Genotype-Phenotype Correlation in Neurofibromatosis Type 1: Evidence for a Mild Phenotype Associated with Splicing Variants Leading to In-Frame Skipping of NF1 Exon 24 [19a].

Neurofibromatosis type 1 (NF1) is an autosomal dominant neurocutaneous disorder caused by loss-of-function variants in the NF1 gene. As of 20 November 2023, over 5000 distinct pathogenic or likely pathogenic variants have been reported in public databases. However, only a few NF1 genotype-phenotype correlations have been established so far. In this study, we present findings on 40 individuals with NF1, comprising 26 unrelated probands and 14 affected relatives, who carry one of nine NF1 heterozygous pathogenic splicing variants, all of which result in the in-frame skipping of exon 24 [19a] (NM_000267.3:r.3114_3197del, p.Asn1039_Arg1066del). These variants include c.3114-2A>G, c.3114-1G>A, c.3196A>G, c.3197G>A, c.3197G>T, c.3197+1G>A, c.3197+1G>T, c.3197+2T>C, and c.3197+3A>T. Among individuals with these variants, none exhibit externally visible plexiform neurofibromas, histopathologically confirmed cutaneous or subcutaneous neurofibromas, symptomatic spinal neurofibromas, or symptomatic optic pathway gliomas. The most prevalent, and sometimes sole, clinical feature observed in this cohort is multiple café-au-lait macules, with or without skinfold freckles: 85% and 60.5% of the individuals display six or more café-au-lait macules and freckles, respectively. In comparison to established NF1 genotype-phenotype correlations, these patients demonstrate highly similar clinical presentations to those associated with the NF1 pathogenic variant c.2970_2972del (p.Met992del), known for resulting in the mildest clinical features. Despite the generally mild phenotype, cognitive impairment, developmental delay, and/or learning difficulties are still observed in 33.3% of these patients, suggesting that learning challenges remain a prominent aspect of the phenotypic presentation in these individuals and necessitate specialized care. This newly established genotype-phenotype correlation will assist clinicians in improving the management of patients harboring NF1 exon 24 [19a] skipping variants and provide a new therapeutic target for NF1 treatment.

Unilateral severe gynecomastia in a 14 year-old adolescent with neurofibromatosis type 1 undergoing endoscopic mastectomy: a case report.

Gynecomastia can be caused by neurofibromas but has rarely been reported. The present case report describes the clinical appearance, diagnosis, and therapy of a rare combination of a 14 year-old adolescent male unilateral severe gynecomastia with NF-1 neurofibromatosis. In this particular case, we successfully performed minimally invasive surgery using endoscopic mastectomy, which not only resulted in a satisfactory appearance but also confirmed the presence of neurofibroma type 1 by detecting typical immunohistochemical indicators associated with the disease. Additionally, we analyzed the gene responsible for the disease, c.1431del: p. F477Lfs*21, based on the patient's family history.

Chemical genetic screens reveal defective lysosomal trafficking as synthetic lethal with NF1 loss.

Neurofibromatosis type 1, a genetic disorder caused by germline mutations in NF1, predisposes patients to the development of tumors, including cutaneous and plexiform neurofibromas (CNs and PNs), optic gliomas, astrocytomas, juvenile myelomonocytic leukemia, high-grade gliomas, and malignant peripheral nerve sheath tumors (MPNSTs), which are chemotherapy- and radiation-resistant sarcomas with poor survival. Loss of NF1 also occurs in sporadic tumors such as glioblastoma (GBM), melanoma, breast, ovarian, and lung cancers. We performed a high-throughput screen for compounds that were synthetic lethal with NF1 loss, which identified several leads, including the small molecule Y102. Treatment of cells with Y102 perturbed autophagy, mitophagy, and lysosome positioning in NF1-deficient cells. A dual proteomics approach identified the BORC complex, which is required for lysosome positioning and trafficking, as a potential target of Y102. Knockdown of a BORC complex subunit using siRNA recapitulated the phenotypes observed with Y102 treatment. Our findings demonstrate that the BORC complex may be a promising therapeutic target for NF1-deficient tumors.

