Search Results (200)

Background/Objectives: Neurofibromatosis type 1 (NF1) and Noonan syndrome spectrum disorders (NSSD) are the most common RASopathies, resulting from germline mutations that affect the RAS-MAPK signaling pathway. Both are associated with increased risk for neurodevelopmental and psychiatric conditions, yet few studies have used structured diagnostic interviews to compare their psychiatric comorbidities. Methods: We conducted clinician-administered DSM-5 diagnostic assessments (KSADS) in 123 children with RASopathies (NF1 = 29, NSSD = 94; ages 5–15). Diagnosis prevalence was compared within each group and to population-based estimates. Results: Psychiatric diagnoses were highly prevalent, at 79.3% in NF1 and 76.6% in NSSD, with ADHD (NF1 = 72.4%, NSSD = 51.1%) and anxiety disorders (NF1 = 37.9% and NSSD = 43.6%) being the most common, rates substantially higher than those reported in general population estimates. Behavioral and sleep disorders were identified in approximately 25% of both groups. Notably, social anxiety disorder was identified in 14.9% of NSSD but not in NF1. Full-scale IQ did not significantly differ by diagnosis status. Specific anxiety disorders, elimination disorders, obsessive–compulsive disorder, and post-traumatic stress disorder were characterized, expanding the known psychiatric phenotype of RASopathies. Conclusions: Children with NF1 and NSSD demonstrate similarly high rates of ADHD, anxiety, and behavioral disorders compared to the general population; in addition, we report sleep disorders in NSSD and characterize psychiatric disorders not previously described in RASopathies. The shared psychiatric profiles may reflect the common effect of RAS-MAPK pathway dysregulation on psychiatric outcomes. These findings highlight the need for early, syndrome-informed mental health screening and intervention in the clinical care of individuals with RASopathies. Full article

Introduction: Primary extracranial vertebral artery aneurysms are sporadic in the general population. They are uncommon in individuals with neurofibromatosis type 1. During pregnancy or in the puerperium, the risk of aneurysm rupture in individuals with neurofibromatosis type 1 and extracranial aneurysms is elevated. Rupture of a vertebral artery aneurysm is an emergency condition and can be fatal. Case presentation: We present the case of a 33-year-old woman in the puerperium with neurofibromatosis type 1 who had a vertebral symptomatic artery aneurysm. During a previous hospitalization, two months before the treatment of the vertebral aneurysm, a same-sided aneurysm of the thyrocervical trunk was successfully treated with endovascular coiling because of aneurysm rupture. In this case report, the vertebral artery aneurysm was successfully managed using a flow diverter stent graft. Conclusions: This is the first reported case of a successfully treated symptomatic vertebral artery aneurysm with a flow diverter stent graft in a patient with neurofibromatosis type 1 during the early puerperium. Endovascular treatment with a stent graft is a minimally invasive, safe, and effective treatment for patients with vertebral artery aneurysms. Early diagnosis of non-ruptured vertebral artery aneurysms is a crucial as well as appropriate treatment, which should be undertaken in a timely manner to prevent serious complications or a fatal outcome. Full article

Neurofibromatosis type 1 (NF1) is a genetic disorder characterized by a wide range of clinical manifestations, including café-au-lait macules, cutaneous neurofibromas, and an increased risk of certain malignancies. Historically, there has been no approved medical therapy specifically aimed at achieving tumor shrinkage or regression. Surgical intervention is often limited by factors such as the inaccessibility of the tumor location, involvement of critical tissues, suboptimal timing, or the inability to achieve complete resection. Recent advancements in targeted therapies, particularly MEK inhibitors, have introduced promising treatment options for patients with severe manifestations of NF1. This review highlights the pathophysiology of NF1 and the therapeutic role of MEK inhibitors and presents a detailed case study of a patient treated with selumetinib, a novel MEK inhibitor. While the therapeutic potential of selumetinib has been demonstrated in preclinical and clinical studies, including those involving Japanese patients, this review aims to evaluate its application in real-world clinical practice. A comprehensive discussion of the case study provides insights into the efficacy, safety, and clinical challenges associated with selumetinib treatment, offering valuable perspectives for its use in managing NF1. Full article

