Search

Neurofibromatosis type 1 (NF1) is a multisystemic autosomal dominant disorder that includes intracranial lesions such as unidentified bright objects (UBOs)—areas of increased T2 signal on magnetic resonance imaging (MRI)—and tumors known as gliomas. The presence of these lesions in the corpus callosum (CC) has not been previously studied in a large cohort. We reviewed medical records of 681 patients (aged three months to 86 years) followed at our institution from 2000 to 2023 with NF1 and one or more brain MRI. Patients with lesions in the CC were identified, and RAPNO/RANO criteria were used to determine changes in size over time, where a change of 25% in the product of perpendicular measurements indicates growth or shrinkage. Forty-seven patients had CC UBOs, most of which were in the splenium (66.0%). Seventeen patients had CC gliomas (10% of those with any glioma), two of whom had two gliomas. Seventeen of 19 gliomas were in the splenium. Over follow-up, eight of 19 remained stable, three shrunk, and eight grew. The mean percentage change in the product of the dimensions was 311.5% (ranging from −46.7% to 2566.6%). Of the eight lesions that grew, one required treatment. There is a 6.9% and 2.5% prevalence of CC UBOs and gliomas, respectively, in our cohort of patients with NF1. Most lesions are present in the splenium, and although some gliomas demonstrate significant growth, they rarely require treatment. This work is the largest series of CC lesions in NF1 and adds to the growing data to inform appropriate follow-up. [ABSTRACT FROM AUTHOR]

Attentional and executive dysfunctions are the most frequent cognitive disorders in neurofibromatosis type 1 (NF1), with a high prevalence of attention deficit-hyperactivity disorder (ADHD). We (i) compared attentional profiles between NF1 children with and without ADHD and children with primary ADHD criteria and (ii) investigated the possible relationship between attentional disorders and "unidentified bright objects" (UBOs) in NF1. This retrospective study included 47 NF1 children, 25 with ADHD criteria (NF1+adhd group), matched for age, sex, and cognitive level with 47 children with primary ADHD (ADHD group). We collected computer task (sustained-attention, visuomotor-decision, inhibition, and cognitive-flexibility tasks) scores normalized for age and sex, and brain magnetic resonance imaging data. (i) Working memory was impaired in all groups. (ii) Omissions (p < 0.002) and response-time variability (p < 0.05) in sustained-attention and visuomotor-decision tasks and errors (p < 0.02) in the cognitive-flexibility task were lower for the NFI+adhd and ADHD groups than for the NF1-no-adhd group. (iii) The NF1+adhd group had slower response times (p ≤ 0.02) for inhibition and visuomotor-decision tasks than the other groups. (iv) We found no relevant association between cognitive performance and UBOs. NF1 children with ADHD have an attentional and executive functions deficit profile similar to that of children with primary ADHD, but with a slower response-time, increasing learning difficulties. The atypical connectivity of fronto-striatal pathways, poorer dopamine homeostasis, and increased GABA inhibition observed in NF1 renders vulnerable the development of the widely distributed neural networks that support attentional, working-memory, and executive functions. • NF1 children show working-memory impairment as primary ADHD children • NF1+adhd and primary ADHD children show similar attentional and executive profiles • NF1+adhd children differ from primary ADHD by being slower on visuomotor tests • Unidentified bright objects in NF1 do not correlate with cognitive performance [ABSTRACT FROM AUTHOR]

Neurofibromatosis type 1 (NF1) is the most common neurocutaneous disease and is caused by mutations in the NF1 gene. The most common clinical features of NF1 are pigmentary abnormalities such as café-au-lait spots and inguinal or axillary freckling, cutaneous and plexiform neurofibromas, hamartomas of the iris, optic gliomas, and bone lesions. The aim of this retrospective study was to define the clinical and molecular characteristics of a pediatric sample of NF1, as well as the mutational spectrum and genotype-phenotype correlation. The study included 40 children with clinically suspected NF1. The patients were screened for NF1 mutations by DNA-based sequencing. In addition, all the patients were studied by multiplex ligation-dependent probe amplification (MLPA) to identify any duplications or deletions in NF1. The demographic, clinical, and genetic features of the children were characterized. A total of 40 children with NF1 were included. Of those, 28 were female and 12 were male. The mean age was 8.91 years. An NF1 variant was discovered in 28 of 40 patients (70%). Among these mutations, intronic mutations were the most frequently detected mutations; 15 of these variants had not been previously reported. Only one patient had a whole NF1 gene deletion. This study expands the spectrum of mutations in the NF1 gene. This study also showed that genetic screening using both next-generation sequencing and MLPA had a positive effect on diagnosis and genetic counseling in patients with suspected NF1. [ABSTRACT FROM AUTHOR]

Cutaneous neurofibromas (cNFs) are a hallmark of patients with the neurofibromatosis type 1 (NF1) genetic disorder. These benign nerve sheath tumors, which can amount to thousands, develop from puberty onward, often cause pain and are considered by patients to be the primary burden of the disease. Mutations of NF1 , encoding a negative regulator of the RAS signaling pathway, in the Schwann cell (SCs) lineage are considered to be at the origin of cNFs. The mechanisms governing cNFs development are poorly understood, and therapeutics to reduce cNFs are missing, mainly due to the lack of appropriate animal models. To address this, we designed the Nf1-KO mouse model that develops cNFs. Using this model, we found that cNFs development is a singular event and goes through 3 successive stages: initiation, progression, and stabilization characterized by changes in the proliferative and MAPK activities of tumor SCs. We found that skin trauma accelerated the development of cNFs and further used this model to explore the efficacy of the MEK inhibitor binimetinib to cure these tumors. We showed that while topically delivered binimetinib has a selective and minor effect on mature cNFs, the same drug prevents their development over long periods. [ABSTRACT FROM AUTHOR]

This study aims to (1) investigate health-related quality of life (HRQoL) in children with Neurofibromatosis Type 1 (NF1) using the Pediatric Quality of Life inventory (PedsQL) and the Child Health Questionnaire (CHQ); and (2) compare the psychometric properties and content of these questionnaires in NF1 patients. PedsQL and CHQ proxy-reports were administered to parents/caregivers of 160 patients with NF1 aged 5–12 years. HRQoL scores were compared with Dutch population norms using independent t-tests. Psychometric properties (feasibility and reliability) were assessed by floor/ceiling effects and Cronbach's alpha coefficient. A principal component analysis (PCA) with varimax rotation was performed to identify the data's internal structure. By content mapping, we identified unique constructs of each questionnaire. Proxy-reported HRQoL was significantly lower on all PedsQL subscales for children aged 5–7 years, and on 4/6 subscales for children aged 8–12 years compared to norms. Significantly lower HRQoL was reported on 6/14 CHQ subscales (children 5–7 years) and 9/14 subscales (children 8–12 years). The PedsQL showed slightly better feasibility and reliability. The PCA identified two components, representing psychosocial and physical aspects of HRQoL, explaining 63% of total variance. Both questionnaires showed relevant loadings on both components. The CHQ subscales concerning parents and family were considered unique contributions. Proxy-reported HRQoL of children with NF1 is significantly lower compared to norms on multiple domains. Both questionnaires adequately measure HRQoL in children with NF1. However, the PedsQL has slightly better psychometric properties, while the CHQ covers a unique dimension of HRQoL associated with disease impact on parents and family. • PedsQL and CHQ scores were compared to population norms. • Proxy-reported Quality of Life of children with Neurofibromatosis Type 1 is reduced. • Principal component analysis: questionnaires adequately measure Quality of Life. • CHQ covers a unique dimension of Quality of Life: disease impact on family. [ABSTRACT FROM AUTHOR]

Neurofibromatosis type 1 (NF1) is an autosomal dominant neurocutaneous syndrome that affects multiple organ systems resulting in widespread symptoms, including cognitive deficits. In addition to the criteria required for an NF1 diagnosis, approximately 70% of children with NF1 present with Unidentified Bright Objects (UBOs) or Focal Areas of Signal Intensity, which are hyperintense bright spots seen on T2-weighted magnetic resonance images and seen more prominently on FLAIR magnetic resonance images (Sabol et al., 2011). Current findings relating the presence/absence, quantities, sizes, and locations of these bright spots to cognitive abilities are mixed. To contribute to and hopefully disentangle some of these mixed findings, we explored potential relationships between metrics related to UBOs and cognitive abilities in a sample of 28 children and adolescents with NF1 (M=12.52 years; SD=3.18 years; 16 male). We used the Lesion Segmentation Tool (LST) to automatically detect and segment the UBOs. The LST was able to qualitatively and quantitatively reliably detect UBOs in images of children with NF1. Using these automatically detected and segmented lesions, we found that while controlling for age, biological sex, perceptual IQ, study, and scanner, "total UBO volume", defined as the sum of all the voxels representing all of the UBOs for each participant, helped explain differences in word reading, phonological awareness, and visuospatial skills. These findings contribute to the emerging NF1 literature and help parse the specific deficits that children with NF1 have, to then help improve the efficacy of reading interventions for children with NF1. • Children with Neurofibromatosis type 1 often present with Unidentified Bright Objects (UBOs). • The Lesion Segmentation Tool can be used to segment UBOs. • In previous literature, findings linking UBOs to cognition are inconsistent. • UBO volume relates to word reading, phonological awareness, visuospatial, and language skills. [ABSTRACT FROM AUTHOR]

