Neurofibromatosis 1 Gene Research Articles

It is Not a Curse! It is Neurofibromatosis 1 (NF1): A Case Report from Rural Kenya

Neurofibromatosis 1 (NF1) is an autosomal dominant genetic disorder caused by mutations in the NF1 gene, with near complete penetrance and variable clinical presentation. Patients classically have café-au-lait macules, neurofibromas, skin freckles, and Lisch nodules, among other multisystemic features. Long-term management in a multidisciplinary team focuses on surveillance and treating complications. NF1 is a rare disease in Kenya, often leading to myths and misconceptions about its nature, especially among rural communities. We present a classical case from rural Kenya whose diagnosis was delayed by a belief that it was the result of a curse. We aim to highlight the importance of making this diagnosis and its linkage to a long-term care plan within a primary health care setting.

Multiple Cranial Nerve Involvement in a Complex Case of MISME Syndrome in a Paediatric Patient: A Case Report

Neurofibromatosis 2 (NF2) is characterised by numerous tumours in the central and peripheral nervous systems due to NF2 gene abnormalities that cause the tumour suppressor protein, Merlin, to disappear. Often referred to as Multiple Inherited Schwannomas, Meningiomas, and Ependymomas (MISME), a distinctive characteristic of NF2 is bilateral vestibular schwannomas manifesting in late adolescence with symptoms such as sensorineural hearing loss, tinnitus, and balance issues. Two distinct phenotypes, Wishart and Feiling-Gardner, characterise NF2. This case report discusses the case of a paediatric patient who presented with bilateral hearing loss, giddiness, and blurring of vision and sought a Magnetic Resonance Imaging (MRI) examination which revealed bilateral vestibular schwannomas, non vestibular schwannomas, left sphenoid wing meningiomas, multidirectional spinal schwannomas, spinal nerve sheath tumours, and lesions in the retroperitoneal region. Despite an absent family history, significant involvement of cranial nerves strongly indicates classical NF2. Management focuses on preserving function, and surgery is contemplated for symptomatic lesions and tumours causing cord compression. Gamma Knife radiosurgery and targeted therapies have been investigated.

The Contribution of Oxidative Stress to NF1-Altered Tumors.

The neurofibromatosis-1 gene (NF1) was initially characterized because its germline mutation is responsible for an inherited syndromic disease predisposing tumor development, in particular neurofibromas but also various malignancies. Recently, large-scale tumor sequencing efforts have demonstrated NF1 as one of the most frequently mutated genes in human cancer, being mutated in approximately 5-10% of all tumors, especially in malignant peripheral nerve sheath tumors and different skin tumors. NF1 acts as a tumor suppressor gene that encodes neurofibromin, a large protein that controls neoplastic transformation through several molecular mechanisms. On the other hand, neurofibromin loss due to NF1 biallelic inactivation induces tumorigenic hyperactivation of Ras and mTOR signaling pathways. Moreover, neurofibromin controls actin cytoskeleton structure and the metaphase-anaphase transition. Consequently, neurofibromin deficiency favors cell mobility and proliferation as well as chromosomal instability and aneuploidy, respectively. Growing evidence supports the role of oxidative stress in NF1-related tumorigenesis. Neurofibromin loss induces oxidative stress both directly and through Ras and mTOR signaling activation. Notably, innovative therapeutic approaches explore drug combinations that further increase reactive oxygen species to boost the oxidative unbalance of NF1-altered cancer cells. In our paper, we review NF1-related tumors and their pathogenesis, highlighting the twofold contribution of oxidative stress, both tumorigenic and therapeutic.

