background Neural Tube Defects (NTD) are a common class of birth defects that occur in approximately 1 in 1000 live births. Both genetic and nongenetic factors are involved in the etiology of NTD. Planar cell polarity (PCP) genes plays a critical role in neural tube closure in model organisms. Studies in humans have identified nonsynonymous mutations in PCP pathway genes, including the VANGL genes, that may play a role as risk factors for NTD. Methods Here, we present the results of VANGL1 and VANGL2 mutational screening in a series of 53 NTD patients and 27 couples with a previous NTD affected pregnancy. Results We identified three heterozygous missense variants in VANGL1, p.Ala187Val, p.Asp389His, and p.Arg517His, that are absent in controls and predicted to be detrimental on the protein function and, thus, we expanded the mutational spectrum of VANGL1 in NTD cases. We did not identify any new variants having an evident pathogenic effect on protein function in VANGL2. Moreover, we reviewed all the rare nonsynonymous or synonymous variants of VANGL1 and VANGL2 found in patients and controls so far published and re-evaluated them for their pathogenic role by in silico prediction tools. Association tests were performed to demonstrate the enrichment of deleterious variants in reviewed cases versus controls from Exome Variant Server (EVS). Conclusion We showed a significant (p = 7.0E-5) association between VANGL1 rare genetic variants, especially missense mutations, and NTDs risk. Birth Defects Research (Part A) 103:51–61, 2015. © 2014 Wiley Periodicals, Inc.

Atypical teratoid/rhabdoid tumor (AT/RT) of the central nervous system and malignant rhabdoid tumor of the kidney (MRTK) may present with different responses to chemotherapy and outcomes. We describe the case of an infant with multifocal rhabdoid tumor with different behavior and response to treatment, depending on the anatomic site.

Neural Tube Defects (NTDs) are congenital malformations that involve failure of the neural tube closure during the early phases of development at any level of the rostro-caudal axis. The planar cell polarity (PCP) pathway is a highly conserved, noncanonical Wnt-Frizzled-Dishevelled signaling cascade, that was first identified in the fruit fly Drosophila. We are here reviewing the role of the PCP pathway genes in the etiology of human NTDs, updating the list of the rare and deleterious mutations identified so far. We report 50 rare nonsynonymous mutations of PCP genes in 54 patients having a pathogenic effect on the protein function. Thirteen mutations that have previously been reported as novel are now reported in public databases, although at very low frequencies. The mutations were private, mostly missense, and transmitted by a healthy parent. To date, no clear genotype-phenotype correlation has been possible to create. Even if PCP pathway genes are involved in the pathogenesis of neural tube defects, future studies will be necessary to better dissect the genetic causes underlying these complex malformations.

BACKGROUND Neural tube defects (NTDs) are severe malformations that arise when the neural tube fails to close during embryogenesis. The planar cell polarity pathway is involved in neural tube closure and has been implicated in the pathogenesis of NTDs both in animal models and human cohorts. Dishevelled (Dvl/Dsh) is a multi-module protein and a key regulator of both the canonical Wnt and the PCP pathway. In mouse, all Dvl1−/−; Dvl2−/− double mutants display craniorachischisis, a severe form of open NTDs. Recently, we have reported a possible role for rare variants of DVL2 as risk factors for NTDs. METHODS In view of these data, we hypothesized that DVL1 mutations might increase the risk for NTDs in some cases. Resequencing of the DVL1 gene in a cohort of 473 NTDs patients and 150 ethnically matched controls was performed. Prediction of the downstream effects of the nonsynonymous variants was done using computational methods. RESULTS We identified six missense variants that were absent in our ethnically matched controls group, and four of them (p.Arg153Cys; p.Glu544Arg; p.Arg568Trp; p.Val644Phe) were predicted to have a functional effect on protein structure by one or more bioinformatic programs. However, there was no difference in the overall rate of deleterious variants between the patients and controls (four in patients and three in controls; p = 0.36). CONCLUSION Our findings did not provide evidence for the implication of DVL1 in the pathogenesis of human NTDs. Birth Defects Research (Part A) 97:452–455, 2013. © 2013 Wiley Periodicals, Inc.

