Vascular Abnormalities and Neurofibromatosis Type 1: A Paediatric Case Series.

Neurofibromatosis type 1 (NF1) is a multisystemic neurocutaneous disease caused by a heterozygous mutation of the NF1 gene that encodes neurofibromin. Complications include vascular and neurologic abnormalities such as moyamoya syndrome, a cerebrovascular disorder with progressive occlusion of the large intracranial arteries, leading to ischemic events and the formation of abnormal vascular networks. Stenosis of the renal artery is another frequent complication of neurofibromatosis type 1, and it represents the most common cause of secondary hypertension in these patients. The purpose of the article is to describe the clinical manifestations of neurofibromatosis type 1 vasculopathy in 4 patients presenting with a wide range of neurologic and reno-vascular manifestations, as well as to examine current diagnostic management and follow-up, current therapeutic options, and to discuss further perspectives in terms of screening, diagnosis, and treatment.

Social Communication in Ras Pathway Disorders: A Comprehensive Review from Genetics to Behavior in Neurofibromatosis Type 1 and Noonan Syndrome.

Neurofibromatosis type 1 (NF1) and Noonan syndrome (NS) are neurogenetic syndromes caused by pathogenetic variants encoding components of the Ras-ERK-MAPK signaling pathway (Ras pathway). NF1 and NS are associated with differences in social communication and related neuropsychiatric risks. During the last decade, there has been growing interest in Ras-linked syndromes as models to understand social communication deficits and autism spectrum disorders. We systematically review the literature between 2010-2023 focusing on the social communication construct of the RDoC framework. We provide an integrative summary of the research on facial and non-facial social communication processes in NF1 and NS across molecular, cellular, neural circuitry, and behavioral domains. At the molecular and cellular levels, dysregulation in the Ras pathway is intricately tied to variations in social communication through changes in GABAergic, glutamatergic, and serotonergic transmission, as well as inhibitory/excitatory imbalance. Neural circuitry typically associated with learning, attention, and memory in NF1 and NS (e.g., cortico-striatal connectivity), is also implicated in social communication. We highlight less researched, potential mechanisms for social communication, such as white matter connectivity and the default mode network. Finally, key gaps in NF1 and NS literature are identified and a roadmap for future research is provided. By leveraging genetic syndromes research, we can understand the mechanisms associated with behaviors and psychiatric disorders.

Coronary Artery Aneurysm Thrombosis Causing Acute Myocardial Infarction in an Adolescent With Neurofibromatosis Type 1.

Acute myocardial infarction is a rare though possible occurrence in young patients, especially with predisposing conditions, and the treatment is still debated. We present the case of a teenager known to have neurofibromatosis type 1 with acute coronary syndrome caused by coronary aneurysms and thrombotic occlusion of the left circumflex artery treated with a stent-sparing strategy.

Neurofibromatosis to neoplasia transition: a rare case report of spindle cell malignant peripheral nerve sheath tumor with literature review.

Introduction and importance: Malignant peripheral nerve sheath tumor (MPNST) is a rare and aggressive soft tissue malignant tumor. MPNST in the spinal canal is rarely seen except in cases of neurofibromatosis type 1. However, a long-segment extradural spinal malignant spindle cell neoplasm has not been reported in the current literature. Case presentation: We present the first reported case of spinal malignant spindle cell neoplasm extended along the spine. The detected lesion is responsible for compressing various segments of the spinal cord, causing thinning of the cord and secondary stenosis of the spinal canal, leading to a condition known as multisegment compression myelopathy. Clinical discussion: MPNSTs are typically detected late due to nonspecific symptoms, with a higher incidence in extremities and a notable occurrence in unusual locations. Diagnosis relies on MRI and histopathology, with S_100 positivity as a neural marker. MPNSTs can arise from neurofibromas or Schwann cells, with a significant portion resulting from TP53 mutations or secondary to radiation exposure. Conclusion: This case stands out due to its unique presentation, characterized by a predominantly spindle cell morphology with certain epithelioid features. It is imperative to recognize this condition for an accurate diagnosis, emphasizing the spindle cell-type MPNST and highlighting its exceptionally poor prognosis.

Managing neurofibromatosis type I and vision impairment in a resource-limited setting: a case study and multidisciplinary approach.