Neurofibromatosis 2: A Case Report

Neurofibromatosis 2 (NF2) is caused by inactivating alterations in the NF2 gene on chromosome 22q12.2. The 100-kb NF2 gene is encoded by 17 exons. Patients with NF2 may present with distinctive “plaque-like” cutaneous schwannomas, ophthalmologic findings, or neurologic deficits such as hearing loss or peripheral neuropathies which may prompt further radiologic or genetic evaluation. Café au lait spots may be present in up to 50% of patients but they are typically fewer in number and not associated with freckling as in NF1. This is a case report of a 20 year old female who presented to us with left parapharyngeal schwannoma along with bilateral vestibular schwannoma. Keywords: NF 2- Neurofibromatosis 2, VS- Vestibular Schwannoma, CECT-Contrast enhanced computed tomography, MRI-Magnetic resonance imaging

Neurofibromatosis 1 (von Recklinghausen Disease).

Neurofibromatosis 1 (NF1), also known as von Recklinghausen disease, is one of the most common neurocutaneous genetic disorders. Loss of function of the NF1 gene results in overactivation of the RAS/MAPK pathway, leading to neurocutaneous manifestations and osseous abnormalities. Because of medical progress, molecular testing for NF1 after genetic counseling is now available in Japan. In addition, revised diagnostic criteria for NF1 were proposed by NF1 experts of an international panel in 2021. Because the overall degree of severity and manifestations in each patient are not predictable, age-specific annual monitoring and patient education by a multidisciplinary team are important for the management of NF1. Although treatment of plexiform neurofibroma has been challenging, selumetinib (an oral selective MEK1/2 inhibitor), which targets a pathway downstream of RAS, was approved in 2022 for use in children with inoperable, symptomatic plexiform neurofibromas in Japan. This article summarizes recent progress in diagnosis, clinical characteristics, and treatment of various manifestations of NF1 and proposes the future direction required to resolve unmet needs in patients with NF1 in Japan.

Transplanting neurofibromatosis-1 gene knockout neural stem cells improve functional recovery in rats with spinal cord injury by enhancing the mTORC2 pathway

The poor survival and low efficiency of neuronal differentiation limits the therapeutic effects of transplanted neural stem cells in the treatment of spinal cord injury. Neurofibromatosis-1 (NF-1) is a tumor suppressor gene that restricts the rapid and abnormal growth and differentiation of neural cells. In the present study, lentiviral vectors were used to knock out NF-1, Ricotr (the core member of mTORC2) or NF-1+Ricotr in neural stem cells in vitro, and the NF-1, Ricotr or NF-1+Ricotr knockout neural stem cells were transplanted at the lesion site in a rat model of spinal cord injury (SCI). We first demonstrated that targeted knockout of NF-1 had an antiapoptotic effect and improved neuronal differentiation by enhancing the mTORC2/Rictor pathway of neural stem cells in vitro. Subsequently, transplanting NF-1 knockout neural stem cells into the injured site sufficiently promoted the tissue repair and functional recovery of rats with spinal cord injury by enhancing the survival and neuronal differentiation of grafted neural stem cells. Collectively, these findings reveal a prominent role of NF-1 in neural stem cell biology, which is an invaluable step forward in enhancing the benefit of neural stem cell-mediated regenerative cell therapy for spinal cord injury and identifies the transplantation of NF-1 knockout neural stem cells as a promising strategy for spinal cord injury.

Modeling Relapsed, Refractory Acute Lymphoblastic Leukemia from a Child with Neurofibromatosis

