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Neurofibromatosis type 1 (NF1), an autosomal dominant genetic disorder, is caused by mutations in the NF1 gene, which encodes the GTPase-activating protein neurofibromin. The pathogenesis of the tumor progression of benign plexiform neurofibromas (PNs) and malignant peripheral nerve sheath tumors (MPNSTs) remain unclear. Here, we found that interferon-induced transmembrane protein 1 (IFITM1) was downregulated in MPNST tissues compared to those in PN tissues from patients with NF1. Overexpression of IFITM1 in NF1-associated MPNST cells resulted in a significant decrease in Ras activation (GTP-Ras) and downstream extracellular regulatory kinase 1/2 (ERK1/2) phosphorylation, whereas downregulation of IFITM1 via treatment with small interfering RNA in normal Schwann cells had the opposite result, indicating that expression levels of IFITM1 are closely associated with tumor progression in NF1. Treatment of MPNST cells with interferon-gamma (IFN-γ) significantly augmented the expression of IFITM1, thereby leading to a decrease in Ras and ERK1/2 activation. Despite the small number of patient samples, these findings may potentially provide a new target for chemotherapy in patients with NF1-associated MPNSTs. In xenograft mice injected with MPNST cells, IFN-γ treatment successfully suppressed tumor progression with increased IFITM1 expression and decreased Ras and ERK1/2 activation in tumor tissues. Collectively, these results suggest that IFITM1 is closely involved in MPNST pathogenesis and that IFN-γ is a good candidate for the therapeutic treatment of MPNSTs in NF1. [ABSTRACT FROM AUTHOR]

Neurofibromatosis type 1 (NF1) is an autosomal dominant genetic disorder caused by mutations of the NF1 gene, which is characterized by multiple café-au-lait macules and neurofibromas. There are still no standardized treatment strategies for NF1 internationally. The NF1 gene is large and encodes neurofibromin (NF) that participates in cell proliferation. The disease mechanism is complex, which presents major challenges for drug development. Various signaling pathways including the RAF/MEK/ERK, PI3K/AKT/mTOR, WNT/β-catenin, and HIPPO/TAZ/YAP pathways have been studied in NF1. MEK1/2 inhibitors targeting the RAF/MEK/ERK pathway, such as selumetinib, have been approved for the treatment of NF1 and inoperable plexiform neurofibromas (PNF). Recent studies highlighted the crucial role of the NF1 tumor microenvironment, comprising Schwann cells (SCs) and their precursors, mast cells, macrophages, T cells, dendritic cells, the extracellular matrix, and surrounding blood vessels, in NF1 pathogenesis. Current treatments for NF1 include tumor resection, radiotherapy, and pharmacotherapy, all of which have limitations. There is an urgent need for exploration of novel therapeutic agents targeting NF1 signaling pathways and the tumor microenvironment. This review summarizes the current research progress in NF1-related signaling pathways and the microenvironment components. It specifically highlights the changes of the signaling pathways caused by NF1 gene mutations and the abnormal tumor microenvironment components, and analyzes the possible pathogenesis of NF1 to provide new insights for early diagnosis, treatment, prevention, and drug development in clinical NF1 management. [ABSTRACT FROM AUTHOR]

Context: Neurofibromatosis type 1 (NF1) is a complex system disorder, caused by alterations in RAS pathways. NF1 adults often suffer from chronic and severe fatigue, for which they are frequently referred to Internal Medicine/Endocrinology. Seeking medical help often leads to (invasive) diagnostic procedures. To prevent the personal and financial burden of this disabling fatigue, it is crucial to know the causes. Objective: To explore somatic causes and provide practical recommendations for the approach to fatigue in adults with NF1. Design: Cross-sectional. All adults with NF1 (N = 133) who visited our Endocrinology department underwent a systematic health screening, including a medical questionnaire, structured interview, complete physical examination, biochemical measurements and additional tests if indicated. Main outcome measure: Prevalence of endocrine and non-endocrine health problems between NF1 adults with and without fatigue. Results: In our cohort, 75% of NF1 adults experienced fatigue. The most frequent endocrine disorders were vitamin D deficiency (28%), obesity (18%) and hypothyroidism (8%). The most frequent non-endocrine internal disorder was high blood pressure (42%). None of the disorders differed significantly between adults with and without fatigue. Conclusions: Endocrine and non-endocrine disorders were equally present in our cohort of NF1 adults with and without fatigue. This suggests that the high prevalence of fatigue in NF1 adults is not explained by these somatic disorders. An alternative explanation for fatigue might be deficits in cognitive functioning and other neuropsychological processes in NF1. Based on our results and review of the literature, we provide a clinical algorithm for the approach to fatigue in NF1 adults, including somatic and psychological assessment. [ABSTRACT FROM AUTHOR]

Simple Summary: In this review, we explore how interactions between tumorigenic Schwann cells and infiltrating immune cells shape the development and malignant transformation of peripheral nerve sheath tumors in neurofibromatosis type 1. We summarize the current state of the field and address key knowledge gaps surrounding the impact of neurofibromin haploinsufficiency on immune cell function, as well as the impact of Schwann cell lineage states on immune cell recruitment and activation within the tumor microenvironment. Furthermore, we discuss emerging evidence suggesting a dueling role of the immune system in promoting benign tumor initiation while potentially restraining malignant outgrowth. Finally, we highlight the potential implications of these findings and suggest future directions for research relevant to the diagnosis, risk-assessment, and treatment of peripheral nerve sheath tumors, utilizing immunomodulatory therapeutics. Neurofibromatosis type 1 (NF1) is a common genetic disorder resulting in the development of both benign and malignant tumors of the peripheral nervous system. NF1 is caused by germline pathogenic variants or deletions of the NF1 tumor suppressor gene, which encodes the protein neurofibromin that functions as negative regulator of p21 RAS. Loss of NF1 heterozygosity in Schwann cells (SCs), the cells of origin for these nerve sheath-derived tumors, leads to the formation of plexiform neurofibromas (PNF)—benign yet complex neoplasms involving multiple nerve fascicles and comprised of a myriad of infiltrating stromal and immune cells. PNF development and progression are shaped by dynamic interactions between SCs and immune cells, including mast cells, macrophages, and T cells. In this review, we explore the current state of the field and critical knowledge gaps regarding the role of NF1(Nf1) haploinsufficiency on immune cell function, as well as the putative impact of Schwann cell lineage states on immune cell recruitment and function within the tumor field. Furthermore, we review emerging evidence suggesting a dueling role of Nf1+/- immune cells along the neurofibroma to MPNST continuum, on one hand propitiating PNF initiation, while on the other, potentially impeding the malignant transformation of plexiform and atypical neurofibroma precursor lesions. Finally, we underscore the potential implications of these discoveries and advocate for further research directed at illuminating the contributions of various immune cells subsets in discrete stages of tumor initiation, progression, and malignant transformation to facilitate the discovery and translation of innovative diagnostic and therapeutic approaches to transform risk-adapted care. [ABSTRACT FROM AUTHOR]