Background: Neurofibromatosis type I (NF1) is a genetic disorder characterized by the development of multiple benign tumors along nerves in the skin, brain, and other parts of the body. It is associated with a range of clinical manifestations, including skin lesions, neurofibromas, and ocular abnormalities, which can significantly impact a patient's quality of life. Management of NF1 is particularly challenging in resource-limited settings due to limited access to diagnostic and therapeutic resources. Clinical presentation: A 62-year-old woman with a known history of NF1 presented with progressive visual impairment. Her condition began in childhood with multiple hyperpigmented skin macules, which developed into numerous cutaneous tumors over time. Examination revealed numerous neurofibromas, café-au-lait spots, and axillary freckling. Significant visual impairment was caused by large fibromas on her eyelids. Histological analysis confirmed benign nerve tissue tumors. Clinical discussion: The management strategy in this resource-limited setting focused on regular monitoring, patient education, symptomatic treatment, and multidisciplinary care. Despite the limitations, the patient's condition was managed effectively through these adapted strategies. The importance of genetic testing for confirmation and further management was noted but not performed due to resource constraints. Conclusion: This case highlights the complexities of managing NF1 in resource-limited settings, emphasizing the need for adaptable management approaches. Multidisciplinary care and patient education were crucial in improving the patient's quality of life. This case underscores the importance of early diagnosis and intervention to prevent complications like visual impairment.

Recurrence of spinal schwannomas in a patient with neurofibromatosis type 1: a case report.

Introduction and importance: Spinal schwannomas are benign tumors usually attached to peripheral nerves, consisting of a clonal population of Schwann cells. Neurofibromatosis type 1 is an autosomal dominant neurocutaneous disorder that predominantly affects the skin, bone and nervous system. Neurofibromatosis type 1 is a clinically and genetically distinct from neurofibromatosis type 2. This case report highlights the rare association between spinal schwannoma and neurofibromatosis type 1. Case presentation: The patient with a past medical history of spinal schwannoma, operated 1 year back, presented with back pain, weakness of lower limbs and urge incontinence. On examination, she had cutaneous features suggestive of neurofibromatosis type 1 and there was impairment of all sensory modalities below hip region. MRI revealed spinal schwannoma at D9 level for which laminectomy with removal of schwannoma was performed. Clinical discussion: The occurrence and recurrence of spinal schwannoma in neurofibromatosis type 2 is a common finding. But such an association has not been established between spinal schwannoma and neurofibromatosis type 1. In this case, the recurrence of spinal schwannoma has been linked to neurofibromatosis type 1 in the absence of other well-defined etiologies. Conclusion: The occurrence of spinal schwannoma can be genetic or sporadic. The recurrence is usually associated with familial tumor syndrome. The available literature has not established association between neurofibromatosis type 1 and spinal schwannoma, thus, emphasizing the need of more focused studies.

Proof of Concept for Genome Profiling of the Neurofibroma/Sarcoma Sequence in Neurofibromatosis Type 1.

Neurofibromatosis type 1 (NF1) is an autosomal dominant genetic disorder characterized by the predisposition to develop tumors such as malignant peripheral nerve sheath tumors (MPNSTs) which represents the primary cause of death for NF1-affected patients. Regardless of the high incidence and mortality, the molecular mechanisms underneath MPNST growth and metastatic progression remain poorly understood. In this proof-of-concept study, we performed somatic whole-exome sequencing (WES) to profile the genomic alterations in four samples from a patient with NF1-associated MPNST, consisting of a benign plexiform neurofibroma, a primary MPNST, and metastases from lung and skin tissues. By comparing genomic patterns, we identified a high level of variability across samples with distinctive genetic changes which allow for the definition of profiles of the early phase with respect to the late metastatic stages. Pathogenic and likely pathogenic variants were abundant in the primary tumor, whereas the metastatic samples exhibited a high level of copy-number variations (CNVs), highlighting a possible genomic instability in the late phases. The most known MPNST-related genes, such as TP53 and SUZ12, were identified in CNVs observed within the primary tumor. Pathway analysis of altered early genes in MPNST pointed to a potential role in cell motility, division and metabolism. Moreover, we employed survival analysis with the TCGA sarcoma genomic dataset on 262 affected patients, in order to corroborate the predictive significance of the identified early and metastatic MPNST driver genes. Specifically, the expression changes related to the mutated genes, such as in RBMX, PNPLA6 and AGAP2, were associated with reduced patient survival, distinguishing them as potential prognostic biomarkers. This study underlines the relevance of integrating genomic results with clinical information for early diagnosis and prognostic understanding of tumor aggressiveness.

