FASI and Cognitive Dysfunction in Pediatric NF-1: A Case-BasedDiscussion

Neurofibromatosis type 1 (NF1) is one of the most common autosomal dominant genetic diseases with a variety of changes and complications of the peripheral and central nervous system. In this article we discuss the prevalence, clinical manifestations and general recommendations for the treatment of children with NF1. The most common neurological disturbances in NF during childhood are cognitive deficits and specific learning difficulties (up to 80 %). Peripheral cutaneous /subcutaneous neurofibromas are usually present in puberty, while plexiform neurofibromas, as inherited lesions in the first years of life, could remain unrecognized. Incidence of malignant peripheral nerve sheath tumors (neurofibrosarcomas) is higher in NF1 than in the general population, with an estimated value of 2%-5%. The most common brain changes are multiple T2-hyperintensities presented in 43% to 93% of children with NF1 age dependent. They are usually localized in basal ganglia, brainstem and cerebellum. Their clinical importance is still unknown which is why they are called „unidentified bright objects“. Visual pathway gliomas (pilocytic astrocytomas) are the most common brain tumors in children with NF1 with the prevalence of 20%. Second in the range are the brainstem tumors. Aqueductal stenosis is the most common reason for hypertensive hydrocephalus in children with NF1. The medical treatment of neurological complications in children with NF1 does not differ from the treatment of equivalent neurological changes in children without NF1.

Are morphological and structural MRI characteristics related to specific cognitive impairments in neurofibromatosis type 1 (NF1) children?

BackgroundMany children with neurofibromatosis type 1 (NF1) have focal abnormal signal intensities (FASI) on brain MRI, whose full clinical impact and natural history have not been studied systematically. Our aims are to describe the clinical and neuroradiological features in children with NF1 and cerebellar FASI, and report on the natural history of FASI that display atypical features such as enhancement and mass effect.MethodA retrospective review of the hospital charts and brain MRIs was performed on children from Manitoba diagnosed between 1999 and 2008 with NF1, who also had cerebellar FASI on MRI.ResultsFifty patients (mean age: 16.1y, minimum-maximum: 6.4 - 30y, 27 M) were identified. Mean duration of follow up was 10.1y. Developmental delay, learning disabilities, tumors, and visual signs occurred commonly. Cerebellar signs were not reported. Mean age of the patients at baseline MRI was 7.8 (SD: 4.5) years. FASI occurred in several brain locations and were rarely confined to the cerebellum. FASI displayed mass effect and enhancement infrequently but were associated with malignancy only once. The number of FASI at baseline MRI was significantly less in patients with attention deficient hyperactivity disorder and more if a first degree relative had NF1 or if they had decreased visual acuity.DiscussionPatients with NF1 and cerebellar FASI do not have motor or consistent non-motor (e.g. developmental delay or learning disabilities) cerebellar features. The number of FASI may correlate with some clinical features. FASI may display enhancement and mass effect but they rarely become malignant.

Purpose: Neurofibromatosis type 1 (NF1), which is caused by mutations of the NF1 gene, is the most frequent single gene disorder to affect the nervous system. Unidentified bright objects (UBOs) are commonly observed on brain magnetic resonance imaging (MRI) in patients with NF1. However, their clinical and pathologic significance is not well understood. The purpose of this study was to investigate the correlation between UBOs and cerebral glucose metabolism measured by F-2Fluoro-2-deoxy-D-glucose (F-FDG) positron emission tomography (PET) in Korean patients with NF1. Materials and Methods: Medical records of 75 patients (34 males and 41 females) with NF1 who underwent brain MRI and PET between 2005 and 2011 were evaluated retrospectively. Clinical data including demographics, neurological symptoms, and brain MRI and PET findings, were reviewed. Results: UBOs were detected in the brain MRI scans of 31 patients (41%). The region most frequently affected by UBOs was the basal ganglia. The most frequent brain PET finding was thalamic glucose hypometabolism (45/75, 60%). Of the 31 patients with UBOs, 26 had thalamic glucose hypometabolism on brain PET, but the other 5 had normal brain PET findings. Conversely, of the 45 patients with thalamic glucose hypometabolism on brain PET, 26 showed UBOs on their brain MRI scans, but 19 had normal findings on brain MRI scans. Conclusion: UBOs on brain MRI scans and thalamic glucose hypometabolism on PET appear to be 2 distinctive features of NF1 rather than correlated symptoms. Because the clinical significance of these abnormal imaging findings remains unclear, a longitudinal follow-up study of changes in clinical manifestations and imaging findings is necessary.