Neurofibromatosis type 1 (NF-1) is an autosomal dominant disorder affecting approximately 1:3000 individuals globally. While approximately 50% are familial, with over 3000 causative germline variants in the neurofibromatosis (NF1) gene identified, the remainder occur sporadically. These mutations lead to haploinsufficiency of NF1 and neurofibromin, a tumor suppressor and important negative regulator of RAS signaling. Children with NF-1 have a higher risk of developing juvenile myelomonocytic leukemia and acute myeloid leukemia, but rarely develop acute lymphoblastic leukemia (ALL).A 9-year-old male presented in 2015 with persistent migratory subcutaneous swellings and multiple bony aches with lytic lesions on bone imaging. He had a high white cell count with eosinophilia (WCC 43.4 x 10 9/L, eosinophils 23.87 x 10 9/L) with no circulating blasts, 10% marrow blasts (CD10+/CD19+/CD34+) and was CNS negative. Although previously undiagnosed, NF-1 was clinically suspected due to typical skin changes.He was diagnosed with iAMP21 ALL and NF-1 was confirmed with the identification of a germline NF1 donor splice site mutation (c.1845G>A:p.L615=). Bone marrow cells were sorted by flow cytometry on CD19 positivity and underwent transcriptomic sequencing. This revealed a P2RY8-CRLF2 gene fusion, with no other clinically relevant variants, while a custom Taqman low density array indicated high-risk B-ALL subtype Ph-like ALL. Multiplex ligation-dependent probe amplification (MLPA) confirmed iAMP21 and also identified IKZF1 exon 2-3 and BTG1 deletions.Treatment followed the high-risk B-ALL arm of the AEIOP-BFM ALL2009 protocol due to persistent end-consolidation MRD in addition to iAMP21 and the Ph-like phenotype. He relapsed three years later off treatment and was refractory to both salvage chemotherapy and blinatumomab. The iAMP21, P2RY8-CRLF2 gene fusion, IKZF1 exon 2-3 and BTG1 deletions remained detectable. Whole exome sequencing of CD19 positive samples from diagnosis, relapse and mesenchymal stem cells (germline control) was performed, identifying a NF1 c.7400dupT:p.L2467 frameshift (fs) mutation only at relapse.To understand the implications of NF1 p.L2467fs, the P2RY8-CRLF2 gene fusion was first transduced into the interleukin 3 (IL3) dependent murine pro-B cell line Ba/F3. P2RY8-CRLF2 alone is not transforming and is thought to be a secondary event in iAMP21 ALL, providing an ideal model to study the cumulative effect of the NF1fs. The NF1fs was then introduced to the P2RY8-CRLF2 cells by CRISPR/Cas9. A proliferation assay was performed without IL3 and demonstrated the P2RY8-CRLF2+NF1fs cell line was IL3 independent, indicative of leukemic transformation, whereas all other lines were not (vs Ba/F3, p = 0.001).Neurofibromin can be constitutively phosphorylated at the c-terminus, negatively regulating NF1-GAP activity, suppressing RAS signaling and inducing cell cycle arrest. Therefore, to demonstrate loss of function due to the c-terminus NF1 p.L2467fs and increased RAS signaling, western blotting for pERK was performed. Significant upregulation of pERK was confirmed in P2RY8-CRLF2+NF1fs in comparison to Ba/F3 control cells (p=0.007) (Figure 1).The MEK inhibitors trametinib and mirdametinib are in clinical trials for NF-1 patients and have shown efficacy in ALL models with RAS mutations. In a 3-day cell death assay, only P2RY8-CRLF2+NF1fs demonstrated sensitivity to trametinib (LD 50 P2RY8-CRLF2 = >6.4 µM, NF1fs = >6.4 µM, P2RY8-CRLF2+NF1fs =1.7µM; p < 0.001) and mirdametinib (LD 50 P2RY8-CRLF2 = >16 µM, NF1fs = >16 µM, P2RY8-CRLF2+NF1fs = 8.3 µM; p < 0.0001) (Figure 2).Here, we have demonstrated a LOF NF1fs mutation using an in-vitro model of ALL. Germline NF1 haploinsufficiency and a second hit NF1 mutation in ALL is limited to one report of monozygotic twins with neurofibromatosis. We propose that NF1 p.L2467fs caused bi-allelic LOF and therefore contributed to relapse in this patient. An understanding of the genomic complexities that lead to relapse may also inform personalized treatment strategies. While this patient subsequently achieved remission with inotuzomab and underwent successful stem cell transplantation, the sensitivity to MEK inhibitors is an exciting development for neurofibromatosis patients with ALL. [Display omitted] DisclosuresYeung: Amgen: Honoraria; BMS: Honoraria, Research Funding; Pfizer: Honoraria; Novartis: Honoraria, Research Funding. White: BMS: Honoraria, Research Funding; Novartis: Research Funding.