Orbital and Lumbosacral Plexiform Neurofibroma with PTPN11 Mutation: A Form of the RASopathy.

RASopathies are a group that encompasses a spectrum of related disorders caused by mutations linked to the RAS/mitogen-activated protein kinase (RAS/MAPK) pathway, including neurofibromatosis type 1 (NF1), Noonan syndrome (NS), neurofibromatosis-Noonan syndrome (NFNS), Noonan syndrome with multiple lentigines (NSML). Neurofibromas, as a hallmark of NF1, are extremely rare in patients with other RASopathies. Here we present a case of a 39-year-old Chinese male displaying orbital neurofibromas and lumbosacral plexiform neurofibromas. Histopathology of a CT-guided biopsy of the mass revealed it to be a neurofibroma. The targeted sequencing analysis did not find any pathogenic sequence alteration in the NF1 or NF2 causative genes in blood lymphocytes and hypertrophic nerve tissue, and no additional signs of NF1 were detected, thereby not meeting the diagnostic criteria for NF1. However, we identified a heterozygous mutation (c.836A>G, p.Y279C) in the PTPN11 gene, which is one of the key components of the RAS-MAPK signaling pathway and is associated with NS, NFNS, and NSML. Nonetheless, a thorough examination did not reveal any signs of these syndromes in the patient. Consequently, it was inferred that this patient likely falls within the spectrum of the RASopathies. This represents a unique case manifesting as orbital and lumbosacral plexiform neurofibromas carrying a PTPN11 gene mutation, thereby broadening the phenotype spectrum of PTPN11 mutations. Our results also highlight the overlap between RASopathies. Neurofibromas should be considered indicative of a broader spectrum of disorders resulting from mutations in RASopathies other than NF1.

Genetic Rearrangements in Different Salivary Gland Tumors: A Systematic Review.

Salivary gland tumors (SGT) encompass a wide range of neoplasms, each with its own unique histological type and clinical presentation. This review hones in on prevalent subtypes of SGTs, including adenoid cystic carcinoma (ACC), salivary duct carcinoma (SDC), and polymorphous adenocarcinoma (PAC). The articles, identified through specific keywords, were meticulously screened in databases like PubMed, Scopus, Google Scholar, and Web of Science from 2018 to 2023. Eight articles delved into genetic modifications among the selected SGT types. A fusion protein known as MYB-NF1B is typically associated with ACC, promoting cell proliferation while inhibiting apoptosis. The presence of MYB modifications in ACCs is a beacon of hope, as it is linked to a more favorable prognosis. In contrast, SDCs often exhibit HER2 expression. The invasive nature of SGTs contributes to their resistance to treatment. In the case of PAC, the role of PRKD1 is particularly noteworthy. PRKD1, integrated with other genes from the PRKD1/2/3 cluster, helps to differentiate PAC from other diseases. Furthermore, the genetic profiles of KTN1-PRKD1) and PPP2R2A:PRKD1 are distinct. The significant genetic variability among SGTs necessitates meticulous examination. This field is in a constant state of evolution, with new discoveries reshaping our understanding. Genetics is a key player in deciphering SGTs and tailoring treatments. This complex neoplasm demands ongoing research to uncover all genetic influences, thereby enhancing diagnostic methodologies, therapeutic strategies, and patient outcomes.

Sporadic neurofibroma of facial nerve presenting as parotid gland tumor: a rare case report.

Intraparotid gland neurofibroma is a rare benign tumor that arises from Schwann cells of the facial nerve within the parotid gland. This case report discusses a 41-year-old woman who experienced a painless preauricular swelling on her right side for over 5 years. Clinical examination and ultrasound revealed a well-defined mass in the parotid gland. The patient underwent total mass excision, resulting in transient facial nerve dysfunction but complete recovery. These tumors often manifest as solitary masses in the parotid region and may compress nearby structures, causing facial paralysis or numbness. Their diagnosis can be challenging due to similarities with other parotid gland tumors and possible associations with neurofibromatosis. Managing intraparotid tumors, including neurofibromas, involves a multidisciplinary approach with input from cytopathologists, radiologists, and surgeons.

