Mutations In Neurofibromatosis Type 1 Gene Research Articles

Generation of a human iPSC line CIPi004-A from a patient with neurofibromatosis type 1 and epilepsy harboring a heterozygous mutation in NF1 gene

The NF1 gene is related to neurofibromatosis type 1 (NF1), which is an autosomal dominant disorder associated with multisystem involvement and epilepsy susceptibility. A human induced pluripotent stem cell (iPSC) line was derived from a pediatric patient with NF1 and epilepsy, harboring a heterozygous NF1 gene mutation. The iPSC line exhibits high levels of pluripotency markers, maintains the NF1 gene mutation, and demonstrates the capacity to undergo differentiation potential in vitro into three germ layers. The iPSC line will serve as a valuable resource for investigating the underlying mechanisms and conducting drug screening related to NF1 and NF1-associated epilepsy.

SOX9 Promotes Collagen VI Secretion by Upregulating PCOLCE in Neurofibroma.

Neurofibromatosis type 1 (NF1) is caused by NF1 gene mutations. Patients with NF1 often have complications with tumors, such as neurofibroma. In order to investigate the pathogenesis of human neurofibroma, a systematic comparison of protein expression levels between Schwann cell-like sNF96.2 cells, which originated from malignant peripheral nerve sheath tumors (MPNST), and normal Schwann cells was performed using 4-D label-free proteomic analysis. In addition, the expression levels and localization of dysregulated proteins were confirmed using a Gene Expression Omnibus (GEO) transcriptomic dataset, Western blot analysis, and immunofluorescence labeling. The effects of SRY-box transcription factor 9 (SOX9) in the neurofibroma and surrounding microenvironment were evaluated in vivo using a tumor transplantation model. The present study observed that SOX9 and procollagen C-endopeptidase enhancer (PCOLCE) were significantly altered. NF1 mutation promoted the nuclear translocation and transcriptional activity of SOX9 in neurofibromas. SOX9 increased collagen VI secretions by enhancing the activation of PCOLCE in neurofibroma cells. These findings might provide new perspectives on the pathophysiological significance of SOX9 in neurofibromas and elucidate a novel molecular mechanism underlying neurofibromas.

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

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

Drug Responses in Plexiform Neurofibroma Type I (PNF1) Cell Lines Using High-Throughput Data and Combined Effectiveness and Potency.

Background: Neurofibromatosis type 1 (NF1) is a genetic disorder characterized by heterozygous germline NF1 gene mutations that predispose patients to developing plexiform neurofibromas, which are benign but often disfiguring tumors of the peripheral nerve sheath induced by loss of heterozygosity at the NF1 locus. These can progress to malignant peripheral nerve sheath tumors (MPNSTs). There are no approved drug treatments for adults with NF1-related inoperable plexiform neurofibromas, and only one drug (selumetinib), which is an FDA-approved targeted therapy for the treatment of symptomatic pediatric plexiform neurofibromas, highlighting the need for additional drug screening and development. In high-throughput screening, the effectiveness of drugs against cell lines is often assessed by measuring in vitro potency (AC50) or the area under the curve (AUC). However, the variability of dose-response curves across drugs and cell lines and the frequency of partial effectiveness suggest that these measures alone fail to provide a full picture of overall efficacy. Methods: Using concentration-response data, we combined response effectiveness (EFF) and potency (AC50) into (a) a score characterizing the effect of a compound on a single cell line, S = log[EFF/AC50], and (b) a relative score, ΔS, characterizing the relative difference between a reference (e.g., non-tumor) and test (tumor) cell line. ΔS was applied to data from high-throughput screening (HTS) of a drug panel tested on NF1-/- tumor cells, using immortalized non-tumor NF1+/- cells as a reference. Results: We identified drugs with sensitivity, targeting expected pathways, such as MAPK-ERK and PI3K-AKT, as well as serotonin-related targets, among others. The ΔS technique used here, in tandem with a supplemental ΔS web tool, simplifies HTS analysis and may provide a springboard for further investigations into drug response in NF1-related cancers. The tool may also prove useful for drug development in a variety of other cancers.

Neurofibromin 1 mutations impair the function of human induced pluripotent stem cell-derived microglia.