Moyamoya syndrome (MMS) is the most common cerebral vasculopathy among children with neurofibromatosis type 1 (NF1). In this study, we clinically, radiologically, and genetically examined a cohort that was not previously described, comprising European children with NF1 and MMS. The NF1 genotyping had been registered. This study included 18 children. The mean age was 2.93 ± 3.03 years at the NF1 diagnosis and 7.43 ± 4.27 years at the MMS diagnosis. In seven patients, MMS was diagnosed before or at the same time as NF1. Neuroimaging was performed in 10 patients due to clinical symptoms, including headache (n = 6), cerebral infarction (n = 2), and complex partial seizures (n = 2). The remaining eight children (47%) had MMS diagnosed incidentally. Sixteen children were characterized molecularly. The features of MMS were similar between patients with and without NF1. Additionally, the NF1 phenotype and genotype were similar between children with and without MMS. Interestingly, three children experienced tumors with malignant histology or behavior. The presence of two first cousins in our cohort suggested that there may be potential genetic factors, not linked to NF1, with an additional role respect of NF1 might play a role in MMS pathogenesis. The incidental diagnosis of MMS, and the observation that, among children with NF1, those with MMS were clinically indistinguishable from those without MMS, suggested that it might be worthwhile to add an angiographic sequence to brain MRIs requested for children with NF1. A MMS diagnosis may assist in properly addressing an NF1 diagnosis in very young children who do not fulfill diagnostic criteria.

EPN-02. FINAL RESULTS OF THE 2ND AIEOP PROTOCOL FOR INTRACRANIAL EPENDYMOMA (EPD) Maura Massimino1, Rosalba Miceli1, Felice Giangaspero2,3, Luna Boschetti1, Paolo Ferroli4, Paola Peretta5, Emilia Pecori1, Laura Valentini4, Veronica Biassoni1, Maria Luisa Garre6, Elisabetta Schiavello1, Iacopo Sardi7, Armando Cama6, Silvia Scoccianti8, Maurizio Mascarin9, Lorenzo Genitori7, Daniele Bertin5, Anna Mussano10, Elisabetta Viscardi11, Piergiorgio Modena12, GiuseppinaCalareso1, Salvina Barra13, Giovanni Scarzello14, LuciaQuaglietta15, Giuseppe Cinalli15, Angela Mastronuzzi16, Carlo Giussani17, Carlo Marras16, Rita Balter18, Patrizia Bertolini19, Ermanno Giombelli19, Francesca Buttarelli2, Manila Antonelli2, and Lorenza Gandola1; Fondazione IRCCS Istituto Nazionale dei Tumori, Milano, Italy; Universita Sapienza Roma, Roma, Italy; Neuromed Pozzilli, Pozzilli, Italy; Fond IRCCS Istituto Neurologico Carlo Besta, Milano, Italy; Ospedale Infantile Regina Margherita, Torino, Italy; Istituto Giannina Gaslini, Genova, Italy; Ospedale Pediatrico Meyer, Firenze, Italy; OspedaleCareggi,Firenze, Italy;CRO,Aviano, Italy;OspedaleS.Anna, Torino, Italy; Clinica di Oncoematologia Pediatrica, Padova, Italy; Genetica, Osp S. Anna, Como, Italy; Istituto dei Tumori, Genova, Italy; Istituto Oncologico del Veneto, Padova, Italy; Ospedale Pausillipon, Napoli, Italy; Ospedale Bambino Gesu, Roma, Italy; Ospedale S. Gerardo, Monza, Italy; Ospedale Borgo Roma, Verona, Italy; Ospedale, Parma, Italy This study stratified patients after surgical resection (complete 1⁄4 NED vs incomplete 1⁄4 ED) and centrally reviewed histology(gr.2 vs gr. 3). Gr2 tumors/NEDpts were focally irradiated with a 3D-conformal technique 1.8Gy/d up to 59.4 Gy, gr3/NED received also 4 VEC(Cyclo,VP16,VCR) after irradiation. EDpts received 1-4 VEC, second-look surgery whenever possible,59.4 Gy followed by 8 Gy boost into 2 fractions on still measurable residue. Children aged 1-3 yrs received the same treatment but for those gr2/NED who could receive only 6 VEC. Between January 2002/December 2014, 160 consecutive children, median age 4.9 years, entered the protocol; follow-up was a median 67 months. M/F was 100/60, infratentorial origin in 110(2 plus metastasis). After surgery, NEDpts were 110,grade 3 was assessed in 84. 100 resections were performed in 46/160 children with another 12 rendered NED after first excision,10 after 1-4 VEC,2 after radiation. Boost was applied to 24/40 still ED patients after surgery/ies and VEC obtaining PFS/OS of 58.1%/68.7% in this severe prognosis subgroup. For the whole series,5-year PFS/OS were 65.4%/81.1% with no toxic deaths. In univariable analysis, female gender, supratentorial origin, NED status before RT, grade 2, shunt absence were favourable for OS, in multivariable NED status and grade 2 were. For PFS, female gender, NED status before RT, grade 2 were significant in univariable, only grade in multivariable. In a multicentric collaboration this trial accrued the highest patient number so far published with comparable results to best monoinstitutional series. Radiation boost was feasible and efficacious in improving local control. Complete surgery, also through multiple excisions, still confirmed its prognostic strength as well as grade. Further biological parameter definition on this series will be the object of next coming studies. Neuro-Oncology 18:iii30–iii39, 2016. doi:10.1093/neuonc/now070.2 #The Author(s) 2016. Published by Oxford University Press on behalf of the Society for Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.