Neurofibromatosis type 1 (NF1), an autosomal dominant genetic disorder, is caused by mutations in the NF1 gene, which encodes the GTPase-activating protein neurofibromin. The pathogenesis of the tumor progression of benign plexiform neurofibromas (PNs) and malignant peripheral nerve sheath tumors (MPNSTs) remain unclear. Here, we found that interferon-induced transmembrane protein 1 (IFITM1) was downregulated in MPNST tissues compared to those in PN tissues from patients with NF1. Overexpression of IFITM1 in NF1-associated MPNST cells resulted in a significant decrease in Ras activation (GTP-Ras) and downstream extracellular regulatory kinase 1/2 (ERK1/2) phosphorylation, whereas downregulation of IFITM1 via treatment with small interfering RNA in normal Schwann cells had the opposite result, indicating that expression levels of IFITM1 are closely associated with tumor progression in NF1. Treatment of MPNST cells with interferon-gamma (IFN-γ) significantly augmented the expression of IFITM1, thereby leading to a decrease in Ras and ERK1/2 activation. Despite the small number of patient samples, these findings may potentially provide a new target for chemotherapy in patients with NF1-associated MPNSTs. In xenograft mice injected with MPNST cells, IFN-γ treatment successfully suppressed tumor progression with increased IFITM1 expression and decreased Ras and ERK1/2 activation in tumor tissues. Collectively, these results suggest that IFITM1 is closely involved in MPNST pathogenesis and that IFN-γ is a good candidate for the therapeutic treatment of MPNSTs in NF1.

ContextNeurofibromatosis type 1 (NF1) is a complex system disorder, caused by alterations in RAS pathways. NF1 adults often suffer from chronic and severe fatigue, for which they are frequently referred to Internal Medicine/Endocrinology. Seeking medical help often leads to (invasive) diagnostic procedures. To prevent the personal and financial burden of this disabling fatigue, it is crucial to know the causes.ObjectiveTo explore somatic causes and provide practical recommendations for the approach to fatigue in adults with NF1.DesignCross-sectional. All adults with NF1 (N = 133) who visited our Endocrinology department underwent a systematic health screening, including a medical questionnaire, structured interview, complete physical examination, biochemical measurements and additional tests if indicated.Main outcome measurePrevalence of endocrine and non-endocrine health problems between NF1 adults with and without fatigue.ResultsIn our cohort, 75% of NF1 adults experienced fatigue. The most frequent endocrine disorders were vitamin D deficiency (28%), obesity (18%) and hypothyroidism (8%). The most frequent non-endocrine internal disorder was high blood pressure (42%). None of the disorders differed significantly between adults with and without fatigue.ConclusionsEndocrine and non-endocrine disorders were equally present in our cohort of NF1 adults with and without fatigue. This suggests that the high prevalence of fatigue in NF1 adults is not explained by these somatic disorders. An alternative explanation for fatigue might be deficits in cognitive functioning and other neuropsychological processes in NF1. Based on our results and review of the literature, we provide a clinical algorithm for the approach to fatigue in NF1 adults, including somatic and psychological assessment.

Abstract Background Neurofibromatosis type 1 (NF1) is a genetic neurodevelopmental disorder commonly associated with impaired cognitive function. Despite the well-explored functional roles of neural oscillations in neurotypical populations, only a limited number of studies have investigated oscillatory activity in the NF1 population. Methods We compared oscillatory spectral power and theta phase coherence in a paediatric sample with NF1 (N = 16; mean age: 13.03 years; female: n = 7) to an age/sex-matched typically developing control group (N = 16; mean age: 13.34 years; female: n = 7) using electroencephalography measured during rest and during working memory task performance. Results Relative to typically developing children, the NF1 group displayed higher resting state slow wave power and a lower peak alpha frequency. Moreover, higher theta power and frontoparietal theta phase coherence were observed in the NF1 group during working memory task performance, but these differences disappeared when controlling for baseline (resting state) activity. Conclusions Overall, results suggest that NF1 is characterised by aberrant resting state oscillatory activity that may contribute towards the cognitive impairments experienced in this population. Trial registration ClinicalTrials.gov, NCT03310996 (first posted: October 16, 2017).

Neurofibromatosis Type 1 (NF1) is one of the most common genetically inherited disorders that affects 1 in 3000 children annually. Clinical manifestations vary widely but nearly always include the development of cutaneous, plexiform and diffuse neurofibromas that are managed over many years. Recent single-cell transcriptomics profiling efforts of neurofibromas have begun to reveal cell signaling processes. However, the cell signaling networks in mature, non- cutaneous neurofibromas remain unexplored. Here, we present insights into the cellular composition and signaling within mature neurofibromas, contrasting with normal adjacent tissue, in a porcine model of NF1 using single-cell RNA sequencing (scRNA-seq) analysis and histopathological characterization. These neurofibromas exhibited classic diffuse-type histologic morphology and expected patterns of S100, SOX10, GFAP, and CD34 immunohistochemistry. The porcine mature neurofibromas closely resemble human neurofibromas histologically and contain all known cellular components of their human counterparts. The scRNA-seq confirmed the presence of all expected cell types within these neurofibromas and identified novel populations of fibroblasts and immune cells, which may contribute to the tumor microenvironment by suppressing inflammation, promoting M2 macrophage polarization, increasing fibrosis, and driving the proliferation of Schwann cells. Notably, we identified tumor-associated IDO1+/CD274+ (PD-L1)+ dendritic cells, which represent the first such observation in any NF1 animal model and suggest the role of the upregulation of immune checkpoints in mature neurofibromas. Finally, we observed that cell types in the tumor microenvironment are poised to promote immune evasion, extracellular matrix reconstruction, and nerve regeneration. [ABSTRACT FROM AUTHOR]

Background: Malignant peripheral nerve sheath tumors (MPNSTs) are aggressive sarcomas that typically develop in the setting of neurofibromatosis type 1 (NF1) and cause significant morbidity. Conventional therapies are often ineffective for MPNSTs. Ribonucleotide reductase subunit M2 (RRM2) is involved in DNA synthesis and repair, and is overexpressed in multiple cancers. However, its role in NF1-associated MPNSTs remains unknown. Our objective was to determine the therapeutic and prognostic potential of RRM2 in NF1-associated MPNSTs. Methods: Identification of hub genes was performed by using NF1-associated MPNST microarray datasets. We detected RRM2 expression by immunochemical staining in an MPNST tissue microarray, and assessed the clinical and prognostic significance of RRM2 in an MPNST cohort. RRM2 knockdown and the RRM2 inhibitor Triapine were used to assess cell proliferation and apoptosis in NF1-associated MPNST cells in vitro and in vivo. The underlying mechanism of RRM2 in NF1-associated MPNST was revealed by transcriptome analysis. Results: RRM2 is a key hub gene and its expression is significantly elevated in NF1-associated MPNST. We revealed that high RRM2 expression accounted for a larger proportion of NF1-associated MPNSTs and confirmed the correlation of high RRM2 expression with poor overall survival. Knockdown of RRM2 inhibited NF1-associated MPNST cell proliferation and promoted apoptosis and S-phase arrest. The RRM2 inhibitor Triapine displayed dose-dependent inhibitory effects in vitro and induced significant tumor growth reduction in vivo in NF1-associated MPNST. Analysis of transcriptomic changes induced by RRM2 knockdown revealed suppression of the AKT-mTOR signaling pathway. Overexpression of RRM2 activates the AKT pathway to promote NF1-associated MPNST cell proliferation. Conclusions: RRM2 expression is significantly elevated in NF1-associated MPNST and that high RRM2 expression correlates with poorer outcomes. RRM2 acts as an integral part in the promotion of NF1-associated MPNST cell proliferation via the AKT-mTOR signaling pathway. Inhibition of RRM2 may be a promising therapeutic strategy for NF1-associated MPNST. [ABSTRACT FROM AUTHOR]