Neurofibromatosis type 1 (NF1) is a hereditary disease with a dominant autosomal pattern. In children and adolescents, it is frequently associated with the appearance of T2-weighted hyperintensities in the brain's white matter. MRI with diffusion tensor imaging (DTI) is used to detect white matter abnormalities by measuring fractional anisotropy (FA). This study employed DTI to evaluate the relationship between FA patterns and the findings of T2 sequences, with the aim of improving our understanding of anatomical changes and microstructural brain abnormalities in individuals with NF1. Forty-four individuals with NF1 and 20 control subjects were evaluated. The comparative analysis of FA between NF1 and control groups was based on four predetermined anatomical regions of the brain hemispheres (basal ganglia, cerebellum, pons, thalamus) and related the presence or absence of T2-weighted hyperintensities in the brain, which are called unidentified bright objects (UBOs). The FA values between the groups demonstrated statistically significant differences (P ≤ 0.05) for the cerebellum and thalamus in patients with NF1, independent of the occurrence of UBOs. Diffusion tensor MR imaging confirms the influence of UBOs in the decrease of FA values in this series of patients with NF1. Additionally, this technique allows the characterization of microstructural abnormalities even in some brain regions that appear normal in conventional MR sequences.

Objectives: Epilepsy is one of the complications of neurofibromatosis type 1 (NF1). The aim of this study was to investigate the relationship between risk factors and epileptic seizures in NF1 patients. Materials & Methods: We retrospectively studied 105 Turkish children with NF1 in this study. Results: We found 15 (14.3%) patients epilepsy patients in our study. The mean age at onset of seizures was 7.33± 4.33 years (range 1 to 15 years). The most common seizure type was partial onset seizures. In the epilepsy patients, unidentified bright objects (UBOs) were present in seven patients, brain tumors in four patients, mesial temporal sclerosis in one patient, hydrocephalus in one patient, and cortical dysplasia in one patient. One patient had normal neuroimaging findings. There was no correlation between epilepsy and age, sex, consanguinity, family history of NF1, family history of epilepsy, neurologic deficits, presence of UBOs, location of UBOs, and presence of optic pathway glioma. We found that intellectual disability, and brain tumors were a significant risk factors for epilepsy development. Conclusions: The occurrence of epileptic seizures in NF1 patients is related to intellectual disability and brain tumors.

Neurofibromatosis type 1 (NF1) is the most common neurocutaneous disease. The NF1 gene is located on chromosome 17q11.2 and codes for a large tumor suppressor protein, called neurofibromin. The prevalence is around 1 in 3,000 individuals, and it is inherited dominantly with a 98% penetrance, but with high phenotypic variability. Neurologic manifestations are mainly tumors, such as optic gliomas, focal areas of high T2-weighted magnetic resonance imaging signals known as unidentified bright objects, mental retardation or learning disabilities, and epilepsy. Other neurologic problems, including attention deficits and headaches, have been described. The prevalence of seizures in patients with NF1 is around 3.8 to 6%. This is considerably higher than the 1 to 2% reported for the general population, or the 4% of children who have experienced a seizure. The majority of classifiable seizures are focal in origin with or without secondary generalization. Most abnormal electroencephalography recordings reveal focal abnormalities. Overall, more than half of the electroencephalography studies are abnormal. The most frequent structural lesions found in patients with NF1 and epilepsy are tumors and malformations of cortical development. Other types of epilepsies and epileptic syndromes have also been described to be associated with NF1, such as West syndrome, Lennox-Gastaut syndrome, myoclonic epilepsy, epilepsy with generalized tonic-clonic seizures, childhood absence epilepsy, and juvenile myoclonic epilepsy. In patients with focal epilepsy, neuroimaging should be performed to exclude neoplastic and other types of focal lesions. In patients with NF1 and seizures, optimal management of antiepileptic drugs and eventually surgery should be considered.