A Comprehensive Overview of NF1 Mutations in Iranian Patients.

Neurofibromatosis type 1 (NF1) is a genetic disorder caused by mutations in the NF1 gene. This disorder shows nearly complete penetrance and high phenotypic variability. We used the whole-exome sequencing technique to identify mutations in 32 NF1 cases from 22 Iranian families. A total of 31 variants, including 30 point mutations and one large deletion, were detected. In eight cases, variants were inherited, while they were sporadic in the remaining. Seven novel variants, including c.5576 T > G, c.6658_6659insC, c.2322dupT, c.92_93insAA, c.4360C > T, c.3814C > T, and c.4565_4566delinsC, were identified. The current study is the largest in terms of the sample size of Iranian NF1 cases with identified mutations. The results can broaden the spectrum of NF1 mutations and facilitate the process of genetic counseling in the affected families.

Case report: Treatment response of NF-1-associated bladder ganglioneuroma to trametinib.

We present the clinical course of a 4-year-old girl with neurofibromatosis type 1-associated, unresectable, symptomatic urinary bladder ganglioneuroma. She was initially trialed on sirolimus without response and subsequently responded to MEK inhibitor trametinib, with improvement clinically and radiographically over 10 months. This report broadens the repertoire of therapeutic strategies for MEK inhibition in diseases related to the MAPK pathway.

Historical Development of Diagnostic Criteria for NF2-related Schwannomatosis.

NF2-related schwannomatosis (NF2; previously termed neurofibromatosis type 2) is a tumor-prone disorder characterized by development of multiple schwannomas and meningiomas. The diagnostic criteria of NF2 have been regularly revised. Clinical criteria for NF2 were first formulated at the National Institutes of Health Consensus Conference in 1987 and revised in 1990. Revised criteria were also proposed by the Manchester group in 1992 and by the National Neurofibromatosis Foundation (NNFF) in 1997. The 2011 Baser criteria improved the sensitivity of diagnostic criteria, particularly for patients without bilateral vestibular schwannomas. Revisions to the Manchester criteria were published in 2019, with replacement of "glioma" by "ependymoma," removal of "neurofibroma," addition of an age limit of 70 years for development of vestibular schwannomas, and introduction of molecular criteria, which led to the most widely used criteria. In 2022, the criteria were reviewed and updated by the international committee of NF experts. In addition to changes in diagnostic criteria, the committee recommended the use of "schwannomatosis" as an umbrella term for conditions that predispose to schwannomas. Each type of schwannomatosis was classified by the gene containing the disease-causing pathogenic variant. Molecular data from NF2 patients led to further clarification of the diagnostic criteria for NF2 mosaic phenotypes. Given all these changes, the diagnostic criteria of NF2 may be confusing. Herein, to help healthcare professionals who diagnose NF2 conditions in the clinical setting, we review the historical development of diagnostic criteria.

Leveraging murine models of the neurofibromatosis type 1 cancer predisposition syndrome to elucidate the cellular circuits that drive pediatric low-grade glioma formation and progression.

Brain tumors are the leading cause of cancer-related death in children, where low-grade gliomas (LGGs) predominate. One common hereditary cause for LGGs involves neurofibromatosis-1 (NF1) gene mutation, as seen in individuals with the NF1 cancer predisposition syndrome. As such, children with NF1 are at increased risk of developing LGGs of the optic pathway, brainstem, cerebellum, and midline brain structures. Using genetically engineered mouse models, studies have revealed both cell-intrinsic (MEK signaling) and stromal dependencies that underlie their formation and growth. Importantly, these dependencies represent vulnerabilities against which targeted agents can be used for preclinical investigation prior to clinical translation.

Lipomatoses.