Neurofibromatosis type 1 (NF1) is an autosomal dominant condition caused by germline mutations in the neurofibromin 1 (NF1) gene. Children with NF1 are prone to the development of multiple nervous system abnormalities, including autism and brain tumors, which could reflect the effect of NF1 mutation on microglia function. Using heterozygous Nf1-mutant mice, we previously demonstrated that impaired purinergic signaling underlies deficits in microglia process extension and phagocytosis in situ. To determine whether these abnormalities are also observed in human microglia in the setting of NF1, we leveraged an engineered isogenic series of human induced pluripotent stem cells to generate human microglia-like (hiMGL) cells heterozygous for three different NF1 gene mutations found in patients with NF1. Whereas all NF1-mutant and isogenic control hiMGL cells expressed classical microglia markers and exhibited similar transcriptomes and cytokine/chemokine release profiles, only NF1-mutant hiMGL cells had defects in P2X receptor activation, phagocytosis and motility. Taken together, these findings indicate that heterozygous NF1 mutations impair a subset of the functional properties of human microglia, which could contribute to the neurological abnormalities seen in children with NF1.

Development of a novel treatment by inhibition of mast cell-associated proteins in neurofibroma tumours

Neurofibromatosis type 1 (NF1), also known as von Recklinghausen's disease, is an inherited disorder that will (with high probability) lead to multiple benign tumors in the future. There are several types of NF1 tumors and there is no way to control their incidence other than surgical resection. Associate Professor Misa Yamamoto, an expert in regenerative medicine, is currently conducting a project to elucidate the tumor growth mechanism in NF1 patients. This will lead to the development of innovative treatments for this disease. The researchers are affiliated with the Department of Clinical Laboratory Sciences, Graduate School of Medicine, Yamaguchi University, Japan. Currently, we have worked on analyzing the function of mast cells in cutaneous neurofibroma and aim to develop a new treatment method that suppresses the function of mast cells involved in tumor growth. There are still many gaps in knowledge regarding NF1. Neurofibroma tumors are known to contain a considerable number of mast cells though Professor Yamamoto found with the research has shown that each cell has an abnormally high concentration of an inflammatory substance called tryptase. This means that neurofibromas are constantly exposed to a strong inflammatory state, suggesting that it is difficult to stop tumor growth unless inflammation is stopped. Professor Yamamoto investigated the differences in the properties of disease-specific mast cells with NF1 gene mutations and mast cells derived from healthy subjects, and clarified differences in the production of tryptase, TGF-β1, and Stem Cell Factor. These findings suggest that tumor growth is driven by the overexpression of these proteins, and researchers believe that blocking the pathways that suppress the expression of these proteins can reduce inflammation and tumor growth.

Germline Neurofibromin 1 mutation enhances the anti-tumour immune response and decreases juvenile myelomonocytic leukaemia tumourigenicity.

Juvenile myelomonocytic leukaemia (JMML) is an aggressive paediatric leukaemia characterized by mutations in five canonical RAS pathway genes, including the NF1 gene. JMML is driven by germline NF1 gene mutations, with additional somatic aberrations resulting in the NF1 biallelic inactivation, leading to disease progression. Germline mutations in the NF1 gene alone primarily cause benign neurofibromatosis type 1 (NF1) tumours rather than malignant JMML, yet the underlying mechanism remains unclear. Here, we demonstrate that with reduced NF1 gene dose, immune cells are promoted in anti-tumour immune response. Comparing the biological properties of JMML and NF1 patients, we found that not only JMML but also NF1 patients driven by NF1 mutations could increase monocytes generation. But monocytes cannot further malignant development in NF1 patients. Utilizing haematopoietic and macrophage differentiation from iPSCs, we revealed that NF1 mutations or knockout (KO) recapitulated the classical haematopoietic pathological features of JMML with reduced NF1 gene dose. NF1 mutations or KO promoted the proliferation and immune function of NK cells and iMacs derived from iPSCs. Moreover, NF1-mutated iNKs had a high capacity to kill NF1-KO iMacs. NF1-mutated or KO iNKs administration delayed leukaemia progression in a xenograft animal model. Our findings demonstrate that germline NF1 mutations alone cannot directly drive JMML development and suggest a potential cell immunotherapy for JMML patients.