Since 1990's, the cognitive profile of children with a neurofibromatosis type 1 (NF1) has been refined by many different studies. Children with NF1 may exhibit a variety of cognitive dysfunctions. Memory difficulties have been reported, but the results are contradictory and, compared to other cognitive functions, memory has been less evaluated. The aim of this study was to investigate the memory profile in NF1 with a particular population, children with NF1 without attention deficit hyperactivity disorder (ADHD). Eighteen children with NF1 without ADHD and eighteen typically developing aged from 8 to 12.6 years were compared in terms of both their verbal and visual working memory, anterograde memory, and procedural perceptual-motor memory. We also assessed semantic and autobiographical memory. Our results indicate the existence of memory difficulties in children with NF1 without ADHD in verbal working and anterograde memory but not in terms of the visual domain. They also experienced difficulties recalling personal memories but these were improved by cueing. However, semantic memory and procedural perceptual-motor memory was preserved. These results highlight a difference between memory systems in children with NF1 without ADHD and the importance to assess the different memory systems, the nature of information and the processes in long-term memory in NF1 population. However, our results raise questions about the possible links between these difficulties and the executive functions. The specifics of memory profile in children with NF1 must be taken into consideration in these children's clinical follow-up, in order to understand their learning difficulties and to make adaptations to their care. [ABSTRACT FROM AUTHOR]

Neurofibromatosis type 1 (NF1) is a phenotypically heterogenous multisystem cancer predisposition syndrome manifesting in childhood and adolescents. Central nervous system (CNS) manifestations include structural, neurodevelopmental, and neoplastic disease. We aimed to (1) characterize the spectrum of CNS manifestations of NF1 in a paediatric population, (2) explore radiological features in the CNS by image analyses, and (3) correlate genotype with phenotypic expression for those with a genetic diagnosis. We performed a database search in the hospital information system covering the period between January 2017 and December 2020. We evaluated the phenotype by retrospective chart review and imaging analysis. 59 patients were diagnosed with NF1 [median age 10.6 years (range, 1.1–22.6); 31 female] at last follow-up, pathogenic NF1 variants were identified in 26/29. 49/59 patients presented with neurological manifestations including 28 with structural and neurodevelopmental findings, 16 with neurodevelopmental, and 5 with structural findings only. Focal areas of signal intensity (FASI) were identified in 29/39, cerebrovascular anomalies in 4/39. Neurodevelopmental delay was reported in 27/59 patients, learning difficulties in 19/59. Optic pathway gliomas (OPG) were diagnosed in 18/59 patients, 13/59 had low-grade gliomas outside the visual pathways. 12 patients received chemotherapy. Beside the established NF1 microdeletion, neither genotype nor FASI were associated with the neurological phenotype. NF1 was associated with a spectrum of CNS manifestations in at least 83.0% of patients. Regular neuropsychological assessment complementing frequent clinical and ophthalmologic testing for OPG is necessary in the care of each child with NF1. • Neurological manifestations were present in 83.0% of children/adolescents with NF1. • Cerebrovascular anomalies were identified in 6.8% of patients, 3.4% sustained a stroke. • Optic pathway and other low-grade gliomas were diagnosed in 30.5% and 22.0% patients. • Neither genotype nor FASI were associated with the neurological phenotype. • Regular neuropsychological and ophthalmological assessments are indicated. [ABSTRACT FROM AUTHOR]

A retrospective observational study. To introduce a novel hybrid technique using segmentation correction (SC) and to compare it with traditional correction (TC) in treating dystrophic scoliosis secondary to neurofibromatosis type 1 (NF1-S) lacking pedicles in the apical area. We reviewed the NF1-S cases lacking pedicles diagnosed in our hospital between January 2015 and December 2019. Patients were divided into the SC and TC groups and were followed up for at least 2 years. The degree of deformities, correction rate, and vertebral rotatory subluxation (RS) were assessed before the operation, post-traction, post operation, and during follow-up visits. A total of 27 patients were included in the SC group and 21 in the TC group. There was no significant difference in the 2 groups before the surgery regarding age, height, weight, degree of deformities, and spinal flexibility. The correction rate of patients in the SC group was higher (57.7% ± 17.3% vs. 40.9% ± 19.0%, P = 0.002) than in the TC group. During the 2-year follow-up, the loss of Cobb angles of the SC group in both coronal and sagittal planes were lower than those of the TC group (coronal plane, 1.2° ± 1.1° vs. 2.0° ± 1.4°, P = 0.039; sagittal plane, 0.9° ± 0.5° vs. 1.7° ± 1.0°, P = 0.002). The SC technique showed better deformity correction than TC, suggesting that SC may be an alternative method for treating NF1-S patients lacking pedicles in the apical area. [ABSTRACT FROM AUTHOR]

Spinal lesions are a known manifestation of neurofibromatosis type 1 (NF1). The aim of this retrospective review was to analyze and report the prevalence of spinal lesions on imaging in a large NF1 center. The data were collected from a period of 62 months from a cohort of 514 patients. Data were collected from multidisciplinary team meeting reports that included radiologic reports of each patient investigating 20 distinct variables. The prevalence of each of these lesions was calculated, and any statistically significant associations were investigated using the χ2 test. Four-hundred forty-seven patients had classic NF1, and 67 patients had spinal NF1. Many of the patients had spinal abnormalities; 25.7% of these patients were found to have dural ectasia, whereas 44.9% of patients had a spinal deformity. A statistically significant association between dural ectasia and spinal neurofibromatosis was established (P < 0.05). An additional statically significant association was established between dural ectasia and spinal deformity (P < 0.00001). The patients with spinal nerve root tumors were identified, and it was found that 49.8% of patients possessed these tumors, whereas 56.3% of these tumors were intraspinal tumors. The most common region affected was the cervical spine, and the most common spinal level was C2. This high prevalence of spinal tumours in mobile areas of the spine is possibly the result of a combination of genetic predisposition and repeated microtraumas resulting in tumor formation. This is the largest reported study of spinal lesions in NF1 based on imaging and offers insights into the etiology and relationships between lesions. [ABSTRACT FROM AUTHOR]

Although musculoskeletal involvement of Neurofibromatosis type 1 (NF1) has been well documented, bone formation, or ossification, within neurofibroma, has been scarcely documented in literature. Here, we report a rare case of ossified neurofibroma in a patient with long history of NF1. 73-Year-old female with childhood-onset NF1 and surgical history of resection for multiple neurofibromas, presented with right ptosis and eyebrow ptosis. A growing tumor on the right eyebrow was surgically resected. Microscopically, the dermal tumor consists of bland spindle cells with thin, wavy nuclei, without atypia, showing S100 immunoreactivity, consistent with neurofibroma. Multiple metaplastic bone formation composed of mature bone trabeculae surrounding adipose tissue were apparent. Up to date, ossification of neurofibroma has been scarcely reported in literature. The etiology is unclear but might involve the response to chronic stress and tissue damage over the years, and/or might indicate the potential differentiation plasticity of mesenchymal stem cell-like population. The unusual presentation of ossification provides insights on the pathogenesis and differentiation plasticity of neurofibroma. • Rare presentation of ossification in forehead neurofibroma from a patient with long history of neurofibromatosis type 1. • Bone formation in neurofibroma has been scarcely reported in literature. • The etiology of ossification might involve the metaplastic change over the tissue damage, chronic stress and aging. • Ossification can provide insights on the potential differentiation plasticity of mesenchymal stem cell-like population. [ABSTRACT FROM AUTHOR]