Lipomatoses are benign proliferation of adipose tissue. Lipomas (benign fat tumors) are the most common component of lipomatosis. They may be unique or multiple, encapsulated or not, subcutaneous or sometimes visceral. In some cases, they form large areas of non-encapsulated fat hypertrophy, with a variable degree of fibrosis. They can develop despite the absence of obesity. They may be familial or acquired. At difference with lipodystrophy syndromes, they are not associated with lipoatrophy areas, except in some rare cases such as type 2 familial partial lipodystrophy syndromes (FPLD2). Their metabolic impact is variable in part depending on associated obesity. They may have functional or aesthetic consequences. Lipomatosis may be isolated, be part of a syndrome, or may be visceral. Isolated lipomatoses include multiple symmetrical lipomatosis (Madelung disease or Launois-Bensaude syndrome), familial multiple lipomatosis, the painful Dercum's disease also called Adiposis Dolorosa or Ander syndrome, mesosomatic lipomatosis also called Roch-Leri lipomatosis, familial angiolipomatosis, lipedema and hibernomas. Syndromic lipomatoses include PIK3CA-related disorders, Cowden/PTEN hamartomas-tumor syndrome, some lipodystrophy syndromes, and mitochondrial diseases, especially MERRF, multiple endocrine neoplasia type 1, neurofibromatosis type 1, Wilson disease, Pai or Haberland syndromes. Finally, visceral lipomatoses have been reported in numerous organs and sites: pancreatic, adrenal, abdominal, epidural, mediastinal, epicardial… The aim of this review is to present the main types of lipomatosis and their physiopathological component, when it is known.

Case Report: Low-grade glioma with NF1 loss of function mimicking diffuse intrinsic pontine glioma.

Intrinsic, expansile pontine tumors typically occur in the pediatric population. These tumors characteristically present as diffuse intrinsic pontine glioma (DIPG), which is now considered as diffuse midline glioma (DMG), H3K27-mutated of the pons. DIPG has limited treatment options and a poor prognosis, and the value of tissue diagnosis from an invasive biopsy remains controversial. This study presents the case of a 19-year-old female with clinical and imaging hallmarks of DIPG, who underwent a biopsy of a tumor in the region of the right middle cerebellar peduncle. Her lesional cells were negative for H3K27M alterations and had low-grade histologic features. Next-generation sequencing revealed a frameshift mutation in the NF1 gene as the likely driver mutation. These features suggest a diagnosis of a low-grade glioma associated with NF1 loss of function, with far-reaching consequences regarding both treatment strategy and prognosis. This case provides support for the utility of diagnostic tissue biopsy in cases of suspected DIPG.

First Co-Occurrence of Griscelli Syndrome Type 2 and Neurofibromatosis Type 1.

Introduction: Griscelli syndrome type 2 (GS2) and neurofibromatosis type 1 (NF1) are both rare genetic disorders, but their coexistence has not been documented prior to this report. Case Presentation: We present the case of a 4-year-old girl initially diagnosed with GS2 due to albinism and immunodeficiency, and later with NF1, manifested by the development of multiple café-au-lait macules (CALMs) and MRI findings. The patient was the second child of consanguineous parents and exhibited symptoms early, with silver-gray hair at birth and subsequent health complications at 9 months. GS2 was confirmed via the identification of a homozygous frameshift variant in the RAB27A gene, and a de novo heterozygous splice site mutation in the NF1 gene established the NF1 diagnosis. Her treatment included hematopoietic stem cell transplantation and ongoing surveillance for NF1-associated complications. Discussion/Conclusion: This case emphasizes the importance of considering the potential for concurrent rare genetic diseases in clinical evaluations, especially with progressive or evolving symptomatology.

Human Genetics of Ventricular Septal Defect.