Background This prospective study stratified patients by surgical resection (complete = NED vs incomplete = ED) and centrally reviewed histology (World Health Organization [WHO] grade II vs III). Methods WHO grade II/NED patients received focal radiotherapy (RT) up to 59.4 Gy with 1.8 Gy/day. Grade III/NED received 4 courses of VEC (vincristine, etoposide, cyclophosphamide) after RT. ED patients received 1-4 VEC courses, second-look surgery, and 59.4 Gy followed by an 8-Gy boost in 2 fractions on still measurable residue. NED children aged 1-3 years with grade II tumors could receive 6 VEC courses alone. Results From January 2002 to December 2014, one hundred sixty consecutive children entered the protocol (median age, 4.9 y; males, 100). Follow-up was a median of 67 months. An infratentorial origin was identified in 110 cases. After surgery, 110 patients were NED, and 84 had grade III disease. Multiple resections were performed in 46/160 children (28.8%). A boost was given to 24/40 ED patients achieving progression-free survival (PFS) and overall survival (OS) rates of 58.1% and 68.7%, respectively, in this poor prognosis subgroup. For the whole series, 5-year PFS and OS rates were 65.4% and 81.1%, with no toxic deaths. On multivariable analysis, NED status and grade II were favorable for OS, and for PFS grade II remained favorable. Conclusions In a multicenter collaboration, this trial accrued the highest number of patients published so far, and results are comparable to the best single-institution series. The RT boost, when feasible, seemed effective in improving prognosis. Even after multiple procedures, complete resection confirmed its prognostic strength, along with tumor grade. Biological parameters emerging in this series will be the object of future correlatives and reports.

Cerebral cavernous malformations (CCMs) are vascular malformations mostly located within the central nervous system. Heterozygous loss of function mutations in CCM1/KRIT1, CCM2/MGC4607, and CCM3/PDCD10 genes are identified in about 90 % of familial cases of CCMs and two thirds of sporadic cases with multiple lesions. In this study, we performed genetic screening of a cohort of 31 patients, mainly pediatric. We analyzed the CCM1, CCM2, and CCM3 genes by multiplex ligation-dependent probe amplification (MLPA) and direct sequencing of exons and intronic boundaries. A total of 9 typical pathogenic loss-of-function mutations were identified in 10 out 31 patients (32 %). The 75 % of familial cases were mutated and the percentage reached to 85 % when we consider only pediatric cases. Detection rate in sporadic cases with multiple lesions was considerably lower (16 %). We identified a novel variant of CCM3, the c.130-131insT (p.R45Efs*8), in 1 pediatric sporadic case with multiple lesions that introduced a premature termination codon into the messenger RNA (mRNA), most likely leading to mRNA decay. Similar to other CCM pediatric series, the main symptoms associated to clinical debut consisted of cerebral hemorrhage. In conclusion, the penetrance of CCM mutations in familial pediatric cases is high (85 %). The genetic workup could improve clinical and genetic counseling in CCM patients. Moreover, we confirmed the high risk of hemorrhage in children with CCMs.