Simple SummaryNeurofibromatosis type 1 (NF1) is a genetic disorder caused by pathogenic variants in the NF1 tumor suppressor gene. In 5–10% of NF1 patients, a large heterozygous deletion of the whole NF1 gene is identified, leading to the commonly called “NF1 microdeletion syndrome”. NF1-deleted patients were previously reported to develop a particularly severe form of the disease with frequent cognitive impairment and an increased risk of benign and malignant tumors. Here, we performed a comprehensive clinical assessment of the largest NF1-deleted cohort to date, including 126 NF1 patients with a deletion of the NF1 gene. This work provides new insights into the specific phenotype associated with NF1 deletions and may contribute to improve the follow-up care of NF1 patients. Complete deletion of the NF1 gene is identified in 5–10% of patients with neurofibromatosis type 1 (NF1). Several studies have previously described particularly severe forms of the disease in NF1 patients with deletion of the NF1 locus, but comprehensive descriptions of large cohorts are still missing to fully characterize this contiguous gene syndrome. NF1-deleted patients were enrolled and phenotypically characterized with a standardized questionnaire between 2005 and 2020 from a large French NF1 cohort. Statistical analyses for main NF1-associated symptoms were performed versus an NF1 reference population. A deletion of the NF1 gene was detected in 4% (139/3479) of molecularly confirmed NF1 index cases. The median age of the group at clinical investigations was 21 years old. A comprehensive clinical assessment showed that 93% (116/126) of NF1-deleted patients fulfilled the NIH criteria for NF1. More than half had café-au-lait spots, skinfold freckling, Lisch nodules, neurofibromas, neurological abnormalities, and cognitive impairment or learning disabilities. Comparison with previously described “classic” NF1 cohorts showed a significantly higher proportion of symptomatic spinal neurofibromas, dysmorphism, learning disabilities, malignancies, and skeletal and cardiovascular abnormalities in the NF1-deleted group. We described the largest NF1-deleted cohort to date and clarified the more severe phenotype observed in these patients.

How far is arterial spin labeling MRI from a clinical reality? Insights from arterial spin labeling comparative studies in Alzheimer's disease and other neurological disorders.

