Pediatric pituitary adenoma with mixed FSH and TSH immunostaining and FSH hypersecretion in a 6 year-old girl with precocious puberty: case report and multidisciplinary management.

OBJECTIVE: 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. MATERIALS AND METHODS: 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. RESULTS: 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. CONCLUSIONS: Early and accurate diagnosis, multidisciplinary approach and close follow up are crucial factors for the favorable outcome.

Post-haemorrhagic hydrocephalus management: Delayed neonatal transport negatively affects outcome.

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 <70 (-2 SD or less). RESULTS: Twelve outborn and 15 inborn infants were included. Age at intervention (31.6 vs 17.4 days) and VI-p97 (left 10.0 vs 5.1 mm, right 7.7 vs 5.1 mm) were significantly higher among outborn infants. A permanent shunt was inserted in 66.7% of outborn and in 40.0% of inborn infants (p = 0.18). After excluding subjects with parenchymal lesions, a significantly higher rate of developmental delay was observed at 5 years in outborn patients compared to inborn patients (66.7% of outborn vs 18.2% of inborn patients with VABS-II composite score <70, p = 0.04). CONCLUSIONS: Outborn infants reached a significantly more severe ventricular dilatation than inborn infants, largely exceeding the recommended cutoff for intervention. Our follow-up data showed a trend towards a higher rate of permanent shunt and developmental delay in outborn than in inborn patients. Infants requiring treatment should be timely transported to centres with adequate expertise in PHVD management.

Limits and pitfalls of indirect revascularization in moyamoya disease and syndrome.

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.

Spontaneous rupture of middle fossa arachnoid cysts: surgical series from a single center pediatric hospital and literature review.

PURPOSE: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Cranial and ventricular size following shunting or endoscopic third ventriculostomy (ETV) in infants with aqueductal stenosis: further insights from the International Infant Hydrocephalus Study (IIHS).

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.

Tonsillar herniation spectrum: more than just Chiari I. Update and controversies on classification and management.

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.

Management: opinions from different centers-the Istituto Giannina Gaslini experience.

PURPOSE: 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. METHODS: 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. RESULTS: 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%). CONCLUSIONS: 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.

Chiari malformation type I: what information from the genetics?

PURPOSE: 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. METHODS: 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. RESULTS: 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. CONCLUSIONS: 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.

Moyamoya syndrome in children with neurofibromatosis type 1: Italian-French experience.

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.

Spinal lipoma as a dysembryogenetic anomaly: Four unusual cases of ectopic iliac rib within the spinal lipoma.

BACKGROUND: Congenital spinal lipomas are closed spinal dysraphisms belonging to the neural tube defects (NTDs) group. They include a broad spectrum of lesions ranging from simple lipomas of the filum terminale to complex malformations. On histological evaluation, various tissue components of ectodermal, mesodermal or endodermal origin are found within the lipomas, with prevalence for nerves and striated muscle and, more rarely, cartilage and bone. Overall, rib malformations have been occasionally observed in patients with NTDs and in NTD mouse models. However, an ectopic rib arising within the spinal lipoma and articulating with the iliac crest has not been reported in either animal models or in humans. CASES: We describe four patients affected by lipomyeloschisis or lipomyelomeningocele, with an unusual fibrocartilaginous protuberance arising within the lipoma and connecting to one iliac crest, strongly resembling an ectopic rib. Histological evaluation confirmed the presence of cartilaginous tissue. CONCLUSION: We expand the clinical spectrum of fibrocartilaginous anomalies associated with spinal lipoma, suggesting the presence of an ectopic rib as a new possible phenotype in NTDs. A careful analysis by neuroradiologists and pathologists should be performed in spinal lipomas to assess the presence of an ectopic rib or other uncommon developmental anomalies. Furthermore, molecular studies are required to detect the genetic cause of this unusual phenotype. Birth Defects Research (Part A) 106:530-535, 2016. © 2016 Wiley Periodicals, Inc.

A rare case of osteoblastoma associated to aneurysmal bone cyst of the spine. Case report.

Osteoblastoma is a rare bone tumour. It is occasionally associated with an aneurysmal bone cyst (ABC). Several treatment strategies can be adopted. We report a challenging case of an osteoblastoma associated with ABC of the lumbar spine in a 2-year-old boy. The pathogenesis and the critical management of the disease are discussed.

Natural history of cavernous malformations in children with brain tumors treated with radiotherapy and chemotherapy.

