Giant cell granuloma and neurofibroma in the mandible of a patient with neurofibromatosis type 1: a long-term follow-up case report with radiological and surgical aspects and a review of the literature.

BACKGROUND: Magnetic resonance imaging (MRI) of the brain is frequently performed on patients with neurofibromatosis type 1 (NF1), to detect and follow-up intracranial findings. In addition, NF1-related pathologies can appear in the jaws. This case study investigates if it is advantageous to assess the depicted parts of the jaws in the imaging of NF1 patients with intracranial findings, thereby detecting jaw pathologies in their initial stages. CASE PRESENTATION: We report on the 3-year management with clinical and radiological follow-ups of a central giant cell granuloma and a neurofibroma in the mandible of a patient with NF1 who underwent examinations with brain MRIs. A review of the mandible in the patient's MRIs disclosed lesions with clear differences in progression rates. CONCLUSION: NF1-related jaw pathologies may be detected in the early stages if the depicted parts of the jaws are included in the assessment of the imaging of NF1 patients with intracranial findings. This could impact the treatment of eventual pathologies before lesion progression and further damage to the vicinity.

Neurofibromatosis Type 1-Retinal Alterations Detectable with Optical Coherence Tomography Angiography.

Neurofibromatosis type 1 (NF 1) is a multisystemic genetic disorder involving aberrant proliferation of multiple tissues of a neural crest origin. It represents a tumor predisposition syndrome characterized by a wide range of clinical manifestations, such as benign tumors, which primarily affect the skin and the nervous system. The most frequent clinical signs of NF 1 include café-au-lait spots all over the surface of the skin and axillary freckling; however, these signs can be accompanied by more severe manifestations such as the growth of both benign and malignant nervous system tumors and skeletal dysplasia, as well as a wide range of ocular manifestations. We report the rare case of retinal microvascular alterations and choroidal nodules in a 15 year old male patient with NF 1, detectable on optical coherence tomography angiography (OCTA). The hyperreflective choroidal nodules modified the profile of the choroidal vasculature. The retinal microvascular alterations in the form of clustered capillaries were detected in the superficial capillary plexus located nasally to the macular region. Retinal vascular abnormalities undetectable on fundus photography or fundoscopy can be present in patients with NF 1. Indirect ophthalmoscopy of our study patient was unremarkable. However, retinal vascular abnormalities were seen on OCTA scans in the superficial capillary plexus and choroidal nodules were detected on raster OCT scans. OCTA represents a useful imaging technique for detecting retinal microvascular abnormalities, which can be considered additional distinctive signs of NF 1.

Survival after resection of malignant peripheral nerve sheath tumors: Introducing and validating a novel type-specific prognostic model.

Background: This study aimed to assess the performance of currently available risk calculators in a cohort of patients with malignant peripheral nerve sheath tumors (MPNST) and to create an MPNST-specific prognostic model including type-specific predictors for overall survival (OS). Methods: This is a retrospective multicenter cohort study of patients with MPNST from 11 secondary or tertiary centers in The Netherlands, Italy and the United States of America. All patients diagnosed with primary MPNST who underwent macroscopically complete surgical resection from 2000 to 2019 were included in this study. A multivariable Cox proportional hazard model for OS was estimated with prespecified predictors (age, grade, size, NF-1 status, triton status, depth, tumor location, and surgical margin). Model performance was assessed for the Sarculator and PERSARC calculators by examining discrimination (C-index) and calibration (calibration plots and observed-expected statistic; O/E-statistic). Internal-external cross-validation by different regions was performed to evaluate the generalizability of the model. Results: A total of 507 patients with primary MPNSTs were included from 11 centers in 7 regions. During follow-up (median 8.7 years), 211 patients died. The C-index was 0.60 (95% CI 0.53-0.67) for both Sarculator and PERSARC. The MPNST-specific model had a pooled C-index of 0.69 (95%CI 0.65-0.73) at validation, with adequate discrimination and calibration across regions. Conclusions: The MPNST-specific MONACO model can be used to predict 3-, 5-, and 10-year OS in patients with primary MPNST who underwent macroscopically complete surgical resection. Further validation may refine the model to inform patients and physicians on prognosis and support them in shared decision-making.