The Multimodality Management of Malignant Peripheral Nerve Sheath Tumours.

Malignant peripheral nerve sheath tumours (MPNST) are aggressive sarcomas that have nerve sheath differentiation and can present at any anatomical site. They can arise from precursor neurofibroma in the context of neurofibromatosis type 1 (NF1) or as de novo and sporadic tumours in the absence of an underlying genetic predisposition. The primary therapeutic approach is most often radical surgery, with non-surgical modalities playing an important role, especially in locally advanced or metastatic cases. The aim of multimodality approaches is to optimize both local and systemic control while keeping to a minimum acute and late treatment morbidity. Advances in the understanding of the underlying biology of MPNSTs in both sporadic and NF-1-related contexts are essential for the management and implementation of novel therapeutic approaches.

Social cognition in adults with neurofibromatosis type 1.

OBJECTIVE: Adult patients with the genetic disease neurofibromatosis type 1 (NF1) frequently report social difficulties. To date, however, only two studies have explored whether these difficulties are caused by social cognition deficits, and these yielded contradictory data. The aim of the present study was to exhaustively assess social cognition abilities (emotion, theory of mind, moral reasoning, and social information processing) in adults with NF1, compared with a control group, and to explore links between social cognition and disease characteristics (mode of inheritance, severity, and visibility). METHOD: We administered a social cognition battery to 20 adults with NF1 (mean age = 26.5 years, SD = 7.4) and 20 healthy adults matched for sociodemographic variables. RESULTS: Patients scored significantly lower than controls on emotion, theory of mind, moral reasoning, and social information processing tasks. No effects of disease characteristics were found. CONCLUSIONS: These results appear to confirm that adults with NF1 have a social cognition weaknesses that could explain, at least in part, their social difficulties, although social abilities are not all impaired to the same extent. Regarding the impact of the disease characteristics, the patient sample seemed slightly insufficient for the power analyses performed. Thus, this exploratory study should form the basis of further research, with the objective of replicating these results with larger and more appropriately matched samples.

Generation of a zebrafish neurofibromatosis model via inducible knockout of nf2.

Neurofibromatosis Type 2 (NF-2) is a dominantly inherited genetic disorder that results from mutations in the tumor suppressor gene, neurofibromin 2 (NF2) gene. Here, we report the generation of a conditional zebrafish model of neurofibromatosis established by an inducible genetic knockout of nf2a/b, the zebrafish homolog of human NF2. Analysis of nf2a and nf2b expression reveals ubiquitous expression of nf2b in the early embryo, with overlapping expression in the neural crest and its derivatives and in the cranial mesenchyme. In contrast, nf2a displays lower expression levels. Induction of nf2a/b knockout at early stages increases the proliferation of larval Schwann cells and meningeal fibroblasts. Subsequently, in adult zebrafish, nf2a/b knockout triggers the development of a spectrum of tumors, including vestibular Schwannomas, spinal Schwannomas, meningiomas, and retinal hamartomas, mirroring the tumor manifestations observed in patients with NF-2. Collectively, these findings highlight the generation of a novel zebrafish model that mimics the complexities of the human NF-2 disorder. Consequently, this model holds significant potential for facilitating therapeutic screening and elucidating key driver genes implicated in NF-2 onset.

Mechanical properties of pediatric low-grade gliomas in children with and without neurofibromatosis type 1.

