Search

Bilateral adrenal neuroblastoma (NB) is rare and is mainly stage 4S. Its incidence, presenting features, management, and outcome have not been fully defined yet. We searched the Italian NB Registry (RINB) for stage 4S NB infants with bilateral adrenal primary tumor to compare them with stage 4S NB with unilateral tumor. Between 1979 and 2016, the RINB enrolled 3731 NB patients aged 0-18 years including 317 infants (8.5%) diagnosed with stage 4S NB. Eleven/317 (3.5%) had a bilateral adrenal primary tumor (Group 1) and 190/317 (59.9%) had a unilateral tumor (Group 2). Group 1 infants were significantly younger (51 vs. 89 days) but were comparable with Group 2 for any other presenting features. In the absence of specific protocols, upfront treatment was based on symptoms, size of adrenal tumors, and biology, and consisted of observation in 5 cases, radiotherapy in one, chemotherapy in 2, and surgery in 3. Five/11 developed progression and 2 of them, both with

The authors describe a newborn diagnosed with localized neuroblastoma that evolved to stage 4s at the age of 5 months. Peculiar features of the case included a bilateral adrenal primary, the skin as the only metastatic site, and the development of a muscular lesion late in the clinical course. The patient underwent left adrenalectomy and all other lesions regressed without further therapy. The case prompted a search for similar cases both in the Italian Neuroblastoma Registry and in the literature. All patients identified, although variously treated, survived with the exception of the 2 with MYCN gene amplification. We conclude that infants with neuroblastoma who undergo a transition from a localized to stage 4s disease could be less rare than expected. In the absence of unfavorable biology, a wait-and-see policy with strict follow-up could be adopted for these patients, avoiding potentially damaging systemic therapy.

Background Infants diagnosed with stage 4 s neuroblastoma commonly experience spontaneous disease regression, with few succumbing without response to therapy. We analyzed a large cohort of such infants enrolled in the Italian Neuroblastoma Registry to detect changes over time in presenting features, treatment and outcome. Methods Of 3355 subjects aged 0–18 years with previously untreated neuroblastoma diagnosed between 1979 and 2013, a total of 280 infants (8.3%) had stage 4 s characteristics, 268 of whom were eligible for analyses. Three treatment eras were identified on the basis of based diagnostic and chemotherapy adopted. Group 1 patients received upfront chemotherapy; Group 2 and 3 patients underwent observation in the absence of life-threatening symptoms (LTS), except for Group 3 patients with amplified MYCN gene, who received more aggressive therapy. Results The three groups were comparable, with few exceptions. Ten-year overall survival significantly increased from 76.9 to 89.7% and was worse for male gender, age 0–29 days and presence of selected LTS on diagnosis, elevated LDH, and abnormal biologic features. Infants who underwent primary resection ± chemotherapy did significantly better. On multivariate analysis, treatment eras and the association of hepatomegaly to dyspnea were independently associated with worse outcome. Conclusions Our data confirm that stage 4 s neuroblastoma is curable in nearly 90% of cases. Hepatomegaly associated to dyspnea was the most important independent risk factor. The cure rate could be further increased through timely identification of patients at risk who might benefit from surgical techniques, such as intra-arterial chemoembolization and/or liver transplantation, which must be carried out in institutions with specific expertise. Electronic supplementary material The online version of this article (10.1186/s13052-018-0599-1) contains supplementary material, which is available to authorized users.

Purpose Stage 4S neuroblastoma, a tumor affecting infants, is characterized by the capacity to regress spontaneously and high cure rate. About a third of these infants undergo tumor progression requiring antitumor treatment and 10-15% eventually die. In case of metastatic progression, it may occur either at 4S sites (mainly liver) or sites characterizing stage 4 (mainly bone). Aim of this study was to estimate incidence, presenting features and outcome of infants who progressed to stage 4S or stage 4 sites. Patients Of 280 Italian infants diagnosed with stage 4S neuroblastoma between 1979 and 2013 and registered in the Italian Neuroblastoma Registry, 268 were evaluable for this study, of whom 57 developed metastatic progression. Results Progression to stage 4S sites occurred in 29/268 infants (10.8%) (Group A) and to stage 4 in 28/268 (10.4%) (Group B). No significant difference was observed between the two groups at the time of diagnosis. At the time of progression, Group A infants were younger (7.3 vs 14.4 months, P = .001) and had a shorter interval from diagnosis to progression (3.8 vs 9.6 months, P = .001). Survival after progression was worse for Group B infants (45% vs 69%, P = .058) and was associated with age at diagnosis lower than 2 months (P = .005) and adrenal primary tumor site (P = .008). Survival rates increased for both groups along the study period. Conclusions Infants who progressed to stage 4 did worse, possibly in relation to older age at progression and longer interval between diagnosis and progression. Large prospective studies of these patients may lead to more effective treatments.

Purpose To clarify the role of primary tumor resection in stage 4S neuroblastoma. Methods We investigated a cohort of 172 infants diagnosed with stage 4S neuroblastoma between 1994 and 2013. Of 160 evaluable patients, 62 underwent upfront resection of the primary tumor and 98 did not. Results Five-year progression-free and overall survival were significantly better in those who had undergone upfront surgery (83.6% vs 64.2% and 96.8% vs 85.7%, respectively). One post-operative death and four non-fatal complications occurred in the resection group. Three patients who had not undergone resection died of chemotherapy-related toxicity. Thirteen patients underwent late surgery to remove a residual tumor, without complications: all but one alive. Outcomes were better in patients diagnosed from 2000 onwards. Conclusion Infants diagnosed with stage 4S neuroblastoma who underwent upfront tumor resection had a better outcome. However, this result cannot be definitely attributed to surgery, since these patients were selected on the basis of their favorable presenting features. Although the question of whether to operate or not at disease onset is still unsolved, this study confirms the importance of obtaining enough adequate tumor tissue to enable histological and biological studies to properly address treatment, to achieve the best possible outcome.

In this systematic review the diagnostic capabilities of post-mortem MR (PMMR) concerning brain and spinal cord abnormalities compared to traditional autopsy were analyzed. A computerized online search of scientific articles was performed using Medline (PubMed) databases in June 2016 to identify all studies comparing PMMR with conventional autopsy in detecting fetal central nervous system alterations. Titles and abstracts were screened based on these exclusion criteria: no paediatric cases, neuroradiological alterations not reported, studies not in English, case reports and reviews, less than 10 subjects analyzed, PMMR performed on MR Units with magnetic field different from 1,5 or 3 T. Full texts of potentially relevant publications were read. Only articles with a clearly stated comparison between PMMR and autopsy results were included. 467 abstracts were identified; 14 papers met the inclusion criteria; data from 8 studies were extracted (467 cases). Of the 8 papers examined all regarded fetuses; only one analyzed also children Based on these results, PMMR might be considered a valid support/substitute to traditional autopsy for studying fetal central nervous system.