Moyamoya Vasculopathy in Neurofibromatosis Type 1 Pediatric Patients: The Role of Rare Variants of RNF213

Neurofibromatosis type 1 (NF1) is a neurocutaneous disorder caused by mutations in NF1 gene, coding for neurofibromin 1. NF1 can be associated with Moyamoya disease (MMD), and this association, typical of paediatric patients, is referred to as Moyamoya syndrome (MMS). MMD is a cerebral arteriopathy characterized by the occlusion of intracranial arteries and collateral vessel formation, which increase the risk of ischemic and hemorrhagic events. RNF213 gene mutations have been associated with MMD, so we investigated whether rare variants of RNF213 could act as genetic modifiers of MMS phenotype in a pediatric cohort of 20 MMS children, 25 children affected by isolated MMD and 47 affected only by isolated NF1. By next-generation re-sequencing (NGS) of patients' DNA and gene burden tests, we found that RNF213 seems to play a role only for MMD occurrence, while it does not appear to be involved in the increased risk of Moyamoya for MMS patients. We postulated that the loss of neurofibromin 1 can be enough for the excessive proliferation of vascular smooth muscle cells, causing Moyamoya arteriopathy associated with NF1. Further studies will be crucial to support these findings and to elucidate the possible role of other genes, enhancing our knowledge about pathogenesis and treatment of MMS.

Identifying a novel frameshift pathogenic variant in a Chinese family with neurofibromatosis type 1 and review of literature.

To detect the pathogenic gene variant in a family with neurofibromatosis type 1 (NF1). This patient with NF1 was sequenced using target sequence capture and high-throughput sequencing technology. After detecting the suspicious pathogenic variant type, the pathogenic variant sites of the patient and the patient's family members were verified by multiple ligation dependent probe amplification and Sanger sequencing. Sift, polyphen-2, Mutation Taster and GERP++ software were used to predict the pathogenicity of the unknown loci. The clinical data, diagnosis and treatment process of the patients were reviewed. Using the keyword "NF1; frameshift pathogenic variant", relevant literature was gathered for analysis from Chinese and international databases, with articles dating from the establishment of each database to April 2022. A heterozygous frameshift pathogenic variant of NF1 in exon 33 was detected in the patient. The insertion of adenine in coding region 4486 resulted in the replacement of isoleucine with asparagine in protein 1497. Sanger sequencing validation and segregation analysis were performed, which demonstrated that the NF1 gene was cosegregated with the disease phenotype in this family. This study identified a novel NF1 heterozygous frameshift mutation c.4486dupA (p.I1497Nfs*12). Relevant literature retrieval found 7 Chinese articles and 12 foreign articles. With NF1 gene mutation, mutation types are diverse, including point mutation, frameshift mutation, splice site mutation, exon mutation, chimeric mutation and de novo mutation. Foreign reports are based on autosomal dominant inheritance. This study's results demonstrate that a novel deletion in exon 33 caused NF1 in this Chinese family, expanding the mutational spectrum of the NF1 gene.

Role of nerves in neurofibromatosis type 1-related nervous system tumors.

Neurofibromatosis type 1 (NF1) is an autosomal dominant genetic disorder that affects nearly 1 in 3000 infants. Neurofibromin inactivation and NF1 gene mutations are involved in various aspects of neuronal function regulation, including neuronal development induction, electrophysiological activity elevation, growth factor expression, and neurotransmitter release. NF1 patients often exhibit a predisposition to tumor development, especially in the nervous system, resulting in the frequent occurrence of peripheral nerve sheath tumors and gliomas. Recent evidence suggests that nerves play a role in the development of multiple tumor types, prompting researchers to investigate the nerve as a vital component in and regulator of the initiation and progression of NF1-related nervous system tumors. In this review, we summarize existing evidence about the specific effects of NF1 mutation on neurons and emerging research on the role of nerves in neurological tumor development, promising a new set of selective and targeted therapies for NF1-related tumors.

