An Overview of Optic Pathway Glioma With Neurofibromatosis Type 1: Pathogenesis, Risk Factors, and Therapeutic Strategies.

Optic pathway gliomas (OPGs) are most predominant pilocytic astrocytomas, which are typically diagnosed within the first decade of life. The majority of affected children with OPGs also present with neurofibromatosis type 1 (NF1), the most common tumor predisposition syndrome. OPGs in individuals with NF1 primarily affect the optic pathway and lead to visual disturbance. However, it is challenging to assess risk in asymptomatic patients without valid biomarkers. On the other hand, for symptomatic patients, there is still no effective treatment to prevent or recover vision loss. Therefore, this review summarizes current knowledge regarding the pathogenesis of NF1-associated OPGs (NF1-OPGs) from preclinical studies to seek potential prognostic markers and therapeutic targets. First, the loss of the NF1 gene activates 3 distinct Ras effector pathways, including the PI3K/AKT/mTOR pathway, the MEK/ERK pathway, and the cAMP pathway, which mediate glioma tumorigenesis. Meanwhile, non-neoplastic cells from the tumor microenvironment (microglia, T cells, neurons, etc.) also contribute to gliomagenesis via various soluble factors. Subsequently, we investigated potential genetic risk factors, molecularly targeted therapies, and neuroprotective strategies for tumor prevention and vision recovery. Last, potential directions and promising preclinical models of NF1-OPGs are presented for further research. On the whole, NF1-OPGs develop as a result of the interaction between glioma cells and the tumor microenvironment. Developing effective treatments require a better understanding of tumor molecular characteristics, as well as multistage interventions targeting both neoplastic cells and non-neoplastic cells.

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.

Past, Present, and Future Therapeutic Strategies for NF-1-Associated Tumors.

PURPOSE OF REVIEW: Neurofibromatosis type 1 (NF-1) is a cancer predisposition syndrome caused by mutations in the NF1 tumor suppressor gene that encodes the neurofibromin protein, which functions as a negative regulator of Ras signaling. We review the past, current, and future state of therapeutic strategies for tumors associated with NF-1. RECENT FINDINGS: Therapeutic efforts for NF-1-associated tumors have centered around inhibiting Ras output, leading to the clinical success of downstream MEK inhibition for plexiform neurofibromas and low-grade gliomas. However, MEK inhibition and similar molecular monotherapy approaches that block Ras signaling do not work for all patients and show limited efficacy for more aggressive cancers such as malignant peripheral nerve sheath tumors and high-grade gliomas, motivating novel treatment approaches. We highlight the current therapeutic landscape for NF-1-associated tumors, broadly categorizing treatment into past strategies for serial Ras pathway blockade, current approaches targeting parallel oncogenic and tumor suppressor pathways, and future avenues of investigation leveraging biologic and technical innovations in immunotherapy, pharmacology, and gene delivery.

Recurrent spontaneous pneumothorax in an NF1 patient with a novel causative variant: broadening genotype-phenotype correlations.

Neurofibromatosis type 1 (NF1) is an autosomal dominant disease with complete penetrance, most commonly known to affect the skin and eyes. Although lung involvement in the form of cysts and bullae occurs in up to 20% of adults, the seemingly intuitive association of NF1 and spontaneous pneumothorax is not widely recognised among clinicians. Here, we report the second case of recurring spontaneous pneumothorax in the context of NF1 with a confirmed molecular diagnosis. In both cases, the NF1 variants featured a premature stop codon in the C-terminal protein domain. Interestingly, our patient had mild skin symptoms, suggesting that spontaneous pneumothorax may not be correlated with cutaneous disease severity. More genotype-phenotype correlation studies are needed for NF1 in general and for its link to spontaneous pneumothorax in particular.

NF1-Driven Rhabdomyosarcoma Phenotypes: A Comparative Clinical and Molecular Study of NF1-Mutant Rhabdomyosarcoma and NF1-Associated Malignant Triton Tumor.