Neurofibromatosis type 1 (NF1) is an autosomal dominant cancer predisposition syndrome caused by pathogenic variants in NF1 , which negatively regulates the RAS pathway. Knowledge of the genotype-phenotype correlation in this disease is an important tool for prognostic evaluation and early detection of malignant peripheral nerve sheath tumors (MPNST), present in approximately 10% of these patients. We present the case of a teenager with a left jaw MPNST and a previously unreported germline pathogenic variant on NF1. An 11-year-old female with a NF1 clinical diagnosis was referred to our hospital with a MPNST in an advanced state. A previously unreported NF1 pathogenic variant was obtained (GRCh37: NM_182493.2 c.3299C>G, p.Ser1100*). Despite great efforts from the surgical and medical teams, the tumor progression couldn't be halted, resulting in the patient's death. As MPNSTs are refractory to current treatment regimens, early diagnosis, and development of new therapies, such as MEK inhibitors, is necessary for reducing morbidity and mortality within NF1 patients. This increases the importance of a more widespread genetic testing strategy. The report of a novel NF1 pathogenic variant in a patient with maternally inherited neurofibromatosis type 1 and a MPNST increases the knowledge of the genotype-phenotype correlation in the disease. [ABSTRACT FROM AUTHOR]

• Studying VEP plasticity might be a novel neurophysiological outcome measure associated with cognitive disability in NF1. • The NF1 group had a non-potentiated response to VEP induction. • The control group revealed a potentiated VEP response during continuous visual stimulation without delay. The inability to properly process visual information has been frequently associated with neurofibromatosis type 1 (NF1). Based on animal studies, the cause of cognitive disabilities in NF1 is hypothesized to arise from decreased synaptic plasticity. Visual cortical plasticity in humans can be investigated by studying visual evoked potentials (VEPs) in response to visual stimulation. VEP plasticity was assessed by measuring the increase of the peak amplitudes C1, P1, and N1 induced by 10-min modulation of checkerboard reversals in 22 adult NF1 patients and 30 controls. VEP signals were recorded pre-modulation, during modulation, and at 2, 7, 12, 17, 22, 27 min post-modulation. The P1 amplitude increased significantly comparing post-modulation to pre-modulation in the control group. This potentiation was not observed in the NF1 group. Visual cortical plasticity could be measured using VEPs in response to visual stimulation in the control group. Individuals with NF1 may have reduced visual cortical plasticity, as indicated by their non-potentiated response to VEP induction. These findings should be interpreted with caution due to high inter-subject variability. The present study contributes to an improved assessment of the feasibility for using neurophysiological outcome measures in intervention studies of cognitive deficits among patients with NF1. [ABSTRACT FROM AUTHOR]

Background: Moyamoya syndrome (MMS) is a progressive cerebral arteriopathy with increased incidence in children with neurofibromatosis type 1 (NF1). Despite the potential for significant neurological morbidity including stroke, little is known about the natural history, and no guidelines exist for screening and management of NF1-associated MMS.Methods: We identified 152 literature cases of children aged ≤18 years with NF1-associated MMS. A meta-analysis was performed evaluating clinical and neuroimaging findings and patient outcomes. Data from 19 patients with NF1-associated MMS from our center treated from January 1995 to July 2020 were abstracted via chart review and similarly analyzed for clinical and neuroimaging features.Results: Meta-analysis of literature cases showed a median age of MMS diagnosis of 6 years (interquartile range 3 to 10.8 years). Optic pathway gliomas were more common in patients with MMS (42%) compared with historical prevalence. Stroke or transient ischemic attack (TIA) was present at diagnosis in 46%. TIA and stroke were more common in patients with bilateral versus unilateral MMS (62% vs 34%, P = 0.001) and in children aged <4 years versus those aged ≥4 years (61% vs 40%, P = 0.02). Compared with the literature cases, our cohort was more frequently asymptomatic (42% vs 25%) and less likely to present with TIA or stroke (32% vs 46%) at diagnosis.Conclusions: These data suggest there is an aggressive form of MMS in children with NF1 <4 years of age. Therefore, early screening should be considered to facilitate early detection and treatment of cerebral arteriopathy. [ABSTRACT FROM AUTHOR]

Neurofibromatosis type 1 (NF-1) is the most common neurocutaneous syndrome with an autosomal dominant inheritance. However, half of the cases are de novo mutations. Involvement of bone, skin (cafe au lait macules), as well as ocular and tumoral formations is also associated with NF-1. Here, we present our case series of patients with bone deformities. The medical files of patients with NF-1 who were followed up by the same doctor in the pediatric neurology outpatient clinic over 2 years were retrospectively analyzed. Overall, 19 girls and 13 boys were diagnosed with NF-1. Of these 32 patients, 12 (nine girls, three boys) were found to have bone pathologies. The average age was of these patients with bone pathology was 7.5 and 9.5 years. Scoliosis, bowing, short stature, and long bone cysts were found in descending order of frequency. Severe adhesions in the hands and feet as well as phalangeal hypoplasia were noted in one patient. NF-1 requires a multidisciplinary approach. Routine follow-up is very important as it is known that deformities that affect different systems may appear or increase with age. Severe hand and foot anomalies seen in one of our patients did not seem to be associated with NF-1. [ABSTRACT FROM AUTHOR]

Today's estimates indicate that nearly 50% of children with Neurofibromatosis type 1 (NF1) suffer from reading disabilities, with a high impact on their academic achievement. In addition to the well-documented importance of phonological skills in reading acquisition and neurodevelopmental disorders, visual-attention processes also appear as important factors in learning to read. The present study aimed at assessing the role of visual-processing dysfunction in the high prevalence of reading disabilities in NF1 children and providing a useful tool for clinician in the early detection of reading impairment in this neurogenetic disorder. Forty-two children with NF1 and 42 typically developing children (TD) participated in the study. All were right-handed and did not present intellectual disability or attention deficit hyperactivity disorder. Visual-attention processes were assessed with the Developmental Eye Movement (DEM) test, together with the NF1 children's reading level. NF1 children with and without reading disabilities were then compared. The results showed that visual-processing deficits were highly present among the NF1 children included in our study. Furthermore, poor readers with NF1 presented an increased risk of visual-processing deficits compared to peers. This finding supports the role of visual-processing deficits in the reading difficulties encountered in nearly half of children with NF1. Finally, in NF1 children without intellectual or attention disability, visual-processing deficits emerge as one of the clinical markers of reading disabilities. The study holds important clinical implications both for the identification, by providing a useful screening tool, and the management of reading disabilities in NF1 children. • Visual-processing deficits are highly present among NF1 children without ADHD. • Poor readers appeared to be at increased risk for visual deficits. • Visual-processing deficits emerge as a clinical marker of reading impairment in our NF1 sample. • Visual processes assessment should become systematic to improve schooling in NF1. • The DEM-test is a useful tool in the clinical management of the NF1 without ADHD. [ABSTRACT FROM AUTHOR]

Giant cell rich lesions are frequently encountered in the head and neck region, particularly within the jaw bones. Giant cell rich lesions often require a combination of the clinical presenting features, radiology, and histology to be taken into account before a definitive diagnosis can be achieved. Within this article we aim to highlight the key multinucleated giant cell lesions that show a predilection for the head and neck region, discussing the clinical presentation, radiographic appearance, histological findings, differential diagnosis and treatment options for such lesions. [ABSTRACT FROM AUTHOR]

Cognitive impairment is a common neurologic complication of neurofibromatosis type 1 (NF-1) in childhood. A great number of learning disabilities appear in 30%−65% of children with NF-1. The aim of the study is to compare intelligence quotient (IQ) scores between children with NF-1 and comparable control groups. A literature review was conducted using the following databases: Cochrane, PubMed, Wiley, Microsoft Academic, and Google Scholar. We identified 180 papers. The pertinence of any study to the inclusion criteria was determined by assessing the title, key words, and abstracts. Data were extracted using multiple variables that were formulated incongruent with the study aim and then further analyzed. Eleven articles met our criteria, with the highest level of evidence of 3c. A total of 483 NF1 and 443 control participants were included in this meta-analysis. The average and standard deviation of the age was 9.15 ± 3.15 years with an age range of 3.3−18 including 488 male and 438 female. The pooled estimate of the mean difference in all 3 parameters used full-scale IQ, verbal IQ, and performance IQ. Statistically, there was a significantly lower IQ in the NF-1 group compared with the control group with a 95% CI and (P < 0.00001). The current meta-analysis illustrated a significant intellectual deficit in children with NF-1 compared with their typically developed peers who were matched by age. Performance IQ was significantly impaired compared with verbal IQ in NF-1 children. The current findings may guide experts to tailor individualized educational programs for children with NF-1. [ABSTRACT FROM AUTHOR]

