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BMC Neurology Nov 2023Plexiform neurofibromas (PN) are complex, benign nerve-sheath tumours that occur in 30-50% of patients with neurofibromatosis type 1 (NF1), a rare, genetic disorder. PN...
Impact of neurofibromatosis type 1 with plexiform neurofibromas on the health-related quality of life and work productivity of adult patients and caregivers in the UK: a cross-sectional survey.
BACKGROUND
Plexiform neurofibromas (PN) are complex, benign nerve-sheath tumours that occur in 30-50% of patients with neurofibromatosis type 1 (NF1), a rare, genetic disorder. PN are associated with substantial, heterogeneous morbidities that impact health-related quality of life (HRQoL), including affecting motor function and causing pain, though HRQoL and work productivity data are scarce. This UK cross-sectional study explored HRQoL and work productivity in adult patients with NF1 PN and caregivers of paediatric patients.
METHODS
Adult patients and caregivers of paediatric patients self-enrolled in an online survey (March-April 2021). Outcomes included EQ-5D-5L, PROMIS® GH and INF1-QOL (adult patients only), and EQ-5D-5L, CarerQol and WPAI (caregivers only). Utilities were estimated from EQ-5D-5L responses using the UK crosswalk value set. Linear regression models explored univariable associations between adult patient characteristics and HRQoL.
RESULTS
Mean (± standard deviation) EQ-5D utility in adult patients with NF1 PN was 0.65 (± 0.29; n = 35; age-/sex-matched norm: 0.89 [± 0.04]). Moderate-extreme pain/discomfort and anxiety/depression were reported by 14/35 (40.0%) and 18/35 (51.4%) patients, respectively. Mean PROMIS® GH physical and mental health scores were 43.6 (± 9.19) and 41.7 (± 11.5; n = 35; matched norm: 50.0 [± 10.0]). Mean INF1-QOL score was 11.03 (± 6.02; n = 33). Chronic itching, at least one symptom, at least one comorbidity, PN location at extremities (arms/legs) and pain were associated with worse HRQoL scores. Mean caregiver EQ-5D utility was 0.72 (± 0.24; n = 8; age-/sex-matched norm: 0.88 [± 0.03]). Moderate pain/discomfort and moderate-severe anxiety/depression were reported by 4/8 (50.0%) and 2/8 (25.0%) caregivers, respectively. Mean CarerQol score was 69.3 (± 13.9; n = 8). Mean WPAI regular activity productivity loss was 36.3% (± 31.6%; n = 8).
CONCLUSIONS
NF1 PN worsens adult patient and caregiver HRQoL compared to the general population, notably affecting pain and discomfort, anxiety and depression and caregiver productivity.
Topics: Adult; Child; Humans; Caregivers; Cross-Sectional Studies; Health Status; Neurofibroma, Plexiform; Neurofibromatosis 1; Pain; Quality of Life; Surveys and Questionnaires; United Kingdom
PubMed: 37996843
DOI: 10.1186/s12883-023-03429-7 -
Clinical Trials (London, England) Apr 2024We developed an observer disfigurement severity scale for neurofibroma-related plexiform neurofibromas to assess change in plexiform neurofibroma-related disfigurement...
BACKGROUND/AIMS
We developed an observer disfigurement severity scale for neurofibroma-related plexiform neurofibromas to assess change in plexiform neurofibroma-related disfigurement and evaluated its feasibility, reliability, and validity.
METHODS
Twenty-eight raters, divided into four cohorts based on neurofibromatosis type 1 familiarity and clinical experience, were shown photographs of children in a clinical trial (NCT01362803) at baseline and 1 year on selumetinib treatment for plexiform neurofibromas ( = 20) and of untreated participants with plexiform neurofibromas ( = 4). Raters, blinded to treatment and timepoint, completed the 0-10 disfigurement severity score for plexiform neurofibroma on each image (0 = not at all disfigured, 10 = very disfigured). Raters evaluated the ease of completing the scale, and a subset repeated the procedure to assess intra-rater reliability.
RESULTS
Mean baseline disfigurement severity score for plexiform neurofibroma ratings were similar for the selumetinib group (6.23) and controls (6.38). Mean paired differences between pre- and on-treatment ratings was -1.01 (less disfigurement) in the selumetinib group and 0.09 in the control ( = 0.005). For the disfigurement severity score for plexiform neurofibroma ratings, there was moderate-to-substantial agreement within rater cohorts (weighted kappa range = 0.46-0.66) and agreement between scores of the same raters at repeat sessions ( > 0.05). In the selumetinib group, change in disfigurement severity score for plexiform neurofibroma ratings was moderately correlated with change in plexiform neurofibroma volume with treatment ( = 0.60).
CONCLUSION
This study demonstrates that our observer-rated disfigurement severity score for plexiform neurofibroma was feasible, reliable, and documented improvement in disfigurement in participants with plexiform neurofibroma shrinkage. Prospective studies in larger samples are needed to validate this scale further.