Neurofibromatosis type 1 (NF1) is a rare inherited neurocutaneous disorder with a major impact on the skin, nervous system and eyes. The ocular diagnostic hallmarks of this disease include iris Lisch nodules, ocular and eyelid neurofibromas, eyelid café-au-lait spots and optic pathway gliomas (OPGs). In the last years, new manifestations have been identified in the ocular district in NF1 including choroidal abnormalities (CAs), hyperpigmented spots (HSs) and retinal vascular abnormalities (RVAs). Recent advances in multi-modality imaging in ophthalmology have allowed for the improved characterization of these clinical signs. Accordingly, CAs, easily detectable as bright patchy nodules on near-infrared imaging, have recently been added to the revised diagnostic criteria for NF1 due to their high specificity and sensitivity. Furthermore, subclinical alterations of the visual pathways, regardless of the presence of OPGs, have been recently described in NF1, with a primary role of neurofibromin in the myelination process. In this paper, we reviewed the latest progress in the understanding of choroidal and retinal abnormalities in NF1 patients. The clinical significance of the recently revised diagnostic criteria for NF1 is discussed along with new updates in molecular diagnosis. New insights into NF1-related neuro-ophthalmic manifestations are also provided based on electrophysiological and optical coherence tomography (OCT) studies. [ABSTRACT FROM AUTHOR]

Background: Neurofibromatosis type 1 (NF1) is a genetic neurodevelopmental disorder commonly associated with impaired cognitive function. Despite the well-explored functional roles of neural oscillations in neurotypical populations, only a limited number of studies have investigated oscillatory activity in the NF1 population. Methods: We compared oscillatory spectral power and theta phase coherence in a paediatric sample with NF1 (N = 16; mean age: 13.03 years; female: n = 7) to an age/sex-matched typically developing control group (N = 16; mean age: 13.34 years; female: n = 7) using electroencephalography measured during rest and during working memory task performance. Results: Relative to typically developing children, the NF1 group displayed higher resting state slow wave power and a lower peak alpha frequency. Moreover, higher theta power and frontoparietal theta phase coherence were observed in the NF1 group during working memory task performance, but these differences disappeared when controlling for baseline (resting state) activity. Conclusions: Overall, results suggest that NF1 is characterised by aberrant resting state oscillatory activity that may contribute towards the cognitive impairments experienced in this population. Trial registration: ClinicalTrials.gov, NCT03310996 (first posted: October 16, 2017). [ABSTRACT FROM AUTHOR]

Congenital pseudarthrosis of forearm fractures is rare and is strongly associated with neurofibromatosis type 1 (NF1). Our case report illustrates the progression of a non-union of the ulna after minor trauma in a twelve-year-old boy, newly diagnosed with NF1, and presents the technique of microsurgical bone reconstruction, including the growth plate. More than seven years after the first operation, follow-up presents a favorable outcome with a pain-free patient and unrestricted function of the forearm after a secondary correction of the remaining radial bowing. This treatment is discussed with a comprehensive review of the current literature on ulnar congenital pseudarthrosis in PubMed and Google Scholar and free fibular growth plate transfer in PubMed and Google Scholar. Nine publications reporting on 20 cases of congenital ulnar non-unions were identified. With this reconstructive option, favorable outcomes were achieved in all cases with the union after primary surgery and complications requiring further surgeries in nine cases. The benefit of vascularized growth plate bone transfer in congenital ulna non-union seems to be significant compared to other therapies such as open reduction internal fixation (ORIF), non-vascularized bone grafts, or one-bone-forearms and beneficial when growth reconstruction is needed. Other techniques might be necessary to improve insufficient long-term results. [ABSTRACT FROM AUTHOR]

Abstract Neurofibromatosis type 1 (NF1) presents an autosomal dominant, haploinsufficient, and multisystemic disorder with patches of skin café-au-lait spots, lisch nodules in the iris, even tumors in the peripheral nervous system or fibromatous skin. In this study, a Chinese young woman who suffered from NF1 disease with first-trimester spontaneous abortion was recruited. Analysis for whole exome sequencing (WES), Sanger sequencing, short tandem repeat (STR), and co-segregation was carried out. As results, a novel, heterozygous, de novo pathogenic variant (c.4963delA:p.Thr1656Glnfs*42) of the NF1 gene in the proband was identified. This pathogenic variant of the NF1 gene produced a truncated protein that lost more than one-third of the NF1 protein at the C-terminus including half of the CRAL-TRIO lipid-binding domain and nuclear localization signal (NLS), thus leading to pathogenicity (ACMG criteria: PVS1 + PM2 + PM2). Analysis for NF1 conservation in species revealed high conservation in different species. Analysis of NF1 mRNA levels in different human tissues showed low tissue specificity, which may affect multiple organs presenting other symptoms or phenotypes. Moreover, prenatal NF1 gene diagnosis showed both alleles as wild types. Thus, this NF1 novel variant probably underlays the NF1 pathogenesis in this pedigree, which would help for the diagnosis, genetic counseling, and clinical management of this disorder.

Neurofibromatosis Type 1 (NF1) is one of the most common genetically inherited disorders that affects 1 in 3000 children annually. Clinical manifestations vary widely but nearly always include the development of cutaneous, plexiform and diffuse neurofibromas that are managed over many years. Recent single-cell transcriptomics profiling efforts of neurofibromas have begun to reveal cell signaling processes. However, the cell signaling networks in mature, non-cutaneous neurofibromas remain unexplored. Here, we present insights into the cellular composition and signaling within mature neurofibromas, contrasting with normal adjacent tissue, in a porcine model of NF1 using single-cell RNA sequencing (scRNA-seq) analysis and histopathological characterization. These neurofibromas exhibited classic diffuse-type histologic morphology and expected patterns of S100, SOX10, GFAP, and CD34 immunohistochemistry. The porcine mature neurofibromas closely resemble human neurofibromas histologically and contain all known cellular components of their human counterparts. The scRNA-seq confirmed the presence of all expected cell types within these neurofibromas and identified novel populations of fibroblasts and immune cells, which may contribute to the tumor microenvironment by suppressing inflammation, promoting M2 macrophage polarization, increasing fibrosis, and driving the proliferation of Schwann cells. Notably, we identified tumor-associated IDO1+/CD274+ (PD-L1)+ dendritic cells, which represent the first such observation in any NF1 animal model and suggest the role of the upregulation of immune checkpoints in mature neurofibromas. Finally, we observed that cell types in the tumor microenvironment are poised to promote immune evasion, extracellular matrix reconstruction, and nerve regeneration.