In patients with neurofibromatosis type 1 (NF1), it is important to accurately determine when plexiform neurofibroma (pNF) transforms to a malignant peripheral nerve sheath tumor (MPNST). The purpose of this study is to investigate the usefulness of diffusion-weighted imaging (DWI) in differentiating pNF and MPNST in NF1 patients. Among the NF1 patients who were referred to our hospital between 1985 and 2015, 10 cases of MPNST and 19 cases of pNF were included. We evaluated features of standard magnetic resonance imaging according to the differentiation criteria of malignancy from benignancy as previously reported, apparent diffusion coefficient (ADC) value based on the DWI and the correlation between ADC value and benignancy/malignancy. ROC analysis was performed to determine the appropriate cutoff value of ADC. There were significant differences between MPNST and pNF in the size of the tumor (P = 0.009), peripheral enhancement pattern (P = 0.002), perilesional edema-like zone (P = 0.0008), and intratumoral cystic change (P = 0.02). The mean and minimum values of ADC were significantly lower in MPNST than those in pNF (P = 0.03 and P = 0.003, respectively). When we set a cutoff value of mean ADC as 1.85 × 10–3 mm2/s, the sensitivity and specificity were 80% and 74%, respectively. The area under the curve value improved by adding the Wasa score to the mean ADC evaluation. ADC values determined by DWI are useful in differentiating MPNST from pNF and adding ADC evaluation to standard MRI evaluation improved the diagnostic accuracy. [ABSTRACT FROM AUTHOR]

A 2-month-old girl presented with malignant arterial hypertension revealing bilateral renal artery stenosis secondary to neurofibromatosis type 1 (NF1). Life-supporting care was initiated immediately. High-dose peripheral vasodilator therapy induced life-threatening toxicity; vascular surgery was therefore performed. Technical difficulties due to the young age and low body weight of the patient resulted in fatal bleeding. Renovascular disease is an important cause of pediatric hypertension. NF1-associated renovascular hypertension in young pediatric patients is rare, and its highly specialized management is best delivered via a multidisciplinary approach. The long-term prognosis remains poor. [ABSTRACT FROM AUTHOR]

Neurofibromatosis type 1 (NF1) is a genetic syndrome associated with multiple complications that cause chronic pain, including plexiform neurofibroma (PN) tumors. However, no randomized studies have examined non-pharmacological interventions for pain specifically targeting individuals with NF1 and PNs. In the current randomized controlled trial, an Acceptance and Commitment Therapy intervention was conducted with older adolescents and adults ages 16–59 years with NF1, PNs, and chronic pain. We hypothesized that pain interference would decrease from pre-to post-intervention compared to a wait-list control group. We also examined potential mediators, including pain acceptance and inflexibility. The intervention consisted of two 2-h in-person sessions followed by 8 weeks of online training including weekly email assignments and biweekly video chats. Outcome measures evaluating pain interference, pain intensity, pain anxiety, and depression and process measures evaluating pain acceptance and pain inflexibility were administered at baseline and after the 8-week intervention. Sixty-two participants (M age = 30.7 ± 11.5 years, 61.3% female) completed the intervention. Results indicated that the ACT intervention significantly reduced how much pain interfered with daily functioning. Improvements in pain acceptance and, separately, pain inflexibility, mediated the treatment benefit for individuals in the ACT group. No improvements in pain intensity, pain anxiety, or depression were noted following the intervention. Durable treatment benefits were seen at 6 months albeit only among those who improved more during the 8-week intervention. While the immediate post-intervention effects were seen after 4 h of in-person training and limited online sessions, more support is likely needed to maintain these effects long-term. Results indicate that remote ACT interventions have promise and could make this treatment accessible to more patients with NF1, PNs and chronic pain. • This is the first randomized trial to show that ACT treatment reduces pain interference in NF1. • Mediation models showed that acceptance and inflexibility mediated treatment benefit. • The mixed-methods intervention (in-person and remote) increases treatment accessibility. [ABSTRACT FROM AUTHOR]

• In a selected group of Neurofibromatosis type 1 gene carriers, procedural learning performance was intact. • No abnormalities were seen in short interval intracortical inhibition of the motor cortex in rest and movement. • According to phenotype severity the population of gene carriers most likely comprises different subgroups. Neurofibromatosis type 1 (NF1) 1 NF1 Neurofibromatosis type 1 1 is known to cause learning deficits in affected individuals. There has been evidence linking altered gamma-aminobutyric acid (GABA) 2 GABA Gamma-aminobutyric acid 2 mediated inhibition to learning impairments in rodent models and humans with NF1. Still, evidence on the role of GABA in learning deficits associated with NF1 is inconclusive. We examined procedural learning and motor cortex excitability through intracortical facilitation and short interval intracortical inhibition and its activity dependent modulation while performing a procedural sequence learning task in 16 asymptomatic NF1 gene carriers. We aimed to analyze potential brain-behavior correlations in a carefully selected sample of gene carriers in order to minimize confounding factors. Gene carriers did not differ from healthy controls when learning the task with their non-dominant hand over three days of training. Electrophysiological data did not reveal alterations in patients' inhibitory function of the motor cortex. In contrast with previous publications reporting various cognitive deficits in clinically asymptomatic individuals with NF1, here asymptomatic gene carriers did not show major neuropsychological or behavioral abnormalities. Our results support the concept that gene carriers may not always be impaired by the condition and the population of individuals with NF1 most likely comprises different subgroups according to patients' phenotype severity. [ABSTRACT FROM AUTHOR]

• Patient with NF1 disease presented with multifocal head and neck paragangliomas. • Further genetic analysis to investigate his clinical phenotype identified a second paraganglioma-predisposing pathogenic variant in SDHD. • This is the first report of a case with NF1 disease and a concurrent pathogenic variant in another paraganglioma-predisposing gene. • Tumor exhibited cardinal features of SDH-related disease (loss of both 11p15 and of SDHB staining with DNA hypermethylation) but no loss-of-heterozygosity of SDHD. We report a novel case of multiple paragangliomas in a patient who was identified with pathogenic variants in both NF1 and SDHD genes. The proband is a man with known familial NF1 disease, diagnosed clinically in childhood. Multiple head and neck paragangliomas (HNPGL) were found during investigations for acute left sided neurological symptoms, in the region of his known plexiform neurofibroma. He was referred for genetic counselling. He underwent surgery to remove a left carotid body tumor (CBT). A pheochromocytoma and paraganglioma gene panel was tested. Blood and HNPGL tumor DNA were analyzed by whole exome sequencing. In addition to the NF1 truncating variant c.5107delA, p.(Ser1703AlafsTer7), the SDHD truncating pathogenic variant c.3G > A, p.(Met1?) was found. Tumor sequencing showed no LOH of SDHD or NF1 , but monoallelic loss of 11p15 and 11q12.2-q12.3 was observed. Co-occurrence of pathogenic variants in multiple cancer susceptibility genes is rare but possible, identified by the increased use of panel testing. This is the first description of a patient presenting with NF1 and SDHD dual pathology, with HNPGL development due to SDHD. This case illustrates the central role of genetic sequencing in PPGLs and the strong genotype-phenotype correlations of different genes. [ABSTRACT FROM AUTHOR]

Background: Given the expanding evidence of clinico-radiological differences between moyamoya disease (MMD) and moyamoya syndrome (MMS), we compared the clinical and radiographic features of childhood MMD and MMS to identify predictors of ischemic event recurrence.Methods: We reviewed a pediatric moyamoya cohort followed between 2003 and 2019. Clinical and radiographic characteristics at diagnosis and follow-up were abstracted. Comparisons between MMD and MMS as well as between MMD and two MMS subgroups (neurofibromatosis [MMS-NF1] and sickle cell disease [MMS-SCD]) were performed.Results: A total of 111 patients were identified. Patients with MMD presented commonly with transient ischemic attacks (TIAs) (35 % MMD versus 13% MMS-NF1 versus 9.5% MMS-SCD; P = 0.047). Symptomatic stroke presentation (MMD 37% versus MMS-NF1 4% versus 33%; P = 0.0147) and bilateral disease at diagnosis (MMD 73% versus MMS-NF1 22 % versus MMS-SCD 67%; P = 0.0002) were uncommon in MMS-NF1. TIA recurrence was common in MMD (hazard ratio 2.86; P = 0.001). The ivy sign was absent on neuroimaging in a majority of patients with MMS-SCD (MMD 67% versus MMS-NF1 52% versus MMS-SCD 9.5%; P = 0.0002). Predictors of poor motor outcome included early age at diagnosis (odds ratio [OR] 8.45; P = 0.0014), symptomatic stroke presentation (OR 6.6; P = 0.019), and advanced Suzuki stage (OR 3.59; P = 0.019).Conclusions: Moyamoya exhibits different phenotypes based on underlying etiologies. Frequent TIAs is a common phenotype of MMD and symptomatic stroke presentation a common feature of MMD and MMS-SCD, whereas unilateral disease and low infarct burden are common in MMS-NF1. In addition, absence of ivy sign is a common phenotype in MMS-SCD. [ABSTRACT FROM AUTHOR]