INTRODUCTION: Prognoses for pediatric brain tumors are suboptimal, as even in low-grade tumors, management techniques can lead to damage in the developing brain. Therefore, advanced neuroimaging methods are critical for developing optimal management plans and improving patient care. Magnetic resonance elastography (MRE) has allowed for the characterization of adult gliomas by their mechanical properties, which are uniquely sensitive to the complex interplay of cellularity, vasculature, and interstitium. However, pediatric tumors differ in behavior and cytoarchitecture, and their mechanical properties have never been assessed. METHODS: Here, we conduct the first study of pediatric brain tumor mechanical properties by using MRE to measure tissue stiffness and damping ratio in low grade gliomas (LGGs). We additionally measure the mechanical properties of non-neoplastic focal abnormal signal intensities (FASIs) in children with neurofibromatosis type 1 (NF1). RESULTS: 23 patients age 4-17 years who had MR imaging results consistent with a primary LGG or with NF1 were included in this study. We found that pediatric gliomas are on an average 10.9% softer (p = 0.010) with a 17.3% lower (p = 0.009) viscosity than reference tissue. Softness of tumors appeared consistent across tumor subtypes and unrelated to tumor size or contrast-enhancement. In NF1 we found that, unlike gliomas, FASIs are stiffer, though not significantly, than reference tissue by an average of 10.4% and have a 16.7% lower damping ratio. CONCLUSIONS: Measuring tumor mechanical properties patterning and heterogeneity has potential to aid in prediction of biological behavior and inform management strategies for pediatric patients.

Duodenal ampulla neuroendocrine tumor and gastrointestinal stromal tumors in a case of neurofibromatosis type 1: a case report.

Neurofibromatosis type 1 (NF-1) is commonly associated with a variety of rare tumors. However, no case of multiple gastric gastrointestinal stromal tumors (GISTs) or duodenal ampulla neuroendocrine tumors (NETs) with multiple liver metastases in a patient with NF-1 has yet been reported. Here, we describe a case of a 55-year-old female patient with NF-1 whose serum Pro-Gastrin-Releasing Peptide (pro-GRP) levels were elevated. Gastrointestinal endoscopy and biopsy showed duodenal papilla space-occupying mass, and the pathological diagnosis turned out to be neuroendocrine tumors (NETs). During surgical exploration, multiple tumors were found on the serosal surface of the stomach and numerous miliary metastases in the liver. Following histopathological examination, it was determined that the liver metastases were NF-1 and the tumors in the gastric wall were GISTs. The patient benefited from targeted therapy and had an uneventful hospital stay. In this case, we emphasize treating patients with neurofibromatosis type 1 who exhibit abdominal symptoms with a high degree of clinical suspicion and performing thorough evaluations to rule out multiple tumors.

Pulsatile Proptosis and Sphenoid Wing Dysplasia with no Evidence of Neurofibromatosis Type 1: A Case Report and Review of the Literature.

In this study, we aimed to present a rare case of pulsatile proptosis due to sphenoid wing dysplasia without the features of neurofibromatosis type 1 (NF1). A 17-year-old male patient presented with swelling in the superotemporal region of the right eye. Physical examination revealed facial asymmetry with a pulsatile, ill-defined, soft lesion with in the superotemporal region of the right orbit associated with pulsatile proptosis, downward dystopia, and hypotropia. Computer tomography imaging to establish a differential diagnosis showed temporal lobe herniation secondary to sphenoid wing dysplasia. The patient was assessed for NF1, which is most commonly associated with sphenoid wing dysplasia, but no evidence supporting the diagnosis was found. Patients presenting with proptosis should be carefully examined for pulsation and murmurs, and a trauma history should be investigated. Radiological imaging should be used to facilitate the differential diagnosis, and the current clinical condition should be managed with a multidisciplinary approach.

Molecular markers for pediatric low-grade glioma.

Over the past decade, our understanding of the molecular drivers of pediatric low-grade glioma (PLGG) has expanded dramatically. These tumors are predominantly driven by RAS/MAPK pathway activating alterations (fusions and point mutations), most frequently in BRAF, FGFR1, and NF1. Furthermore, additional second hits in tumor suppressor genes (TP53, ATRX, CDKN2A) can portend more aggressive behaviour. Accordingly, comprehensive molecular profiling-specifically genetic sequencing, often plus copy number profiling-has become critical for guiding the diagnosis and management of PLGG. In this review, we discuss the most important genetic alterations that inform on classification and prognosis of PLGG, highlighting their diagnostic and therapeutic relevance.

Periampullary duodenal neuroendocrine tumor in a patient with neurofibromatosis-1: A case report.