Background: Neurofibromatosis type 1 (NF-1) is a dominant genetic disorder often accompanied by lesions of the neurovascular system. Patients with NF-1 are predisposed to unique vertebral artery fistula (AVF). Case description: We report on a rare case of multiple neurovascular abnormalities in a 47-year-old man with neurofibromatosis. He was admitted due to a sudden headache and was found to have suffered a subarachnoid hemorrhage from a left vertebral arteriovenous fistula. He underwent two endovascular procedures complicated by a delayed extraspinal mass 7 days after treatment. Angiography revealed a new vascular abnormality, and although we performed another embolization, it failed to respond to further embolization. Conclusion: Vascular abnormalities in patients with NF-1 can be complex. Endovascular intervention remains feasible for NF-1 related AVF, however, partial occlusion of the fistula should be avoided to limit and iatrogenic damage to the blood vessels. [ABSTRACT FROM AUTHOR]

Neurofibromatosis type 1 (NF1) presents an autosomal dominant, haploinsufficient, and multisystemic disorder with patches of skin café-au-lait spots, lisch nodules in the iris, even tumors in the peripheral nervous system or fibromatous skin. In this study, a Chinese young woman who suffered from NF1 disease with first-trimester spontaneous abortion was recruited. Analysis for whole exome sequencing (WES), Sanger sequencing, short tandem repeat (STR), and co-segregation was carried out. As results, a novel, heterozygous, de novo pathogenic variant (c.4963delA:p.Thr1656Glnfs*42) of the NF1 gene in the proband was identified. This pathogenic variant of the NF1 gene produced a truncated protein that lost more than one-third of the NF1 protein at the C-terminus including half of the CRAL-TRIO lipid-binding domain and nuclear localization signal (NLS), thus leading to pathogenicity (ACMG criteria: PVS1 + PM2 + PM2). Analysis for NF1 conservation in species revealed high conservation in different species. Analysis of NF1 mRNA levels in different human tissues showed low tissue specificity, which may affect multiple organs presenting other symptoms or phenotypes. Moreover, prenatal NF1 gene diagnosis showed both alleles as wild types. Thus, this NF1 novel variant probably underlays the NF1 pathogenesis in this pedigree, which would help for the diagnosis, genetic counseling, and clinical management of this disorder. [ABSTRACT FROM AUTHOR]

Simple Summary: In the last few years, an increasing number of genotype–phenotype correlations has been described for neurofibromatosis type 1 (NF1), impacting on the clinical follow-up of patients, especially in pediatric age. The widespread use of molecular diagnosis, made easier by next generation sequencing technology, now allows very early confirmation of clinical diagnosis, even in the case of non-canonical presentation of the disorder with other overlapping conditions. Here, we review the main clinical characteristics and complications related to NF1, particularly those occurring in children. We also describe currently known genotype–phenotype associations that need to be considered because of their effect on genetic counseling and prognosis. Molecular diagnosis is today fundamental for the confirmation of doubtful clinical diagnoses, especially in the light of recently revised diagnostic criteria, and for the early identification of genotypes, albeit few, that correlate with specific phenotypes. Neurofibromatosis type 1 (NF1) is an autosomal dominant condition, with a birth incidence of approximately 1:2000–3000, caused by germline pathogenic variants in NF1, a tumor suppressor gene encoding neurofibromin, a negative regulator of the RAS/MAPK pathway. This explains why NF1 is included in the group of RASopathies and shares several clinical features with Noonan syndrome. Here, we describe the main clinical characteristics and complications associated with NF1, particularly those occurring in pediatric age. NF1 has complete penetrance and shows wide inter- and intrafamilial phenotypic variability and age-dependent appearance of manifestations. Clinical presentation and history of NF1 are multisystemic and highly unpredictable, especially in the first years of life when penetrance is still incomplete. In this scenario of extreme phenotypic variability, some genotype–phenotype associations need to be taken into consideration, as they strongly impact on genetic counseling and prognostication of the disease. We provide a synthetic review, based on the most recent literature data, of all known genotype–phenotype correlations from a genetic and clinical perspective. Molecular diagnosis is fundamental for the confirmation of doubtful clinical diagnoses, especially in the light of recently revised diagnostic criteria, and for the early identification of genotypes, albeit few, that correlate with specific phenotypes. [ABSTRACT FROM AUTHOR]

Neurofibromatosis type 1 (NF1) is an autosomal dominant condition, associated with neurocutaneous manifestations and neuropsychiatric manifestations. The present study explored the prevalence of bullying/cyberbullying behaviors and victimization behaviors in a cohort of children and adolescents with NF1. Possible gender differences and predictors of psychological symptoms, quality of life (QoL), and self-esteem were also examined. Thirty-eight school-aged participants with NF1 completed a psychological evaluation designed to assess anxiety and depression symptomatology, QoL, self-esteem, and the prevalence and extent of bullying/cyberbullying and victimization behaviors. We found that our participants frequently reported victimization behaviors rather than bullying/cyberbullying ones. Moreover, participants complained of depressive and anxiety symptomatology together with reduced self-esteem, and low psychosocial quality of life, with females reporting more severe performances than males. Furthermore, we found that reduced self-esteem was associated with more visibility of the NF1 symptoms, and victimization behaviors were found to mediate the relationship between anxiety and psychosocial QoL. Our findings indicated the presence of a maladaptive loop in children and adolescents with NF1 patients characterized by psychological symptoms, unfavorable self-perception, low self-esteem, and psychosocial difficulties that might be worsened by experiencing victimization behaviors. These results suggest the need to use a multidisciplinary approach in the diagnosis and treatment of NF1. [ABSTRACT FROM AUTHOR]

Background: Neurofibromatosis type 1 (NF1) is an autosomal dominant with haploinsufficient, and multisystemic disorder including patches of skin Café-au-lait spots, Lisch nodules in the iris, and tumors in the peripheral nervous systems or fibromatous skin. Methods: Blood samples were collected and DNA was extracted from a large Chinese pedigree suffering from NF1 disease with three spontaneous abortions or death for proband. Analysis for whole exome sequencing (WES), Sanger sequencing, and co-segregation was carried out. Prenatal gene diagnosis was also carried out in amniotic fluid DNA. The expression of NF1 was conducted by bioinformatics. Results: A large Chinese pedigree with NF1 was recruited and a novel, heterozygous, variant (c.4272delA: p.I1426Ffs*2) for the NF1 gene in the proband was identified. This variant of NF1 produced a truncated protein that losses half of NF1 protein at the C-terminus including the CRAL-TRIO lipid-binding domain, NLS, and a small portion of Ras-GAP domain, thus leading to pathogenicity (ACMG criteria: PVS1 + PM2). NF1 expressions in different human tissues showed low tissue specificity, which may affect multiple organs presenting different phenotypes. Moreover, prenatal gene diagnosis for NF1 showed both alleles as wild types in the fetus of the proband. Conclusion: We thus successfully identified a novel, pathogenic, heterozygous variant (c.4272delA:p.I1426Ffs*2) in the NF1 gene of NF1 disorder, expanding the NF1 mutation spectrum, that will help elucidate the molecular pathogenesis of NF1 disease and to contribute to the NF1 diagnosis, genetic counseling, clinical management in this large Chinese family. [ABSTRACT FROM AUTHOR]

