Characterizing the microstructural basis of “unidentified bright objects” in neurofibromatosis type 1:A combined in vivo multicomponent T2 relaxation and multi-shell diffusion MRI analysis

AbstractIntroductionThe histopathological basis of “unidentified bright objects” (UBOs) (hyperintense regions seen on T2-weighted magnetic resonance (MR) brain scans in neurofibromatosis-1 (NF1)) remains unclear. New in vivo MRI-based techniques (multi-exponential T2 relaxation (MET2) and diffusion MR imaging (dMRI)) provide measures relating to microstructural change. We combined these methods and present previously unreported data on in vivo UBO microstructure in NF1.Methods3-Tesla dMRI data were acquired on 17 NF1 patients, covering 30 white matter UBOs. Diffusion tensor, kurtosis and neurite orientation and dispersion density imaging parameters were calculated within UBO sites and in contralateral normal appearing white matter (cNAWM). Analysis of MET2 parameters was performed on 24 UBO–cNAWM pairs.ResultsNo significant alterations in the myelin water fraction and intra- and extracellular (IE) water fraction were found. Mean T2 time of IE water was significantly higher in UBOs. UBOs furthermore showed increased axial, radial and mean diffusivity, and decreased fractional anisotropy, mean kurtosis and neurite density index compared to cNAWM. Neurite orientation dispersion and isotropic fluid fraction were unaltered.ConclusionOur results suggest that demyelination and axonal degeneration are unlikely to be present in UBOs, which appear to be mainly caused by a shift towards a higher T2-value of the intra- and extracellular water pool. This may arise from altered microstructural compartmentalization, and an increase in ‘extracellular-like’, intracellular water, possibly due to intramyelinic edema. These findings confirm the added value of combining dMRI and MET2 to characterize the microstructural basis of T2 hyperintensities in vivo

Unidentified Bright Objects on Brain Magnetic Resonance Imaging Affect Vestibular Neuritis

ObjectivesThe aim of this study was to investigate the differences in clinical manifestations of in two groups of vestibular neuritis (VN) patients with or without unidentified bright objects (UBOs).MethodsA prospective, observational study with 46 patients diagnosed with VN between May 2013 and November 2013 was executed. A caloric test, a cervical vestibular-evoked myogenic potentials (cVEMPs) test, brain magnetic resonance imaging (MRI), spontaneous nystagmus test, head impulse test, and head-shaking nystagmus test were performed.ResultsOf the patients, 56.5% (n=26) were classified as UBO-positive by MRI. These showed lower caloric weakness and more prominent cVEMP asymmetry compared with the UBO-negative group (P0.05).ConclusionUBOs on T2-weighted or fluid attenuated inversion recovery MRI may affect the patterns of the vestibular nerve in patients with VN

Neurofibromatosis type 1: ocular electrophysiological and perimetric anomalies

Introduction: Neurofibromatosis type 1 (NF1) is a multisystemic disease caused by the mutation of Nf1 gene located on chromosome 17q11.2. The mutation determines the loss of function of the protein neurofibromin with consequent uncontrolled cellular proliferation. Patients are characterized by a wide range of dermatological, neurological, and ophthalmological symptoms. Purpose: The aim of the study was to evaluate, through pattern visual evoked potentials (p-VEPs) and frequency doubling technology (FDT) Matrix perimetry, the objective and psychophysical functionality of the optic pathways in a group of NF1 patient. Methods: The study group consisted of 26 patients affected by NF1 and 17 healthy controls. Each patient underwent a complete ophthalmological examination, p-VEPs with the evaluation of amplitude and latency of the P100 wave, and FDT perimetry, with the evaluation of central sensitivity (CS), mean deviation (MD), pattern standard deviation (PSD) and glaucoma hemifield test (GHT). Results: NF1 patients showed a statistically significant alteration in the transmission of visual impulse. P-VEPs results highlighted a reduced amplitude and an increased latency of the P100 wave, suggesting an involvement of the visual pathway. Visual field analysis showed a significant reduction in all the observed parameters as well (CS, MD, PSD, and GHT). Conclusion: The present study showed, in NF1 patients, a qualitative and quantitative alteration in the conduction of stimuli through the visual pathways. The observed alterations are present, although, only at a subclinical level. None of the patients included in the study showed any manifest visual deficit nor had any concomitant pathology that might have affected the outcome of the study. In conclusion, electrophysiological exams and computer perimetry may take part, alongside a wider array of exams, in the differential diagnosis and later monitoring of NF1