Pulmonary Arterial Hypertension in Neurofibromatosis Type 1: A Case with a Novel NF1 Gene Mutation.

Neurofibromatosis type 1 (NF1) is an autosomal dominant multi-organ disease. The clinical manifestations include not only skin lesions and malignant tumors but also lung complications, including pulmonary arterial hypertension (PAH). However, the association between gene mutations in NF1 and the occurrence of PAH has not yet been elucidated. We herein report a case of isolated PAH in a 67-year-old woman with NF1, presumably caused by a novel heterozygous mutation, c.4485_4486delinsAT (p.Lys1496Ter), in the NF1 gene.

Low back pain with axillary mass in a perimenopausal woman: A case of schwannomatosis mimicking metastasis.

Schwannomatosis is a rare neurocutaneous syndrome characterized by the presence of multiple schwannomas along the peripheral nerves, distinctly excluding the vestibular nerves. It is recognized as the third principal form of neurofibromatosis, alongside neurofibromatosis types 1 and 2. In this report, we discuss the case of a 45-year-old woman who initially sought medical attention for low back pain and swelling in her left axilla. Her magnetic resonance imaging revealed multiple enhancing intradural extramedullary lesions, along with a mass in the right upper thoracic region and another in the left axilla, raising suspicions of metastasis. However, a comprehensive analysis that aligned imaging results with histopathological findings confirmed the diagnosis of schwannomatosis. This case highlights the importance of differentiating between various conditions that can cause multiple intradural extramedullary masses, such as nerve sheath tumors, meningiomas, and metastasis. The presence of multiple schwannomas suggests a diagnosis of either neurofibromatosis type 2 or schwannomatosis, making the distinction between these two conditions critical for appropriate management.

The Use of Hexokinase 2-Displacing Peptides as an Anti-Neoplastic Approach for Malignant Peripheral Nerve Sheath Tumors.

Malignant Peripheral Nerve Sheath Tumors (MPNSTs) are aggressive sarcomas that can arise both sporadically and in patients with the genetic syndrome Neurofibromatosis type 1 (NF1). Prognosis is dismal, as large dimensions, risk of relapse, and anatomical localization make surgery poorly effective, and no therapy is known. Hence, the identification of MPNST molecular features that could be hit in an efficient and selective way is mandatory to envision treatment options. Here, we find that MPNSTs express high levels of the glycolytic enzyme Hexokinase 2 (HK2), which is known to shield cancer cells from noxious stimuli when it localizes at MAMs (mitochondria-associated membranes), contact sites between mitochondria and endoplasmic reticulum. A HK2-targeting peptide that dislodges HK2 from MAMs rapidly induces a massive death of MPNST cells. After identifying different matrix metalloproteases (MMPs) expressed in the MPNST microenvironment, we have designed HK2-targeting peptide variants that harbor cleavage sites for these MMPs, making such peptides activatable in the proximity of cancer cells. We find that the peptide carrying the MMP2/9 cleavage site is the most effective, both in inhibiting the in vitro tumorigenicity of MPNST cells and in hampering their growth in mice. Our data indicate that detaching HK2 from MAMs could pave the way for a novel anti-MPNST therapeutic strategy, which could be flexibly adapted to the protease expression features of the tumor microenvironment.

Platform trial design for neurofibromatosis type 1, NF2-related schwannomatosis and non-NF2-related schwannomatosis: A potential model for rare diseases.

Background: Neurofibromatosis type 1, NF2-related schwannomatosis and non-NF2-related schwannomatosis (grouped under the abbreviation "NF") are rare hereditary tumor predisposition syndromes. Due to the low prevalence, variability in the range, and severity of manifestations, as well as limited treatment options, these conditions require innovative trial designs to accelerate the development of new treatments. Methods: Within European Patient-Centric Clinical Trial Platforms (EU-PEARL), we designed 2 platform-basket trials in NF. The trials were designed by a team of multidisciplinary NF experts and trial methodology experts. Results: The trial will consist of an observational and a treatment period. The observational period will serve as a longitudinal natural history study. The platform trial design and randomization to a sequence of available interventions allow for the addition of interventions during the trial. If a drug does not meet the predetermined efficacy endpoint or reveals unacceptable toxicities, participants may stop treatment on that arm and re-enter the observational period, where they can be re-randomized to a different treatment arm if eligible. Intervention-specific eligibility criteria and endpoints are listed in intervention-specific-appendices, allowing the flexibility and adaptability needed for highly variable and rare conditions like NF. Conclusions: These innovative platform-basket trials for NF may serve as a model for other rare diseases, as they will enhance the chance of identifying beneficial treatments through optimal learning from a small number of patients. The goal of these trials is to identify beneficial treatments for NF more rapidly and at a lower cost than traditional, single-agent clinical trials.