Ventricular septal defects (VSDs) are recognized as one of the commonest congenital heart diseases (CHD), accounting for up to 40% of all cardiac malformations, and occur as isolated CHDs as well as together with other cardiac and extracardiac congenital malformations in individual patients and families. The genetic etiology of VSD is complex and extraordinarily heterogeneous. Chromosomal abnormalities such as aneuploidy and structural variations as well as rare point mutations in various genes have been reported to be associated with this cardiac defect. This includes both well-defined syndromes with known genetic cause (e.g., DiGeorge syndrome and Holt-Oram syndrome) and so far undefined syndromic forms characterized by unspecific symptoms. Mutations in genes encoding cardiac transcription factors (e.g., NKX2-5 and GATA4) and signaling molecules (e.g., CFC1) have been most frequently found in VSD cases. Moreover, new high-resolution methods such as comparative genomic hybridization enabled the discovery of a high number of different copy number variations, leading to gain or loss of chromosomal regions often containing multiple genes, in patients with VSD. In this chapter, we will describe the broad genetic heterogeneity observed in VSD patients considering recent advances in this field.

K128 ubiquitination constrains RAS activity by expanding its binding interface with GAP proteins.

The RAS pathway is among the most frequently activated signaling nodes in cancer. However, the mechanisms that alter RAS activity in human pathologies are not entirely understood. The most prevalent post-translational modification within the GTPase core domain of NRAS and KRAS is ubiquitination at lysine 128 (K128), which is significantly decreased in cancer samples compared to normal tissue. Here, we found that K128 ubiquitination creates an additional binding interface for RAS GTPase-activating proteins (GAPs), NF1 and RASA1, thus increasing RAS binding to GAP proteins and promoting GAP-mediated GTP hydrolysis. Stimulation of cultured cancer cells with growth factors or cytokines transiently induces K128 ubiquitination and restricts the extent of wild-type RAS activation in a GAP-dependent manner. In KRAS mutant cells, K128 ubiquitination limits tumor growth by restricting RAL/ TBK1 signaling and negatively regulating the autocrine circuit induced by mutant KRAS. Reduction of K128 ubiquitination activates both wild-type and mutant RAS signaling and elicits a senescence-associated secretory phenotype, promoting RAS-driven pancreatic tumorigenesis.

Subperiosteal hematoma as a rare complication of neurofibromatosis 1: A case report and review of the literature.

INTRODUCTION: Subperiosteal hematoma (SPH) is a rare complication of neurofibromatosis type 1 (NF-1) which can be presented spontaneously or after a minor trauma a painful or painless growing lesion. PRESENTATION OF CASE: Here, we presented a 10-year-old boy, a known case of NF-1, who presented with a painless growing leg lesion. The bony wall cystic lesion was suggested based on radiologic and pathologic investigation. During the operation, an SPH was detected and excised completely. DISCUSSION: Consistent with previous reports, our case of subperiosteal hematoma in an NF-1 patient predominantly presented with well-established subperiosteal bone proliferation on plain radiographs, with the hematoma most commonly affecting the tibia. CONCLUSION: The SPH in NF-1 and differentiating it from a malignant transformation should be considered for the rapidly enlarging bony mass.

Visual Deficits and Diagnostic and Therapeutic Strategies for Neurofibromatosis Type 1: Bridging Science and Patient-Centered Care.

Neurofibromatosis type 1 (NF1) is an inherited autosomal dominant disorder primarily affecting children and adolescents characterized by multisystemic clinical manifestations. Mutations in neurofibromin, the protein encoded by the Nf1 tumor suppressor gene, result in dysregulation of the RAS/MAPK pathway leading to uncontrolled cell growth and migration. Neurofibromin is highly expressed in several cell lineages including melanocytes, glial cells, neurons, and Schwann cells. Individuals with NF1 possess a genetic predisposition to central nervous system neoplasms, particularly gliomas affecting the visual pathway, known as optic pathway gliomas (OPGs). While OPGs are typically asymptomatic and benign, they can induce visual impairment in some patients. This review provides insight into the spectrum and visual outcomes of NF1, current diagnostic techniques and therapeutic interventions, and explores the influence of NF1-OPGS on visual abnormalities. We focus on recent advancements in preclinical animal models to elucidate the underlying mechanisms of NF1 pathology and therapies targeting NF1-OPGs. Overall, our review highlights the involvement of retinal ganglion cell dysfunction and degeneration in NF1 disease, and the need for further research to transform scientific laboratory discoveries to improved patient outcomes.

Nf1 deficiency modulates the stromal environment in the pretumorigenic rat mammary gland.