BACKGROUND: Patients with neurofibromatosis type 1 (NF1) are exposed to a higher risk of developing neuroendocrine tumors (NETs). Periampullary neuroendocrine neoplasms (NENs) in NF1 patients primarily affect the duodenum and periampullary region. CASE SUMMARY: A 50-year-old male patient was admitted to our hospital due to progressive skin and scleral yellowing for over 6 months. An abdominal contrast-enhanced computed tomography scan revealed a tumor in the periampullary region, which measured 1.2 cm × 1.4 cm in size and showed a progressive enhancement. Magnetic resonance cholangiopancreatography indicated the dilation of intrahepatic and extrahepatic bile ducts. The patient was diagnosed with an ampullary tumor with the possibility of malignancy. A Whipple procedure was performed. Microscopically, the duodenum tumor was found to invade the mucosa, sphincter, and muscular layer of the duodenal papilla. Histologic hematoxylin and eosin staining confirmed the presence of duodenal G1 NET. Subsequently, a bibliometric analysis was performed to evaluate the state of NEN research. Publications about periampullary NENs showed an annual increase, with most of them focusing on the treatment and diagnosis of NENs. CONCLUSION: This article reported a case of periampullary duodenal NET in a patient with NF1, and a bibliometric analysis was conducted.

A successful combined spinal-epidural anesthesia for cesarean section in a patient with neurofibromatosis type 1-associated dural ectasia.

BACKGROUND: Dural ectasia is a common manifestation of neurofibromatosis type 1. Although there have been reports of unsuccessful spinal anesthesia due to dual ectasia in Marfan syndrome, reports describing similar unsuccessful spinal anesthesia in neurofibromatosis type 1 are lacking. CASE PRESENTATION: A parturient with neurofibromatosis type 1 was scheduled for a repeat cesarean section. During a previous cesarean section, she had experienced a failed spinal anesthesia, which resulted in a conversion to general anesthesia. Preoperative lumbar magnetic resonance imaging revealed dural ectasia, which was speculated to be the cause of the previous spinal anesthesia failure. Therefore, combined spinal-epidural anesthesia was implemented. Because the block level of spinal anesthesia was insufficient as predicted, supplemental administration of epidural anesthesia successfully provided adequate analgesia for the surgery. CONCLUSIONS: Combined spinal-epidural anesthesia can be useful for the management of cesarean sections in patients with neurofibromatosis type 1-associated dural ectasia.

Autism Spectrum Disorder Symptom Profiles in Fragile X Syndrome, Angelman Syndrome, Tuberous Sclerosis Complex and Neurofibromatosis Type 1.

Studying Autism Spectrum Disorder (ASD) heterogeneity in biologically homogeneous samples may increase our knowledge of ASD etiology. Fragile X syndrome (FXS), Angelman syndrome (AS), Tuberous Sclerosis Complex (TSC), and Neurofibromatosis type 1 (NF1) are monogenic disorders with high a prevalence of ASD symptomatology. This study aimed to identify ASD symptom profiles in a large group of children and adolescents (0;9-28 years) with FXS, AS, TSC, and NF1. Data on ASD symptomatology (Autism Diagnostic Observation Scale (ADOS-2) & Social Responsiveness Scale (SRS-2)) were collected from children and adolescents with FXS (n = 54), AS (n = 93), TSC (n = 112), and NF1 (n = 278). To identify groups of individuals with similar ASD profiles, we performed two latent profile analyses. We identified a four-profile model based on the ADOS-2, with a (1) 'Non-spectrum symptom profile', (2) 'Social Affect symptom profile', (3)'Restricted/Repetitive Behaviors symptom profile', and (4)'ASD symptom profile'. We also identified a four-profile model based on the SRS, with a (1)'Non-clinical symptom profile', (2)'Mild symptom profile', (3)'Moderate symptom profile', and (4)'Severe symptom profile'. Although each syndrome group exhibited varying degrees of severity, they also displayed heterogeneity in the profiles in which they were classified. We found distinct ASD symptom profiles in a population consisting of children and adolescents with FXS, AS, TSC, and NF1. Our study highlights the importance of a personalized approach to the identification and management of ASD symptoms in rare genetic syndromes. Future studies should aim to include more domains of functioning and investigate the stability of latent profiles over time.

Neurofibromatosis type-2-related schwannomatosis presenting as peripapillary hamartoma: report on a novel NF2 mutation.