Background and Clinical Significance: Neurofibromatosis type 1 (NF1) predisposes individuals to various peripheral nerve sheath tumors (PNSTs), including benign neurofibromas, malignant peripheral nerve sheath tumors (MPNSTs), and intermediate lesions known as atypical neurofibromatous neoplasms of uncertain biologic potential (ANNUBP), previously often termed atypical neurofibroma. These atypical lesions are considered premalignant precursors to MPNST. Case Presentation: We present the case of a 33-year-old male with NF1 who developed a rapidly growing, painful mass in his right calf. Clinical examination revealed signs consistent with NF1. Magnetic resonance imaging showed a large, heterogeneous mass in the lateral compartment. Biopsy revealed a neurofibroma with hypercellularity, moderate atypia, scarce S100 positivity, focal CD34 positivity, and an elevated Ki-67 proliferation index of 10–12%, consistent with ANNUBP. The patient underwent wide surgical resection, including the fibula and peroneal muscles. At the 30-month follow-up, there was no local recurrence, though the patient had a mild residual limp. Discussion: This case highlights the clinical presentation, diagnostic features, and management considerations for ANNUBP in NF1, emphasizing the importance of recognizing warning signs and the role of pathology in guiding treatment for these high-risk precursor lesions. Full article

Background/Objectives: Neurofibromatosis Type 1 (NF1) plexiform neurofibroma (PN) can cause morbidity, including disfigurement that can negatively impact social functioning. Historically, the mainstay treatment is surgical resection. However, complete resection is often prohibitive due to multiple nerve involvement. Moreover, post-operative recurrence is common. MEK inhibitors, including selumetinib and mirdametinib, have recently changed the treatment paradigm for these tumors. In 2020, selumetinib was FDA-approved for pediatric NF1 patients with inoperable symptomatic PNs, but selumetinib remains under investigation for their adult counterparts. In 2025, mirdametinib was FDA-approved for use in adults with symptomatic incompletely resectable NF1 PNs. Lower partial response rates have been reported with mirdametinib compared to selumetinib, but direct comparative analyses have not been conducted to establish the superiority of one agent over the other. Results: We present a case of a 38-year-old male with a right facial PN successfully treated with selumetinib, resulting in a 16.77% tumor volumetric reduction over 7 months. Selumetinib was well tolerated in our patient, with an asymptomatic Grade 3 CPK elevation that subsequently improved with a dose reduction. Conclusion: Our case adds to the growing body of evidence suggesting that selumetinib is effective and well tolerated in adult patients with NF1-associated PNs. Full article

Malignant peripheral nerve sheath tumors (MPNSTs) are a rare type of soft tissue sarcoma associated with poor prognoses. The standard of care for non-resectable tumors consists of surgical excision followed by radiation and chemotherapy. MPNSTs are most common in patients with neurofibromatosis type 1 but can also occur sporadically. Regardless of origin, MPNSTs most often rely on signaling pathways that increase basal oxidative stress. This provides the basis for developing therapeutics with mechanisms that can potentiate oxidative stress to selectively eradicate tumor cells at doses that are tolerable for normal cells. Artemisinin derivatives are a mainstay of malaria therapy worldwide, with a well-established safety profile. Artemisinin’s antimalarial effects are due to an endoperoxide bridge in its chemical structure that induces oxidative stress. We found that artesunate (ARS) and metabolite dihydroartemisinin (DHA) are selectively cytotoxic to MPNST cells relative to normal Schwann cells with the endoperoxide bridge required for activity. Mechanistically, DHA induced oxidative stress, lipid peroxidation, and DHA-mediated cytotoxicity could be prevented with co-administration of the antioxidant N-acetyl-cysteine. Furthermore, we found that DHA was able to selectively remove MPNST from co-culture with normal Schwann cells. These data supports the further development of artemisinins for the clinical management of MPNST. Full article

Cutaneous manifestations can serve as early and sometimes the first clinical indicators in various hereditary cancer predisposition syndromes. This review provides a comprehensive overview of the dermatological signs associated with these syndromes, aiming to facilitate their recognition in clinical practice. Hereditary Breast and Ovarian Cancer syndrome is notably linked to an increased risk of melanoma. BAP1 tumor predisposition syndrome is characterized by BAP1-inactivated melanocytic tumors. Muir–Torre syndrome, a variant of Lynch syndrome, presents with distinctive cutaneous neoplasms such as sebaceous carcinomas, sebaceous adenomas, and keratoacanthomas. PTEN hamartoma tumor syndrome commonly features hamartomatous growths, trichilemmomas, acral keratoses, oral papillomas, and genital lentiginosis. Gorlin syndrome is marked by basal cell carcinomas and palmoplantar pits, while Peutz–Jeghers syndrome is identified by mucocutaneous pigmentation. In familial adenomatous polyposis, the cutaneous findings include epidermoid cysts, fibromas, desmoid tumors, and lipomas. Additionally, we examined monogenic disorders associated with cancer risk and skin involvement, such as xeroderma pigmentosum, neurofibromatosis type 1, familial atypical multiple-mole melanoma syndrome, and Fanconi anemia. The early recognition of these dermatologic features is essential for a timely diagnosis and the implementation of appropriate surveillance strategies in individuals with hereditary cancer syndromes. Full article