PURPOSE: Alterations of the NF1 tumor suppressor gene is the second most frequent genetic event in embryonal rhabdomyosarcoma (ERMS), but its associations with clinicopathologic features, outcome, or coexisting molecular events are not well defined. Additionally, NF1 alterations, mostly in the setting of neurofibromatosis type I (NF1), drive the pathogenesis of most malignant peripheral nerve sheath tumor with divergent RMS differentiation (also known as malignant triton tumor [MTT]). Distinguishing between these entities can be challenging because of their pathologic overlap. This study aims to comprehensively analyze the clinicopathologic and molecular spectrum of NF1-mutant RMS compared with NF1-associated MTT for a better understanding of their pathogenesis. METHODS: We investigated the clinicopathologic and molecular landscape of a cohort of 22 NF1-mutant RMS and a control group of 13 NF1-associated MTT. Cases were tested on a matched tumor-normal hybridization capture-based targeted DNA next-generation sequencing. RESULTS: Among the RMS group, all except one were ERMS, with a median age of 17 years while for MTT the mean age was 39 years. Three MTTs were misdiagnosed as ERMS, having clinical impact in one. The most frequent coexisting alteration in ERMS was TP53 abnormality (36%), being mutually exclusive from NRAS mutations (14%). MTT showed coexisting CDKN2A/B and PRC2 complex alterations in 38% cases and loss of H3K27me3 expression. Patients with NF1-mutant RMS exhibited a 70% 5-year survival rate, in contrast to MTT with a 33% 5-year survival. All metastatic NF1-mutant ERMS were associated with TP53 alterations. CONCLUSION: Patients with NF1-mutant ERMS lacking TP53 alterations may benefit from dose-reduction chemotherapy. On the basis of the diagnostic challenges and significant treatment and prognostic differences, molecular profiling of challenging tumors with rhabdomyoblastic differentiation is recommended.

Whole-exome sequencing revealed a likely pathogenic variant in NF1 causing neurofibromatosis type I and Arrhythmogenic Cardiomyopathy.

BACKGROUND: Neurofibromatosis type I (NF1) is a genetic disorder characterized by the tumor's development in nerve tissue. Complications of NF1 can include pigmented lesions, skin neurofibromas, and heart problems such as cardiomyopathy. In this study, we performed whole-exome sequencing (WES) on an Iranian patient with NF1 to identify the genetic cause of the disease. METHODS: Following clinical assessment, WES was used to identify genetic variants in a family with a son suffering from NF1. No symptomatic manifestations were observed in other family members. In the studied family, in silico and segregation analysis were applied to survey candidate variants. RESULTS: Clinical manifestations were consistent with arrhythmogenic cardiomyopathy (ACM). WES detected a likely pathogenic heterozygous missense variant, c.3277G > A:p.Val1093Met, in the NF1 gene, confirmed by PCR and Sanger sequencing. The patient's parents and brother had a normal sequence at this locus. CONCLUSIONS: Although there is no cure for NF1, genetic tests, such as WES, can detect at-risk asymptomatic family members. Furthermore, cardiac evaluation could also help these patients before heart disease development.

Raman difference spectroscopy and U-Net convolutional neural network for molecular analysis of cutaneous neurofibroma.

In Neurofibromatosis type 1 (NF1), peripheral nerve sheaths tumors are common, with cutaneous neurofibromas resulting in significant aesthetic, painful and functional problems requiring surgical removal. To date, determination of adequate surgical resection margins-complete tumor removal while attempting to preserve viable tissue-remains largely subjective. Thus, residual tumor extension beyond surgical margins or recurrence of the disease may frequently be observed. Here, we introduce Shifted-Excitation Raman Spectroscopy in combination with deep neural networks for the future perspective of objective, real-time diagnosis, and guided surgical ablation. The obtained results are validated through established histological methods. In this study, we evaluated the discrimination between cutaneous neurofibroma (n = 9) and adjacent physiological tissues (n = 25) in 34 surgical pathological specimens ex vivo at a total of 82 distinct measurement loci. Based on a convolutional neural network (U-Net), the mean raw Raman spectra (n = 8,200) were processed and refined, and afterwards the spectral peaks were assigned to their respective molecular origin. Principal component and linear discriminant analysis was used to discriminate cutaneous neurofibromas from physiological tissues with a sensitivity of 100%, specificity of 97.3%, and overall classification accuracy of 97.6%. The results enable the presented optical, non-invasive technique in combination with artificial intelligence as a promising candidate to ameliorate both, diagnosis and treatment of patients affected by cutaneous neurofibroma and NF1.

Autism spectrum disorder profiles in RASopathies: A systematic review.