Pediatric Patient With Neurofibromatosis I Presenting With Perceptual Disturbances and a Suicide Attempt.

This is a case of a pediatric patient with a history of neurofibromatosis I (NFI) presenting to the emergency department secondary to a suicide attempt via self-strangulation after being verbally and physically bullied at school. Upon hospital admission, the 10-year-old patient was found to have significant auditory and visual perceptual hallucinations in addition to suicidal ideations, for which psychiatry was consulted. The patient underwent magnetic resonance imaging (MRI) of the brain to evaluate for intracranial neurofibromas as a potential etiology of his behavior. There is evidence that the growth of neurofibromas in the brain can be associated with psychosis. His brain MRI was significant for multiple foci of non-enhancing lesions seen in the cerebellum, white matter, supratentorial white matter, and bilateral hippocampi that can be seen in NFI, highlighting a medical etiology for the patient's auditory and visual perceptual disturbances. The objective of this case report is to explore medical causes of psychosis including metabolic disorders, neurodegenerative diseases, metabolic disturbances, parathyroid diseases, genetic disorders (Fragile X, Prader-Willi, etc.), autoimmune disorders, multiple sclerosis, temporal lobe epilepsy, infections, and brain tumors.

A case of malignant pheochromocytoma with neurofibromatosis type 1 having difficulty in differentiating spinal tumor.

Introduction: Neurofibromatosis type 1 is a hereditary condition often associated with pheochromocytomas but rarely with malignant pheochromocytomas. Neurofibromatosis type 1 is often associated with bone lesions, which complicates the distinction between malignant and benign tumors. Case presentation: A 46-year-old man with a medical history of neurofibromatosis type 1 presented with right abdominal pain. Computed tomography revealed a right adrenal tumor, and metaiodobenzylguanidine scintigraphy showed accumulation in the right adrenal gland and thoracic vertebrae. He was diagnosed with pheochromocytoma, and a right adrenalectomy was performed. After surgery, a bone biopsy was conducted on the spinal lesion, confirming metastasis of pheochromocytoma, prompting irradiation. After that, lung and liver metastases emerged, and chemotherapy with cyclophosphamide, vincristine, and dacarbazine was initiated; however, the disease progressed, and he died 11 months after surgery. Conclusion: We report a case of malignant pheochromocytoma associated with neurofibromatosis type 1 in which bone metastasis was difficult to diagnose.

Spectrum of cutaneous lesions in a cohort of patients with neurofibromatosis type 2.

BACKGROUND: Neurofibromatosis type 2 (NF2) is a rare autosomal dominant syndrome with a predisposition to the development of central nervous system tumors, ophthalmic manifestations, and dermatological lesions. The latter are present in 70-95% of patients and can precede the evolution of other tumors. However, they are not included in the diagnostic criteria and are frequently undervalued during follow-up. METHODS: An observational cross-sectional study characterizing cutaneous lesions in a cohort of NF2 patients was carried out. Dermatological examinations were performed, and lesions were classified into neural cutaneous tumors (superficial, SNCT, and deep, DNCT), hyperpigmented patches (HyperP), and hypopigmented patches (HypoP). The Dermatology Life Quality Index (DLQI) and EQ-5D questionnaires were applied to evaluate the impact on quality of life. RESULTS: Nineteen patients with a mean age of 36 years were included. Sixteen (84%) patients had cutaneous lesions, mostly developed 10 or more years before the diagnosis. SNCT, DNCT, and HyperP showed similar frequencies (58%). HypoP were observed in only one patient. HyperP developed, on average, earlier than NCT (9.6 vs. 16.5 SNCT, 17.0 DNCT; years). The excised lesions had different histological patterns, including neurofibromas, schwannomas, and a hybrid tumor. Most patients reported a low impact of cutaneous manifestations on the quality of life (DLQI 0 or 1). CONCLUSIONS: Cutaneous lesions are frequent in NF2 and may precede the diagnosis by several years. Their identification is important to establish the diagnosis earlier and potentially reduce morbidity and mortality.