Approximately 15% of children with peripheral neuroblastic tumors (PNTs) present with spinal canal involvement (SCI) by the tumor, and half of them develop important related symptoms. Symptomatic SCI requires prompt treatment: chemotherapy, neurosurgical intervention and radiation therapy may all be effective, but there is no consent on which should be given first in the different clinical presentations. The literature regarding PNT with SCI does not provide convincing guidelines, thus encouraging the establishment of a specific International Registry to provide data that could lead to the definition of a suitable therapeutic and follow-up algorithm.

Cerebral sinovenous thrombosis (CSVT) is a relatively uncommon and potentially life-threatening condition in childhood, occurring in various clinical settings. Nowadays, however, it is increasingly diagnosed as related to many causes, likely due to greater clinical awareness and improvement of neuroradiologic techniques. The prompt diagnosis is an important goal to significantly reduce the risk of acute complications and long-term sequelae. The purpose of this narrative overview is to provide a useful educational tool in daily clinical practice for radiologists with a broad perspective of CSVT including a discussion of more common potential pitfalls related to misinterpretation of images in children. This paper will also review the normal venous anatomy, its variants, risk factors that contribute to cause CSVT (neonates with their specific causes of CSVT are not included in this review) and the practical imaging feature of cerebral sinovenous thrombosis on MRI and CT. Finally, a brief overview of frequent and severe CSVT conditions in children with key points in imaging is shown.

The employment of graph theory to analyze spontaneous fluctuations in resting state BOLD fMRI data has become a dominant theme in brain imaging studies and neuroscience. Analysis of resting state functional brain networks based on graph theory has proven to be a powerful tool to quantitatively characterize functional architecture of the brain and it has provided a new platform to explore the overall structure of local and global functional connectivity in the brain. Due to its increased use and possible expansion to clinical use, it is essential that the reliability of such a technique is very strongly assessed. In this review, we explore the outcome of recent studies in network reliability which apply graph theory to analyze connectome resting state networks. Therefore, we investigate which preprocessing steps may affect reproducibility the most. In order to investigate network reliability, we compared the test-retest (TRT) reliability of functional data of published neuroimaging studies with different preprocessing steps. In particular we tested influence of global signal regression, correlation metric choice, binary versus weighted link definition, frequency band selection and length of time-series. Statistical analysis shows that only frequency band selection and length of time-series seem to affect TRT reliability. Our results highlight the importance of the choice of the preprocessing steps to achieve more reproducible measurements.

Background The European multicenter study LNESG1 was designed to evaluate the safety and efficacy of surgical treatment alone in patients with localised neuroblastoma. In a retrospective, observational study we examined the impact of image-defined risk factors (IDRF) on operative complications and survival (EFS and OS). Procedure 534 patients with localised, non-MYCN amplified neuroblastoma were recruited between 1995 and 1999. Group 1 consisted of 291 patients without IDRF (Stage L1 in the International Neuroblastoma Risk Group (INRG) staging system), all treated with primary surgery. Group 2: 118 patients with IDRF (INRG Stage L2), also treated with primary surgery. Group 3: 125 patients in whom primary surgery was not attempted, 106 receiving neo-adjuvant chemotherapy. Results In L1 patients (Group 1) 5-year EFS was 92% and OS 98%. In L2 patients (Group 2 and 3) EFS was 79% and OS 89%. The differences in both EFS and OS were significant. EFS and OS in Group 2 (86% and 95%) were significantly better than 73% and 83% in Group 3. In INSS stage 1, 2 and 3, EFS were respectively 94%, 81% and 76%. Except between stage 2 and 3 the differences were significant. OS were respectively 99%, 93% and 83%, all significantly different. The 17% operative complication rate in L2 patients was significantly higher than 5% in L1 patients. Conclusions In localised neuroblastoma, IDRF at diagnosis are associated with worse survival rates and higher rates of operative complications. The impact of IDRF should become an integrated part of therapy planning. Pediatr Blood Cancer 2015;62:1536–1542. © 2015 Wiley Periodicals, Inc.

A magnetic resonance diffusion fiber tracking study in neonate diagnosed with left hemisphere hemimegalencephaly is presented. Despite diffuse morphologic deformities identified in conventional imaging, all major pathways were identifiable bilaterally with minor aberrations in vicinity of morphologic lesions.

Background Symptoms of epidural compression (SEC) in children with neuroblastoma (particularly infants) may be misinterpreted, leading to delay in diagnosis. Patients and Methods Clinical, imaging and follow-up data of 34 infants with neuroblastoma and SEC diagnosed between 2000 and 2011 at Italian AIEOP centers were retrieved and reviewed. Results Median age at initial SEC was 104 days (IQR 47–234). Main symptoms included motor deficit (85.3%), pain (38.2%), bladder and bowel dysfunctions (20.6% each). In the symptom-diagnosis interval (S-DI) (median, 12 days; IQR 7–34), the frequency of grade 3 motor deficit increased from 11.8% to 44.1% and that of bladder dysfunction from 20.6% to 32.4%. S-DI was significantly longer (P = 0.011) for patients developing grade 3 motor deficit. First treatment of SEC was neurosurgery in 14 patients, and chemotherapy in 20. SEC regressed in 11 patients (32.3%), improved in 9 (26.5%), and remained stable in 14 (41.2%), without treatment-related differences. Median follow-up was 82 months. At last visit, 11 patients (32.3%) were sequelae-free while 23 (67.7%) had sequelae, including motor deficit (55.9%), bladder (50.0%) and bowel dysfunctions (28.4%), and spinal abnormalities (38.2%). Sequelae were rated severe in 50% of patients. Severe sequelae scores were more frequent in patients presenting with spinal canal invasion >66% (P = 0.039) and grade 3 motor deficit (P = 0.084). Conclusions Both neurosurgery and chemotherapy provide unsatisfactory results once paraplegia has been established. Sequelae developed in the majority of study patients and were severe in a half of them. Greater awareness by parents and physicians regarding SEC is warranted. Pediatr Blood Cancer 2014; 61:1369–1375. © 2014 Wiley Periodicals, Inc.