Prospects for the treatment of neurofibromatosis type 1: A review

Neurofibromatosis type 1 (NF1) is an autosomal dominant hereditary tumor syndrome with a prevalence of 1:3000 in human population. About 50% of NF1 cases are sporadic due to newly emerging germline mutations in NF1 gene. Protein product of NF1 is a neurofibromin, which inhibits RAS-RAF-MEK-ERK system. The prevalence of NF1 is increasing as patients are fertile. Therefore, it is important to use rapid diagnostic methods for NF1 mutations in NF1 families for prenatal prophylaxis. Mutations in NF1 gene play roles in sporadic carcinogenesis and in development of cancer resistance to chemotherapy. Specific for NF1 are multiple subcutaneous and cutaneous neurofibromas, age spots, skeletal abnormalities, mental retardation, tumors of the brain and optic nerves. Half of patients with NF1 develop plexiform neurofibromas, which disfigure them or compress vital organs. The difficulty in treating NF1 is due to involvement of immune system, since a large number of degranulating mast cells are found in neurofibromas. Mast cells secrete cytokines that dont provide a proper anti-tumor immune response, but initiate formation and growth of new neurofibromas. Therefore, long-term administration of ketotiphen was proposed for treatment of NF1 patients. Surgical removal of neurofibromas causes relapses and induction of the growth of new tumors; therefore, it is necessary to develop an effective therapy for NF1. The effectiveness of complex therapy of NF1 with use of ketotiphen, Lydase and Aevit, as well as monotherapy with an ATP-independent inhibitor of mitogen-activated protein kinase, has been described. For widespread clinical implementation of these methods, it is necessary to conduct studies on large sample of patients, as well as to make medicines available for patients. Gene therapy may become promising in the treatment of NF1, which requires identification of the type of mutation in NF1 gene in each individual and the use of specific microRNAs.

The NF1 microdeletion syndrome: early genetic diagnosis facilitates the management of a clinically defined disease.

Neurofibromatosis type-1 (NF1) is a genodermatosis frequently encountered in general dermatology. In many patients, the diagnosis of NF1 is made clinically based on the presence of café-au-lait macules and skinfold freckling, as well as plexiform neurofibromas detectable during early childhood. Later in life, cutaneous neurofibromas often represent important diagnostic features. NF1 is characterized by extreme clinical variability and a broad heterogeneity of NF1 gene mutations which impede genotype/phenotype correlations. Notable exceptions are NF1 microdeletions observed in 5-11% of all NF1 patients. Patients with NF1 microdeletions frequently exhibit facial dysmorphic features and a tall stature as rather specific clinical signs. Furthermore, cutaneous and subcutaneous neurofibromas present at an early age, severe global developmental delay and cognitive disability are pathognomonic for the "NF1 microdeletion syndrome". Importantly, NF1 microdeletions are associated with an approximately twofold higher risk for malignant peripheral nerve sheath tumors than intragenic NF1 gene mutations. The severe clinical manifestations of patients with NF1 microdeletions require early multidisciplinary clinical care and frequent tumor surveillance. Therefore, when red flag features for the "NF1 microdeletion syndrome" are present in a patient, genetic testing is necessary to confirm or exclude an NF1 microdeletion.

Reduction Surgery of Giant Hemifacial Neurofibromas: A Case Report

Neurofibromatosis type 1 (NF-1), first described by Von Recklinghausen (1882), is an autosomal dominant disease caused by a spectrum of mutations in NF-1 gene. We reported a case of giant facial neurofibromas in 26 years old male patient without family history of neurofibromatosis type 1. Features typical of neurofibroma, including an enlarged nerve fascicle composed of elongated nuclei and scant cytoplasmic cells, were identified. Excision was performed with preservation of parotid duct. The mass weight was about 5,5 kg. There were some challenges during the procedure, such as bleeding, hypovolemia, and preservation of vital structure.

How to Distinguish Solitary Neurofibroma From Neurofibromatosis Type 1.

Neurofibroma is a benign tumor originating from Schwann cells. It is diagnosed as a symptom of neurofibromatosis type 1 (NF1) or solitary neurofibroma. Neurofibromatosis type 1 belongs to a class of hereditary diseases, whereas solitary neurofibroma is not. Presence of germline NF1 gene mutations can be used to distinguish the 2 conditions. However, due to false negative results in gene tests, NF1 may be misdiagnosed as solitary neurofibroma. This calls for development of more accurate diagnostic methods. The authors report 2 patients with neurofibroma who required surgery and fertility consulting. using primary cell culture and next-generation sequencing experiments, the authors found NF1 mutation in neurofibroma Schwann cells. But this mutation was not exit in peripheral blood, hence demonstrate this NF1 mutation was somatic rather than germline. These results confirmed the diagnosis of solitary neurofibroma rather than NF1. The presented method is, therefore, suitable for fertility consultation and diagnosis of solitary neurofibroma patient.