Neurofibromatosis type 1 (NF1) is a neurocutaneous syndrome caused by mutations on the NF1 gene, which is located at chromosome 17q11.2. Although an autosomal dominant inheritance pattern is well-established, about half of new cases are the result of de novo NF1 mutations. Neurofibromatosis type 1 has an incidence rate of 1/2600–3000 individuals, making it a major public health problem. The product of the NF1 gene, the neurofibromin protein, is known to play a critical role in cellular differentiation and in tumor suppression. Due to widespread expression of neurofibromin in numerous tissues, particularly in cutaneous and nervous systems, NF1 mutations cause a wide variety of clinical symptoms, including cutaneous and ocular lesions such as café au lait spots, axillary and inguinal freckling, multiple cutaneous neurofibromas, iris Lisch nodules, choroidal freckling and internal tumors. In this article, we report the cases of two siblings with NF1, a 21-year-old male and his 24-year-old sister, who have the same c.5392C>T mutation on the NF1 gene (p.Gln1798 Ter). Café au lait macules and freckling were the prominent clinical features in both siblings. However, a plexiform neurofibroma was also observed on the left arm of the sister, which is known to carry potential risk for malignant transformation. Although the mutation was previously described once, to the best of our knowledge, no case report has been published since then.

Abstract Neurofibromatosis Type 1 (NF1) is a rare neurocutaneous disorder transmitted in an autosomal dominant fashion, mainly affecting the nervous system, the eye and skin. Ocular diagnostic hallmarks of NF1 include iris Lisch nodules, optic gliomas, orbital and eyelid neurofibromas, eyelid café-au-lait spots. In recent years, a new ocular sign represented by choroidal abnormalities (CAs) has been characterized in NF1. The CAs, identified with near-infrared reflectance, have been reported with a frequency of up to 100% in NF1, and have recently been added to the actual diagnostic criteria for NF1. The present Letter to the journal is intended to provide an update on features and clinical significance of CAs in NF1. Moreover, the relation with other ocular manifestations recently described in NF1 including hyperpigmented spots and retinal microvascular abnormalities is discussed.

Tuberous sclerosis complex (TSC) is an inherited disorder that typically presents with seizures, developmental delay, cutaneous lesions, and facial angiomas. Clinical diagnosis of TSC based on symptoms is sometimes challenging due to its clinical similarities with neurofibromatosis type 1 (NF1), another type of neurogenetic tumor syndrome. Differential diagnosis should be carefully performed on the basis of clinical presentations, imaging, laboratory, and genetic testing. Here, we presented a case of a patient with an aggressively enlarged right upper limb in the NF1 clinic, who was initially suspected of a giant plexiform neurofibroma. However, differential diagnosis revealed TSC as the final diagnosis. The treatments for NF1 and TSC vary significantly, and misdiagnoses can lead to serious threat to the patients’ health. We also systematically reviewed all previous cases regarding differential diagnoses between NF1 and TSC. This case report can help clinicians make more accurate diagnoses and benefit the potential patient community. [ABSTRACT FROM AUTHOR]

Aim: Muscle weakness, fatigue and speech problems can occur in neurofibromatosis type 1 (NF1). The pathogenesis of these symptoms is unclear, likely multifactorial. We examined motor function in limb and speech muscles in NF1 patients. Methods: We evaluated NF1 and control groups aged 4–18 years for muscle strength, tone and mobility using standard manual testing, joint motion and Beighton score measurements. Speech and language functions were assessed by speech articulation and resonance. As a marker of muscle tissue turnover, we determined collagen degradation products in urine before and after submaximal exercise. Results: NF1 patients had reduced strength in proximal limb muscles compared to control subjects. Speech articulation problems and hypernasality were more common in NF1 (47% and 38%, respectively). Collagen products excreted in urine correlated with gluteal and biceps muscle strength. Conclusion: Muscle dysfunction can be detected in some children with NF1 and may explain certain clinical features including fatigue, speech and articulation problems. If confirmed by further research, these findings may be relevant to the management of this condition. [ABSTRACT FROM AUTHOR]

Neurofibromatosis type 1 is an autosomal dominant genetic disorder with multisystem manifestations including vascular abnormalities. The condition is also associated with an increased risk of both ischemic and hemorrhagic stroke. Here we report a case of a 60-year-old male with known neurofibromatosis who presented with right sided hemiparesis. Neuroimaging work-up revealed left internal carotid artery dissection and tandem occlusion of the left internal carotid artery and left middle cerebral artery. There was associated territorial ischemic infarction. The patient was found to have extensive intra and extra cranial vasculopathy including gross basilar dolichoectasia and a right-sided cervical internal carotid artery pseudoaneurysm. This case highlights the clinical significance of neurofibromatosis associated vasculopathy which can result in stroke.

Neurofibromatosis type 1 (NF1) is a rare inherited neurocutaneous disorder with a major impact on the skin, nervous system and eyes. The ocular diagnostic hallmarks of this disease include iris Lisch nodules, ocular and eyelid neurofibromas, eyelid café-au-lait spots and optic pathway gliomas (OPGs). In the last years, new manifestations have been identified in the ocular district in NF1 including choroidal abnormalities (CAs), hyperpigmented spots (HSs) and retinal vascular abnormalities (RVAs). Recent advances in multi-modality imaging in ophthalmology have allowed for the improved characterization of these clinical signs. Accordingly, CAs, easily detectable as bright patchy nodules on near-infrared imaging, have recently been added to the revised diagnostic criteria for NF1 due to their high specificity and sensitivity. Furthermore, subclinical alterations of the visual pathways, regardless of the presence of OPGs, have been recently described in NF1, with a primary role of neurofibromin in the myelination process. In this paper, we reviewed the latest progress in the understanding of choroidal and retinal abnormalities in NF1 patients. The clinical significance of the recently revised diagnostic criteria for NF1 is discussed along with new updates in molecular diagnosis. New insights into NF1-related neuro-ophthalmic manifestations are also provided based on electrophysiological and optical coherence tomography (OCT) studies.