Few studies have been conducted on the relations between T1-weighted signal intensity changes in the pediatric brain following gadolinium-based contrast agent (GBCA) exposure. The purpose of this study is to investigate the effect of multiple administrations of a macrocyclic GBCA on signal intensity in the globus pallidus and dentate nucleus of the pediatric brain on unenhanced T1-weighted MR images. This retrospective study included 50 patients, mean age: 8 years (standard deviation: 4.8 years), with normal renal function exposed to ≥6 administrations of the same macrocyclic GBCA (gadoterate meglumine) and a control group of 59 age-matched GBCA-naive patients. The globus pallidus-to-thalamus signal intensity ratio and dentate nucleus-to-pons signal intensity ratio were calculated from unenhanced T1-weighted images for both patients and controls. A mixed linear model was used to evaluate the effects on signal intensity ratios of the number of GBCA administrations, the time interval between administrations, age, radiotherapy and chemotherapy. T-test analyses were performed to compare signal intensity ratio differences between successive administrations and baseline MR signal intensity ratios in patients compared to controls. P-values were considered significant if

GPR56-related bilateral frontoparietal polymicrogyria (BFPP) is a rare recessively inherited disorder of neuronal migration caused by mutations of GPR56. To better delineate the clinical, molecular, and neuroradiological phenotypes associated with BFPP, we performed conventional magnetic resonance imaging and diffusion tensor imaging studies in a series of prospectively enrolled patients carrying novel GPR56 mutations. All subjects with GPR56-related BFPP showed a characteristic morphological pattern, including abnormalities of the cerebellar cortex with cerebellar cysts located at the periphery, a mildly thick corpus callosum, and a flat pons. Significant alterations of myelination and white matter tract abnormalities were documented. The present study confirms the phenotypic overlap between GPR56-related brain dysgenesis and other cobblestone-like syndromes and illustrates the contribution of 3D neuroimaging in the characterization of malformations of cortical development. © 2012 Springer-Verlag Berlin Heidelberg.

A high metabolic demand, rich vascularization and high concentrations of ionic elements leading to the generation of oxygen free radicals, give to the deep grey matter (DGM) nuclei specific susceptibility to both acute and chronic insults, especially in paediatric patients. Reaching a diagnosis in the early stages of acute diseases in many patients is crucial for instigating prompt specific therapy leading to a favourable outcome. On the basis of a review of a 10-year in-house database and a review of the literature on CNS pathology involving the DGM nuclei in paediatric patients, we summarize the MR findings and clinical clues that may help the radiologist in the difficult differential diagnosis process. The terms "acute" and "chronic" refer to the clinical onset of the disease. MR imaging allows the detection of an injury, determination of its precise anatomical location and characterization of the signal changes. This, combined with a knowledge of specific MRI patterns, may be a roadmap to a definite diagnosis. Clinical history, physical and laboratory findings, timing of the MR examination and advanced MR imaging techniques (diffusion-weighted imaging and (1)H-MR spectroscopy), are crucial in some patients.

Background and aims White matter is diffusely altered in tuberous sclerosis complex (TSC), and these alterations appear to be more evident in subjects with a more severe neurologic phenotype. However, little is known on the correlation between white matter alterations and epilepsy in TSC. The aims of this study were to evaluate the effects of early onset and refractory seizures on white matter by using diffusion tensor imaging (DTI). Methods We enrolled 20 children with TSC and epilepsy onset in the first 3 years of life and grouped them according to seizure persistence or freedom. All patients underwent brain MRI with DTI. Specific ROIs have were placed to generate tracks to calculate fractional anisotropy (FA) and apparent diffusion coefficient (ADC). Statistical analysis was performed by ANOVA. Results Children with persistent seizures presented an overall reduced FA, with statistically significant differences on the cingulum (right p = 0.003, left p = 0.016), the left cerebral peduncle (p = 0.020), the superior cerebellar peduncles (right p = 0.008, left p = 0.002), the posterior limbs of internal capsule (right p = 0.037, left p = 0.015), the external capsule (right p = 0.018, left p = 0.031), the inferior frontooccipital fasciculus (right p = 0.010, left p = 0.026), and the temporal trunk (right p = 0.017, left p = 0.001). Conclusions Our study demonstrated that children with persistent seizures present more significant alterations of brain connectivity in areas crucial for global cognitive maturation, executive functions, and verbal abilities, implying a higher risk of cognitive impairment, attention-deficit hyperactivity disorder, and autism.

We studied the prevalence and degree of tumor cell infiltration (TCI) in bone marrow (BM) aspirates of 89 infants with stage 4/4 S neuroblastoma and correlated them with MYCN gene status and patient outcome. TCI was scored 0, +, ++, and +++, the last corresponding to an infiltration greater than 10%. TCI 0 was more frequent in stage 4 than in stage 4 S. TCI + and ++ were equally represented. TCI +++ was found only in 9 patients, all with typical stage 4 features (bone or lung involvement). Overall survival was not significantly influenced by the presence and degree of TCI.

Peripheral neuroblastic tumours (PNTs), a family of tumours arising in the embryonal remnants of the sympathetic nervous system, account for 7-10% of all tumours in children. In two-thirds of cases, PNTs originate in the adrenal glands or the retroperitoneal ganglia. At least one third present metastases at onset, with bone and bone marrow being the most frequent metastatic sites. Disease extension, MYCN oncogene status and age are the most relevant prognostic factors, and their influence on outcome have been considered in the design of the recent treatment protocols. Consequently, the probability of cure has increased significantly in the last two decades. In children with localised operable disease, surgical resection alone is usually a sufficient treatment, with 3-year event-free survival (EFS) being greater than 85%. For locally advanced disease, primary chemotherapy followed by surgery and/or radiotherapy yields an EFS of around 75%. The greatest problem is posed by children with metastatic disease or amplified MYCN gene, who continue to do badly despite intensive treatments. Ongoing trials are exploring the efficacy of new drugs and novel immunological approaches in order to save a greater number of these patients.

Aim To describe a spectrum of intracerebral large artery disease in Aicardi–Goutieres syndrome (AGS) associated with mutations in the AGS5 gene SAMHD1. Method We used clinical and radiological description and molecular analysis. Results Five individuals (three males, two females) were identified as having biallelic mutations in SAMHD1 and a cerebral arteriopathy in association with peripheral vessel involvement resulting in chilblains and ischaemic ulceration. The cerebral vasculopathy was primarily occlusive in three patients (with terminal carotid occlusion and basal collaterals reminiscent of moyamoya syndrome) and aneurysmal in two. Three of the five patients experienced intracerebral haemorrhage, which was fatal in two individuals. Post-mortem examination of one patient suggested that the arteriopathy was inflammatory in origin. Interpretation Mutations in SAMHD1 are associated with a cerebral vasculopathy which is likely to have an inflammatory aetiology. A similar disease has not been observed in patients with mutations in AGS1 to AGS4, suggesting a particular role for SAMHD1 in vascular homeostasis. Our report raises important questions about the management of patients with mutations in SAMHD1.