BACKGROUND: RASopathies are associated with an increased risk of autism spectrum disorder (ASD). For neurofibromatosis type 1 (NF1) there is ample evidence for this increased risk, while for other RASopathies this association has been studied less. No specific ASD profile has been delineated so far for RASopathies or a specific RASopathy individually. METHODS: We conducted a systematic review to investigate whether a specific RASopathy is associated with a specific ASD profile, or if RASopathies altogether have a distinct ASD profile compared to idiopathic ASD (iASD). We searched PubMed, Web of Science, and Open Grey for data about ASD features in RASopathies and potential modifiers. RESULTS: We included 41 articles on ASD features in NF1, Noonan syndrome (NS), Costello syndrome (CS), and cardio-facio-cutaneous syndrome (CFC). Individuals with NF1, NS, CS, and CFC on average have higher ASD symptomatology than healthy controls and unaffected siblings, though less than people with iASD. There is insufficient evidence for a distinct ASD phenotype in RASopathies compared to iASD or when RASopathies are compared with each other. We identified several potentially modifying factors of ASD symptoms in RASopathies. CONCLUSIONS: Our systematic review found no convincing evidence for a specific ASD profile in RASopathies compared to iASD, or in a specific RASopathy compared to other RASopathies. However, we identified important limitations in the research literature which may also account for this result. These limitations are discussed and recommendations for future research are formulated.

Drosophila Contributions towards Understanding Neurofibromatosis 1.

Neurofibromatosis 1 (NF1) is a multisymptomatic disorder with highly variable presentations, which include short stature, susceptibility to formation of the characteristic benign tumors known as neurofibromas, intense freckling and skin discoloration, and cognitive deficits, which characterize most children with the condition. Attention deficits and Autism Spectrum manifestations augment the compromised learning presented by most patients, leading to behavioral problems and school failure, while fragmented sleep contributes to chronic fatigue and poor quality of life. Neurofibromin (Nf1) is present ubiquitously during human development and postnatally in most neuronal, oligodendrocyte, and Schwann cells. Evidence largely from animal models including Drosophila suggests that the symptomatic variability may reflect distinct cell-type-specific functions of the protein, which emerge upon its loss, or mutations affecting the different functional domains of the protein. This review summarizes the contributions of Drosophila in modeling multiple NF1 manifestations, addressing hypotheses regarding the cell-type-specific functions of the protein and exploring the molecular pathways affected upon loss of the highly conserved fly homolog dNf1. Collectively, work in this model not only has efficiently and expediently modelled multiple aspects of the condition and increased understanding of its behavioral manifestations, but also has led to pharmaceutical strategies towards their amelioration.

STING activation reprograms the microenvironment to sensitize NF1-related malignant peripheral nerve sheath tumors for immunotherapy.

Neurofibromatosis type 1 (NF1) is caused by mutations in the NF1 gene that encodes neurofibromin, a RAS GTPase-activating protein. Inactivating NF1 mutations cause hyperactivation of RAS-mediated signaling, resulting in the development of multiple neoplasms, including malignant peripheral nerve sheath tumors (MPNSTs). MPNSTs are an aggressive tumor and the main cause of mortality in patients with NF1. MPNSTs are difficult to resect and refractory to chemo- and radiotherapy, and no molecular therapies currently exist. Immune checkpoint blockade (ICB) is an approach to treat inoperable, undruggable cancers like MPNST, but successful outcomes require an immune cell-rich tumor microenvironment. While MPNSTs are noninflamed "cold" tumors, here, we converted MPNSTs into T cell-inflamed "hot" tumors by activating stimulator of IFN genes (STING) signaling. Mouse genetic and human xenograft MPNST models treated with a STING agonist plus ICB exhibited growth delay via increased apoptotic cell death. This strategy offers a potential treatment regimen for MPNSTs.

p53 modulates kinase inhibitor resistance and lineage plasticity in NF1-related MPNSTs.

Malignant peripheral nerve sheath tumors (MPNSTs) are chemotherapy resistant sarcomas that are a leading cause of death in neurofibromatosis type 1 (NF1). Although NF1-related MPNSTs derive from neural crest cell origin, they also exhibit intratumoral heterogeneity. TP53 mutations are associated with significantly decreased survival in MPNSTs, however the mechanisms underlying TP53-mediated therapy responses are unclear in the context of NF1-deficiency. We evaluated the role of two commonly altered genes, MET and TP53, in kinome reprograming and cellular differentiation in preclinical MPNST mouse models. We previously showed that MET amplification occurs early in human MPNST progression and that Trp53 loss abrogated MET-addiction resulting in MET inhibitor resistance. Here we demonstrate a novel mechanism of therapy resistance whereby p53 alters MET stability, localization, and downstream signaling leading to kinome reprogramming and lineage plasticity. Trp53 loss also resulted in a shift from RAS/ERK to AKT signaling and enhanced sensitivity to MEK and mTOR inhibition. In response to MET, MEK and mTOR inhibition, we observed broad and heterogeneous activation of key differentiation genes in Trp53-deficient lines suggesting Trp53 loss also impacts lineage plasticity in MPNSTs. These results demonstrate the mechanisms by which p53 loss alters MET dependency and therapy resistance in MPNSTS through kinome reprogramming and phenotypic flexibility.