Cavernous malformations (CM) are cerebral irradiation-related late complications. Little is known about their natural history and the pathogenetic role of concomitant chemotherapy. We present a retrospective, single-institution study of 108 children affected with medulloblastoma, ependymoma, or germinoma treated with radio- and chemotherapy. The frequency, clinical and radiological presentations, and outcomes were analyzed to investigate the relationship among radiation dose, associated chemotherapy, age, latency and localization of radiation-induced CM. 100 out of 108 children were treated with radiotherapy for primary brain tumor; 34 (27 with medulloblastoma and 7 with other histologies) out of 100 patients developed CM. No significant relationship was found between CM and gender (p = 0.70), age (p = 0.90), use of specific chemotherapy (standard versus high-dose, p = 0.38), methotrexate (p = 0.49), and radiation dose (p = 0.45). However, CM developed more frequently and earlier when radiotherapy was associated with methotrexate (70 % of cases). Radiation-induced CM prevailingly occurred in the cerebral hemispheres (p = 0.0001). Only 3 patients (9 %) were symptomatic with headache. Three patients underwent surgery for intra- or extra-lesional hemorrhage. CM was confirmed by histopathology for all 3 patients. The vast majority of radiation-induced CM is asymptomatic, and macro-hemorrhagic events occur rarely. Concomitant therapy with methotrexate seems to favor their development. We recommend observation for asymptomatic lesions, while surgery should be reserved to symptomatic growth or hemorrhage.

Planar cell polarity gene mutations contribute to the etiology of human neural tube defects in our population.

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.

White matter characteristics in children with cerebral palsy prior to selective dorsal rhizotomy: a multicenter diffusion tensor imaging study.

OBJECTIVE: The aims of this study were to 1) assess and quantify white matter (WM) microstructural characteristics derived from diffusion tensor imaging (DTI) in children with cerebral palsy (CP) prior to selective dorsal rhizotomy (SDR), and 2) investigate potential associations between WM diffusion properties and gross motor function and spasticity in children with spastic CP who underwent SDR. METHODS: This study is a multisite study based on DT images acquired prior to SDR as well as postoperative outcome data. DTI data collected from two sites were harmonized using the ComBat approach to minimize intersite scanner difference. The DTI abnormalities between children with spastic CP and controls were analyzed and correlated with the severity of impaired mobility based on the Gross Motor Function Classification System (GMFCS). The improvement in gross motor function and spasticity after SDR surgery was assessed utilizing the Gross Motor Function Measure-66 (GMFM-66), the Modified Tardieu Scale (MTS), and the modified Ashworth scale (MAS). Alterations in these outcome measures were quantified in association with DTI abnormalities. RESULTS: Significant DTI alterations, including lower fractional anisotropy (FA) in the genu of the corpus callosum (gCC) and higher mean diffusivity (MD) in the gCC and posterior limb of the internal capsule (PLIC), were found in children in the SDR group when compared with the age-matched control group (all p < 0.05). Greater DTI alterations (FA in gCC and MD in gCC and PLIC) were associated with lower mobility levels as determined based on GMFCS level (p < 0.05). The pre- to post-SDR improvement in motor function based on GMFM-66 was statistically significant (p = 0.006 and 0.002 at 6-month and 12-month follow-ups, respectively). The SDR efficacy was also identified as improving spasticity in lower-extremity muscle groups assessed with the MTS and MAS. Partial correlation analysis presented a significant association between pre- to post-SDR MTS alteration and DTI abnormalities. CONCLUSIONS: The findings in the present study provided initial quantitative evidence to establish the WM microstructural characteristics in children with spastic CP prior to SDR surgery. The study generated data for the association between baseline DTI characteristics and mobility in children with CP prior to SDR surgery. The study also demonstrated SDR efficacy in improving motor function and spasticity based on the GMFM-66, MTS, and MAS, respectively, in association with DTI data.

Molecular fingerprinting reflects different histotypes and brain region in low grade gliomas.