Characteristic Features of Children with Neurofibromatosis Type 1

Neurofibromatosis Type 1 (NF-1) is the most common, progressive, multisystemic, autosomal dominant neurocutaneous syndrome. Its clinical features begin to present during childhood. Early diagnosis and follow-up of children with NF-1 is necessary due to predisposition to tumors and complications. Herein we aimed to evaluate patient characteristics', neuroradiologic findings and frequency of tumors in children with NF-1 who have been followed up at our center from January 1989 to June 2008. Medical records of 64 children with NF-1 were analized retrospectively for age, gender, diagnostic criteria for NF-1, unidentified bright objects (UBOs) on magnetic resonance imaging (MRI), complications related to NF-1, and tumors. The median age of patients was 9.5 years (0.5 18), M:F ratio was 1.2. The incidence of the diagnostic criteria were as following, café au lait spots: 100%, freckling: 62.5%,neurofibromas ± plexiform neurofibromas: 47%, Lisch nodules: 38%, optic gliomas: 11%,distinctive osseous lesions: 11%, and first degree relative with NF- 1: 30%. Cranial MRI had been performed in 38 patients, and 58% of them revealed UBOs. The most common complications were kyphoscoliosis (19%), convulsion (11%). Benign tumors and malignant ± benign tumors developed in52%and19%of patients, respectively. The importance of careful physical examination was showed by the high frequency of positive clinical diagnostic criteria of NF-1. The frequency of UBOs on MRI was high in children with NF-1. This was suggested that neuroradiologic findings may be proposed as an additional diagnostic criterion for NF-1, particularly for young children who didn't meet the diagnostic criteria. Management and follow up of complications related to NF-1, and offering genetic counseling to parents could be making by early diagnosis of NF-1 in childhood. The predisposition to tumors and the high frequencies of complications related to NF-1 were showed that the importance of multidisciplinary follow up of children with NF-1.Nörofibromatozis Tip1 (NF1) toplumda en sık karsılasılan, klinik bulguları çocukluk çagında ortaya çıkmaya baslayan, zamanla ilerleyici seyir göstererek pek çok sistemi etkileyebilen otozomal dominant geçisli bir nörokutan sendromdur. Beniyn ve maliyn tümör gelismesine yatkınlık yaratması ve NF1 iliskili komplikasyonlar nedeniyle, NF1' in çocukluk çagında erken tanısı ve klinik izlemi önemlidir. Bu çalısmada merkezimizde Ocak 1989-Haziran 2008 tarihleri arasında, NF1 tanısıyla izlenen çocuk hastaların karakteristik özellikleri, nöroradyolojik bulguları ve tümör sıklıgınındegerlendirilmesi amaçlanmıstır. Nörofibromatozis Tip1 tanı kriterlerini karsılayan 64 hastanın dosyaları retrospektif olarak incelendi. Hastaların yas, cinsiyet, NF1 tanı kriterleri, manyetik rezonans görüntülemede (MRG) tanımlanmamıs parlak objelerin (UBO: unidentified bright objects) görülme sıklıgı, NF1 iliskili komplikasyonlar, gelisen tümörler degerlendirildi. Hastaların ortanca tanı yası 9.5 yas (0.5 18), E:K oranı 1.2 bulundu. Tanı kriterlerinin sıklıgı: sütlü kahve lekeleri %100, çillenme %62.5, nörofibrom veya pleksiform nörofibrom %47, Lisch nodülü %38, optik gliom %11, kemik lezyonu %11, birinci derece akrabalarda NF1 tanısı %30 bulundu. Kraniyal MRG yapılan 38 hastadan 58%'inde UBO mevcuttu. En sık gelisen komplikasyonlar; kifoskolyoz (%19) ve konvülzyondu (%11). Hastaların %52'inde beniyn, %19'inde maliyn±beniyn tümörler gelismisti. Nörofibromatozis Tip1'in fizik inceleme ile saptanabilen klinik tanısal kriterlerinin sıklıgı, iyi bir fizik incelemenin önemini göstermektedir. Kraniyal MRG ile NF1 tanılı çocuk hastalarda yüksek oranda UBO pozitifligi izlendigi görülmüstür. Bu bulgu, özellikle henüz klinik bulguları NF1 kriterlerini karsılamayan küçük yas grubunda nöroradyolojik bulguların ek bir kriter olarak arastırılmasının hastaların erken tanısını saglayabilecegini düsündürmektedir. Erken tanı ile hem çocukta gelisebilecek problemlerin izlemi ve tedavisi, hem de ailelere genetik danısma verilmesi saglanabilecektir. Beniyn ve maliyn tümörlere yatkınlık ve diger NF1 iliskili komplikasyonların sıklıgının yüksek olması, NF1 tanılı çocukların multidisipliner izleminin önemini göstermistir

Somatic NF1 loss of heterozygosity associated with NF1-related pectus excavatum deformity: a new insight in pathogenesis?

Neurofibromatosis type 1 (NF1) is a neurocutaneous genetic disorder with a broad spectrum of associated signs and symptoms, including skeletal anomalies. The association of NF1 with anterior chest wall deformities has been recently reported, especially the pectus excavatum (PE). Over the years, several authors have suggested loss of heterozygosity (LOH) as the possible pathogenic mechanism underlying the development of the typical NF1 skeletal features. Here, we report a NF1 patient with severe chest deformity and harboring the germline heterozygous pathogenic NF1 variant NM_001042492.3: c.4271delC p.(Ala1424Glufs*4). Through Next Generation Sequencing (NGS), we investigated the affected cartilage from the PE deformity and identified the additional frameshift variant NM_001042492.3: c.2953delC p.(Gln985Lysfs*7), occurring as a somatic NF1 second hit mutation. Western blot analysis showed the absence of wild-type NF1 protein in the cartilage of the patient, consistent with a somatic LOH. Taken together, our findings support the role of LOH in NF1-related PE, widening the spectrum of the pathophysiological mechanisms involved in NF1-related skeletal features. This mechanism can be studied in the future in our center and applied to other tissues, including non-skeletal tissues (plexiform neurofibromas, vasculopathy and many others). The discovery of this possible pathogenetic mechanism helps us in understanding a varied and complex disease and tells us to pay attention to the possible exposure of patients to sources emitting ionizing radiation, trying to spare exams such as CT and similar