175 Concomitant LZTR1 and NF1 mutations contribute to the diversity of the Neurofibromatosis 1 phenotypic spectrum

Neurofibromatosis 1 (NF1) is a genetic disorder caused by germline mutations in the NF1 gene, manifested by various tissues proliferation, including plexiform neurofibromas. Even though somatic loss of NF1 is a common molecular mechanism, plexiform neurofibroma phenotype, varies from indolent to locally aggressive, suggesting contribution of additional modifiers. We investigated the development of a life-threatening, rapidly progressive plexiform neurofibroma in a 9-month-old female infant with NF1. Germline and somatic genetic analysis was conducted through whole exome sequencing and chromosomal microarray analysis. Site-directed mutagenesis, Lentiviral transduction, cell culture and western blot were used for functional studies. In addition to a de-novo pathogenic variant in the NF1 gene, the proband harbored a known pathogenic variant in another Rasopathy gene, LZTR1 which was inherited from the patient’s mother. Further somatic analysis revealed NF1 loss of heterozygosity and a variant in the gene encoding a G Protein Coupled Receptor, GNAZ. Cells expressing the mutant GNAZ exhibited increased ERK activation compared to those expressing the wild type GNAZ. We suggest that variants in NF1, LZRT1, and GNAZ act synergistically in our patient, leading to activation of the MAPK pathway and contributing to the severity of her plexiform neurofibromatosis. This case study demonstrates the power of next generation sequencing in understanding the patho-mechanisms of complex cases, and contributes to the knowledge of germline and somatic non-NF1 variants affecting the clinical phenotype.

Genetic diagnosis and follow-up study in pediatric neurofibromatosis 1 patients

Objective: Based on the genetic diagnosis and follow-up study on pediatric neurofibromatosis 1 (NF1) patients, interrogating the genotype-phenotype correlations of patients with NF1 mutations. Methods: 32 Patients from age of 2 months to 5 years old (17 male and 15 female) suspected for neurofibromatosis 1 were recruited during September 2016 to January 2018 in Shanghai Children's Medical Center retrospectively. Genetic diagnosis was applied to detect pathogenic variants. Long-term follow-up study were conducted to reveal progress of the disease and genotype-phenotype correlations. Results: 27 patients were detected with pathogenic NF1 variants, among them three were not reported. 3 patients inherited pathogenic variants from their NF1 diagnosed parents, all the other variants were de novo. Progressive development of phenotypes wasn't observed in most patients during the follow-up (14/27). Some patients were diagnosed with short stature, pulmonary artery stenosis and developmental delay during the follow-up(7/27). Short stature and pulmonary artery stenosis may be associated with missense mutation and severe truncation mutation of NF1 gene, respectively. Conclusions: Genetic diagnosis is required in young patients of NF1.Follow-up plan of pediatric patients should be adjusted based on genetic findings. Early follow-up of cardiovascular abnormalities should be noted in patients with missense mutation. Height development in patients with severe truncating variants are needed.

Genotype-Phenotype Correlations in Neurofibromatosis and Their Potential Clinical Use.

Because clinically validated biomarkers for neurofibromatosis 1 (NF1) and neurofibromatosis 2 (NF2) have not been identified, we aimed to determine whether genotype-phenotype correlations are useful in clinical trials in NF1 and NF2. The Response Evaluation in Neurofibromatosis and Schwannomatosis (REiNS) Biomarker Group first performed a systematic literature search and reviewed existing data on genetic biomarkers in NF1 and NF2 and in in malignant peripheral nerve sheath tumors. The group then met during a series of consensus meetings to develop a joint report. We found that in NF2, the genetic severity score is clearly of potential clinical use. In NF1, despite over 3,000 constitutional variants having been described in the NF1 gene, only 4 actionable genotype-phenotype correlations exist. The diagnosis and treatment decision of these tumors should ideally include histopathology and compilation of some of the genetic markers. We summarized emerging clinical use of genotype-phenotype correlations in neurofibromatosis.