BACKGROUND: Paediatric low-grade gliomas (LGGs) encompass a heterogeneous set of tumours of different histologies, site of lesion, age and gender distribution, growth potential, morphological features, tendency to progression and clinical course. Among LGGs, Pilocytic astrocytomas (PAs) are the most common central nervous system (CNS) tumours in children. They are typically well-circumscribed, classified as grade I by the World Health Organization (WHO), but recurrence or progressive disease occurs in about 10-20% of cases. Despite radiological and neuropathological features deemed as classic are acknowledged, PA may present a bewildering variety of microscopic features. Indeed, tumours containing both neoplastic ganglion and astrocytic cells occur at a lower frequency. METHODS: Gene expression profiling on 40 primary LGGs including PAs and mixed glial-neuronal tumours comprising gangliogliomas (GG) and desmoplastic infantile gangliogliomas (DIG) using Affymetrix array platform was performed. A biologically validated machine learning workflow for the identification of microarray-based gene signatures was devised. The method is based on a sparsity inducing regularization algorithm l1l2 that selects relevant variables and takes into account their correlation. The most significant genetic signatures emerging from gene-chip analysis were confirmed and validated by qPCR. RESULTS: We identified an expression signature composed by a biologically validated list of 15 genes, able to distinguish infratentorial from supratentorial LGGs. In addition, a specific molecular fingerprinting distinguishes the supratentorial PAs from those originating in the posterior fossa. Lastly, within supratentorial tumours, we also identified a gene expression pattern composed by neurogenesis, cell motility and cell growth genes which dichotomize mixed glial-neuronal tumours versus PAs. Our results reinforce previous observations about aberrant activation of the mitogen-activated protein kinase (MAPK) pathway in LGGs, but still point to an active involvement of TGF-beta signaling pathway in the PA development and pick out some hitherto unreported genes worthy of further investigation for the mixed glial-neuronal tumours. CONCLUSIONS: The identification of a brain region-specific gene signature suggests that LGGs, with similar pathological features but located at different sites, may be distinguishable on the basis of cancer genetics. Molecular fingerprinting seems to be able to better sub-classify such morphologically heterogeneous tumours and it is remarkable that mixed glial-neuronal tumours are strikingly separated from PAs.

Rare missense variants in DVL1, one of the human counterparts of the Drosophila dishevelled gene, do not confer increased risk for neural tube defects.

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.

Naso-ethmoidal encephalocele with bilateral orbital extension: report of a case in a western country.

INTRODUCTION: Encephalocele is a rare congenital malformation of the central nervous system with protrusion of cranial content (meninges, brain, and ventricles in different combinations) beyond the normal confines of the skull. Anterior encephaloceles occur with a high frequency in Southeast Asia, while in the Western countries occipital encephaloceles prevail. The treatment of an anterior (naso-ethmoidal) encephalocele involves a neurosurgeon or a multidisciplinary team (neurosurgeon, maxillofacial surgeon, plastic surgeon, and ENT surgeon) dealing with craniofacial surgery. Goals of surgery include removal or repositioning of nonfunctional cerebral tissue, closure of the dura, and reconstruction of skeletal and cutaneous structures. The prognosis depends from the anatomical site, volume of neural contents, and the presence of coexisting malformations. CASE REPORT: We report the case of an Italian child suffering from a naso-ethmoidal encephalocele with bilateral orbital extension. The surgical treatment was performed in two steps. CONCLUSION: Sincipital encephalocele is a complex pathology without a unique standardized surgical treatment. Its low incidence in Western countries can make its management particularly tricky.

Ultrasonography as first line imaging for the diagnosis of positional plagiocephaly.

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. 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 pediatric neurosurgeon or a pediatrician 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.

Non-robotized frameless stereotactic magnetic resonance guided laser interstitial thermal therapy for hypothalamic hamartoma.

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. 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. 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 perioperative 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. 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.

FZD6 is a novel gene for human neural tube defects.

Neural tube defects (NTDs) are severe malformations of the central nervous system, affecting 1 of 1,000 live births. Mouse models were instrumental in defining the signaling pathways defective in NTDs, including the planar cell polarity (PCP), also called noncanonical Frizzled/Disheveled pathway. Based on the highly penetrant occurrence of NTDs in double Fzd3/Fzd6(-/-) mutant mice, we investigated the role of the human orthologues, FZD3 and FZD6, by resequencing a cohort of 473 NTDs patients and 639 ethnically matched controls. While we could not demonstrate a significant contribution of FZD3 gene, we identified five rare FZD6 variants that were absent in all controls and predicted to have a functional effect by computational analysis: one de novo frameshift mutation (c.1843_1844insA), three missense changes (p.Arg405Gln, p.Arg511Cys p.Arg511His), and one substitution (c.*20C>T) affecting the 3'-untranslated region (UTR) of the gene. The overall rate of predicted deleterious variants of FZD6 was 5.1-fold higher in cases compared to controls, resulting in a significantly increased NTDs mutation burden. This study demonstrates that rare nonsynonymous variants in FZD6 may contribute to NTDs in humans and enlarges the spectrum of mutations that link PCP pathway to NTDs.