OBJECTIVE Cranioplasty is a reconstructive procedure used to restore skull anatomy and repair skull defects. Optimal skull reconstruction is a challenge for neurosurgeons, and the strategy used to achieve the best result remains a topic of debate, especially in pediatric patients for whom the continuing skull growth makes the choice of material more difficult. When the native bone flap, which is universally accepted as the preferred option in pediatric patients, is unavailable, the authors' choice of prosthetic material is a polymethylmethacrylate (PMMA) implant designed using a custom-made technique. In this paper the authors present the results of their clinical series of 12 custom-made PMMA implants in pediatric patients. METHODS A retrospective study of the patients who had undergone cranioplasty at Gaslini Children's Hospital between 2006 and 2013 was conducted. A total of 12 consecutive cranioplasties in 12 patients was reviewed, in which a patient-specific PMMA implant was manufactured using a virtual 3D model and then transformed into a physical model using selective laser sintering or 3D printing. All patients or parents were administered a questionnaire to assess how the patient/parent judged the aesthetic result. RESULTS Patient age at craniectomy ranged from 5 months to 12.5 years, with a mean age of 84.33 months at cranioplasty. The mean extension of the custom-made plastic was 56.83 cm2. The mean time between craniectomy and cranioplasty was 9.25 months. The mean follow-up duration was 55.7 months. No major complications were recorded; 3 patients experienced minor/moderate complications (prosthesis dislocation, granuloma formation, and fluid collection). CONCLUSIONS In this patient series, PMMA resulted in an extremely low complication rate and the custom-made technique was associated with an excellent grade of patient or parent satisfaction on long-term follow up.

Neural tube defects are severe malformations affecting 1/1,000 live births. The planar cell polarity pathway controls the neural tube closure and has been implicated in the pathogenesis of neural tube defects both in animal models and human cohorts. In mouse disruption ofDvl2alone (Dvl2−/−) orDvl2andDvl3(Dvl2−/−;Dvl3+/−,Dvl2+/−;Dvl3−/−) results in incomplete neurulation, suggesting a role for Disheveled in neural tube closure. Disheveled is a multifunctional protein that is involved in both the canonical Wnt signaling and the noncanonical planar cell polarity pathway. In this study, we analyzed the role of the human orthologsDVL2andDVL3in a cohort of 473 patients with neural tube defects. Rare variants were genotyped in 639 ethnically matched controls. We identified seven rare missense mutations that were absent in all controls analyzed. Two of these mutations, p.Tyr667Cys and p.Ala53Val, identified inDVL2were predicted to be detrimental in silico. Significantly, a 1-bp insertion (c.1801_1802insG) in exon 15 ofDVL2predicted to lead to the truncation of the protein was identified in a patient with a complex form of caudal agenesis. In summary, we demonstrate a possible role for rare variants inDVL2gene as risk factors for neural tube defects.

Somatic mutations of the isocitrate dehydrogenase-1 gene (IDH1), most commonly resulting in replacement of arginine at position 132 by histidine (p.R132H), have been reported for WHO grade II and III diffuse gliomas and secondary glioblastomas. We investigated IDH1/2 mutations in a retrospective series of 165 pediatric brain tumors, including atypical teratoid/rhabdoid tumors (AT/RT) and choroid plexus tumors, which had not previously been investigated. Mutation analysis was performed by use of pyrosequencing and, additionally, data were validated for a cohort of 70 gliomas from among the series by use of the arrayed primer extension technique. We identified one tumor which harbored mutation of IDH1 at codon 132 and no alteration was identified in the matched-germline DNA. No IDH2 mutations were detected. Most noteworthy, the IDH1 mutant tumor was an anaplastic astrocytoma involving the cortex in the left frontal lobe which appeared seven years after radiation treatment for an extensive sellar/suprasellar craniopharyngioma. This anaplastic astrocytoma was regarded as secondary to radiation treatment because it seemed to originate within the irradiation field that received a dose varying from a maximum of 30.6 Gy of 4 MV X-rays down to very few Gy of lower-energy scattered radiation. In this work our observations agree with those in previous reports showing the rarity of IDH1/2 mutations in childhood tumors. The interesting identification of an IDH1 mutation in a radiation-induced secondary malignant glioma raises the likelihood that these types of tumor may develop IDH1/2 mutations. Thus, caution is needed when dealing with these tumors, and further genetic analysis is warranted.