Isolated intestinal Ganglioneuromatosis: case report and literature review

BackgroundIntestinal Ganglioneuromatosis (IG) is a rare disorder of the enteric nervous system. In pediatric age it is often associated with genetic syndromes such as Neurofibromatosis 1 (NF1), multiple endocrine neoplasia type 2B (MEN2B) and Cowden syndrome (PTEN mutation), and ganglioneuromas (GNs) may be sometimes the first sign of the disease. Isolated GNs are rare and sporadic. Clinical symptom vary and depend on the size and on the location of the GNs. This disorder affects intestinal motility and it, consequently, causes changes in bowel habits, abdominal pain, occlusive symptoms and rarely lower gastrointestinal bleeding secondary to ulceration of the intestinal mucosa. On the other hand, patients can remain asymptomatic for many years.Case presentationWe describe a 9-year-old boy referred to our emergency department for right lower quadrant abdominal pain. No familial history for gastrointestinal disorders. No history of fever or weight loss. At physical examination, he had diffused abdominal pain. Abdominal ultrasonography showed a hypoechoic formation measuring 41.8 mm by 35 mm in the right lower quadrant of the abdomen. Routine blood tests were normal, but fecal occult blood test was positive. Abdominal TC confirmed the hypodense formation, of about 5 cm in transverse diameter, in the right hypochondrium that apparently invaginated in the caecum-last ileal loop. Colonoscopy showed in the cecum an invaginated polypoid lesion of the terminal ileal loop. Laparoscopic resection of the polypoid lesion was performed. Histological diagnosis of the large neoplasm observed in the terminal ileum was diffuse ganglioneuromatosis. NF1, RET and PTEN gene tests resulted negative for specific mutations. At the 1 year follow-up, the patient presented good general condition and blood tests, fecal occult blood test, esophagogastroduodenoscopy, colonoscopy and MR-enterography were negative.ConclusionsOnly few cases are reported in literature of IG in pediatric age. Although rare, the present case suggests that this disorder must be taken in consideration in every patient with GI symptoms such as abdominal pain, constipation, lower intestinal bleeding, in order to avoid a delayed diagnosis.

Abstract PS18-30: Loss of NF1 leads to rho GTPase activation and sensitivity to multiple agents in breast cancer