Background/Objectives: Karyomapping, a genome-wide SNP analysis, has drastically changed the approach to preimplantation genetic testing for monogenic disorders (PGT-M). However, there are cases in which karyomapping cannot be applied due to an insufficient number of informative SNPs. In this study, we aimed to analyze for the first time whether an insufficient number of informative SNPs is related to the family member used as a reference. Methods: For the karyomapping pre-clinical test, in addition to the couple, one of the DNA samples from an additional family member (children, parent, sibling) is used as a reference for phasing the SNP allele. We analyzed 263 couples who underwent karyomapping for PGT-M at the CHA Fertility Center from May 2020 to December 2022. karyomapping data was scanned on an Illumina NextSeq and analyzed through the BlueFuse Multi software version 4.5. Results: Preclinical karyomapping tests were performed in 263 couples with 58 monogenic diseases. Karyomapping was applicable to PGT-M for 241 (91.6%) couples and not applicable for 22 (8.4%) couples. The percentages of “not applicable” cases according to the reference family member were 1.3% (1/80) in the children group, 5.4% (8/148) in the parent group, and 37.1% (13/35) in the sibling group. Among the genetic diseases studied, couples with neurofibromatosis type 1 (6/27, 22.2%) and Kennedy disease (5/5, 100%) had the highest rate of non-applicable cases. Conclusions: Our results suggest that a child or parent may be better than the sibling for karyomapping in PGT-M. These data provide useful information for selecting a reference among the family members for preclinical karyomapping tests. Full article

Background/Objectives: Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive malignancies with a challenging prognosis, especially for patients with Neurofibromatosis type 1 (NF1). Their low incidence necessitates comprehensive studies to investigate the survival outcome. Methods: We conducted a systematic review and meta-analysis, including data from 16 studies and 4265 patients, to explore surgical outcomes and survival rates, focusing on time-related outcomes, including overall survival (OS), progression-free survival (PFS), and recurrence rate. Results: The analysis revealed that the OS rate was 86% [95% CI: 75–97%] at 1 year, decreasing to 60% [95% CI: 45–75%] at 3 years, and further declining to 47% [95% CI: 35–58%] by 5 years. For PFS, the 1-year rate was 61% [95% CI: 25–98%], which remained similar at 62% [95% CI: 35–89%] for 3 and 5 years. In NF1-associated MPNSTs, the 1-year OS was relatively high at 93% [95% CI: 83–100%], but it dropped to 68% [95% CI: 53–84%] at 3 years and further to 50% [95% CI: 31–68%] at 5 years. Additionally, the hazard ratio indicated a 38% lower survival rate in NF1 patients than those with sporadic MPNSTs when data were presented in the same study. Recurrence rates were high, with 56% of patients experiencing a relapse, primarily as local recurrences (70.6%). Mortality was significant, with over 50% of patients dying within an average follow-up period of 33.45 months. Conclusions: MPNSTs, particularly in NF1 patients, are associated with poor prognosis and high recurrence rates. These results underline the necessity of targeted therapeutic strategies and improved programs for screening, mainly through a multidisciplinary approach to optimize management. Full article

Background/Objectives: The present investigation quantifies the striking predisposition for small intestinal GISTs in NF-1 patients, examining both multifocal and solitary tumor patterns while establishing critical epidemiological comparisons with the general population. By elucidating these distinct clinical and biological profiles, the study aims to transform the understanding of NF1-associated tumorigenesis and optimize patient surveillance strategies. Methods: This systematic review and meta-analysis was conducted in strict accordance with PRISMA guidelines, the gold-standard framework for minimizing bias and maximizing reproducibility in evidence synthesis. Prospectively registered in PROSPERO, the study employed a PICO framework to evaluate interventions, outcomes, and comparisons. Results: This systematic review and meta-analysis reveals a profound oncogenic propensity for small intestinal GISTs in NF-1 patients, demonstrating markedly increased prevalence relative to population baselines. The tumors display characteristic presentation and histological profiles, with a distribution of 54% multifocal lesions, 41% solitary SI-GIST, and 5% solitary duodenal GIST cases, demonstrating the diverse clinical manifestations of NF-1-associated tumors. These compelling findings not only redefine the epidemiological landscape of NF1-associated malignancies but also underscore extraordinary disease susceptibility, far surpassing previous estimates and sporadic occurrence rates in the general population. Conclusions: The distinct clinical patterns and high frequency of these tumors among NF-1 patients provide important insights into GIST development while underscoring the need for heightened clinical suspicion, particularly in patients manifesting gastrointestinal hemorrhage. These findings highlight the unique challenges in managing these cases—including diagnostic limitations and therapeutic constraints—underscoring the imperative for multidisciplinary therapeutic frameworks for detection, monitoring and treatment in this high-risk population. Full article