Neurofibromatosis type 1 (NF1) is a common (affects ∼1 in 4000 individuals worldwide) autosomal dominant neurocutaneous syndrome, resulting from functional inactivation of the NF1 gene. The main clinical features include dermal pigmentary changes (cafe-au-lait spots and skin fold freckling), development of benign peripheral nerve sheath-derived tumors (neurofibromas) and hamartomas of the iris (Lisch nodules). Benign tumor development, involving peripheral nerves and the central nervous system, are hallmark features of NF1. Associated clinical manifestations can include abnormalities of the cardiovascular, gastrointestinal, renal and endocrine systems, orthopedic problems, macrocephaly, small stature, facial and body dysmorphism, learning disabilities, and an increased malignancy risk. Neurofibromin, the NF1 gene product, is a mammalian Ras GTPase-activating protein expressed in most tissues, with functional inactivation leading to increased cellular Ras signaling, resulting in cell growth, proliferation and tumorigenesis, underlining its role as a tumor suppressor gene. At least 1050 different disease-causing NF1 mutations are known, although correlating different mutations with specific clinical features has proved largely unsuccessful, with only two such associations identified. One relating to severely affected NF1 patients with large genomic deletions that involve the entire NF1 gene, and the other, relating to some mildly affected NF1 patients without any cutaneous neurofibromas, who have the same specific 3bp NF1 gene deletion. Several animal NF1 models have been developed that have allowed analysis of NF1 gene inactivation and proved crucial in unravelling the complexity of the Ras signaling pathway and its role in regulating cell proliferation, differentiation, motility, apoptosis and tumorigenesis. Such models have also better defined the probable causes of NF1-related learning difficulties, skeletal abnormalities, and also identified neurofibromin as a cellular cyclic AMP regulator. It is now recognized that mutations of a number of the genes in the complex RAS-MAPK signaling pathway are associated with several neuro-cardio-facial-cutaneous syndromes, a group of pheno- and genotypically similar developmental disorders, that includes NF1. The recent identification of SPRED1 gene mutations in individuals with mild NF1-like features extends this disease association with spred proteins known to be directly involved in RAS-MAPK pathway. No effective treatment for NF1 is currently available, with many proposed therapies, often aimed at preventing tumor growth, showing little success, although a statin-based treatment has proved useful in treating a mouse NF1 model with learning disability and tibial dysplasia. Several proposed therapies targeting mast cell function, different Ras signaling pathway components, as well as growth factor receptors, may hopefully prove more successful.

PurposeCognitive impairment is described in 80% of Neurofibromatosis type 1 (NF1) patients. Brain focal areas of T2w increased signal intensity on MRI, the so-called Unidentified Bright Objects (UBOs) have been hypothesized to be related to cognitive dysfunction, although conflicting results are available in literature. Here, we investigated the possible relation between UBOs’ volume, cognitive impairment, and language disability in NF1 patients.Material and methodsIn this retrospective study, clinical and MRI data of 21 NF1 patients (M/F = 12/9; mean age 10.1 ± 4.5) were evaluated. Brain intellectual functioning and language abilities were assessed with specific scales, while the analyzed MRI sequences included axial 2D-T2-weighted and FLAIR sequences. These images were used independently for UBOs segmentation with a semiautomatic approach and obtained volumes were normalized for biparietal diameters to take into account for brain volume. Possible differences in terms of normalized UBOs volumes were probed between cognitively affected and preserved patients, as well as between subjects with or without language impairment.ResultsPatients cognitively affected were not different in terms of UBOs volume compared to those preserved (p = 0.35 and p = 0.30, for T2-weighted and FLAIR images, respectively). Similarly, no differences were found between patients with and without language impairment (p = 0.47 and p = 0.40, for the two sequences).ConclusionsThe relation between UBOs and cognition in children with NF1 has been already investigated in literature, although leading to conflicting results. Our study expands the current knowledge, showing a lack of correlation between UBOs volume and both cognitive impairment and language disability in NF1 patients.

We sought to define the radiologic features that differentiate neoplastic from non-neoplastic T2 hyperintensities (T2Hs) in neurofibromatosis type 1 (NF1) and identify those lesions most likely to require oncologic surveillance. We conducted a single-center retrospective review of all available brain MRIs from 68 children with NF1 (n = 190) and 46 healthy pediatric controls (n = 104). All T2Hs identified on MRI were characterized based on location, border, shape, degree of T1 hypointensity, and presence of mass effect or contrast enhancement, and subsequently classified using newly established radiologic criteria as either unidentified bright objects (UBOs) or probable tumors. Lesion classification was pathologically confirmed in 10 NF1 cases. T2Hs were a highly sensitive (94.4%; 95% confidence interval [CI] 86.4%-98.5%) and specific (100.0%; 95% CI 92.3%-100.0%) marker for the diagnosis of NF1. UBOs constituted the majority of T2Hs (82%) and were most frequently located in cerebellar white matter, medial temporal lobe, and thalamus, where they were more likely than probable tumors to be bilateral (p < 0.001) and have nondiscrete borders (p < 0.001). Surprisingly, 57% of children with T2Hs harbored lesions classified as probable tumors, and 28% of children with probable tumors received treatment. In contrast to UBOs, probable tumors were most frequently located within the globus pallidus and medulla, and rarely occurred prior to 3 years of age. With the implementation of standardized radiologic criteria, a high prevalence of brain tumors was identified in this at-risk population of children, of which nearly one-third required treatment, emphasizing the need for appropriate oncologic surveillance for patients with NF1 harboring nonoptic pathway brain tumors.