BACKGROUND: Neurofibromatosis type-2-related schwannomatosis (NF2-SWN, formerly neurofibromatosis type 2) is a rare genetic disorder marked by the development of multiple nervous system tumors. CASE PRESENTATION: We report a 21-month-old female patient who presented for left eye deviation. Upon examination, intermittent exotropia and a fundus mass were detected. Wide field fundus examination revealed the presence of a combined hamartoma involving the optic nerve and retina. This finding was supported by MRI highlighting the lesion's characteristics. The patient's father and other relatives on the paternal side displayed symptoms of NF2-SWN, evident through the presence of acoustic neuroma, although they did not exhibit any ocular symptoms. DNA analysis revealed a novel loss-of-function mutation in exon 15 of the NF2 gene (NM_000268.3: c.1627_1628del, p.Lys543Aspfs *21) in both the patient and her father at a heterozygous state. By the age of three, her vision worsened, and optical coherence tomography showed vitreomacular traction and intraretinal fluid surrounding the lesion. CONCLUSION: This case underscores the need to consider NF2- SWN in peripapillary hamartoma diagnoses and highlights the importance of genetic testing for early detection and management.

T2 Hyperintensities in Children with Neurofibromatosis Type 1.

OBJECTIVE: Areas of increased signal intensity, known as T2 hyperintensities (T2Hs), observed on T2-weighted magnetic resonance imaging (MRI) scans, are linked to a spectrum of brain abnormalities in children with neurofibromatosis type 1 (NF1). Defining the radiological characteristics that distinguish non-neoplastic from neoplastic T2Hs in children with NF1 is crucial. Then, we could identify lesions that were most likely to require oncologic surveillance. METHODS: We conducted a single-center retrospective review of all available brain MRIs from 98 children with NF1 and 50 healthy pediatric controls. All T2Hs identified on MRI were characterized based on location, imaging features, and the presence of lesion-related symptoms. Subsequently, all T2Hs were classified using newly established criteria and categorized into 3 distinct groups: low-risk tumor lesions, medium-risk tumor lesions, and high-risk tumor lesions. Lesions deemed to be high-risk will be recommended for surgical treatment. RESULTS: T2Hs were present in 61 (62.2%) individuals of the NF1 cohort. T2Hs were a highly sensitive (100%; 95% confidence interval 92.9%-100.0%) and specific (62.2%; 95% confidence interval 51.9%-71.8%) marker for the diagnosis of NF1. In children aged 4-10, the detection rate of T2Hs is significantly higher than in children under 4 years old and those aged between 10 and 18 (P < 0.05). T2Hs were most frequently located in basal ganglia, cerebellar hemispheres, and brainstem. During the follow-up process, none of the lesions categorized as low-risk or medium-risk tumor lesions progressed to high-risk tumor lesions. Seven patients had high-risk tumor lesions and underwent surgical treatment. The pathological assessment identified 5 cases of glioma among the 7 patients, along with 1 case of gliosis and 1 case of vascular dysplasia. CONCLUSIONS: Low-risk and medium-risk tumor lesions can both be classified as unidentified bright objects . Unidentified bright objects constituted the majority of T2Hs in children with NF1. High-risk tumor lesions should be considered as probable tumors. With the application of standardized radiologic criteria, a high prevalence of probable brain tumors will be identified in this at-risk population of children, which underscores the importance of vigilant and appropriate oncological surveillance to ensure timely detection and intervention for these tumors.

[Clarification the terms and definitions related to neurofibromatosis type 1].

Objective: To summarize the terms and definitions related to neurofibromatosis type 1 (NF1) with a view to standardizing and unifying the existing terminology system. Methods: To review the research literature related to NF1 at home and abroad, and to summarize the expressions of the disease and related terms. Results: There are still some limitations in the current knowledge of NF1, especially in the expression of the terminology, and there are discrepancies in the description and naming of NF1-related features in different medical literatures and clinical guides. There are differences in the description and naming of NF1-related features in different medical literature and clinical guidelines. Through a systematic review of the literature, this paper provides a detailed compendium and summary of the terms and definitions of NF1-related clinical manifestations, pathological features, and genetic types, and further standardizes and unifies existing diagnostic criteria and terminology systems. Conclusion: The terms and definitions of NF1-related clinical manifestations are summarized to enhance the knowledge of clinicians and researchers related to NF1.