Summary Background More accurate prognostic assessment of patients with neuroblastoma is required to better inform the choice of risk-related therapy. The aim of this study is to develop and validate a gene-expression signature to improve outcome prediction. Methods 59 genes were selected using an innovative data-mining strategy, and were profiled in the largest neuroblastoma patient series (n=579) to date using real-time quantitative PCR starting from only 20 ng of RNA. A multigene-expression signature was built using 30 training samples, tested on 313 test samples, and subsequently validated in a blind study on an independent set of 236 tumours. Findings The signature has a performance, sensitivity, and specificity of 85·4% (95% CI 77·7–93·2), 84·4% (66·5–94·1), and 86·5% (81·1–90·6), respectively, to predict patient outcome. Multivariate analysis indicates that the signature is a significant independent predictor of overall survival and progression-free survival after controlling for currently used risk factors: patients with high molecular risk have a higher risk of death from disease and higher risk of relapse or progression than patients with low molecular risk (odds ratio 19·32 [95% CI 6·50–57·43] and 3·96 [1·97–7·97] for overall survival and progression-free survival, respectively, both p MYCN status, age, International Neuroblastoma Staging System stage, ploidy, International Neuroblastoma Pathology Classification grade of differentiation, and mitosis karyorrhexis index (odds ratios between 4·81 and 10·53 depending on the model for overall survival and 3·68 [95% CI 2·01–6·71] for progression-free survival). Interpretation The 59-gene expression signature is an accurate predictor of outcome in patients with neuroblastoma. The signature is an independent risk predictor, identifying patients with an increased risk of poor outcome in the current clinical-risk groups. The method and signature is suitable for routine laboratory testing, and should be evaluated in prospective studies. Funding The Belgian Foundation Against Cancer, the Children Cancer Fund Ghent, the Belgian Society of Paediatric Haematology and Oncology, the Belgian Kid's Fund and the Fondation Nuovo-Soldati (JV), the Fund for Scientific Research Flanders (KDP, JH), the Fund for Scientific Research Flanders, the Institute for the Promotion of Innovation by Science and Technology in Flanders, Strategisch basisonderzoek, the Fondation Fournier Majoie pour l'Innovation, the Instituto Carlos III, the Italian Neuroblastoma Foundation, the European Community under the FP6, and the Belgian programme of Interuniversity Poles of Attraction.

Purpose To review a historical cohort of childhood ganglioneuroma (GN), the benign representative of the peripheral neuroblastic tumor (PNT) family. Patients and Methods Of 2,286 PNTs enrolled between 1979 and 2005, 146 (6.4%) were registered as GN. Histological revision was carried out on 76 tumors. Diagnosis was confirmed in 45, while 27 were reclassified as ganglioneuroblastoma intermixed (GNBI) and four were reclassified as other PNT subtypes. Results GNs differed from other PNTs for sex, age, tumor site, stage, tumor markers, and scintigraphic results. Characteristics of 76 reviewed and 70 nonreviewed patients were comparable. Reviewed GN and GNBI patients were comparable except for homovanillic acid excretion, metaiodobenzylguanidine scintigraphy, and DNA content. Seven patients were only biopsied and 139 underwent surgery. Twenty-two patients suffered surgery-related complications, of which two were fatal and seven were severe. Radical tumor resection and surgery-related complication rates were comparable for GN, GNBI, and nonreviewed instances. Six patients developed tumor progression but survived. Two patients developed a late malignancy but survived. None of the 146 patients received chemotherapy. Of 146 patients, two died of surgery-related complications and 144 survived. Conclusion Diagnosis was changed to GNBI for approximately one third of 76 reviewed tumors. Patients with confirmed GN, reclassified as GNBI, and nonreviewed histology presented with comparable clinical, biochemical, and biologic features. Surgical results, complication rate, number of progressions, and outcome were similar for the three groups. Surgery was associated with significant risk of complications. Survival was not influenced by extent of tumor resection. Aggressive surgical approach should not be recommended for childhood GN and GNBI.

Tumor specific quantitative RT-PCRs for two neuroblastoma specific molecular markers, tyrosine hydroxylase (TH) and GD2 synthase, were used to unequivocally demonstrate the neoplastic nature of the cells present in the cerebrospinal fluid of a neuroblastoma patient. After radical surgery of two separate tumoral lesions, localized in the extradural area, the patient presented with meningitis. Common sites of neuroblastoma metastatization, e.g. bone and bone marrow, were not infiltrated by tumor cells, as assessed by standard scintigraphy, morphological investigation and by sensitive and specific immunocytochemical and molecular assays. The results presented here demonstrate the successful use of tumor-specific qRT-PCRs in cerebrospinal fluid to investigate questionable clinical cases. The technique, which compared to other detection methods (e.g., immunocytochemistry) requires very few cells, yields unambiguous information once a suspected diagnosis has been formulated and a tumor-specific molecular marker is available.

Objective To assess the feasibility of the prenatal diagnosis using fetal neurosonography of brain injuries in the surviving fetus after the demise of a monochorionic cotwin. Methods This was a retrospective observational study in the period 1990–2004 of monochorionic twin pregnancies with a single fetal demise. A detailed sonographic evaluation of the intracranial anatomy of the surviving twin had been performed whenever possible using a multiplanar approach and from 1999, fetal magnetic resonance imaging was offered as well. Postnatal follow-up was obtained in all cases. Results In six of nine cases, abnormal neurosonographic findings were identified including intracranial hemorrhage, brain atrophy, porencephaly and periventricular echogenicities evolving into polymicrogyria. Prenatal diagnosis of brain lesions was confirmed postnatally and all affected infants who survived had severe neurological sequelae. Two fetuses had normal cerebral structures both on the prenatal neurosonogram and on postnatal imaging and were following normal developmental milestones, one at 1 and the other at 5 years of age. In one case the neurosonographic examination was suboptimal and the infant was found at birth to have a porencephalic cyst. Fetal magnetic resonance imaging was performed in two cases and confirmed the ultrasound diagnosis. Conclusions Prenatal neurosonography is a valuable tool for the prediction of neurological outcome in fetuses surviving after the intrauterine death of a monochorionic cotwin. Although our experience is limited, we suggest that magnetic resonance imaging should also be offered. Copyright © 2006 ISUOG. Published by John Wiley & Sons, Ltd.