The aim of this study was to evaluate the frequency of surgical and organizational events that occurred in the whole Department of Paediatric Surgery at Gaslini Children’s Hospital through an incident-reporting system in order to identify the vulnerabilities of this system and improve it. This is a 6-month prospective observational study (1st January–1st July 2010) of all events (including surgical and organizational events, and near misses) that occurred in our department of surgery (pediatric surgery, orthopedics and neurosurgery units). Over a 6-month study period, 3,635 children were admitted: 1,904 out of 3,635 (52.4%) children underwent a surgical procedure. A total number of 111 adverse events and 4 near misses were recorded in 100 patients. A total of 108 (97.3%) adverse events occurred following a surgical procedure. Of 111 adverse events, 34 (30.6%) required re-intervention. Eighteen of 100 patients (18%) required a re-admission, and 18 of 111 adverse events (16.2%) were classified as organizational. Infection represented the most common event. An electronic physician-reported event tracking system should be incorporated into all surgery departments to report more accurately adverse events and near misses. In this system, all definitions must be standardized and near misses should be considered as important as the other events, being a rich source of learning.

Object Complete ependymoma resection ensures a better prognosis for children with this tumor, but the complete excision of infratentorial ependymomas involves serious risks. Second-look surgery for tumor remnants may be less harmful and enable complete removal. There is a potential, although still unclear, role for neoadjuvant chemotherapy in preparation for further surgery. Methods Since 1994, the authors have adopted two successive protocols for intracranial ependymoma, both including a phase of adjuvant chemotherapy for children with surgical tumor remnants with a plan for potential second-look surgery before radiotherapy. Results In the first protocol, 9 of 63 children underwent further surgery, and 6 became tumor free with no additional sequelae. Their prognosis for progression-free survival and freedom from local relapse was comparable to that of children who were operated on only once. In the second protocol, efforts were made to achieve complete resection and 29 of 110 patients underwent reoperations: 9 after the first surgery, 17 after chemotherapy, and 3 soon after radiotherapy. Fourteen of the 29 patients became tumor free, 1 of them with worsening neurological symptoms. The outcome of the 66 patients who became tumor free after 1 operation was compared with that of the 14 who became tumor free after reoperation. The 3-year progression-free survival of the 66 patients compared with the 14 other patients was 71.4% ± 6.9% and 90% ± 9.5%, respectively; the 3-year freedom from local relapse was 84.7% ± 5.9% and 90% ± 9.5%, respectively; and the 3-year overall survival was 85.9% ± 5.4% and 87.5% ± 11.7%, respectively. Conclusions Second-look surgery proved feasible with no major morbidity, and results improved with time. Local tumor control was comparable in patients undergoing 1 or more resections.

Saethre–Chotzen syndrome (SCS) is an autosomal dominant craniosynostosis syndrome with variable expression. Here we report on a female infant with a de novo balanced translocation 46, XX, t(7;12)(p21.2;p12.3) and presenting at birth brachycephaly, antimongolic palpebral fissures, ocular hypertelorism, broad nose with low nasal bridge and low-set ears. This phenotype is suggestive of a subtle form of SCS, given the absence of limbs anomalies. Cloning of both breakpoints revealed that the translocation does not interrupt the TWIST1 coding region, on 7p21, known to be causative for SCS, but downregulates TWIST1 expression due to a position effect. On chromosome 12, the breakpoint translocates a shorter transcript of PTPRO gene, the osteoclastic protein-tyrosine phosphatase, PTP-oc , near to regulatory region of 7p leading to down-regulation of PTP-oc in the proband’s fibroblasts. This is a confirmatory case report providing further evidence for TWIST1 haploinsufficiency in SCS, although a possible role of PTP-oc as genetic factor underlying or at least influencing the development of craniosynostosis could not be a priori excluded.