Gliomas are incurable, heterogeneous brain tumors, with rare forms often constituting diagnostic and treatment challenges. Molecular diagnostics, mainly implemented through the World Health Organization (WHO) 2021 guidelines, have refined the classification, but highlight difficulties in diagnosing rare gliomas remain. This case series analyzes four patients with rare gliomas treated at the University Hospital, Ulm, between 2002 and 2024. Patients were selected based on unique histopathological features and long-term clinical follow-up. Clinical records, imaging, and histological data were reviewed. Molecular diagnostics followed WHO 2021 guidelines. Quality of life was assessed using standardized tools including the EQ-5D-5L, EQ VAS, the Distress Thermometer, and the Montreal Cognitive Assessment (MoCA). In the first case, a 51-year-old male’s diagnosis evolved from pleomorphic xanthoastrocytoma to a high-grade glioma with pleomorphic and pseudopapillary features, later identified as a neuroepithelial tumor with a PATZ1 fusion over 12 years. Despite multiple recurrences, extensive surgical interventions led to excellent outcomes. The second case involved a young female with long-term survival of astroblastoma, demonstrating significant improvements in both longevity and quality of life through personalized care. The third case involved a patient with oligodendroglioma, later transforming into glioblastoma, emphasizing the importance of continuous diagnostic reevaluation and adaptive treatment strategies, contributing to prolonged survival and quality of life improvements. Remarkably, the patient has achieved over 20 years of survival, including 10 years of being both therapy- and progression-free. The fourth case presents a young woman with neurofibromatosis type 1, initially misdiagnosed with glioblastoma based on histopathological findings. Subsequent molecular diagnostics revealed a subependymal giant cell astrocytoma-like astrocytoma, highlighting the critical role of early advanced diagnostic techniques. These cases underscore the importance of precise molecular diagnostics, individualized treatments, and ongoing diagnostic reevaluation to optimize outcomes. They also address the psychological impact of evolving diagnoses, stressing the need for comprehensive patient support. Even in complex cases, extensive surgical interventions can yield favorable results, reinforcing the value of adaptive, multidisciplinary strategies based on evolving tumor characteristics. Full article

Background/Objectives: Neurofibromatosis type 1 (NF1) is a prevalent inherited disorder, with approximately 50% of affected individuals developing plexiform neurofibromas (PNFs), which can progress to highly aggressive malignant peripheral nerve sheath tumors (MPNSTs). While selumetinib is FDA-approved for PNFs, its efficacy in MPNSTs is limited and associated with dose-limiting toxicities. NF1 deficiency drives tumorigenesis and alters immune dynamics via RAS hyperactivation. Given the substantial macrophage infiltration in NF1 lesions and its association with disease progression, we hypothesized that targeting tumor-promoting immune cells with the retinoid X receptor (RXR) agonist MSU-42011 could be an alternative therapeutic strategy, as it has shown promise in KRAS-driven cancers by decreasing pERK levels and reducing tumor-promoting immune cells. Methods: We examined the effects of MSU-42011 and selumetinib, alone and in combination, on NF1-deficient cells and in a syngeneic MPNST model. Results: In vivo, the combination of MSU-42011 and selumetinib significantly reduced tumor growth, pERK levels, and tumor-promoting macrophages and increased activated CD8⁺ T cells in syngeneic MPNST models. In NF1-deficient cells, MSU-42011 or selumetinib reduced pERK levels, with combination treatment achieving greater reductions. Conditioned media (CM) from NF1-deficient cells increased the protein and mRNA levels of several cytokines and chemokines in human THP1 cells and bone marrow-derived macrophages (BMDMs). MSU-42011 and selumetinib, alone or in combination, partially reversed this induction. Conclusions: These findings suggest RXR agonists may have therapeutic potential against NF1, and their combination with MEK inhibitors could represent a promising strategy for NF1-associated tumors. Further studies are needed to validate these results and assess their translational relevance. Full article