Epilepsy in neurofibromatosis type 1: Prevalence, phenotype, and genotype in adults.

PURPOSE: Studies have shown an increased risk of epilepsy in patients with neurofibromatosis type 1 (NF1). However, most reports focus on the pediatric population. In this study, we describe the trajectory of patients with NF1 and epilepsy beyond childhood. METHODS: Patients with NF1 ≥18 years-old consecutively seen at a multidisciplinary neurofibromatosis clinic during a four-year period were prospectively enrolled and offered routine EEG, MRI, and genetic testing. The lifelong and point prevalence of epilepsy in patients with NF1 were calculated. Demographic, genetic, radiological, and clinical features found to be statistically associated with having received a diagnosis of epilepsy were incorporated into a logistic regression model. RESULTS: Among 113 patients with NF1 included in this study (median age at study inclusion: 33 years), the lifelong prevalence of epilepsy was 11% (CI95%=6-18%) and point prevalence 7% (CI95%= 3-13%). Most patients (73%) were diagnosed with epilepsy before the age of 18 and achieved seizure-freedom by adulthood. At study inclusion, three-quarters of patients with a diagnosis of epilepsy had been seizure-free for more than one year and a third had resolved epilepsy. A routine EEG with epileptiform discharges had a sensitivity of 25% (CI95%=3-65) and specificity of 99% (CI95%=93-100) for identifying adult patients with NF1 and unresolved epilepsy. A history of epilepsy was associated with having a low-grade glioma (OR: 38.2; CI95%=2.2-674.7; p<0.01), learning disability (OR: 5.7; CI95%=1.0-31.5; p<0.05), and no plexiform neurofibroma (OR: 0.05; CI95%=0.0-0.8; p=0.04). No single mutation type was associated with the development of epilepsy. CONCLUSIONS: In patients with NF1, although resolution of epilepsy over time was observed in many cases, the prevalence of epilepsy was higher among adults with NF1 than that reported in the general population. Epileptogenesis in NF1 likely requires the combination of multiple genetic and environmental factors and suggests involvement of a network that spreads beyond the borders of a well-defined parenchymal lesion.

[Analysis of NF1 gene variants in a Chinese pedigree and a sporadic patient with Neurofibromatosis type 1].

OBJECTIVE: To explore the genetic basis for a Chinese pedigree and a sporadic case with Neurofibromatosis type 1 (NF1). METHODS: Clinical data of the pedigree and the sporadic case were collected. Genomic DNA was extracted from peripheral venous blood samples and subjected to whole exome sequencing. Candidate variants were validated by Sanger sequencing and bioinformatic analysis. RESULTS: All patients from the pedigree were found to harbor a c.3251delC variant in exon 25 of the NF1 gene, whilst a c.4312_4314delGAA variant was found in exon 32 of the NF1 gene in the sporadic case. CONCLUSION: Variants of the NF1 gene may account for the occurrence of NF1 in this pedigree and sporadic case.

Neurofibromin 1 controls metabolic balance and Notch-dependent quiescence of murine juvenile myogenic progenitors.

Patients affected by neurofibromatosis type 1 (NF1) frequently show muscle weakness with unknown etiology. Here we show that, in mice, Neurofibromin 1 (Nf1) is not required in muscle fibers, but specifically in early postnatal myogenic progenitors (MPs), where Nf1 loss led to cell cycle exit and differentiation blockade, depleting the MP pool resulting in reduced myonuclear accretion as well as reduced muscle stem cell numbers. This was caused by precocious induction of stem cell quiescence coupled to metabolic reprogramming of MPs impinging on glycolytic shutdown, which was conserved in muscle fibers. We show that a Mek/Erk/NOS pathway hypersensitizes Nf1-deficient MPs to Notch signaling, consequently, early postnatal Notch pathway inhibition ameliorated premature quiescence, metabolic reprogramming and muscle growth. This reveals an unexpected role of Ras/Mek/Erk signaling supporting postnatal MP quiescence in concert with Notch signaling, which is controlled by Nf1 safeguarding coordinated muscle growth and muscle stem cell pool establishment. Furthermore, our data suggest transmission of metabolic reprogramming across cellular differentiation, affecting fiber metabolism and function in NF1.