Neural tube defects (NTDs) are severe congenital malformations affecting 1-2 in 1,000 live births, whose etiology is multifactorial, involving environmental and genetic factors. NTDs arise as consequence of the failure of fusion of the neural tube early during embryogenesis. NTDs' pathogenesis has been linked to genes involved in folate metabolism, consistent with an epidemiologic evidence that 70% of NTDs can be prevented by maternal periconceptional supplementation. However, polymorphisms in such genes are not linked in all populations, suggesting that other genetic factors and environmental factors could be involved. Animal models have provided crucial mechanistic information and possible candidate genes to explain susceptibility to NTDs. A crucial role has been assigned to the planar cell polarity (PCP) pathway, a highly conserved, non-canonical Wnt-frizzled-dishevelled signaling cascade that plays a key role in establishing and maintaining polarity in the plane of the epithelium and in the process of convergent extension during gastrulation and neurulation in vertebrates. The Loop-tail (Lp) mouse that develops craniorachischisis carry missense mutations in the PCP core gene Vangl2, that is the mammalian homolog of the Drosophila Strabismus/Van gogh (Stbm/Vang). The presence of mutations in human VANGL1 and VANGL2 genes encourages us to extend the investigation to other PCP genes that, with VANGL, play an essential role in neurulation during development.

Infantile myofibromatosis is a mesenchymal disorder of early childhood characterized by the formation of tumors in the skin, muscle, viscera, bone, and subcutaneous tissue. Although relatively rare overall, it represents the most common fibrous tumor of infancy. The etiology of this disorder is unknown. Infantile myofibromatosis can present as a solitary or multicentric form. With the multicentric form, bone is often involved, but solitary bone lesions account for only 10% of the cases. Imaging findings are not pathognomonic, and the differential diagnosis usually includes eosinophilic granuloma (Langerhans cell histiocytosis), osteomyelitis, metastasis, osteoblastoma, epidermoid cyst, hemangioma, fibrous dysplasia, fibrosarcoma, and meningioma. A histological pattern is typical, but there are no histopathological differences between the solitary and multicentric forms. Solitary lesions generally have a favorable prognosis if totally removed, with a 10% recurrence rate; incompletely resected lesions recur. We report the case of a 9-year-old boy who came to our attention with a solitary infantile myofibroma of the calvarium, appearing as a tight-elastic, lightly tender mass in the left frontal area, eroding both the inner and the outer tables. Histopathologically, the specimens showed a spindle-cell tumor with dense reticulin fiber network and expression of smooth muscle actin. Fifty-eight months MR follow-up after total removal showed no residual or relapse.

Background Neural tube defects (NTD) are among the most common defects affecting 1:1000 births. They are caused by a failure of neural tube closure during development. Their clinical presentation is diverse and dependent on the site and severity of the original defect on the embryonic axis. The etiology of NTD is multifactorial involving environmental factors and genetic variants that remain largely unknown. Methods We have conducted a whole exome sequencing (WES) study in five new NTD families and pooled the results with WES data from three NTD families and 43 trios that were previously investigated by our group. We analyzed the data using biased candidate gene and unbiased gene burden approaches. Results We identified four novel loss‐of‐function variants in three genes, MTHFR,DLC1, and ITGB1, previously associated with NTD. Notably, DLC1 carried two protein truncating variants in two independent cases. We also demonstrated an enrichment of variants in MYO1E involved in cytoskeletal remodeling. This enrichment reached borderline significance in a replication cohort supporting the association of this new candidate gene to NTD. Conclusion These data provide some key insights into the pathogenic mechanisms of human NTD and demonstrate the power of next‐generation sequencing in deciphering the genetics of this complex trait.

To choose the most appropriate treatment for children affected by a transplacental metastasis, it is crucial to ascertain the maternal origin of the tumor. Up-to-date conclusive diagnosis is generally achieved through fluorescence in situ hybridization or karyotyping analysis. Herein, we report an alternative, reliable assay for rapidly defining vertical cancer transmission to the fetus by using quantitative polymerase chain reaction. Our assay indicates that quantification of the copy number of the sex chromosomes by specific short tandem repeats markers, in genomic DNA purified from the tumor biopsy cells, could be used to correctly evaluate transplacental metastasis events.