Purpose Although tumor resection is the mainstay of treatment for localized neuroblastoma, there are no established guidelines indicating which patients should be operated on immediately and which should undergo surgery after tumor reduction with chemotherapy. In an effort to develop such guidelines, the LNESG1 study defined surgical risk factors (SRFs) based on the imaging characteristics. Patients and Methods A total of 905 patients with suspected localized neuroblastoma were registered by 10 European countries between January 1995 and October 1999; 811 of 905 patients were eligible for this analysis. Results Information on SRFs was obtained for 719 of 811 patients; 367 without and 352 with SRFs. Of these 719 patients, 201 patients (four without and 197 with SRFs) underwent biopsy only. An attempt at tumor excision was made in 518 patients: 363 of 367 patients without and 155 of 352 patients with SRFs (98.9% v 44.0%). Complete excision was achieved in 271 of 363 patients without and in 72 of 155 patients with SRF (74.6% v 46.4%), near-complete excision was achieved in 81 and 61 patients (22.3% v 39.3%), and incomplete excision was achieved in 11 and 22 patients (3.0% v 14.2%), respectively. There were two surgery-related deaths. Nonfatal surgery-related complications occurred in 45 of 518 patients (8.7%) and were less frequent in patients without SRFs (5.0% v 17.4%). Associated surgical procedures were also less frequent in patients without SRFs (1.6% v 9.7%). Conclusion The adoption of SRFs as predictors of adverse surgical outcome was validated because their presence was associated with lower complete resection rate and greater risk of surgery-related complications. Additional studies aiming to better define the surgical approach to localized neuroblastoma are warranted.

The involvement by tumour of intervertebral foramina and the consequent invasion of the spinal space, accompanied or not by neurological symptoms, represent a well-recognised pattern of presentation of neuroblastoma. The main peculiarity of this condition stands in the fact that, in case of its late detection or inadequate treatment, severe, permanent neurological compromise may ensue. Surprisingly enough, remarkable disagreements still exist regarding its optimal treatment and the related literature provide contrasting indications at this respect. The neurosurgical and the chemotherapeutic approaches have equally convinced supporters, while the use of radiation therapy is uncommon, possibly without good reasons. This mini-review intends to report the clinical experiences of the major Paediatric Oncology Groups with the aim to collect as many data as possible in the perspective of establishing common guidelines for proper diagnosing and treatment of this important complication.

Recent evidence suggests that the cut-off for age utilized in neuroblastoma risk groups should be increased from the 365-day cut-off currently in use. Separate cooperative group analyses were performed by German and Italian groups and two analyses by the Children's Oncology Group (North America, Australia, New Zealand, Switzerland, Netherlands). In general, the results are in agreement regarding the prognostic contribution of age. There is strong evidence to support an increase in the age cut-off to a value in the range of 15-18 months based on the results from the German analysis and two COG analyses. However, Italian results in INSS stage 4 patients show that outcome in patients 12-17 months is not better than that of older patients. Further analyses are warrented.

Purpose: Detection of metastatic tumor cells in bone marrow (BM) and peripheral blood (PB) of children with neuroblastoma is crucial for prognosis and planning of therapy. Aims of this large descriptive repeated survey were to evaluate the diagnostic accuracy of different techniques in diagnostic samples obtained at several disease course time points and to correlate positive results with patient clinical features and outcome. Experimental Design: BM aspirates, trephine biopsies, PB, and peripheral blood stem cell (PBSC) samples from Italian children with neuroblastoma were analyzed by morphological and histologic techniques, as well as by immunocytochemistry (IC) for disialoganglioside GD2 and reverse transcription-PCRs (RT-PCRs) for tyrosine hydroxylase (TH) and pgp9.5 genes. The diagnostic odd ratio (DOR) was used to measure the accuracy of the different techniques. Results: A total of 2,247 evaluations were done on 561 BM, 265 PB, and 69 PBSC samples from 247 patients. IC showed the best accuracy. Whereas TH RT-PCR accuracy was satisfactory, that of pgp9.5 was very low. Positive results obtained by IC in BM and PB samples at diagnosis from stage 1, 2, and 3 patients correlated with unfavourable outcome. No correlation was found between positive results obtained by IC or TH RT-PCR in BM, PB, and PBSC samples from stage 4 patients and their outcome. Conclusions: Because of its elevated diagnostic accuracy, IC may represent a useful adjunct to conventional morphological techniques, especially in view of its potential prognostic role in patients with localized disease. Longitudinal multicenter studies are warranted to definitely establish the clinical usefulness of TH RT-PCR.

A newborn girl with genetically confirmed galactosemia (compound heterozygous for p.ARG51Trp [c.151C>T] and p.GLN188ARG [c.563A>G] mutations in galactose-1-phosphate uridyltransferase [ GALT ] gene) presented with jaundice, hypoglycemia, and liver failure. A galactose-free diet was started but she became comatose. Brain MRI with spectroscopy showed diffuse edema (figure 1, A–D) and galactitol peak (figure 2). Despite cerebral edema therapy, she died at 21 days of cerebral herniation. The authors thank the Association “la Vita e un Dono” Onlus for supporting the fellowship of Dr. Martinelli.

Purpose: To compare the outcomes associated with modifications in three consecutive protocols employed by the Italian Co-Operative Group for Neuroblastoma (ICGNB) in disseminated neuroblastoma. Patients and Methods: Between January 1985 and November 1997, a total of 359 children aged 1 to 15 years with newly diagnosed stage 4 neuroblastoma were enrolled in three consecutive protocols. Compared with ICGNB-85, the ICGNB-89 protocol contained two more chemotherapy cycles, and some drugs were given at greater doses, whereas in the ICGNB-92 protocol, the induction phase included a chelating agent, and individual cycles contained four drugs instead of two. Results: A total of 330 of 359 evaluable children were included in this analysis; 106 children were treated with ICGNB-85, 65 children were treated with ICGNB-89, and 159 children were treated with ICGNB-92 protocols. Radical resection of primary tumor was carried out in 59.4%, 50.8%, and 57.9% of the patients, respectively. Major tumor response after induction therapy was achieved in 66.7%, 69.2%, and 68.6% of the patients, respectively. A total of 218 of 232 patients received consolidation therapy consisting of conventional chemotherapy in 65 patients and of high-dose chemotherapy in 153 patients. Disease recurrence or progression occurred in 82.1%, 69.2%, and 74.8% of the patients, respectively. Therapy-related deaths occurred in 1.9%, 12.3%, and 6.9% of the patients, respectively. Five-year overall survival (OS) for the three studies was 26%, 23%, and 28%, and event-free survival (EFS) was 19%, 17%, and 17%, respectively. Conclusion: The therapeutic modifications adopted in the ICGNB-89 and ICGNB-92 protocols were not associated with a significant improvement in response rate or in the 5-year OS and EFS as compared with the ICGNB-85 protocol. Attempts at intensifying chemotherapy were associated with greater toxicity.