Understanding chronic pain in Neurofibromatosis Type 1 using the Neurofibromatosis Pain Module (NFPM).

Neurofibromatosis Type 1 (NF1) is an autosomal dominant genetic disorder that can cause an individual significant chronic pain (CP). CP affects quality of life and daily functioning, yet there are limited effective treatments for CP within NF1. The current study describes the impact of CP using the Neurofibromatosis Pain Module (NFPM). The NFPM is a self-reported clinical assessment that evaluates the impact of CP across multiple domains (e.g., interference, severity, tolerance, and symptomology) and three prioritized pain regions. A cross-sectional study (N = 242) asked adults with NF1 to describe and rate their pain using the NFPM. The results indicated that they reported moderate pain severity (M = 6.6, SD = 2.0) on a 0-10 scale, that 54% (n = 131) had been in pain at least 24 days in the last 30, for 75% (n = 181) sleep was affected, and 16% reported that nothing was effective in reducing their CP for their primary pain region. The current results extend previously published work on CP within adults with NF1 and indicate that more emphasis on understanding and ameliorating CP is required. The NFPM is a sensitive clinical measure that provides qualitative and quantitative responses to inform medical providers about changes in CP.

Schwann cells modulate nociception in neurofibromatosis 1.

Pain of unknown etiology is frequent in individuals with the tumor predisposition syndrome neurofibromatosis 1 (NF1), even when tumors are absent. Nerve Schwann cells (SCs) were recently shown to play roles in nociceptive processing, and we find that chemogenetic activation of SCs is sufficient to induce afferent and behavioral mechanical hypersensitivity in wild-type mice. In mouse models, animals showed afferent and behavioral hypersensitivity when SCs, but not neurons, lacked Nf1. Importantly, hypersensitivity corresponded with SC-specific upregulation of mRNA encoding glial cell line-derived neurotrophic factor (GDNF), independently of the presence of tumors. Neuropathic pain-like behaviors in the NF1 mice were inhibited by either chemogenetic silencing of SC calcium or by systemic delivery of GDNF-targeting antibodies. Together, these findings suggest that alterations in SCs directly modulate mechanical pain and suggest cell-specific treatment strategies to ameliorate pain in individuals with NF1.

NF1 deficiency drives metabolic reprogramming in ER+ breast cancer.

OBJECTIVE: NF1 is a tumor suppressor gene and its protein product, neurofibromin, is a negative regulator of the RAS pathway. NF1 is one of the top driver mutations in sporadic breast cancer such that 27 % of breast cancers exhibit damaging NF1 alterations. NF1 loss-of-function is a frequent event in the genomic evolution of estrogen receptor (ER)+ breast cancer metastasis and endocrine resistance. Individuals with Neurofibromatosis type 1 (NF) - a disorder caused by germline NF1 mutations - have an increased risk of dying from breast cancer [1-4]. NF-related breast cancers are associated with decreased overall survival compared to sporadic breast cancer. Despite numerous studies interrogating the role of RAS mutations in tumor metabolism, no study has comprehensively profiled the NF1-deficient breast cancer metabolome to define patterns of energetic and metabolic reprogramming. The goals of this investigation were (1) to define the role of NF1 deficiency in estrogen receptor-positive (ER+) breast cancer metabolic reprogramming and (2) to identify potential targeted pathway and metabolic inhibitor combination therapies for NF1-deficient ER + breast cancer. METHODS: We employed two ER+ NF1-deficient breast cancer models: (1) an NF1-deficient MCF7 breast cancer cell line to model sporadic breast cancer, and (2) three distinct, Nf1-deficient rat models to model NF-related breast cancer [1]. IncuCyte proliferation analysis was used to measure the effect of NF1 deficiency on cell proliferation and drug response. Protein quantity was assessed by Western Blot analysis. We then used RNAseq to investigate the transcriptional effect of NF1 deficiency on global and metabolism-related transcription. We measured cellular energetics using Agilent Seahorse XF-96 Glyco Stress Test and Mito Stress Test assays. We performed stable isotope labeling and measured [U-13C]-glucose and [U-13C]-glutamine metabolite incorporation and measured total metabolite pools using mass spectrometry. Lastly, we used a Bliss synergy model to investigate NF1-driven changes in targeted and metabolic inhibitor synergy. RESULTS: Our results revealed that NF1 deficiency enhanced cell proliferation, altered neurofibromin expression, and increased RAS and PI3K/AKT pathway signaling while constraining oxidative ATP production and restricting energetic flexibility. Neurofibromin deficiency also increased glutamine influx into TCA intermediates and dramatically increased lipid pools, especially triglycerides (TG). Lastly, NF1 deficiency alters the synergy between metabolic inhibitors and traditional targeted inhibitors. This includes increased synergy with inhibitors targeting glycolysis, glutamine metabolism, mitochondrial fatty acid transport, and TG synthesis. CONCLUSIONS: NF1 deficiency drives metabolic reprogramming in ER+ breast cancer. This reprogramming is characterized by oxidative ATP constraints, glutamine TCA influx, and lipid pool expansion, and these metabolic changes introduce novel metabolic-to-targeted inhibitor synergies.