Background: Neurofibromin, coded by the NF1 tumor suppressor gene, is the main negative regulator of the RAS pathway and is frequently mutated in various cancers. Women with Neurofibromatosis Type I (NF1)-a tumor predisposition syndrome caused by a germline NF1 mutation-have an increased risk of developing aggressive breast cancer with poorer prognosis. The mechanism by which NF1 mutations lead to breast cancer tumorigenesis is not well understood. Therefore, the objective of this work was to identify stromal alterations before tumor formation that result in the increased risk and poorer outcome seen among NF1 patients with breast cancer. Approach: To accurately model the germline monoallelic NF1 mutations in NF1 patients, we utilized an Nf1-deficient rat model with accelerated mammary development before presenting with highly penetrant breast cancer. Results: We identified increased collagen content in Nf1-deficient rat mammary glands before tumor formation that correlated with age of tumor onset. Additionally, gene expression analysis revealed that Nf1-deficient mature adipocytes in the rat mammary gland have increased collagen expression and shifted to a fibroblast and preadipocyte expression profile. This alteration in lineage commitment was also observed with in vitro differentiation, however, flow cytometry analysis did not show a change in mammary adipose-derived mesenchymal stem cell abundance. Conclusion: Collectively, this study uncovered the previously undescribed role of Nf1 in mammary collagen deposition and regulating adipocyte differentiation. In addition to unraveling the mechanism of tumor formation, further investigation of adipocytes and collagen modifications in preneoplastic mammary glands will create a foundation for developing early detection strategies of breast cancer among NF1 patients.

Effect of Heat-Treated Lactiplantibacillus plantarum nF1 on the Immune System Including Natural Killer Cell Activity: A Randomized, Placebo-Controlled, Double-Blind Study.

Heat-treated Lactiplantibacillus plantarum nF1 (HT-nF1) increases immune cell activation and the production of various immunomodulators (e.g., interleukin (IL)-12) as well as immunoglobulin (Ig) G, which plays an important role in humoral immunity, and IgA, which activates mucosal immunity. To determine the effect of HT-nF1 intake on improving immune function, a randomized, double-blind, placebo-controlled study was conducted on 100 subjects with normal white blood cell counts. The HT-nF1 group was administered capsules containing 5 × 1011 cells of HT-nF1 once a day for 8 weeks. After 8 weeks of HT-nF1 intake, significant changes in IL-12 were observed in the HT-nF1 group (p = 0.045). In particular, the change in natural killer (NK) cell activity significantly increased in subjects with low secretory (s) IgA (≤49.61 µg/mL) and low NK activity (E:T = 10:1) (≤3.59%). These results suggest that HT-nF1 has no safety issues and improves the innate immune function by regulating T helper (Th)1-related immune factors. Therefore, we confirmed that HT-nF1 not only has a positive effect on regulating the body's immunity, but it is also a safe material for the human body, which confirms its potential as a functional health food ingredient.

Case of embryonal tumor multilayered rosettes in a patient with neurofibromatosis type 1.

BACKGROUND: ETMR is a unique and highly malignant brain tumor mostly occurring in infants. This report provides a comprehensive overview of the clinical presentation, histological aspects, radiological features, and therapeutic options of ETMR. Being the first report on the co-occurrence of NF1 with ETMR, it highlight the challenges of managing a patient with complex medical conditions. CASE REPORT: We present a case of a 3 and 1/2-year-old girl with neurofibromatosis type 1 (NF1), later diagnosed with a supratentorial brain tumor reported as an embryonal tumor with multilayered rosettes (ETMR), along with possible co-occurrence of constitutional mismatch repair deficiency (CMMRD) on immunohistochemistry (IHC); however, germline testing was not performed. Even though NF1 can be associated with tumors such as gliomas, the literature has no previous case reports of ETMR coexisting with NF1. CONCLUSION: Exploring the link between NF1 and ETMR with CMMRD is crucial to improving and establishing more treatment protocols. Therefore, reporting each case's unique features would be essential in developing appropriate treatment protocols.