The visually striking neurocutaneous findings of neurofibromatosis type 1 (NF1) are well recognized and have been well documented throughout scientific literature. While not uncommon, the pulmonary manifestations of NF1 are unknown to many physicians. Complications of NF1 associated diffuse lung disease (NF-DLD) include pulmonary hypertension, pulmonary artery stenosis, subpleural cysts, and spontaneous pneumothorax. We present a case of a 34-year-old male with NF-DLD found incidentally in adolescence with previous apical bleb repair, presenting nearly twenty years later with spontaneous pneumothorax. In NF1 patients with pulmonary complaints, NF-DLD should be assessed with computed tomography (CT) and physicians should be familiar with associated complications.

Neurofibromatosis Type 1 (NF1) is a rare neurocutaneous disorder transmitted in an autosomal dominant fashion, mainly affecting the nervous system, the eye and skin. Ocular diagnostic hallmarks of NF1 include iris Lisch nodules, optic gliomas, orbital and eyelid neurofibromas, eyelid café-au-lait spots. In recent years, a new ocular sign represented by choroidal abnormalities (CAs) has been characterized in NF1. The CAs, identified with near-infrared reflectance, have been reported with a frequency of up to 100% in NF1, and have recently been added to the actual diagnostic criteria for NF1. The present Letter to the journal is intended to provide an update on features and clinical significance of CAs in NF1. Moreover, the relation with other ocular manifestations recently described in NF1 including hyperpigmented spots and retinal microvascular abnormalities is discussed. [ABSTRACT FROM AUTHOR]

Neurofibromatosis type 1 (NF1) is a dominant hereditary disease characterized by the mutation of the NF1 gene, affecting 1/3000 individuals worldwide. Most NF1 patients are predisposed to benign peripheral nerve sheath tumors (PNSTs), including cutaneous neurofibromas (CNFs) and plexiform neurofibromas (PNFs). However, 5%-10% of PNFs will ultimately develop into malignant peripheral nerve sheath tumors (MPNSTs), which have a poor prognosis. Early and reliable differentiation of benign and malignant tumors in NF1 patients is of great necessity. Pathological evaluation is the "gold standard" for a definite diagnosis, but the invasive nature of the biopsy procedure restricts it from applying as a screening tool during the decades-long follow-up of these patients. Non-invasive image-based diagnostic methods such as CT and MRI are often considered essential screening tools for multiple types of tumors. For NF1 patients' lifelong regular follow-ups, these radiological methods are currently used for tumor evaluation. However, no consensus was established on screening the malignant transformation of benign PNSTs. Moreover, novel technologies like radiogenomics and PET-MRI have not been well evaluated and fully adopted for NF1 patients. This review summarizes current studies of different imaging methods for differentiating benign and malignant tumors in NF1. Meanwhile, we discussed the prospects of the usage of new tools such as radiogenomics and PET-MRI to distinguish MPNST from benign PNSTs more precisely. Summarizing these findings will help clarify the directions of future studies in this area and ultimately contribute to the radiology images-based clinical screening of MPNST in NF1 patients and finally improve the overall survival rates of these patients. [ABSTRACT FROM AUTHOR]

Simple Summary: Germline mutations of NF1 cause neurofibromatosis type 1 (NF1), which is characterized by multiple benign peripheral nerve sheath tumors known as neurofibromas. In some individuals with NF1, plexiform neurofibromas can give rise to malignant peripheral nerve sheath tumors. Here, we applied genomic DNA sequencing to NF1-derived tumors and identified additional genetic alterations in PTPN11 (encoding Src homology region 2 domain-containing phosphatase-2 (SHP)-2) and BRAP associated with NF1 tumor malignancy. We found that the forced expression of the mutant form of SHP-2 activated the protein kinase MEK and increased tumorigenic activity in NF1 cells, and that these effects were attenuated by the forced expression of the mutant form of BRCA1-associated protein (BRAP). This suppressive action of mutant BRAP was not apparent in NF1-intact cells. Our data indicate that the combination of NF1 mutation and PTPN11 mutation drives the malignancy of NF1 cells and that SHP-2 inhibition by BRAP is a potential therapeutic strategy for NF1-associated malignant tumors. Germline mutations of NF1 cause neurofibromatosis type 1 (NF1) through the activation of the RAS signaling pathway, and some NF1 patients develop malignant peripheral nerve sheath tumors (MPNSTs). Here, we established subclones of the human NF1-MPNST cell line sNF96.2 that manifest increased tumorigenic activity and increased phosphorylation of the protein kinases MEK and Akt relative to the parental cells. Genomic DNA sequencing identified 14 additional heterozygous mutations within the coding regions of 13 cancer- and other disease-related genes in these subclones. One of these genes, PTPN11, encodes SHP-2, and the forced expression of the identified G503V mutant of SHP-2 increased both tumorigenic activity and MEK phosphorylation in parental sNF96.2 cells, suggesting that the combination of PTPN11 and NF1 mutations induces the pathological activation of the RAS pathway. These effects of SHP-2 (G503V) were inhibited by the coexpression of the G370A mutant of BRAP, which was also detected in the highly malignant subclones, and this inhibition was accompanied by the calpain-dependent cleavage of SHP-2 (G503V). The cleavage of SHP-2 (G503V) and suppression of MEK phosphorylation mediated by BRAP (G370A) were not detected in NF1-intact (HeLa) cells. Tumor promotion by SHP-2 (G503V) and its suppression by BRAP (G370A) may serve as a basis for the development of new treatment strategies for NF1. [ABSTRACT FROM AUTHOR]

To provide a comprehensive characterization of verbal learning and memory (VLM) abilities in youth with neurofibromatosis type 1 (NF1) and plexiform neurofibromas (PNs) and to evaluate disease severity as a predictor of VLM functioning over time. As part of a longitudinal natural history study, youth with NF1 and PNs were administered repeat neuropsychological assessments, including measures of VLM and ratings of NF1 disease severity completed by a medical professional. This sub-study analyzed data from 89 patients (M age baseline = 13.1, SD = 4.3 years, range 6–24 years) who had completed tests of VLM abilities and verbal attention at either baseline and/or 36 months. VLM scores across the sample fell predominantly within the average range of functioning at both time points. However, relative to peers with mild NF1 disease severity, youth with moderate/severe NF1 disease showed lower functioning across multiple VLM domains at 36 months, even after controlling for the effects of verbal attention. Exclusive use of overall domain scores does not fully characterize VLM functioning in youth with NF1 and PNs. Additionally, children and adolescents with more severe NF1 disease should be monitored more closely for verbal memory challenges and targeted for interventions. • VLM appears to be relatively intact in youth with NF1. • Overall memory scores may not fully represent VLM in youth with NF1. • Youth with moderate/severe NF1 disease have lower VLM functioning over time. [ABSTRACT FROM AUTHOR]