• Single-pulse TMS resulted in lower motor evoked potential amplitudes in NF1 patients than controls. • Intermittent theta burst stimulation (iTBS) increased cortical excitability in both NF1 patients and controls. • After iTBS, NF1 patients showed an attenuation of the initial potentiated response that might be used as an outcome measure. Neurofibromatosis type 1 (NF1) is an autosomal dominant genetic disorder that is associated with cognitive disabilities. Based on studies involving animals, the hypothesized cause of these disabilities results from increased activity of inhibitory interneurons that decreases synaptic plasticity. We obtained transcranial magnetic stimulation (TMS)-based measures of cortical inhibition, excitability and plasticity in individuals with NF1. We included 32 NF1 adults and 32 neurotypical controls. Cortical inhibition was measured with short-interval intracortical inhibition (SICI) and cortical silent period (CSP). Excitability and plasticity were studied with intermittent theta burst stimulation (iTBS). The SICI and CSP response did not differ between NF1 adults and controls. The response upon iTBS induction was significantly increased in controls (70%) and in NF1 adults (83%). This potentiation lasted longer in controls than in individuals with NF1. Overall, the TMS response was significantly lower in NF1 patients (F(1, 41) = 7.552, p = 0.009). Individuals with NF1 may have reduced excitability and plasticity, as indicated by their lower TMS response and attenuation of the initial potentiated response upon iTBS induction. However, our findings did not provide evidence for increased inhibition in NF1 patients. These findings have potential utility as neurophysiological outcome measures for intervention studies to treat cognitive deficits associated with NF1. [ABSTRACT FROM AUTHOR]

NF1 children have cognitive disorders, especially in executive functions, visuospatial, and language domains, the pathophysiological mechanisms of which are still poorly understood. A correlation study was performed from neuropsychological assessments and brain MRIs of 38 NF1 patients and 42 controls, all right-handed, aged 8–12 years and matched in age and gender. The most discriminating neuropsychological tests were selected to assess their visuospatial, metaphonological and visuospatial working memory abilities. The MRI analyses focused on the presence and location of Unidentified Bright Objects (UBOs) (1), volume analysis (2) and diffusion analysis (fractional anisotropy and mean diffusivity) (3) of the regions of interest including subcortical structures and posterior fossa, as well as shape analysis of subcortical structures (4). The level of attention, intelligence quotient, age and gender of the patients were taken into account in the statistical analysis. Then, we studied how diffusion and volumes parameters were associated with neuropsychological characteristics in NF1 children. NF1 children present different brain imaging characteristics compared to the control such as (1) UBOs in 68%, (2) enlarged total intracranial volume, involving all subcortical structures, especially thalamus, (3) increased MD and decreased FA in thalamus, corpus callosum and hippocampus. These alterations are diffuse, without shape involvement. In NF1 group, brain microstructure is all the more altered that volumes are enlarged. However, we fail to find a link between these brain characteristics and neurocognitive scores. While NF1 patients have obvious pathological brain characteristics, the neuronal substrates of their cognitive deficits are still not fully understood, perhaps due to complex and multiple pathophysiological mechanisms underlying this disorder, as suggested by the heterogeneity observed in our study. However, our results are compatible with an interpretation of NF1 as a diffuse white matter disease. • Diffuse enlarged brain volumes are a brain characteristic in NF1 children. • In NF1 children's brain, diffusion parameters are not only altered in UBOs. • Diffusion and volumetric parameters are particularly altered in thalamic regions. • Specific cognitive features of NF1 children are not correlate with brain imaging. • Our results are in accordance with the hypothesis of a looser packing of axons. [ABSTRACT FROM AUTHOR]

Somatic mutations in RAS and related pathway genes such as NF1 have been strongly implicated in the development of cancer while also being implicated in a diverse group of developmental disorders named the 'RASopathies', including neurofibromatosis type 1 (NF1), Noonan syndrome (NS), Noonan syndrome with multiple lentigines (NSML), Costello syndrome (CS), cardiofaciocutaneous syndrome (CFC), and capillary malformation–arteriovenous syndrome (CM-AVM). It remains unclear why (i) there is little overlap in mutational subtype between Ras-driven malignancies associated with sporadic disease and those associated with the RASopathy syndromes, and (ii) RASopathy-associated cancers are usually of different histological origin to those seen with sporadic mutations of the same genes. For instance, germline variants in KRAS and NRAS are rarely found at codons 12, 13 or 61, the most common sites for somatic mutations in sporadic cancers. An exception is CS, where germline variants in codons 12 and 13 of HRAS occur relatively frequently. Given recent renewed drug interest following early clinical success of RAS G12C and farnesyl transferase inhibitors, an improved understanding of this relationship could help guide targeted therapies for both sporadic and germline cancers associated with the Ras pathway. • RAS mutations have been associated with a range of malignancies and with developmental disorders called RASopathies. • Cancers associated with sporadic and germline RAS mutations are dissimilar in histological origins and mutational subtypes. • This disparity highlights our incomplete understanding of the relationship between the RAS–MAPK pathway and cancer. • Recent advances in targeting Ras G12C, HRAS and MEK have led to renewed interest in targeted therapies in this pathway. [ABSTRACT FROM AUTHOR]

• This is the largest reported descriptive study to date of spinal lesions in NF1. • Cutaneous lesions are the most commonly reported clinical feature in NF1. • Spinal tumours (mostly cervical or lumbar) and spinal deformity are common in NF1. • Repetitive movement may be important in the pathogenesis of spinal tumours in NF1. • There is a positive association between dural ectasia and spinal deformity. Neurofibromatosis type 1 (NF1) manifests itself in many ways in the spine. This study aims to report the types of spinal lesions, clinical and demographic data in a large cohort from a complex NF1 centre. The characteristics of those with spinal neurofibromatosis, where neurofibromas are present on every spinal nerve root, were sought for comparison with the wider group of NF1 patients. This is a retrospective review of MDT minutes of 303 patients from a UK NF1 centre and the largest reported series of NF1 patients based on radiological data. Prevalence of each symptom and lesion was calculated and statistically significant associations were established. The most reported findings were cutaneous lesions (44.9%) and neurological deficit (27.4%). 28.4% had dural ectasia, 52.5% had some form of spinal deformity. 57.8% had spinal nerve root tumours, the most common of which were at C2. The most progressive lesions were spinal nerve root tumours (29.1%). The only statistically significant association found was between dural ectasia and spinal deformity (P < 0.003), where dural ectasia is associated with a 32.6% increase in spinal deformity incidence. This is the largest descriptive study of spinal lesions in NF1. Spinal tumours and spinal deformity are prevalent in NF1. The predilection of spinal tumours for flexible spinal regions suggests that repetitive movement might be an important factor in pathogenesis. Physicians and patients should be alert to the observation that although many spinal neurofibromatosis patients display no neurological deficit, they often have significant lesions which require monitoring and sometimes surgery. [ABSTRACT FROM AUTHOR]

Neurofibromatosis type 1 (NF1), a dysregulated neurocutaneous disorder, is an autosomal dominant genetic disease caused by mutations in the NF1 gene. Anaplastic astrocytoma is rare in NF1 patients, and research has proposed that high-grade astrocytomas could be due to larger germ-line mutations in NF1.We present a clinical and molecular study of a Chinese family with NF1. A 28-year-old male patient with NF1 presents with headache, vertigo, and dizziness. Histopathologic examination and molecular features identified a cerebellar anaplastic astrocytoma, IDH -wildtype. The patient underwent gross total resection of the lesion and received radiotherapy and chemotherapy. A rare splice error mutation (c.4110+945A>G) in intron 23–2 of NF1 was identified by next-generation sequencing in the proband. Sanger sequencing identified and confirmed it in some affected family members. We present a unique case of NF1 with anaplastic astrocytoma that revealed a rare splice error mutation in the NF1 gene in the family. [ABSTRACT FROM AUTHOR]