Abstract Background: The Ras signaling pathway is a key oncogenic growth signaling pathway. The neurofibromatosis gene (NF1) is a tumor suppressor gene and negative regulator of Ras. Approximately 20% of breast cancers experience loss of active NF1 protein, leading to unabated Ras activity. Germline inactivation of NF1 leads to neurofibromatosis, which can be treated with MEK inhibitors. The functional consequences of NF1 loss have not been thoroughly explored in breast cancer. Therefore, we created a cellular model for the loss of NF1 in breast cells in order to identify novel therapies that would target NF1 null breast cells. Methods: We used CRISPR CAS9 to knock out (KO) NF1 through targeted disruption of both NF1 alleles in the human non-tumorigenic breast cell line MCF-10A. Immunoblotting confirmed loss of the protein and this cell line was used to identify changes in cellular signaling that resulted from the loss of NF1. We then used a rational approach to select drugs that may target the cellular changes in NF1 null cells. Finally, the candidate drugs were tested in a tumor xenograft model in mice. Results: Loss of NF1 endowed cells with a more transformed phenotype, including EGF growth independence and anchorage-independent growth. We observed increased activation of MAPK and activated Rho GTPase. The MEK inhibitors trametinib and PD0325901 (IC50=0.25 nM and 0.16 nM, respectively) inhibited growth of NF1-null, but not parent cells. We explored inhibitors of other proteins in the MAPK signaling pathway, including the Raf inhibitors sorafenib and vemurafenib and the dual MAP3K1/MAP2K4 inhibitor LY2228820. However, these compounds did not selectively inhibit growth of NF1-null cells, suggesting that Raf and MAP3K1/MAP2K4 are not vulnerable targets in NF1-null cells. Vincristine and zoledronic acid can indirectly affect Rho GTPase function. NF1-null cells were more sensitive to both as single agents (IC50=1.1 nM and 6.9 μM, respectively) than parental cells. We also tested multiple combinations of these drugs and observed benefits from several combinations that exceeded single agent use. Similar sensitivity was not observed to docetaxel or ixabepilone. We then tested the drugs as single agents and in combination against mouse tumor xenograft models with the human breast cancer cell lines Hs578T (NF1 null) or MCF-7 (wild type NF1). Treatment with single agent vincristine or zoledronic acid for 19 days resulted in statistically-significant decreases of 37.3% and 38.9%, respectively (p&amp;lt;0.05) in Hs578T tumor xenografts. The combination treatment resulted in an enhanced reduction in tumor size of 48.8% with a higher level of significance (p&amp;lt;0.01). Treatment of mice with MCF-7 bearing tumors with single agent vincristine resulted in a statistically significant decrease of 35.2% (p&amp;lt;0.05); however, this effect was not observed using the combination treatment, as the change in growth compared to saline treatment was not statistically significant. Conclusions: Our results suggest that loss of NF1 results in a transformed phenotype. Our results provide the first evidence that vincristine in combination with zoledronic acid may be efficacious in treating breast cancers. Additionally, we provide evidence that other drugs and drug combinations may be more effective at treating breast cancers with NF1 loss than MEK inhibitors, warranting further exploration. Citation Format: Melody A. Cobleigh, Matthew Najor, Satnam Brar, Sanja Turturro, Liam Portt, Timothy Yung, Abde M Abukhdeir. Loss of NF1 leads to rho GTPase activation and sensitivity to multiple agents in breast cancer [abstract]. In: Proceedings of the 2020 San Antonio Breast Cancer Virtual Symposium; 2020 Dec 8-11; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2021;81(4 Suppl):Abstract nr PS18-30.

Two cases of aggressive sarcomatoid urothelial carcinoma reveal potential molecular targets

Background: To detail two cases of sarcomatoid urothelial carcinoma (UC) with rapid progression, disseminated metastases, and early death, detailing the results of somatic tumor profiling using next-generation sequencing (NGS). Case Series: The first case presented is a rare case of UC of the renal pelvis with osteosarcomatous differentiation and venous tumor thrombus in a 65-year-old man found to have a heterozygous germline variant of unknown significance in the neurofibromatosis-1 gene. The second case is a 72-year-old woman with sarcomatoid UC of the bladder. Herein, we discuss the presentation and clinical course, histology, immunohistochemical profiles, and somatic tumor testing results. We then review the literature regarding this rare and aggressive entity, detail options for optimal management, and address the role of molecular profiling in these cases. Conclusion: Sarcomatoid UC is a rare and aggressive entity. NGS may be useful in these cases to guide systemic therapy.

Type 1 neurofibromatosis in a three-year-old girl with B-lineage acute lymphocytic leukemia: A case report.

Neurofibromatosis 1 (NF1) is an autosomal dominant genetic disease first manifesting in childhood, which affects multiple organs, childhood development and neurocognitive status. These patients have a high predisposition to develop both benign and malignant tumors. On September 30, 2018, a rare case of NF1 with B-lineage acute lymphocytic leukemia (ALL) was treated in the Department of Pediatrics, Third Xiangya Hospital, Central South University. The child presented with café au lait macules (CALM) since the date of birth. And the diagnosis of B-lineage ALL was made by bone marrow cytomorphologic examination and immunological phenotype detection. ETV6/RUNX1 fusion gene was positive. Also, a de novo mutation of c.2773delT (p.Leu925Ter) was found in the exon of NF1 gene by gene sequencing, which was a nonsense mutation and led to the premature termination of peptide synthesis. Molecular genetic testing is recommended to confirm NF1, particularly in children with only pigmentary features of the diagnostic criteria. NF1-affected individuals should be referred to a specialist of NF1 clinical network for long-term follow-up and surveillance.