BACKGROUND 131I-metaiodobenzylguanidine (131I-MIBG) is selectively taken up by cells of neural crest origin, allowing targeted radiotherapy of tumors such as neuroblastoma (NB) and pheochromocytoma. Radiotherapy may provide additional benefits in the treatment of NB, with moderate side effects such as hematologic and thyroid toxicity. However, with longer follow-up, other complications might occur. We describe our experience with second cancers occurring in children treated with 131I-MIBG and chemotherapy. METHODS The clinical records of 119 consecutive NB cases treated with 131I-MIBG at a single institution between 1984 and 2001 were reviewed for the occurrence of a second malignant neoplasm (SMN). RESULTS Overall, five cases of SMN occurred in the study patients. In particular, two cases of myeloid leukemia, one of angiomatous fibrous histiocytoma, one of malignant schwannoma, and one case of rhabdomyosarcoma were detected. The schwannoma and the rhabdomyosarcoma developed within the residual neuroblastic mass after first-line therapy. CONCLUSIONS Should 131I-MIBG treatment become more broadly employed in the therapeutic strategy for neuroblastoma, the risk of second cancer will have to be taken into consideration. The organization of an international registry of subjects treated with 131I-MIBG might better define the frequency and features of second malignancies following this radiometabolic approach. Cancer 2003;97:1332–38. © 2003 American Cancer Society. DOI 10.1002/cncr.11167

The European multicenter study LNESG1 was designed to evaluate the safety and efficacy of surgical treatment alone in patients with localised neuroblastoma. In a retrospective, observational study we examined the impact of image-defined risk factors (IDRF) on operative complications and survival (EFS and OS).534 patients with localised, non-MYCN amplified neuroblastoma were recruited between 1995 and 1999. Group 1 consisted of 291 patients without IDRF (Stage L1 in the International Neuroblastoma Risk Group (INRG) staging system), all treated with primary surgery. Group 2: 118 patients with IDRF (INRG Stage L2), also treated with primary surgery. Group 3: 125 patients in whom primary surgery was not attempted, 106 receiving neo-adjuvant chemotherapy.In L1 patients (Group 1) 5-year EFS was 92% and OS 98%. In L2 patients (Group 2 and 3) EFS was 79% and OS 89%. The differences in both EFS and OS were significant. EFS and OS in Group 2 (86% and 95%) were significantly better than 73% and 83% in Group 3. In INSS stage 1, 2 and 3, EFS were respectively 94%, 81% and 76%. Except between stage 2 and 3 the differences were significant. OS were respectively 99%, 93% and 83%, all significantly different. The 17% operative complication rate in L2 patients was significantly higher than 5% in L1 patients.In localised neuroblastoma, IDRF at diagnosis are associated with worse survival rates and higher rates of operative complications. The impact of IDRF should become an integrated part of therapy planning.

Atypical teratoid/rhabdoid tumor (ATRT) is a rare embryonal tumor of the central nervous system with preponderance in very young children, the majority of whom are younger than 3 years of age at diagnosis. Historically, outcomes of this aggressive disease, even with extensive multimodal therapy, have been dismal. Recent improvements have come from therapies directed exclusively towards ATRT, but misdiagnosis or delays in the correct diagnosis lead to significantly worse survival rates. ATRTs most commonly occur supratentorially but have been described in virtually all central nervous system locations, including the cerebellopontine angle cistern, meninges, and spinal canal, and extradural locations. ATRTs originating from cranial nerves are rare. Here, we describe three cases of solitary ATRT arising from the 3rd cranial nerve (CN III) or close to its origin in the midbrain, all of which presented in patients within 6 months of birth, with isolated unilateral oculomotor nerve palsy and strikingly similar magnetic resonance imaging (MRI) features. These MRI features include IV contrast enhancement, relative T2 hyposignal, and restricted water diffusion on apparent diffusion coefficient images, findings which are consistent with angiogenesis and high cellularity, and hence, suggestive of malignancy. We conclude that ATRT should be placed high on the differential diagnosis list when encountering a young infant presenting with isolated, unilateral 3rd nerve palsy and a small, solitary tumor arising from CN III that demonstrates malignant conventional and diffusion-weighted imaging features on MRI.

Focal cortical dysplasia (FCD) has been recognized as one of the most frequent causes of drug resistant epilepsy, especially in children. In infancy, onset of FCD-related epilepsy is substantially characterized by epileptic spasms (ES) or focal seizures. Which elements pertaining to the FCD are responsible for the onset of one type of seizure over the other is still unclear. Purpose of our study was to compare the characteristics of FCDs in terms of lateralization and site in patients with epileptic spasms versus patients with focal seizures.We retrospectively reviewed data from 41 patients with FCD related epilepsy with onset during the first 14 months of life. Seizure semeiology and drug resistance were analyzed, as were age at onset and FCD site and lateralization.Twenty-one children had focal seizures, 11 had ES and nine had focal seizures followed by ES. Mean age at onset was respectively 8.2, 5.1 and 1.8 months. Drug resistance was present in respectively 38.5%, 34.6% and 26.9% of children. Among patients with only ES, 90.9% had an exclusively frontal FCD localization, versus 42.9% of patients with focal seizures and 11.1% of patients with focal seizures followed by ES. FCD lateralization was right sided respectively in 47.6%, 81.8% and 66.7% of patients.Frontal lobe localization of FCDs was closely associated with ES (p=0.001). Moreover we also found that patients with focal seizures followed by ES had a significantly earlier age at onset compared to patients with focal seizures only (p0.001). The association between ES and right-sided FCD lateralization, even if numerically suggestive, did not reach statistical significance (p=0.16). There was no significant association between seizure type and drug resistance (p=0.08).