Safety and efficacy of selumetinib in pediatric and adult patients with neurofibromatosis type 1 and plexiform neurofibroma.

BACKGROUND: The MEK inhibitor, selumetinib, reduces plexiform neurofibroma (PN) in pediatric patients with neurofibromatosis type 1 (NF1). Its safety and efficacy in adults with PN and effectiveness in other NF1manifestations (e.g., neurocognitive function, growth reduction, and café-au-lait spots) are unknown. METHODS: This open-label, phase 2 trial enrolled 90 pediatric or adult NF1 patients with inoperable, symptomatic, or potentially morbid, measurable PN (≥ 3 cm). Selumetinib was administered at doses of 20 or 25 mg/m2 or 50 mg q 12 hrs for 2 years. Pharmacokinetics, PN volume, growth parameters, neurocognitive function, café-au-lait spots, and quality of life (QoL) were evaluated. RESULTS: Fifty-nine children and 30 adults (median age, 16 years; range, 3-47) received an average of 22±5 (4-26) cycles of selumetinib. Eighty-eight (98.9%) out of 89 per-protocol patients showed volume reduction in the target PN (median, 40.8%; 4.2%-92.2%), and 81 (91%) patients showed partial response (≥ 20% volume reduction). The response lasted until cycle 26. Scores of neurocognitive functions (verbal comprehension, perceptual reasoning, processing speed, and full-scale IQ) significantly improved in both pediatric and adult patients (P <0.05). Prepubertal patients showed increases in height score and growth velocity (P <0.05). Café-au-lait spot intensity decreased significantly (P <0.05). Improvements in QoL and pain scores were observed in both children and adults. All adverse events were CTCAE grade 1 or 2 and were successfully managed without drug discontinuation. CONCLUSION: Selumetinib decrease PN volume in the majority of pediatric and adult NF1 patients while also showing efficacy in non-malignant diverse NF1 manifestations.

Sporadic neurofibroma of facial nerve presenting as parotid gland tumor: a rare case report.

Intraparotid gland neurofibroma is a rare benign tumor that arises from Schwann cells of the facial nerve within the parotid gland. This case report discusses a 41-year-old woman who experienced a painless preauricular swelling on her right side for over 5 years. Clinical examination and ultrasound revealed a well-defined mass in the parotid gland. The patient underwent total mass excision, resulting in transient facial nerve dysfunction but complete recovery. These tumors often manifest as solitary masses in the parotid region and may compress nearby structures, causing facial paralysis or numbness. Their diagnosis can be challenging due to similarities with other parotid gland tumors and possible associations with neurofibromatosis. Managing intraparotid tumors, including neurofibromas, involves a multidisciplinary approach with input from cytopathologists, radiologists, and surgeons.

Jaffe-Campanacci syndrome; a case series and review of the literature.

BACKGROUND: Jaffe-Campanacci syndrome is a rare syndrome, characterized by multiple non-ossifying fibromas (NOF) and cafe-au-lait patches. The name was coined in 1982 by Mirra after Jaffe who first described the case in 1958. Although it's suggested there is a relation with Neurofibromatosis type 1, there is still no consensus on whether Jaffe-Campanacci syndrome is a subtype or variant of neurofibromatosis-1(NF-1). CASE PRESENTATION: In this article, we present a case series of 2 patients. The first case is a 13-year-old male with Jaffe-Campanacci syndrome who presented with a distal femur fracture. His father had positive features of both Jaffe-Campanacci syndrome and NF-1, while his sister only had features of NF-1, so we presented both. CONCLUSION: Jaffe-Campanacci has a clear relationship with type 1 neurofibromatosis, which still has to be genetically established. Due to the presence of several large non-ossifying fibromas of the long bones, it is linked to a significant risk of pathological fractures. We concur with previous authors, that an osseous screening program should be performed for all patients with newly diagnosed type 1 neurofibromatosis, to identify non-ossifying fibromas and assess the potential for pathological fracture. Moreover, siblings of patients with NF-1 should be screened for multiple NOFs that may carry a high risk of pathological fractures.

snRNA-seq of human cutaneous neurofibromas before and after selumetinib treatment implicates role of altered Schwann cell states, inter-cellular signaling, and extracellular matrix in treatment response.