Atypical NF1 Microdeletions: Challenges and Opportunities for Genotype/Phenotype Correlations in Patients with Large NF1 Deletions.

Patients with neurofibromatosis type 1 (NF1) and type 1 NF1 deletions often exhibit more severe clinical manifestations than patients with intragenic NF1 gene mutations, including facial dysmorphic features, overgrowth, severe global developmental delay, severe autistic symptoms and considerably reduced cognitive abilities, all of which are detectable from a very young age. Type 1 NF1 deletions encompass 1.4 Mb and are associated with the loss of 14 protein-coding genes, including NF1 and SUZ12. Atypical NF1 deletions, which do not encompass all 14 protein-coding genes located within the type 1 NF1 deletion region, have the potential to contribute to the delineation of the genotype/phenotype relationship in patients with NF1 microdeletions. Here, we review all atypical NF1 deletions reported to date as well as the clinical phenotype observed in the patients concerned. We compare these findings with those of a newly identified atypical NF1 deletion of 698 kb which, in addition to the NF1 gene, includes five genes located centromeric to NF1. The atypical NF1 deletion in this patient does not include the SUZ12 gene but does encompass CRLF3. Comparative analysis of such atypical NF1 deletions suggests that SUZ12 hemizygosity is likely to contribute significantly to the reduced cognitive abilities, severe global developmental delay and facial dysmorphisms observed in patients with type 1 NF1 deletions.

Survival and NF1 Analysis in a Cohort of Orthopedics Patients with Malignant Peripheral Nerve Sheath Tumors.

Neurofibromatosis type 1 (NF1) is an autosomal dominant tumor syndrome in which benign plexiform neurofibromas are at risk of transforming into malignant peripheral nerve sheath tumors (MPNSTs), a very rare soft-tissue sarcoma. The prognosis of patients with MPNSTs is poor, with most studies reporting <50% survival at five years. However, studies evaluating MPNSTs are limited and report heterogeneous results. Because no MPNST-specific evidence-based treatment guideline exists, individual institutional experiences are very informative to the field. The main objective of this study was to investigate and report MPNST prognostic clinical and genetic biomarkers from our institution's Orthopedics service experience treating 20 cases from 1992 to 2017. Most patients were treated with resection and adjuvant radiation. Extended follow-up, averaging 11.4 years (ranging 1.1 to 25.1), revealed excellent five-year survival rates: 70% for overall and 60% for metastatic disease. An S100 B immunonegative tumor phenotype was associated with a significantly worse outcome than MPNSTs with positive S100 B stain. In addition, NF1 gene mutation analysis was performed on 27 families with NF1 in which at least one affected family member developed MPNSTs. Of the 27 NF1 germline mutations, five were large deletions spanning (or nearly spanning) the gene (18.5%), substantially more than such deletions in NF1 in general, consistent with increased risk of MPNSTs in such cases.

P70.15 Mutational Subtypes and Prognosis of East Asian Non-Small-Cell Lung Cancer Harboring NF2 Mutations

Neurofibromatosis type 2 (NF2) is an autosomal-dominant disorder caused by mutations in the NF2 gene and predisposing to the development of nervous system. The aim of this study is to investigate mutations and prognosis of NSCLC harboring NF2 mutations. A total of 411 patients with non-small-cell lung cancer were recruited between July 2012 and December 2018. The status of NF2 mutations and other genes were detected by next generation sequencing. NF2 gene mutation rate was 1.70% (7/411) in non-small cell lung cancer, including S138F(1 patient), N563D(1 patient), E530*(1 patient), E392*(1 patient), W74*(1 patient), C300S(1 patient) and E260*(1 patient), and median overall survival (OS) for these patients was 14.0 months. Among them, all patients were NF2 gene with co-occurring mutations. Briefly, patients with (n=2) or without (n=5) co-occurring PTPRD mutations had a median OS of 17.0 months and 14.0 months respectively (P=0.99); patients with (n=2) or without (n=5) co-occurring CIC mutations had a median OS of not up to now and 14.0 months respectively (P=0.27); patients with (n=2) or without (n=5) co-occurring APC mutations had a median OS of 18.5 months and 14.0 months respectively (P=0.44); patients with (n=2) or without (n=5) co-occurring ERBB4 mutations had a median OS of 17.0 months and 14.0 months respectively (P=0.99). NF2 oncogenic activation through mutation defines a novel and distinct subset of NSCLC. Targeted therapy may be considered as a possible treatment for carriers of the mutation. PTPRD, CIC, APC, ERBB4 gene accompanied may have less correlation with NF2 mutation in NSCLC patients.