Malignant Triton Tumors (MTTs) are rare, high-grade malignant peripheral nerve sheath tumors (MPNSTs) frequently associated with Type 1 Neurofibromatosis (NF1). NF1, an autosomal dominant disorder, predisposes approximately 10% of affected individuals to developing MPNSTs, with 50% of these tumors occurring in NF1 patients, while others arise sporadically or in association with radiation exposure. MTTs predominantly affect anatomical regions rich in large nerves, such as the limbs, spinal root, and cranial nerves. Mediastinal presentations are exceedingly rare, posing significant diagnostic and therapeutic challenges. Current treatment strategies include surgical resection, chemotherapy, radiotherapy, and lung-sparing procedures for metastatic disease. Molecular studies of MPNSTs have revealed that NF1 mutations lead to dysregulation of the RAS signalling pathway, while epigenetic alterations (e.g., SUZ12/EED mutations) further contribute to tumor progression. Dysregulated phylogenetically conserved pathways, including Wnt/beta-catenin and non-canonical SHH signalling, play a role in sarcoma progression and Schwann cell transformation. Recent advances in miRNA research highlight their involvement in tumor invasion and progression, with dysregulated miRNA expression and chromatin remodeling contributing to the pathogenesis of these neoplasms. However, the distinct molecular profiles for MTTs remain incompletely understood. Further investigation of the genetic and epigenetic landscape is essential for improving our understanding and identifying potential therapies. Herein, we present a single-center retrospective case series of three patients with an intrathoracic triton tumor treated at our University Hospital between 2000 and 2024, serving as a starting point for future insights into MPNST pathobiology. Full article

Background: Selumetinib, an MEK inhibitor, was approved by the U.S. Food and Drug Administration in April 2020 and became reimbursable in Italy in January 2020, for treating patients aged ≥3 years with neurofibromatosis type 1 (NF1) complicated by symptomatic, inoperable plexiform neurofibromas (PNs). Selumetinib has been shown to effectively reduce the volume of target PNs and alleviate neuropathic pain even in long-term-treated patients. We report the impact of Selumetinib on pain in three NF1 cases with inoperable symptomatic plexiform neurofibromas. Case Series: Three patients with NF1 (aged 13–27 years) presented with symptomatic, inoperable plexiform neurofibromas (PNs) associated with severe neuropathic pain. Following selumetinib administration, a marked reduction in or disappearance of neuropathic pain was observed within a few weeks, allowing the complete discontinuation of pain therapy. Interestingly, pain recurred whenever selumetinib was temporarily suspended, requiring patients to resume analgesic therapy. Conclusions: Selumetinib treatment has been shown to effectively reduce neuropathic pain in patients with NF1. These findings represent a significant advancement in managing pain related to PNs and support its potential application in treating other forms of neuropathic pain. Full article

Neurofibromatosis type 1 (NF1) is an autosomal dominant disorder caused by mutations in the NF1 gene, typically diagnosed during early childhood and characterized by significant phenotypic heterogeneity. Despite advancements in next-generation sequencing (NGS), the diagnostic process remains challenging due to the gene’s complexity, high mutational burden, and frequent identification of variants of uncertain significance (VUS). This review explores the emerging role of artificial intelligence (AI) in enhancing NF1 variant detection, classification, and interpretation. A systematic literature search was conducted across PubMed, IEEE Xplore, Google Scholar, and ResearchGate to identify recent studies applying AI technologies to NF1 genetic analysis, focusing on variant interpretation, structural modeling, tumor classification, and therapeutic prediction. The review highlights the application of AI-based tools such as VEST3, REVEL, ClinPred, and NF1-specific models like DITTO and RENOVO-NF1, which have demonstrated improved accuracy in classifying missense variants and reclassifying VUS. Structural modeling platforms like AlphaFold contribute further insights into the impact of NF1 mutations on neurofibromin structure and function. In addition, deep learning models, such as LTC neural networks, support tumor classification and therapeutic outcome prediction, particularly in NF1-associated complications like congenital pseudarthrosis of the tibia (CPT). The integration of AI methodologies offers substantial potential to improve diagnostic precision, enable early intervention, and support personalized medicine approaches. However, key challenges remain, including algorithmic bias, limited data diversity, and the need for functional validation. Ongoing refinement and clinical validation of these tools are essential to ensure their effective implementation and equitable use in NF1 diagnostics. Full article