Neurofibromatosis Type 1 (NF1) is caused by loss of function variants in the NF1 gene. Most patients with NF1 develop skin lesions called cutaneous neurofibromas (cNFs). Currently the only approved therapeutic for NF1 is selumetinib, a mitogen -activated protein kinase (MEK) inhibitor. The purpose of this study was to analyze the transcriptome of cNF tumors before and on selumetinib treatment to understand both tumor composition and response. We obtained biopsy sets of tumors both pre- and on- selumetinib treatment from the same individuals and were able to collect sets from four separate individuals. We sequenced mRNA from 5844 nuclei and identified 30,442 genes in the untreated group and sequenced 5701 nuclei and identified 30,127 genes in the selumetinib treated group. We identified and quantified distinct populations of cells (Schwann cells, fibroblasts, pericytes, myeloid cells, melanocytes, keratinocytes, and two populations of endothelial cells). While we anticipated that cell proportions might change with treatment, we did not identify any one cell population that changed significantly, likely due to an inherent level of variability between tumors. We also evaluated differential gene expression based on drug treatment in each cell type. Ingenuity pathway analysis (IPA) was also used to identify pathways that differ on treatment. As anticipated, we identified a significant decrease in ERK/MAPK signaling in cells including Schwann cells but most specifically in myeloid cells. Interestingly, there is a significant decrease in opioid signaling in myeloid and endothelial cells; this downward trend is also observed in Schwann cells and fibroblasts. Cell communication was assessed by RNA velocity, Scriabin, and CellChat analyses which indicated that Schwann cells and fibroblasts have dramatically altered cell states defined by specific gene expression signatures following treatment (RNA velocity). There are dramatic changes in receptor-ligand pairs following treatment (Scriabin), and robust intercellular signaling between virtually all cell types associated with extracellular matrix (ECM) pathways (Collagen, Laminin, Fibronectin, and Nectin) is downregulated after treatment. These response specific gene signatures and interaction pathways could provide clues for understanding treatment outcomes or inform future therapies.

Selective nitration of Hsp90 acts as a metabolic switch promoting tumor cell proliferation.

Tumors develop in an oxidative environment characterized by peroxynitrite production and downstream protein tyrosine (Y) nitration. We showed that tyrosine nitration supports schwannoma cell proliferation and regulates cell metabolism in the inheritable tumor disorder NF2-related Schwannomatosis (NF2-SWN). Here, we identified the chaperone Heat shock protein 90 (Hsp90) as the first nitrated protein that acts as a metabolic switch to promote schwannoma cell proliferation. Doubling the endogenous levels of nitrated Hsp90 in schwannoma cells or supplementing nitrated Hsp90 into normal Schwann cells increased their proliferation. Metabolically, nitration on either Y33 or Y56 conferred Hsp90 distinct functions; nitration at Y33 (Hsp90NY33) down-regulated mitochondrial oxidative phosphorylation, while nitration at Y56 (Hsp90NY56) increased glycolysis by activating the purinergic receptor P2X7 in both schwannoma and normal Schwann cells. Hsp90NY33 and Hsp90NY56 showed differential subcellular and spatial distribution corresponding with their metabolic and proliferative functions in schwannoma three-dimensional cell culture models. Collectively, these results underscore the role of tyrosine nitration as a post-translational modification regulating critical cellular processes. Nitrated proteins, particularly nitrated Hsp90, emerge as a novel category of tumor-directed therapeutic targets.

Inflammatory rhabdomyoblastic tumor, pheochromocytoma, and pulmonary hamartoma in a patient with neurofibromatosis type 1: a case report.