Neurofibromatosis type 1 (NF1) is an autosomal dominant disorder. NF1 patients are predisposed to formation of several type solid tumors as well as to juvenile myelomonocytic leukemia. Loss of NF1 results in dysregulation of MAPK, PI3K and other signaling cascades, to promote cell proliferation and to inhibit cell apoptosis. The RUNX1 gene is associated with stem cell function in many tissues, and plays a key role in the fate of stem cells. Aberrant RUNX1 expression leads to context-dependent tumor development, in which RUNX1 may serve as a tumor suppressor or an oncogene in specific tissue contexts. The co-occurrence of mutation of NF1 and RUNX1 is detected rarely in several cancers and signaling downstream of RAS-MAPK can alter RUNX1 function. Whether aberrant RUNX1 expression contributes to NF1- related tumorigenesis is not fully understood. This review focuses on the role of RUNX1 in NF1-related tumors and blood disorders, and in sporadic cancers. [ABSTRACT FROM AUTHOR]

Intracranial tumor growth associated with pregnancy is not an uncommon phenomenon. Pilocytic astrocytoma is typically considered to be an indolent tumor with little to no risk of progression to higher-grade lesion. We present a rare case of cerebellar pilocytic astrocytoma transformation to hemorrhagic high-grade glioma during pregnancy. Patient EK was a 32-year-old female with neurofibromatosis type 1 and known cerebellar pilocytic astrocytoma. For nearly a decade before her pregnancy, her cerebellar tumor was stable on imaging. Routine magnetic resonance imaging (MRI) of the head obtained at 20 weeks' gestation continued to demonstrate tumor stability. At 24 weeks' gestation, the patient had sudden, severe headaches. MRI of the head showed evidence of significant tumor expansion. The following day, the patient was found unresponsive. Computed tomography of the head demonstrated hemorrhage within the tumor and tonsillar herniation. Her neurologic examination revealed no brainstem reflexes; however, given her age and pregnancy, she underwent emergent decompression and tumor debulking. Unfortunately, she never improved neurologically. Final pathology identified the lesion as high-grade glioma with anaplastic changes and hemorrhagic conversion. This is a unique case of indolent cerebellar pilocytic astrocytoma that transformed to high-grade glioma during pregnancy, proven by tumor growth on MRI and anaplasia on pathology. We hypothesize that increased levels of pregnancy hormones (progesterone, vascular endothelial growth factor, placental growth factor, among others) likely contributed to tumor growth. We recommend that all glial tumors be monitored extremely closely throughout pregnancy, and perhaps one should consider surgical treatment (if possible) before patients become pregnant. [ABSTRACT FROM AUTHOR]

Café au lait macules (CALMs) are a common, isolated dermatologic finding in the general population. But when do these irregularly shaped, jagged-edged, flat, hyperpigmented birthmarks suggest something that may warrant referral? Most pediatric providers are familiar with the association of CALMs and neurofibromatosis type 1. There are, however, other genetic conditions associated with these seemingly benign skin spots. This article provides an overview of CALMs, followed by a summary of several conditions associated with CALMs ranging from the most common (neurofibromatosis type 1) to rare, ring chromosome syndromes. It reviews the associated gene(s), pattern of inheritance, incidence, presenting symptoms, diagnosis, and management for these genetic conditions. [ABSTRACT FROM AUTHOR]

The purpose of the study was the investigation of supernumerary teeth (ST) in the permanent dentition of patients with neurofibromatosis type 1 (NF1). The panoramic radiographs of 200 NF1 patients were analysed for ST. The potential impact of certain neurogenic facial tumours on the measured variable was investigated separately. The results were compared to dental findings in panoramic radiographs of 200 age- and sex-matched controls. The total number of ST in all individuals was 23 in 12 patients (3% of total population). However, all ST had developed in the group of NF1 patients (6%), (p = 0.0004). ST were particularly common distal to the molar region. Although ST occur in the region of facial plexiform neurofibroma, the numerical aberrations of the dentition are independent of specific type of facial nerve sheath tumour. The unusual accumulation of ST in the terminal sections of molar development could be an indicator of preferred points of developmental disorder, in which the genetic predisposition of the patient is involved. Reviewing the results of other NF1 patient collectives is desirable. [ABSTRACT FROM AUTHOR]

NF1 is a tumor suppressor gene and its protein product, neurofibromin, is a negative regulator of the RAS pathway. NF1 is one of the top driver mutations in sporadic breast cancer such that 27 % of breast cancers exhibit damaging NF1 alterations. NF1 loss-of-function is a frequent event in the genomic evolution of estrogen receptor (ER)+ breast cancer metastasis and endocrine resistance. Individuals with Neurofibromatosis type 1 (NF) – a disorder caused by germline NF1 mutations – have an increased risk of dying from breast cancer [1–4]. NF-related breast cancers are associated with decreased overall survival compared to sporadic breast cancer. Despite numerous studies interrogating the role of RAS mutations in tumor metabolism, no study has comprehensively profiled the NF1 -deficient breast cancer metabolome to define patterns of energetic and metabolic reprogramming. The goals of this investigation were (1) to define the role of NF1 deficiency in estrogen receptor-positive (ER+) breast cancer metabolic reprogramming and (2) to identify potential targeted pathway and metabolic inhibitor combination therapies for NF1 -deficient ER + breast cancer. We employed two ER+ NF1 -deficient breast cancer models: (1) an NF1 -deficient MCF7 breast cancer cell line to model sporadic breast cancer, and (2) three distinct, Nf1 -deficient rat models to model NF-related breast cancer [1]. IncuCyte proliferation analysis was used to measure the effect of NF1 deficiency on cell proliferation and drug response. Protein quantity was assessed by Western Blot analysis. We then used RNAseq to investigate the transcriptional effect of NF1 deficiency on global and metabolism-related transcription. We measured cellular energetics using Agilent Seahorse XF-96 Glyco Stress Test and Mito Stress Test assays. We performed stable isotope labeling and measured [U–13C]-glucose and [U–13C]-glutamine metabolite incorporation and measured total metabolite pools using mass spectrometry. Lastly, we used a Bliss synergy model to investigate NF1 -driven changes in targeted and metabolic inhibitor synergy. Our results revealed that NF1 deficiency enhanced cell proliferation, altered neurofibromin expression, and increased RAS and PI3K/AKT pathway signaling while constraining oxidative ATP production and restricting energetic flexibility. Neurofibromin deficiency also increased glutamine influx into TCA intermediates and dramatically increased lipid pools, especially triglycerides (TG). Lastly, NF1 deficiency alters the synergy between metabolic inhibitors and traditional targeted inhibitors. This includes increased synergy with inhibitors targeting glycolysis, glutamine metabolism, mitochondrial fatty acid transport, and TG synthesis. NF1 deficiency drives metabolic reprogramming in ER+ breast cancer. This reprogramming is characterized by oxidative ATP constraints, glutamine TCA influx, and lipid pool expansion, and these metabolic changes introduce novel metabolic-to-targeted inhibitor synergies. [Display omitted] • NF1 deficiency drives metabolic reprogramming in ER + breast cancer. • NF1 -driven metabolic reprogramming is characterized by OXPHOS constraints, glutamine TCA influx, and lipid pool expansion. • NF1 -deficient ER + breast cancer cells have increased sensitivity to combined RAS and triglyceride synthesis inhibitors. [ABSTRACT FROM AUTHOR]

To evaluate the incidence and clinical importance of brain gliomas – optic pathway gliomas (OPGs) and especially gliomas outside the optic pathway (GOOP) for children with neurofibromatosis type 1 (NF1), additionally, to assess the causes of obstructive hydrocephalus in NF1 children with an emphasis on cases caused by idiopathic aqueduct stenosis. We analysed data from 285 NF1 children followed up on our department from 1990 to 2010 by the same examination battery. We have found OPGs in 77/285 (27%) children and GOOPs in 29/285 (10,2%) of NF1 children, of who 19 had OPG and GOOP together, so the total number of brain glioma was 87/285 (30,5%). GOOPs were significantly more often treated than OPGs (p > 0.01). OPGs contain clinically important subgroup of 14/285 (4.9%) spreading to hypothalamus. Spontaneous regression was documented in 4/285 (1.4%) gliomas and the same number of NF1 children died due to gliomas. Obstructive hydrocephalus was found in 22/285 (7.7%) patients and 14/22 cases were due to glioma. Idiopathic aqueduct stenosis caused hydrocephalus in 6/22 cases and was found in 2.1% of NF1 children. Two had other cause. The total brain glioma number (OPGs and only GOOPs together) better reflected the overall brain tumour risk for NF1 children. However, GOOPs occur less frequently than OPGs, they are more clinically relevant. The obstructive hydrocephalus was severe and featuring frequent complication, especially those with GOOP. Idiopathic aqueduct stenosis shows an unpredictable cause of hydrocephalus in comparison with glioma and is another reason for careful neurologic follow up. [ABSTRACT FROM AUTHOR]