Nuclear Isoforms of Neurofibromin Are Required for Proper Spindle Organization and Chromosome Segregation.

Mitotic spindles are highly organized, microtubule (MT)-based, transient structures that serve the fundamental function of unerring chromosome segregation during cell division and thus of genomic stability during tissue morphogenesis and homeostasis. Hence, a multitude of MT-associated proteins (MAPs) regulates the dynamic assembly of MTs in preparation for mitosis. Some tumor suppressors, normally functioning to prevent tumor development, have now emerged as significant MAPs. Among those, neurofibromin, the product of the Neurofibromatosis-1 gene (NF1), a major Ras GTPase activating protein (RasGAP) in neural cells, controls also the critical function of chromosome congression in astrocytic cellular contexts. Cell type- and development-regulated splicings may lead to the inclusion or exclusion of NF1exon51, which bears a nuclear localization sequence (NLS) for nuclear import at G2; yet the functions of the produced NLS and ΔNLS neurofibromin isoforms have not been previously addressed. By using a lentiviral shRNA system, we have generated glioblastoma SF268 cell lines with conditional knockdown of NLS or ΔNLS transcripts. In dissecting the roles of NLS or ΔNLS neurofibromins, we found that NLS-neurofibromin knockdown led to increased density of cytosolic MTs but loss of MT intersections, anastral spindles featuring large hollows and abnormal chromosome positioning, and finally abnormal chromosome segregation and increased micronuclei frequency. Therefore, we propose that NLS neurofibromin isoforms exert prominent mitotic functions.

Craniofacial bone alterations in patients with neurofibromatosis type 1.

Osseous manifestations of neurofibromatosis 1 (NF-1) occur in a minority of the affected subjects but may be because of significant clinical impairment. Typically, they involve the long bones, commonly the tibia and the fibula, the vertebrae, and the sphenoid wing. The pathogenesis of NF-1 focal osseous lesions and its possible relationships with other osseous NF-1 anomalies leading to short stature are still unknown, though it is likely that they depend on a common mechanism acting in a specific subgroup of NF-1 patients. Indeed, NF-1 gene product, neurofibromin, is expressed in all the cells that participate to bone growth: osteoblasts, osteoclasts, chondrocytes, fibroblasts, and vascular endothelial cells. Absent or low content of neurofibromin may be responsible for the osseous manifestations associated to NF-1. Among the focal NF-1 osseous anomalies, the agenesis of the sphenoid wing is of a particular interest to the neurosurgeon because of its progressive course that can be counteracted only by a surgical intervention. The sphenoid wing agenesis is regarded as a dysplasia, which is a primary bone pathology. However, its clinical progression is related to a variety of causes, commonly the development of an intraorbital plexiform neurofibroma or the extracranial protrusion of temporal lobe parenchyma and its coverings. Thus, the cranial bone defect resulting by the primary bone dysplasia is progressively accentuated by the orbit remodeling caused by the necessity of accommodating the mass effect exerted by the growing tumor or the progression of the herniated intracranial content. The aim of this paper is to review the neurosurgical and craniofacial surgical modalities to prevent the further progression of the disease by "reconstructing" the normal relationship of the orbit and the skull.

Molecular targets for NF1-associated malignant peripheral nerve sheath tumor.