Neurofibromatosis type 1 (NF1) is a dominant hereditary disease characterized by the mutation of the NF1 gene, affecting 1/3000 individuals worldwide. Most NF1 patients are predisposed to benign peripheral nerve sheath tumors (PNSTs), including cutaneous neurofibromas (CNFs) and plexiform neurofibromas (PNFs). However, 5%-10% of PNFs will ultimately develop into malignant peripheral nerve sheath tumors (MPNSTs), which have a poor prognosis. Early and reliable differentiation of benign and malignant tumors in NF1 patients is of great necessity. Pathological evaluation is the “gold standard” for a definite diagnosis, but the invasive nature of the biopsy procedure restricts it from applying as a screening tool during the decades-long follow-up of these patients. Non-invasive image-based diagnostic methods such as CT and MRI are often considered essential screening tools for multiple types of tumors. For NF1 patients’ lifelong regular follow-ups, these radiological methods are currently used for tumor evaluation. However, no consensus was established on screening the malignant transformation of benign PNSTs. Moreover, novel technologies like radiogenomics and PET-MRI have not been well evaluated and fully adopted for NF1 patients. This review summarizes current studies of different imaging methods for differentiating benign and malignant tumors in NF1. Meanwhile, we discussed the prospects of the usage of new tools such as radiogenomics and PET-MRI to distinguish MPNST from benign PNSTs more precisely. Summarizing these findings will help clarify the directions of future studies in this area and ultimately contribute to the radiology images-based clinical screening of MPNST in NF1 patients and finally improve the overall survival rates of these patients.

Neurofibromatosis type 1 (NF1) is an autosomal dominant condition, associated with neurocutaneous manifestations and neuropsychiatric manifestations. The present study explored the prevalence of bullying/cyberbullying behaviors and victimization behaviors in a cohort of children and adolescents with NF1. Possible gender differences and predictors of psychological symptoms, quality of life (QoL), and self-esteem were also examined. Thirty-eight school-aged participants with NF1 completed a psychological evaluation designed to assess anxiety and depression symptomatology, QoL, self-esteem, and the prevalence and extent of bullying/cyberbullying and victimization behaviors. We found that our participants frequently reported victimization behaviors rather than bullying/cyberbullying ones. Moreover, participants complained of depressive and anxiety symptomatology together with reduced self-esteem, and low psychosocial quality of life, with females reporting more severe performances than males. Furthermore, we found that reduced self-esteem was associated with more visibility of the NF1 symptoms, and victimization behaviors were found to mediate the relationship between anxiety and psychosocial QoL. Our findings indicated the presence of a maladaptive loop in children and adolescents with NF1 patients characterized by psychological symptoms, unfavorable self-perception, low self-esteem, and psychosocial difficulties that might be worsened by experiencing victimization behaviors. These results suggest the need to use a multidisciplinary approach in the diagnosis and treatment of NF1.

Neurofibromatosis type 1 (NF1) is a neurocutaneous syndrome caused by mutations on the NF1 gene, which is located at chromosome 17q11.2. Although an autosomal dominant inheritance pattern is well-established, about half of new cases are the result of de novo NF1 mutations. Neurofibromatosis type 1 has an incidence rate of 1/2600–3000 individuals, making it a major public health problem. The product of the NF1 gene, the neurofibromin protein, is known to play a critical role in cellular differentiation and in tumor suppression. Due to widespread expression of neurofibromin in numerous tissues, particularly in cutaneous and nervous systems, NF1 mutations cause a wide variety of clinical symptoms, including cutaneous and ocular lesions such as café au lait spots, axillary and inguinal freckling, multiple cutaneous neurofibromas, iris Lisch nodules, choroidal freckling and internal tumors. In this article, we report the cases of two siblings with NF1, a 21-year-old male and his 24-year-old sister, who have the same c.5392C>T mutation on the NF1 gene (p.Gln1798 Ter). Café au lait macules and freckling were the prominent clinical features in both siblings. However, a plexiform neurofibroma was also observed on the left arm of the sister, which is known to carry potential risk for malignant transformation. Although the mutation was previously described once, to the best of our knowledge, no case report has been published since then. [ABSTRACT FROM AUTHOR]

Neurofibromatosis type 1 (NF1) is a genetic disease involving neurocutaneous abnormalities. Neurofibromatosis type 1 is an autosomal dominant disorder characterized by the neurofibromas and café-au-lait spots. Mutation in the NF 1 gene causes NF1. The NF 1 gene encodes neurofibromin. In this study, we found a 31-year-old Chinese boy with NF1. He presented only with café-au-lait spots over the whole body. The proband’s mother had a severe phenotype with neurofibroma and café-au-lait macules over her whole body, mostly in the facial region. A novel multi exon deletion c.(4661+1_4662-1)_(5748+1_5749-1)del; [EX36_39DEL] on the NF 1 gene has been identified in the proband. Quantitative real-time polymerase chain reaction (qPCR) confirmed that this mutation is co-segregated well and was inherited from the proband’s mother. The mutation was absent in the proband’s father and normal individuals. The novel multi exon deletion results in the formation of a truncated NF1 protein that caused the NF1 phenotype in this family. Our present study also emphasized the significance of rapid, accurate and cost-effective screening for the patient with NF1 by next generation sequencing (NGS).

Oncolytic adenoviruses (Ads) stand out as a promising strategy for the targeted infection and lysis of tumor cells, with well-established clinical utility across various malignancies. This study delves into the therapeutic potential of oncolytic Ads in the context of neurofibromatosis type 1 (NF1)-associated malignant peripheral nerve sheath tumors (MPNSTs). Specifically, we evaluate conditionally replicative adenoviruses (CRAds) driven by the cyclooxygenase 2 (COX2) promoter, as selective agents against MPNSTs, demonstrating their preferential targeting of MPNST cells compared with non-malignant Schwann cell control. COX2-driven CRAds, particularly those with modified fiber-knobs exhibit superior binding affinity toward MPNST cells and demonstrate efficient and preferential replication and lysis of MPNST cells, with minimal impact on non-malignant control cells. In vivo experiments involving intratumoral CRAd injections in immunocompromised mice with human MPNST xenografts significantly extend survival and reduce tumor growth rate compared with controls. Moreover, in immunocompetent mouse models with MPNST-like allografts, CRAd injections induce a robust infiltration of CD8+ T cells into the tumor microenvironment (TME), indicating the potential to promote a pro-inflammatory response. These findings underscore oncolytic Ads as promising, selective, and minimally toxic agents for MPNST therapy, warranting further exploration., Competing Interests: D.A.L. is the co-founder and co-owner of NeoClone Biotechnologies, Inc., Discovery Genomics, Inc. (acquired by Immusoft, Inc.), B-MoGen Biotechnologies, Inc. (acquired by Bio-Techne corporation), and Luminary Therapeutics, Inc. D.A.L. holds equity in, is a Board of Directors member of, and serves as the Senior Scientific Advisor to Recombinetics, a genome-editing company, and Makana, a xenotransplantation company. D.A.L. consults for Styx Biotechnologies, Inc. and Genentech, Inc., which is funding some of his research. The business of all the companies above is unrelated to the contents of this manuscript.