Neurofibromatosis type 1 (NF1) is a rare disease with an incidence of approximately one in every 3000 births. NF1 is mainly recognized as a tumor suppressor. Vasculopathy in NF1 is well described in the literature, but the association between NF1 and cerebral aneurysm has not been determined. We report a case of a 67-year-old female with NF1 accompanied by 8 cerebral aneurysms. Two of the patient's unruptured aneurysms, the large distal anterior cerebral artery (ACA) aneurysm and anterior communicating artery aneurysm, were initially treated with microsurgical clipping. The peripheral ACA aneurysm gradually increased in size and ruptured after 5 years. Coil embolization was performed for the ruptured aneurysm. Four of the 5 remaining unruptured aneurysms were treated surgically. The patient is currently well, without neurological deficit, and coil embolization is scheduled for the last remaining aneurysm. NF1 is a probable risk factor for multiple cerebral aneurysms due to vessel wall vulnerability. Therapeutic indications for patients with NF1 who show multiple cerebral aneurysms include strict follow-up and aggressive treatment to avoid subarachnoid hemorrhage. [ABSTRACT FROM AUTHOR]

• Coexistence of MS and NF1 is a rare condition. • c.6817delC deletion and rs1801052 polymorphism in NF1 gene are associated with NF1. • Changes in SPG7, SPG15, SPG39 genes are responsible for benign spastic paraplegia. Multiple sclerosis (MS) is a common inflammatory demyelinating disease of the central nervous system. The clinical phenotype is probably modified by interactions from genetic and environmental factors. Neurofibromatosis type 1 (NF1) is an autosomal dominant neurocutaneous disease. NF1 gene mutations lead to clinical manifestation in the peripheral and central nervous system. Coexistence of MS and NF1 is a rare condition. To report the case of the patient with primary progressive MS (PPMS) and NF1. A retrospective analysis of a patient who has undergone whole exome sequencing confirmed by Sanger sequencing. We reported a novel de novo c.6817delC deletion and rs1801052 polymorphism in NF1 gene associated with NF1 symptoms, as well as numerous polymorphisms in SPG7, SPG15, SPG39 genes responsible for benign spastic paraplegia. Co-occurrence of PPMS and NF1 may be a consequence of genetic changes. [ABSTRACT FROM AUTHOR]

To determine the safety and effectiveness of the combined halo gravity traction and dual growing rod technique in achieving and maintaining scoliosis correction while allowing spinal growth. From January 2014 to July 2017, 11 patients with dystrophic neurofibromatosis type 1 (NF1)–associated scoliosis, including 7 men and 4 women, underwent combined halo gravity traction and dual growing rod technique procedures. Diagnoses were all dystrophic NF1-associated scoliosis. Patients with a Cobb angle of major curve >60° and flexibility of spine <30% were included in our research. Analysis included age at the time of treatment, levels of instrumentation, number and frequency of lengthening, lengthening distance, and complications. The changes in Cobb angle of scoliosis and T1-S1 length of spine over the treatment period were measured by radiographic evaluation. The average age of treated patients was 7.2 years (range, 5–9 years). Growing rods were lengthened every 6 months through exposure. The mean number of times of lengthening was 3.9 (range, 3–5). The distance of each extension was 1.6 cm (range, 1.0–2.0 cm). The Cobb angle was corrected 41.7% on average after traction, 48.4% after initial surgery, and 53.3% at the last follow-up. T1-S1 length increased 3.4 cm (range, 1.2–5.1 cm) on average over a mean treatment period of 2.2 years, with an average of 1.5 cm/y (range, 0.5–2.3 cm/y). During the treatment period, complication of hook dislodgement occurred in 1 of 11 patients (9.1%). The combined halo gravity traction and dual growing rod technique can safely and effectively correct NF1-associated scoliosis. This is an ongoing study that requires long-term follow-up. [ABSTRACT FROM AUTHOR]

Highlights • This is the first report of epilepsy surgery for a patient with NF1 and MMS. • More patients with NF1 and MMS could be candidates for epilepsy surgery. • An interdisciplinary approach is warranted for this surgical treatment. Abstract Background Epilepsy associated with neurocutaneous disorders is well known, and the prevalence of epilepsy among patients with neurofibromatosis type 1 (NF1) ranges from 4% to 13%. However, epilepsy surgery for patients with NF1 is not commonly performed. Case description We report the case of a patient with medically intractable mesial temporal lobe epilepsy (mTLE) concomitant NF1 and moyamoya syndrome (MMS) who had already undergone bilateral superficial temporal artery-middle cerebral artery anastomosis at 17 years old. As the standard temporal approach was unavailable, we evaluated the patient with neurologists, radiologists, neurosurgeons and neuropsychologists to identify the safest trajectory for epilepsy surgery. The patient underwent the right selective amygdala hippocampectomy from the posterior auricle part at 32 years old and obtained freedom from seizures. Conclusion To the best of our knowledge, this represents the first surgical case report for mTLE concomitant with NF1 and MMS. [ABSTRACT FROM AUTHOR]

Objective: To assess the health-related quality of life of children with neurofibromatosis type 1-related plexiform neurofibromas (pNF) using a battery of patient-reported outcome measures selected based on a conceptual framework derived from input by patients, parents, and clinicians regarding the most important pNF symptoms and concerns.Study Design: There were 140 children with pNF ages 8-17 years who completed the Patient-Reported Outcomes Measurement Information System (including domains anxiety, depressive symptom, psychosocial stress experiences, fatigue, pain interference, meaning and purpose, positive affect, peer relationships, physical function-mobility) and Quality of Life in Neurological Disorders measurement system (stigma) via an online platform. T-scores for each measure were compared with US population norms.Results: Children with pNF reported significantly worse scores than the population norms on 8 of 10 domains. Children with at least 1 family member having a diagnosis of neurofibromatosis type 1 and those having pain reported significantly worse symptoms and functioning on all domains. Boys reported significantly worse pain interference, stigma, meaning and purpose, mobility function, and upper extremity function than girls.Conclusions: Children with pNF experience significantly worse health-related quality of life on all but 1 domain, highlighting the importance of monitoring children's quality of life over time in clinical research and practice. Future research should evaluate the replicability of these findings and evaluate the validity of the Patient-Reported Outcomes Measurement Information System and Quality of Life in Neurological Disorders measurement system in relation to clinical characteristics among children with pNF. [ABSTRACT FROM AUTHOR]

Highlights • Appendiceal neurofibromas (AN) in Neurofibromatosis type (NF) 1 are rare. • AN in NF1 with Low-grade appendiceal mucinous neoplasms (LAMNs) are extremely rare. • AN and LAMNs have potential for malignant transformation. • Surgical resection is the standard treatment for patients with AN and LAMNs. • However, appropriate surgical procedure remains controversial. Abstract Introduction Neurofibromas are a characteristic of the autosomal dominant disorder Neurofibromatosis type 1 (NF1), also known as von Recklinghausen's disease. Appendiceal neurofibromas are extremely rare, and low-grade appendiceal mucinous neoplasms (LAMNs) have not previously been reported in NF1. Presentation of case A 62-year-old man with NF1 was scheduled for elective surgical treatment of an asymptomatic, enlarged and diffusely thickened appendix that remained after curative antimicrobial treatment of acute appendicitis. Laboratory analysis revealed all normal. Colonoscopy showed thickened appendiceal mucosa projecting into the cecum. A sample of the mucosa was found to be pathologically benign. The patient was preoperatively diagnosed with treated acute appendicitis with chronic appendiceal inflammation versus appendiceal neoplasms. Laparoscopic cecectomy was performed. Multiple neurofibromas were observed in the muscle layer, submucosa, and mucosa of the appendix on histopathological examination. Immunohistochemical examination showed positive staining for S-100. Pathologically, the patient was diagnosed with appendiceal neurofibroma consistent with NF1 with LAMNs. His postoperative course was unremarkable. He was discharged on post-operative day 3 and remained in good health 7 month after surgery. Conclusions Appendiceal neurofibromas are often preoperatively diagnosed as appendicitis. Appendiceal neurofibromas should be considered in patients with NF1 who are suspected of having appendicitis. [ABSTRACT FROM AUTHOR]