Malignant Peripheral Nerve Sheath Tumor (MPNST) is a soft-tissue neurosarcoma. It can occur sporadically, after radiotherapy or in patients with Neurofibromatosis 1 (NF1). The hereditary disorder, NF1, is a common cancer predisposition syndrome. The main genetic feature is the mutation of the NF1 tumor suppressor gene that is inherited in an autosomal dominant, progressive manner. Mutations of the NF1 gene increase the activity of Ras signaling and cause the development of different types of tumors, including subcutaneous and plexiform neurofibromas. These can have further mutations that mediate the transformation into MPNST. Somatic mutations that have been observed are the loss of cell cycle regulators of the CDKN2A gene, and the inactivation of Polycomb Repressive Complex 2 (PRC2), mainly embryonic ectoderm development (EED) or suppressor of zeste 12 homologue (SUZ12). Other molecular pathways that have been targeted for treatment are dual MAPK-mTOR targeting, p53 protein, and MEK-ERK pathway. To advance the therapies focused on delaying or inhibiting malignant tumor formation in NF1, we need to understand the implications of the molecular and genetic pathway that are involved in the transformation into MPNST.

Nf1 deletion results in depletion of the Lhx6 transcription factor and a specific loss of parvalbumin+ cortical interneurons

Neurofibromatosis 1 (NF1) is caused by mutations in the NF1 gene, which encodes the protein, neurofibromin, an inhibitor of Ras activity. Cortical GABAergic interneurons (CINs) are implicated in NF1 pathology, but the cellular and molecular changes to CINs are unknown. We deleted mouse Nf1 from the medial ganglionic eminence, which gives rise to both oligodendrocytes and CINs that express somatostatin and parvalbumin. Nf1 loss led to a persistence of immature oligodendrocytes that prevented later-generated oligodendrocytes from occupying the cortex. Moreover, molecular and cellular properties of parvalbumin (PV)-positive CINs were altered by the loss of Nf1, without changes in somatostatin (SST)-positive CINs. We discovered that loss of Nf1 results in a dose-dependent decrease in Lhx6 expression, the transcription factor necessary to establish SST+ and PV+ CINs, which was rescued by the MEK inhibitor SL327, revealing a mechanism whereby a neurofibromin/Ras/MEK pathway regulates a critical CIN developmental milestone.

Biochemical and structural analyses reveal that the tumor suppressor neurofibromin (NF1) forms a high-affinity dimer

Biochemical and structural analyses reveal that the tumor suppressor neurofibromin (NF1) forms a high-affinity dimer

Clinical Presentation and Novel Pathogenic Variants among 68 Chinese Neurofibromatosis 1 Children.

Background: Neurofibromatosis 1 (NF1) is one of the most common dominantly inherited genetic disorders worldwide, with an age-dependent phenotypic expression. Exploring the mutational spectrum and clinical presentation of NF1 patients at different ages from a diverse population will aid the understanding of genotype–phenotype correlations. Methods: In this study, 95 Chinese children with clinical suspicion of NF1 mainly due to the presence of multiple café-au-lait macules (CALMs) were subjected to medical exome-sequencing analysis and Sanger confirmation of pathogenic variants. Clinical presentations were evaluated regarding dermatological, ocular, neurological, and behavioral features. Results: Pathogenic or likely pathogenic NF1 variants were detected in 71.6% (68/95) of patients; 20 pathogenic variants were not previously reported, indicating that Chinese NF1 patients are still understudied. Parental Sanger sequencing confirmation revealed 77.9% of de novo variants, a percentage that was much higher than expected. The presence of a higher number of NF1-related features at young ages was correlated with positive diagnostic findings. In addition to CALMs, neurological and behavioral features had a high expression among Chinese NF1 children. We attempted to correlate short stature with the locations of the pathogenic variants across the NF1 gene. It is interesting to notice that variants detected in the C-terminal region of the NF1 gene were less likely to be associated with short stature among the NF1 patients, whereas variants at the N-terminal were highly penetrant for the short stature phenotype. Conclusion: Novel NF1 pathogenic variants are yet to be uncovered in under-studied NF1 patient populations; their identification will help to reveal novel genotype–phenotype correlations.