Distinct attentional and executive profiles in neurofibromatosis type 1: Is there difference with primary attention deficit-hyperactivity disorder?

Spinal conditions, such as scoliosis and spinal tumors, are prevalent in neurofibromatosis type 1 (NF1). Despite the recognized importance of their early detection and treatment, there remain knowledge gaps in how to approach these manifestations. The purpose of this study was to utilize the experience of a multidisciplinary committee of experts to establish consensus-based best practice guidelines (BPGs) for spinal screening and surveillance, surgical intervention, and medical therapy in pediatric patients with NF1. Using the results of a prior systematic review, 10 key questions that required further assessment were first identified. A committee of 20 experts across medical specialties was then chosen based on their clinical experience with spinal deformity and tumors in NF1. These were 9 orthopaedic surgeons, 4 neuro-oncologists/oncologists, 3 neurosurgeons, 2 neurologists, 1 pulmonologist, and 1 clinical geneticist. An initial online survey on current practices and opinions was conducted, followed by 2 additional surveys via a formal consensus-based modified Delphi method. The final survey involved voting on agreement or disagreement with 35 recommendations. Items reaching consensus (≥70% agreement or disagreement) were included in the final BPGs. Consensus was reached for 30 total recommendations on the management of spinal deformity and tumors in NF1. These were 11 recommendations on screening and surveillance, 16 on surgical intervention, and 3 on medical therapy. Five recommendations did not achieve consensus and were excluded from the BPGs. We present a set of consensus-based BPGs comprised of 30 recommendations for spinal screening and surveillance, surgical intervention, and medical therapy in pediatric NF1.

Background Malignant peripheral nerve sheath tumors (MPNST) are rare soft tissue sarcomas and although less that 10% occur in the pediatric age, they are the most feared complication in the follow-up of Neurofibromatosis Type 1 (NF1) patients. NF1-children tend to have larger tumors and worse prognosis than non-NF1 patients. There is a lack of data regarding MPNST in pediatric populations with NF1, and the present work aims to characterize a Portuguese population of pediatric NF1 patients who developed a MPNST. Material and Methods Retrospective analysis of all NF1-pediatric patients diagnosed with MPNST between 2000 to 2021, from three centers in Portugal. Patient characteristics, treatment modalities and clinical outcomes were reviewed. Results 12 patients (6 males and 6 females) met the inclusion criteria. 7 had no family history of NF1. Median age at diagnosis was 14.1 years (range 10-18). 5 had been diagnosed previously with Plexiform Neurofibroma and were treated with selumetinib (2) and partial surgery (2). MPNSTs were mostly located in the retroperitoneum (7) and in the proximal lower limbs (2). Only 1 patient had a resectable tumor at diagnosis and 3 patients had metastatic disease. In the FDG-PET scan of evaluated patients (7), the mean maximum standardized uptake value of the main lesion was 6 (range 3.6-9.7).Neoadjuvant ifosfamide plus doxorubicin chemotherapy was used in 4 patients. The median overall survival in this population was 10.3 months (95% CI 0.1-20.6) 2 patients remain alive. Conclusion The prognosis of MPNSTs in NF1 pediatric patients is very poor. In a subset of patients, MPNSTs develop from known Plexiform Neurofibromas. Current surveillance ant treatment protocols need to be improved.