// Annalisa Pezzolo 1 , Angela Pistorio 2 , Claudio Gambini 3 , Riccardo Haupt 2 , Manuela Ferraro 3 , Giovanni Erminio 2 , Bruno De Bernardi 4 , Alberto Garaventa 4 and Vito Pistoia 1 1 Laboratorio di Oncologia Istituto Giannina Gaslini Genova, Italy 2 Epidemiologia e Biostatistica Istituto Giannina Gaslini Genova, Italy 3 Laboratorio di Anatomia Patologica Istituto Giannina Gaslini Genova, Italy 4 Dipartimento di Emato-Oncologia Pediatrica Istituto Giannina Gaslini Genova, Italy Correspondence: Annalisa Pezzolo, email: // Keywords : Telomere length, ALT mechanism, telomerase, neuroblastoma Received : April 17, 2014 Accepted : June 17, 2014 Published : June 18, 2014 Abstract The purpose of the work was to investigate telomere length (TL) and mechanisms involved in TL maintenance in individual neuroblastoma (NB) tumors. Primary NB tumors from 102 patients, ninety Italian and twelve Spanish, diagnosed from 2000 to 2008 were studied. TL was investigated by quantitative fluorescence in situ hybridization (IQ-FISH) that allows to analyze individual cells in paraffin-embedded tissues. Fluorescence intensity of chromosome 2 centromere was used as internal control to normalize TL values to ploidy. Human telomerase reverse transcriptase (hTERT) expression was detected by immunofluorescence in 99/102 NB specimens. The main findings are the following: 1) two intratumoral subpopulations of cancer cells displaying telomeres of different length were identified in 32/102 tumors belonging to all stages. 2) hTERT expression was detected in 99/102 tumors, of which 31 displayed high expression and 68 low expression. Alternative lengthening of telomeres (ALT)-mechanism was present in 60/102 tumors, 20 of which showed high hTERT expression. Neither ALT-mechanism nor hTERT expression correlated with heterogeneous TL. 3) High hTERT expression and ALT positivity were associated with significantly reduced Overall Survival. 4) High hTERT expression predicted relapse irrespective of patient age. Intratumoral diversity in TL represents a novel feature in NB. In conclusion, diversity of TL in individual NB tumors was strongly associated with disease progression and death, suggesting that these findings are of translational relevance. The combination of high hTERT expression and ALT positivity may represent a novel biomarker of poor prognosis that deserves further investigation.

Symptoms of epidural compression (SEC) in children with neuroblastoma (particularly infants) may be misinterpreted, leading to delay in diagnosis.Clinical, imaging and follow-up data of 34 infants with neuroblastoma and SEC diagnosed between 2000 and 2011 at Italian AIEOP centers were retrieved and reviewed.Median age at initial SEC was 104 days (IQR 47-234). Main symptoms included motor deficit (85.3%), pain (38.2%), bladder and bowel dysfunctions (20.6% each). In the symptom-diagnosis interval (S-DI) (median, 12 days; IQR 7-34), the frequency of grade 3 motor deficit increased from 11.8% to 44.1% and that of bladder dysfunction from 20.6% to 32.4%. S-DI was significantly longer (P = 0.011) for patients developing grade 3 motor deficit. First treatment of SEC was neurosurgery in 14 patients, and chemotherapy in 20. SEC regressed in 11 patients (32.3%), improved in 9 (26.5%), and remained stable in 14 (41.2%), without treatment-related differences. Median follow-up was 82 months. At last visit, 11 patients (32.3%) were sequelae-free while 23 (67.7%) had sequelae, including motor deficit (55.9%), bladder (50.0%) and bowel dysfunctions (28.4%), and spinal abnormalities (38.2%). Sequelae were rated severe in 50% of patients. Severe sequelae scores were more frequent in patients presenting with spinal canal invasion66% (P = 0.039) and grade 3 motor deficit (P = 0.084).Both neurosurgery and chemotherapy provide unsatisfactory results once paraplegia has been established. Sequelae developed in the majority of study patients and were severe in a half of them. Greater awareness by parents and physicians regarding SEC is warranted.

On the basis of currently available information, the cumulative incidence of second malignant neoplasm (SMN) for neuroblastoma patients is approximately 2% at 20 years from the initial diagnosis. The most commonly observed SMNs include thyroid carcinomas, osteogenic and soft tissue sarcomas, breast and colon carcinomas, acute myeloid and lymphoid leukemias, Hodgkin’s and non-Hodgkin’s lymphomas, and brain tumors. Female survivors of neuroblastoma seem to be at higher risk of developing an SMN than males. Other predisposing factors include young age at the time of diagnosis of the first cancer, radiotherapy associated with chemotherapy, high-doses of alkylating agents and administration of topo-isomerase II inhibitors, as well as high cumulative doses and protracted schedules of epipodophyllotoxins. Longer and more targeted surveillance should be recommended including specific cancer screening at younger ages compared to the general population. Risk adapted and response-related regimens should be applied to these patients in an effort to decrease SMNs.

Wernicke encephalopathy represents a well-known entity characterized by a set of cognitive and neurologic alterations. Wernicke encephalopathy is rare and under-recognized in childhood and may be fatal. Few cases have been documented in pediatric oncology. We report on 2 Wernicke encephalopathy cases that occurred in children having a brain tumor. The diagnosis of Wernicke encephalopathy was suggested by clinical manifestations associated with the typical radiologic findings and a laboratory evidence of thiamine deficiency. No large series have been published to support the evidence that pediatric malignancies represent a demonstrated factor of increased risk to develop a Wernicke encephalopathy. Moreover, the diagnosis may be even more difficult in brain tumors, considering the overlapping symptoms and the risk of encephalopathy related to both the disease and the treatment. Wernicke encephalopathy should be considered in all children with cancer presenting a neurologic deterioration, mainly in brain tumors. An early diagnosis is imperative for a prompt therapy that might prevent or minimize the irreversible brain damage related to this condition.

Neuroblastoma (NB) is the most common pediatric neuroendocrine tumor, and it is characterized by a quite variable clinical course. We previously found a great variability in the expression of somatostatin receptor type 2 (sst2) in several human NB cell lines and primary tumors. In this report we investigated whether expression of sst2 is somehow related to clinical outcome. We performed a retrospective study on 54 patients with a maximum follow-up of 100 months. The concentration of specific messenger ribonucleic acid (mRNA) for sst2 was measured by competitive RT-PCR and validated, in a small subset of samples, by quantitative imaging of gene (in situ hybridization) and protein (immunohistochemistry) expression. We found that sst2 mRNA was variably expressed in all NB tumors (range, 2.5 × 105 to 8 × 109 molecules/μg RNA) with a relevant reduction in the more advanced stage (P < 0.01). Analysis of Kaplan-Meier curves indicated that sst2 expression is positively related to the overall (P < 0.0001) and even...