[Display omitted] • Preserved suppression of oscillatory activity in response to repeated vowels in school-aged children with NF1. • Children with NF1 show increased spectral power, mainly in the theta frequency band, in the change detection response. • Higher alpha spectral power in response to change was associated with fewer ADHD-related symptoms. Children with neurofibromatosis type 1 (NF1) are at increased risk of developing cognitive problems, including attention deficits and learning difficulties. Alterations in brain response to repetition and change have been evidenced in other genetic conditions associated with cognitive dysfunctions. Whether the integrity of these fundamental neural responses is compromised in school-aged children with NF1 is still unknown. In this study, we examined the repetition suppression (RS) and change detection responses in children with NF1 (n = 36) and neurotypical controls (n = 41) aged from 4 to 13 years old, using a simple sequence of vowels. We performed time–frequency analyses to compare spectral power and phase synchronization between groups, in the theta, alpha and beta frequency bands. Correlational analyses were performed between the neural responses and the level of intellectual functioning, as well as with behavioral symptoms of comorbid neurodevelopmental disorders measured through parental questionnaires. Children with NF1 showed preserved RS, but increased spectral power in the change detection response. Correlational analyses performed with measures of change detection revealed a negative association between the alpha-band spectral power and symptoms of inattention and hyperactivity. These findings suggest atypical neural response to change in children with NF1. Further studies should be conducted to clarify the interaction with comorbid neurodevelopmental disorders and the possible role of altered inhibitory mechanisms in this enhanced neural response. [ABSTRACT FROM AUTHOR]

The finding of variants of uncertain significance (VUS) in the activity of a diagnostic genetic laboratory is a common issue, which is however provisional and needs to be periodically re-evaluated, due to the continuous advancements in our knowledge of the genetic diseases. Neurofibromatosis type 1, caused by the occurrence of heterozygous pathogenic NF1 variants, is a good model for studying the evolution of VUS, due to the widespread use of genetic testing for the disease, the constant enrichment of the international databases with NF1 variants and the full adult penetrance of the disease, which makes genotyping the parents a crucial step in the diagnostic workflow. The present study retrospectively reviewed and reinterpreted the genetic test results of NF1 in a diagnostic genetic laboratory in the period from January 1, 2000 to December 31, 2020. All the VUS were reinterpreted using the 2015 consensus standards and guidelines for the interpretation. Out of 589 NF1 genetic tests which were performed in the period, a total of 85 VUS were found and reinterpreted in 72 cases (84.7%): 21 (29.2%) were reclassified as benign/likely benign, whereas 51 (70.8%) were recoded as pathogenic/likely pathogenic with a significant trend distribution (Chi square test for trend p = 0.005). Synonymous VUS have mainly been reclassified as class 1 and 2 (7/8, 87.5%), whereas missense variants have been attributed to class 4 and 5 in 38 out of the 58 cases (65.5%). These findings underline an improvement in the classification of variants over time, suggesting that a reinterpretation of the genetic tests should be routinely performed to support the physicians in the clinical diagnosis of genetic diseases. [ABSTRACT FROM AUTHOR]

A 43-year-old man was admitted to the emergency department for motor vehicle collision. First clinical impression was traumatic injury of the right eye with bare light perception. A physical examination revealed multiple nodular skin lesions on the head and neck. Head magnetic resonance imaging and computed tomography scans showed intracerebral hemorrhage, trans-orbital brain herniation, and right sphenoid wing dysplasia. A diagnosis of neurofibromatosis type 1 was made. Sphenoid wing dysplasia (also known as bare orbit sign) in neurofibromatosis type 1 was a contributing factor to the trans-orbital herniation, but also helped reduce intracranial pressure after traumatic brain injury in this rare case. Mannitol was administered, and no neurosurgical intervention was needed for traumatic brain injury. Canthorrhaphy of the right eye was performed to preserve patient's right eyeball. At 1-month follow-up, patient's right eyeball was preserved, and vision improved as well. [ABSTRACT FROM AUTHOR]

Background Neurofibromatosis type 1 (NF1) has been identified as a predisposing factor in the development of pilocytic astrocytoma (PA), a common benign central nervous system tumor. Although this is a common association, simultaneous development of multiple lesions is an infrequent finding, especially in nonoptic and hypothalamic locations. Case Description A 41-year-old female patient with NF1 and uncontrolled human immunodeficiency virus (HIV) type 1 infection presented with a first generalized seizure and associated headache and ataxia. Imaging studies revealed 2 large intra-axial PAs, nodular-cystic in the supratentorial compartment and solid in the infratentorial compartment. Both lesions were treated by gross total resection in 2 surgeries performed 1 week apart. Despite their different imaging patterns, the tumors were histologically and genetically identical. Conclusions We present a unique case involving 2 histologically and genetically identical PAs occurring simultaneously in supratentorial and infratentorial locations. We suggest that an intrinsic predisposition to tumor development in patients with NF1 might have been enhanced by the HIV-related immunosuppression in this case. Strict oncologic surveillance is essential in patients with a tumor predisposition syndrome combined with immunosuppression. [ABSTRACT FROM AUTHOR]

Abstract Whereas isolated sphenoid wing dysplasia (SWD) is a well-known clinical feature in neurofibromatosis 1 (NF1), extensive cranial defects involving multiple bones have been rarely reported in this disorder. In this report, we describe the clinical course of a 20-year-old male with NF1 and an extensive cranial bone dysplasia. The large sphenoethmoidal defect was associated with transethmoidal and orbital cephalocele as well as inferolateral herniation of the frontal lobe. In spite of the large defect, the individual did not have any symptoms or complications resulting from the osteopathy. We review the current knowledge of the pathogenesis and management of cranial bone dysplasia in NF1. Highlights • We present an individual with NF1 and a large cranial bone dysplasia. • Our report highlights that even individuals with large cranial defects can be asymptomatic. • We discuss the current knowledge about the pathogenesis of cranial defects in NF1 and potential treatment approaches. [ABSTRACT FROM AUTHOR]

Animal studies of several single-gene disorders demonstrate that reversing the molecular signaling deficits can result in substantial symptomatic improvements in function. Focusing on the ratio of excitation to inhibition as a potential pathophysiological hallmark, seven single-gene developmental CNS disorders are reviewed which are characterized by a striking dysregulation of neuronal inhibition. Deficits in inhibition and excessive inhibition are found. The examples of developmental disorders encompass Neurofibromatosis type 1, Fragile X syndrome, Rett syndrome, Dravet syndrome including autism-like behavior, NONO-mutation-induced intellectual disability, Succinic semialdehyde dehydrogenase deficiency and Congenital nystagmus due to FRMD7 mutations. The phenotype/genotype correlations observed in animal models point to potential treatment options and will continue to inspire clinical research. Three drugs are presently in clinical trials: acamprosate and ganoxolon for Fragile X syndrome and SGS-742 for SSADH deficiency. This article is part of the “Special Issue Dedicated to Norman G. Bowery”. [ABSTRACT FROM AUTHOR]

Neurofibromatosis type 1 (NF1) is a relatively common multisystemic inherited disease and has been extensively studied by multiple disciplines. Although genetic testing and confirmation are available, NF1 remains a clinical diagnosis. Many manifestations of NF1 involve the eye and orbit, and the ophthalmologist, therefore, plays a significant role in the diagnosis and treatment of NF1 patients. Improvements in diagnostic and imaging instruments have provided new insight to study the ophthalmic manifestations of the disease. We provide a comprehensive and up-to-date overview of the ocular and orbital manifestations of NF1. [ABSTRACT FROM AUTHOR]

Purpose Neurofibromatosis type 1 (NF1) is a tumour suppressor syndrome and also a bone disease. In the craniofacial region, local skeletal deformities have been recorded in patients with NF1. Obvious syndrome-related alterations of the jaws are particularly conspicuous in the mandible. Here we aimed to analyse the mandibular alterations of NF1-affected individuals from orthopantomograms (OPGs). Materials and Methods This study analyses 358 OPGs of 358 patients (mean age, 34.63 years; range, 12.57–69.13 years). The OPGs of 179 patients of Caucasian origin with NF1 were investigated (mean age, 34.84 years; range, 12.83–68.89 years; 44.13% male, 55.86% female). The radiographic findings were compared to those obtained from OPGs of sex- and age-matched controls. Results Characteristic deformations of the bone regions of interest occur in NF1 patients, especially in patients with plexiform neurofibroma of trigeminal nerve. These findings are always one-sided. The co-occurrence of several skeletal deformations can be expected with very high probability in this patient group. Conclusion The radiological sign of the unilateral deformed mandible should be included in the diagnostic criteria for NF1. In addition to the diagnostic value in this syndrome, these findings are important for avoiding surgical complications in planned interventions in this region. [ABSTRACT FROM AUTHOR]