Epilepsy in Legius syndrome: Coincidence or causation?

Legius syndrome is a rare genetic disorder, caused by heterozygous SPRED1 pathogenic variants, which shares phenotypic features with neurofibromatosis type 1 (NF1). Both conditions typically involve café-au-lait macules, axillary freckling, and macrocephaly; however, patients with NF1 are also at risk for tumors, such as optic nerve gliomas and neurofibromas. Seizure risk is known to be elevated in NF1, but there has been little study of this aspect of Legius syndrome. The reported epilepsy incidence is 3.3%-5%, well above the general population incidence of ~0.5%-1%, but the few reports in the literature have very little data regarding epilepsy phenotype. We identified two unrelated individuals, both with Legius syndrome and epilepsy, and performed thorough phenotyping. One individual's mother also had Legius syndrome and now-resolved childhood epilepsy, as well as reports of more distant relatives who also had multiple café-au-lait macules and seizures. Both probands had experienced childhood-onset focal seizures, with normal brain MRI. In one patient, EEG later showed apparently generalized epileptiform abnormalities. Based on the data from this small case series and literature review, seizure risk is increased in people with Legius syndrome, but the epilepsy prognosis appears to be generally good, with patients having either self-limited or pharmacoresponsive courses.

The role of scoliosis on the comorbidity and demographics of neurofibromatosis type 1 patients: A retrospective analysis of the National Inpatient Sample database.

Neurofibromatosis type 1 (NF1) is the most common neurocutaneous syndrome in the United States, affecting every 1 in 3000 individuals. NF1 occurs due to non-functional mutations in the NF1 gene, which expresses neurofibromin, a protein involved in tumour suppression. As a result, NF1 typically presents with non-cancerous neoplasm masses called neurofibromas across the body. Out of all NF1 abnormalities, the most common skeletal abnormality seen in around 10%-30% of NF1 patients is scoliosis, an improver curvature of the spine. However, there is a lack of research on the effects of scoliosis on demographics and morbidities of NF1 patients. We performed a national analysis to investigate the complex relationship between NF1 and scoliosis on patients' demographics and comorbidities. We conducted a retrospective cross-sectional analysis of the 2017 US National Inpatient Sample database using univariable Chi-square analysis and multivariable binary logistic regression analysis to determine the interplay of NF1 and scoliosis on patients' demographics and comorbidities. Our query resulted in 4635 total NF1 patients, of which 475 (10.25%) had scoliosis and 4160 (89.75%) did not. Demographic analysis showed that NF1 patients with scoliosis were typically younger, female and white compared to NF1 patients without scoliosis. Comorbidity analysis showed that NF1 patients with scoliosis were more likely to develop malignant brain neoplasms, epilepsy, hydrocephalus, pigmentation disorders, hypothyroidism, diabetes with chronic complications and coagulopathy disorders. NF1 patients with scoliosis were less likely to develop congestive heart failure, pulmonary circulation disease, peripheral vascular disease, paralysis, chronic pulmonary disease, lymphoma and psychosis. NF1 patients with scoliosis were predominantly younger, female, white patients. The presence of scoliosis in NF1 patients increases the risks for certain brain neoplasms and disorders but serves a protective effect against some pulmonary and cardiac complications.