The tp73 gene, a tp53 homologue, has been sub-regionally mapped at 1p36.3, a chromosomal region frequently deleted in neuroblastoma. Due to its chromosomal localization and to the mono-allelic expression observed in some neuroblastoma cell lines, it was proposed that tp73 might be involved in the pathogenesis of neuroblastoma. Functional assays have demonstrated that tp73 can inhibit cell proliferation and induce apoptosis. The role of this gene in tumorigenesis, however, is still unclear. We analyzed tp73 expression in 95 sporadic neuroblastoma samples by RT-PCR and we detected the tp73 transcript in 46 cases (48.4%), without significant correlation with age, clinical stage or 3-year overall survival. A genetic polymorphism in the 2nd exon of tp73 was utilized to identify the transcribed allele in tumor-cell samples. Expression from only one of the tp73 alleles was found in 13 out of 16 heterozygous tumors, while in 3 samples both alleles were present. Genotype analysis of 73 patients and 150 controls showed a significant deviation (p = 0.0308) from the Hardy-Weinberg equilibrium for a tp73 allele only among neuroblastoma patients. The absence of correlation between tp73 expression and clinical stage, age and survival suggests that this gene does not play an essential function in the clinical course of the disease. However, the distribution of genomic tp73 alleles in patients indicates that a role of this gene in the development of neuroblastoma cannot be completely ruled out. Int. J. Cancer (Pred. Oncol.) 84:365–369, 1999. © 1999 Wiley-Liss, Inc.

Familial neuroblastoma occurs rarely. We studied a family with three children; one of them has a disseminated (stage 4) and another has a localized (stage 2) neuroblastoma. We observed subtelomeric locus D1Z2 (1p36) deletion in both tumors by using double-color fluorescence in situ hybridization. The MYNC gene was found in single copy in both tumors. Loss of heterozygosity (LOH) and restriction fragment length polymorphism analyses were performed by using DNA from frozen tumor cells and from microdissected tumor areas excised from paraffin-embedded sections. We detected somatic LOH at locus D1S468 (1p36) in a tumor-cell population with a trisomy 1 of the stage-2 patient. Neuroblastoma cells of the stage-4 patient were diploid and showed allelic loss at the following loci: D1S172, D1S80, D1S94, D1S243, D1S468, D1S214, D1S241, and D1S164. Haplotype study showed that the siblings inherited the same paternal 1p36--pter chromosome region by homologous recombination and that, in the two tumors, arm 1p of different chromosomes of maternal origin was damaged. Our results suggest that the siblings inherited the predisposition to neuroblastoma associated with paternal 1p36 region and that tumors developed as a consequence of somatic loss of the maternal 1p36 allele.

Neuroblastoma (NB) is a tumor of pediatric age that is associated with high mortality in metastatic stages, although stage IVS patients undergo frequent spontaneous regression. Since apoptosis has been proposed as a possible cause of remission among cancer patients, we tested this hypothesis among both localized and metastatic NB and, in particular, NB metastatic stage IVS. We have assayed 36 localized and 117 metastatic neuroblastomas for evidence of internucleosomal DNA degradation and confirmed DNA fragmentation by the flow cytometric Terminal deoxynucleotidyl Transferase method, which also allowed us to measure DNA content and cell cycle phases. These techniques provided evidence of apoptosis in 18 out of 153 samples (11.8%), that were equally distributed among all stages except IVS, i.e. 11.1% in stage I (2/18), 11.1% in stage II (2/18), 13.2% in stage III (5/38), 13.4% in stage IV (9/67), and 0% in stage IVS (0/12). Tumor tissue samples collected at onset and also at relapse for the same patients showed that apoptosis may occur at relapse. In addition, cells appear to undergo apoptosis independently from N-myc amplification, cell cycle phase and DNA ploidy. In conclusion, apoptosis seems to take place with about an equal frequency for both favourable and unfavourable stages with an exception for IVS. Since DNA fragmentation remained undetected in stage IVS, we suggest that apoptosis is not a mechanism of spontaneous regression for these patients. A better basic understanding of the complex molecular mechanisms and biochemical pathways that control apoptosis in neuroblastoma appears to be necessary.

Infants affected by neuroblastoma with symptomatic epidural compression require early diagnosis and appropriate treatment to avoid severe late complications. However, no established guidelines are available regarding the optimal treatment of these patients. We describe 5 such infants. The interval between the onset of symptoms and tumor diagnosis was 3 to 8 days in 4/5 cases. None developed paraplegia before or after treatment. Treatment for epidural compression included first-line laminoplasty followed by chemotherapy in 3 patients, and chemotherapy first in the remaining 2. To date, all are alive and none have developed severe complications after a follow-up of 9 to 39 months (median, 20).

Differential diagnosis of brainstem lesions, either isolated or in association with cerebellar and supra-tentorial lesions, can be challenging. Knowledge of the structural organization is crucial for the differential diagnosis and establishment of prognosis of pathologies with involvement of the brainstem. Familiarity with the location of the lesions in the brainstem is essential, especially in the pediatric population. Magnetic resonance imaging (MRI) is the most sensitive and specific imaging technique for diagnosing disorders of the posterior fossa and, particularly, the brainstem. High magnetic static field MRI allows detailed visualization of the morphology, signal intensity and metabolic content of the brainstem nuclei, together with visualization of the normal development and myelination. In this pictorial essay we review the brainstem pathology in pediatric patients and consider the MR imaging patterns that may help the radiologist to differentiate among vascular, toxico-metabolic, infective-inflammatory, degenerative and neoplastic processes. Helpful MR tips can guide the differential diagnosis: These include the location and morphology of lesions, the brainstem vascularization territories, gray and white matter distribution and tissue selective vulnerability.

Hemimegalencephaly (HME) is a rare congenital malformation of the brain, grossly characterized by enlargement and overdevelopment of one cerebral hemisphere. We describe a 16-month-old patient with facial asymmetry caused by congenital infiltrating lipomatosis of the face (CILF) associated with ipsilateral HME. Although HME has been described as part of different syndromic diseases, the association of HME with CILF has been rarely reported. Our case and literature review suggest that when the diagnosis of CILF is suspected or established, the possible presence of associated HME has to be considered and a magnetic resonance imaging (MRI) must be performed even in absence of neurological features, not always present in early stages. MRI also demonstrates the involvement of intracranial structures outside the affected cerebral hemisphere, such as brain stem, cerebellum, cranial nerves, and blood vessels. In our patient, computed tomography of the brain provided detailed information on osseous hypertrophy and skull-base foramina enlargement.

Mutations of TUBA1A gene were first identified as causing a distinctive neuroradiologic phenotype characterized by cortical abnormalities ranging from classical lissencephaly to perisylvian pachygyria with dysgenetic corpus callosum, brainstem and cerebellum. We describe the clinical and neuroradiological features of a 3 years old girl carrying a novel missense TUBA1A mutation associated with asymmetrical polymicrogyria and provide structural data about the mutation. Our case confirm that the spectrum of tubulin-related cortical phenotypes is wide and that the screening of these genes should be implemented in patients with mid-hindbrain dysgenesis, partial of complete corpus callosum agenesis and varying degrees of cortical abnormalities.