BACKGROUND: Inflammatory rhabdomyoblastic tumors are relatively recently recognized soft tissue tumors with a low malignant potential. Here, we present a case of concurrent inflammatory rhabdomyoblastic tumor (IRMT), adrenal pheochromocytoma, and pulmonary hamartoma in a patient with neurofibromatosis type 1 (NF1). To our knowledge, this is the first time that this constellation of tumors has been described in the literature. CASE PRESENTATION: A female patient in her late 20s with known NF1 was diagnosed with an inflammatory rhabdomyoblastic tumor, pheochromocytoma, and pulmonary hamartoma in a short succession. IRMT was found to harbor a near-haploid genome and displayed a typical immunohistochemical profile as well as a focal aberrant p53 expression pattern. CONCLUSIONS: This case report strengthens the theory that defects in the tumor suppressor NF1 play a central role in the pathogenesis of inflammatory rhabdomyoblastic tumors and that IRMT may be part of the spectrum of neurofibromatosis type 1 related tumors.

Social challenges, autism spectrum disorder, and attention deficit/hyperactivity disorder in youth with neurofibromatosis type I.

OBJECTIVE: Youth with neurofibromatosis type I (NF1) demonstrate high rates of Autism Spectrum Disorder (ASD) and Attention Deficit/Hyperactivity Disorder (ADHD), which often have overlapping behaviors. Diagnostic clarity is important to guide services. This study evaluated ASD classification in NF1 using various methods and whether those with ADHD suspicion have more social challenges associated with ASD. METHOD: 34 youth with NF1 (Mage = 10.5 ± 1.6 years), completed ASD assessments that combined direct observation and informant ratings to yield a Clinician Best Estimate (CBE) classification. Caregivers rated ASD-related social challenges using the Social Responsiveness Scale- 2nd Edition (SRS-2). RESULTS: ASD classification varied depending on the method, ranging from 32% using low-threshold SRS-2 cut-scores (T ≥ 60) to under 6% when combining cut scores for diagnostic observational tools and stringent SRS-2 cut-scores (T ≥ 70). 14.7% had a CBE ASD classification. 44% were judged to have autism traits associated with a non-ASD diagnosis. The 52.9% with a suspicion of ADHD had higher SRS-2 scores than those without ADHD, F (7, 26) = 3.45, p < .05, Wilk's lambda = 0.518, partial eta squared = 0.482. CONCLUSIONS: Findings highlight the importance of rigorous diagnostic methodology when evaluating ASD in NF1 to inform the selection of targeted interventions for socialization challenges in NF1.

Individualized Anesthetic Management of a Patient With Pheochromocytoma and Concurrent Breast Cancer: A Case Report.

Pheochromocytomas are rare tumors that present a challenge for surgical and anesthetic management due to their ability to produce significant amounts of catecholamines. This case report highlights the successful management of a 49-year-old woman simultaneously diagnosed with neurofibromatosis type 1, pheochromocytoma, and breast cancer. A key decision by the multidisciplinary team involving endocrinology, general surgery, senology, intensive care, and anesthesiology was to prioritize breast cancer surgery over pheochromocytoma resection. This decision considered the potential for improved prognosis and the need to minimize chemotherapy dosage. The case emphasizes the importance of thorough perioperative preparation, including assessing end-organ damage and optimizing medical therapy. Intraoperative management effectively navigated periods prone to catecholamine release, and postoperative care was closely monitored. This case demonstrates that with meticulous planning, a multidisciplinary approach, and a precise anesthetic strategy, safe anesthesia is achievable for patients with pheochromocytoma undergoing major elective surgeries other than pheochromocytoma resection, adding valuable knowledge to a scarcely documented clinical area.

First Co-Occurrence of Griscelli Syndrome Type 2 and Neurofibromatosis Type 1.

Introduction: Griscelli syndrome type 2 (GS2) and neurofibromatosis type 1 (NF1) are both rare genetic disorders, but their coexistence has not been documented prior to this report. Case Presentation: We present the case of a 4-year-old girl initially diagnosed with GS2 due to albinism and immunodeficiency, and later with NF1, manifested by the development of multiple café-au-lait macules (CALMs) and MRI findings. The patient was the second child of consanguineous parents and exhibited symptoms early, with silver-gray hair at birth and subsequent health complications at 9 months. GS2 was confirmed via the identification of a homozygous frameshift variant in the RAB27A gene, and a de novo heterozygous splice site mutation in the NF1 gene established the NF1 diagnosis. Her treatment included hematopoietic stem cell transplantation and ongoing surveillance for NF1-associated complications. Discussion/Conclusion: This case emphasizes the importance of considering the potential for concurrent rare genetic diseases in clinical evaluations, especially with progressive or evolving symptomatology.