Analysis of Genetic Mutations and the Clinical Manifestations of Neurofibromatosis Type 2 in Korea: A Single Institutional Experience

Background and Objectives Neurofibromatosis type 2 (NF2) is a rare autosomal dominant disorder characterized as bilateral vestibular schwannoma (VS), various brain and spinal tumors. This study is aimed to investigate the relationship between the genotypes and phenotypes of NF2 found in the Korean population.Subjects and Method We retrospectively reviewed 11 patients who were diagnosed with NF2 and observed them for more than a year. NF2 gene mutations were detected using Sanger sequencing and multiplex ligation-dependent probe amplification (MLPA). The mutations were classified into tissue mosaicism, classic, and severe genotypes according to the UK NF2 genetic severity score. Tumor load was assessed by reviewing MR images and audiological findings were analyzed.Results We identified 7 cases (63.6%) of mutations from 11 patients who were diagnosed with NF2. While three patients showed classic and four showed severe genotypes, four patients were presumed as tissue mosaicism. The patients with severe genotypes didn’t show more severe clinical manifestations in terms of tumor load and hearing. Four patients with tissue mosaicism were detected in the older age group than those with mutation. Of the five patients who had serviceable bilateral hearing at the initial diagnosis, all maintained their serviceable hearing during the follow-up.Conclusion Our results, which showed that the clinical manifestations of NF2 found in the Korean population have no correlation with the genotype findings, are not in agreement with previous studies. However, further studies with larger sample sizes are needed to give more appropriate counsel.

Patient-derived iPSC-cerebral organoid modeling of the 17q11.2 microdeletion syndrome establishes CRLF3 as a critical regulator of neurogenesis.

SUMMARYNeurodevelopmental disorders are often caused by chromosomal microdeletions comprising numerous contiguous genes. A subset of neurofibromatosis type 1 (NF1) patients with severe developmental delays and intellectual disability harbors such a microdeletion event on chromosome 17q11.2, involving the NF1 gene and flanking regions (NF1 total gene deletion [NF1-TGD]). Using patient-derived human induced pluripotent stem cell (hiPSC)-forebrain cerebral organoids (hCOs), we identify both neural stem cell (NSC) proliferation and neuronal maturation abnormalities in NF1-TGD hCOs. While increased NSC proliferation results from decreased NF1/RAS regulation, the neuronal differentiation, survival, and maturation defects are caused by reduced cytokine receptor-like factor 3 (CRLF3) expression and impaired RhoA signaling. Furthermore, we demonstrate a higher autistic trait burden in NF1 patients harboring a deleterious germline mutation in the CRLF3 gene (c.1166T>C, p.Leu389Pro). Collectively, these findings identify a causative gene within the NF1-TGD locus responsible for hCO neuronal abnormalities and autism in children with NF1.

Biofabrication of a three dimensional human-based personalized neurofibroma model.

Neurofibromas are the most characteristic feature of neurofibromatosis type 1 (NF1), a multisystemic disorder caused by aberrations in the neurofibromin gene (NF1). Despite significant progress over the last several years in understanding this disease, a suitable in vitro model to better mimic neurofibroma formation and growth has yet to be described. There is therefore a need to establish an in vitro, three dimensional model that allows the incorporation of multicellular lineages and the modulation of the cellular microenvironment-known to be important for cellular crosstalk and distribution of soluble factors-to study neurofibroma biology and morphogenesis. A self-assembly approach was used to generate tissue-engineered skins (TES) in which patient-derived spheroids made of NF1-associated Schwann cells and fibroblasts were seeded. We describe the first in vitro three dimensional neurofibroma model-directly derived from NF1 patients presenting with histopathological features-having an ECM protein expression profile quite similar to that of a native tumor. We observed efficient incorporation, proliferation, and migration of spheroids within NF1-TES over time. This biotechnological approach could provide a unique tool for precision medicine targeting NF1 and for assessing the tumorigenic properties of each NF1 gene mutation linked to tumor formation.