A 71-year-old man with neurofibromatosis type 1 (NF1) presented to our department with a 1-week history of a painful mass in the left submandibular area. Computed tomography (CT) and magnetic resonance imaging revealed an irregular-shaped tumor with a diameter of 2.0 cm in the left submandibular gland and a metastatic lymph node with a diameter of 1.0 cm adjacent to the tumor. Fluorodeoxyglucose-positron emission tomography/CT revealed increased uptake in the tumor. Fine-needle aspiration cytology revealed atypical cells, suggesting salivary duct carcinoma (SDC). Left neck dissection with resection of the tumor and submandibular gland was performed under general anesthesia. Histologic examination revealed ductal formation with a solid, cystic, cribriform, and papillary structure with intraductal comedonecrosis, diagnosing as SDC originating in the submandibular gland (pT3N1M0 pStage III). Mutational analysis of 160 cancer-related genes by next-generation sequencing (NGS) revealed a germline and frameshift mutation in the NF1 gene (p.R2408Kfs*14) and a somatic and frameshift mutation in the TP53 gene (p.C176Wfs*22). The patient received postoperative radiotherapy to the left neck area at 66 Gy. No evidence of recurrence or metastasis has been observed as of 10 months postoperatively. This is the first reported case of SDC in the submandibular gland in a patient with NF1. The mutational data by NGS may contribute to a better understanding of the oncogenesis of SDC in patients with NF1., Competing Interests: Declaration of Conflicting InterestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Abstract Background Autosomal dominant polycystic kidney disease (ADPKD) and neurofibromatosis type 1 (NF1) are both autosomal dominant disorders with a high rate of novel mutations. However, the two disorders have distinct and well‐delineated genetic, biochemical, and clinical findings. Only a few cases of coexistence of ADPKD and NF1 in a single individual have been reported, but the possible implications of this association are unknown. Methods We report an ADPKD male belonging to a family of several affected members in three generations associated with NF1 and optic pathway gliomas. The clinical diagnosis of ADPKD and NF1 was performed by several image techniques. Results Linkage analysis of ADPKD family was consistent to the PKD2 locus by a nonsense mutation, yielding a truncated polycystin‐2 by means of next‐generation sequencing. The diagnosis of NF1 was confirmed by mutational analysis of this gene showing a 4‐bp deletion, resulting in a truncated neurofibromin, as well. The impact of this association was investigated by analyzing putative genetic interactions and by comparing the evolution of renal size and function in the proband with his older brother with ADPKD without NF1 and with ADPKD cohorts. Conclusion Despite the presence of both conditions there was not additive effect of NF1 and PKD2 in terms of the severity of tumor development and/or ADPKD progression.

Abstract Objective Malignant peripheral nerve sheath tumors (MPNST) are aggressive sarcomas characterized by high recurrence rates and early metastases. These tumors arise more frequently within neurofibromatosis type 1 (NF1) and present with resistance during standard chemotherapy leading to increased mortality and morbidity in those patients. In vitro all-trans retinoic acid (ATRA) and MEK inhibitors (MEKi) were shown to inhibit tumor proliferation, especially when applied in combination. Therefore, we established a nude mouse model to investigate if treatment of xenografts derived from NF1 associated S462 and T265 MPNST cells respond to ATRA and the MEKi PD0325901. Results We demonstrated that human NF1 associated MPNST derived from S462 but not T265 cells form solid subcutaneous tumors in Foxn1 nude mice but not in Balb/c, SHO or Shorn mice. We verified a characteristic staining pattern of human MPNST xenografts by immunohistochemistry. Therapeutic effects of ATRA and/or MEKi PD0325901 on growth of S462 MPNST xenografts in Foxn1 nude mice were not demonstrated in vitro, as we did not observe significant suppression of MPNST growth compared with placebo treatment.

Neurofibromatosis type 1 (NF1) is an autosomal dominant human genetic disorder. The progression of benign plexiform neurofibromas to malignant peripheral nerve sheet tumors (MPNSTs) is a major cause of mortality in patients with NF1. Although elevated epidermal growth factor receptor (EGFR) expression plays a crucial role in the pathogenesis of MPNST, the cause of EGFR overexpression remains unclear. Here, we assessed EGFR expression levels in MPNST tissues of NF1 patients and NF1 patient-derived MPNST cells. We found that the expression of EGFR was upregulated in MPNST tissues and MPNST cells, while the expression of neurofibromin was significantly decreased. Manipulation of NF1 expression by NF1 siRNA treatment or NF1-GAP-related domain overexpression demonstrated that EGFR expression levels were closely and inversely correlated with neurofibromin levels. Notably, knockdown of the NF1 gene by siRNA treatment augmented the nuclear localization of phosphorylated SP1 (pSP1) and enhanced pSP1 binding to the EGFR gene promoter region. Our results suggest that neurofibromin deficiency in NF1-associated MPNSTs enhances the Ras/ERK/SP1 signaling pathway, which in turn may lead to the upregulation of EGFR expression. This study provides insight into the progression of benign tumors and novel therapeutic approaches for treatment of NF1-associated MPNSTs.

Background: Autosomal dominant polycystic kidney disease (ADPKD) and neurofibromatosis type 1 (NF1) are both autosomal dominant disorders with a high rate of novel mutations. However, the two disorders have distinct and well‐delineated genetic, biochemical, and clinical findings. Only a few cases of coexistence of ADPKD and NF1 in a single individual have been reported, but the possible implications of this association are unknown. Methods: We report an ADPKD male belonging to a family of several affected members in three generations associated with NF1 and optic pathway gliomas. The clinical diagnosis of ADPKD and NF1 was performed by several image techniques. Results: Linkage analysis of ADPKD family was consistent to the PKD2 locus by a nonsense mutation, yielding a truncated polycystin‐2 by means of next‐generation sequencing. The diagnosis of NF1 was confirmed by mutational analysis of this gene showing a 4‐bp deletion, resulting in a truncated neurofibromin, as well. The impact of this association was investigated by analyzing putative genetic interactions and by comparing the evolution of renal size and function in the proband with his older brother with ADPKD without NF1 and with ADPKD cohorts. Conclusion: Despite the presence of both conditions there was not additive effect of NF1 and PKD2 in terms of the severity of tumor development and/or ADPKD progression. [ABSTRACT FROM AUTHOR]

Neurofibromatosis type 1 (NF1), neurofibromatosis type 2 (NF2), and schwannomatosis (SWN) are three clinically distinct tumor predisposition syndromes with a shared tendency to develop peripheral and central nervous system neoplasms. Disease expression and complications of NF1, NF2, and SWN are highly variable, necessitating a multidisciplinary approach to care in order to optimize outcomes. This review will discuss the imaging appearance of NF1, NF2, and SWN and highlight the important role that imaging plays in informing management decisions in people with tumors associated with these syndromes. Recent technological advances, including the role of both whole-body and localized imaging strategies, routine anatomic and advanced magnetic resonance (MR) imaging sequences such as diffusion-weighted imaging (DWI) with quantitative apparent diffusion coefficient (ADC) mapping, and metabolic imaging techniques (MR spectroscopy and positron emission testing) are discussed in the context of the diagnosis and management of people with NF1, NF2, and SWN based on the most up-to-date clinical imaging studies. [ABSTRACT FROM AUTHOR]