Topics: Child; Humans; Neurofibroma, Plexiform; Neurofibromatosis 1; Prospective Studies; Reproducibility of Results
PubMed: 37877369
DOI: 10.1177/17407745231206402 -
BMC Research Notes Oct 2023In epidemiological and experimental research, high folic acid intake has been demonstrated to accelerate tumor development among populations with genetic and/or...
OBJECTIVE
In epidemiological and experimental research, high folic acid intake has been demonstrated to accelerate tumor development among populations with genetic and/or molecular susceptibility to cancer. Neurofibromatosis type 1 (NF1) is a common autosomal dominant disorder predisposing affected individuals to tumorigenesis, including benign plexiform neurofibromas; however, understanding of factors associated with tumor risk in NF1 patients is limited. Therefore, we investigated whether pregestational folic acid intake modified plexiform-like peripheral nerve sheath tumor risk in a transgenic NF1 murine model.
RESULTS
We observed no significant differences in overall survival according to folate group. Relative to controls (180 days), median survival did not statistically differ in deficient (174 days, P = 0.56) or supplemented (177 days, P = 0.13) folate groups. Dietary folate intake was positively associated with RBC folate levels at weaning, (P = 0.023, 0.0096, and 0.0006 for deficient vs. control, control vs. supplemented, and deficient vs. supplemented groups, respectively). Dorsal root ganglia (DRG), brachial plexi, and sciatic nerves were assessed according to folate group. Mice in the folate deficient group had significantly more enlarged DRG relative to controls (P = 0.044), but no other groups statistically differed. No significant differences for brachial plexi or sciatic nerve enlargement were observed according to folate status.
Topics: Humans; Pregnancy; Female; Animals; Mice; Neurofibromatosis 1; Folic Acid; Neurofibroma; Neurofibroma, Plexiform; Nerve Sheath Neoplasms
PubMed: 37848948
DOI: 10.1186/s13104-023-06515-8 -
Neuro-oncology Advances 2023
PubMed: 37841697
DOI: 10.1093/noajnl/vdad125 -
Frontiers in Oncology 2023Neurofibromatosis Type 1 (NF1) is one of the most common genetically inherited disorders that affects 1 in 3000 children annually. Clinical manifestations vary widely...
Single-cell RNA sequencing of neurofibromas reveals a tumor microenvironment favorable for neural regeneration and immune suppression in a neurofibromatosis type 1 porcine model.
Neurofibromatosis Type 1 (NF1) is one of the most common genetically inherited disorders that affects 1 in 3000 children annually. Clinical manifestations vary widely but nearly always include the development of cutaneous, plexiform and diffuse neurofibromas that are managed over many years. Recent single-cell transcriptomics profiling efforts of neurofibromas have begun to reveal cell signaling processes. However, the cell signaling networks in mature, non-cutaneous neurofibromas remain unexplored. Here, we present insights into the cellular composition and signaling within mature neurofibromas, contrasting with normal adjacent tissue, in a porcine model of NF1 using single-cell RNA sequencing (scRNA-seq) analysis and histopathological characterization. These neurofibromas exhibited classic diffuse-type histologic morphology and expected patterns of S100, SOX10, GFAP, and CD34 immunohistochemistry. The porcine mature neurofibromas closely resemble human neurofibromas histologically and contain all known cellular components of their human counterparts. The scRNA-seq confirmed the presence of all expected cell types within these neurofibromas and identified novel populations of fibroblasts and immune cells, which may contribute to the tumor microenvironment by suppressing inflammation, promoting M2 macrophage polarization, increasing fibrosis, and driving the proliferation of Schwann cells. Notably, we identified tumor-associated /CD274 ( dendritic cells, which represent the first such observation in any NF1 animal model and suggest the role of the upregulation of immune checkpoints in mature neurofibromas. Finally, we observed that cell types in the tumor microenvironment are poised to promote immune evasion, extracellular matrix reconstruction, and nerve regeneration.
PubMed: 37817770
DOI: 10.3389/fonc.2023.1253659 -
Cureus Sep 2023The most common causes of vision loss in neurofibromatosis 1 (NF1) patients are sequelae from tumors such as optic pathway glioma, plexiform neurofibroma, or secondary...
The most common causes of vision loss in neurofibromatosis 1 (NF1) patients are sequelae from tumors such as optic pathway glioma, plexiform neurofibroma, or secondary glaucoma. Here we report the case of a six-year-old female with anisometropic amblyopia resulting from an isolated unilateral macro-ophthalmia with a known history of NF1. Our patient progressed to light perception vision in the left eye due to a non-neoplastic cause associated with NF1 with at least two years of documented unilateral macro-ophthalmia without any ophthalmology referral or evaluation. This case aims to highlight the importance of early and deliberate ophthalmologic examination in all patients with neurofibromatosis 1 to assess for appropriate visual development and early intervention.
PubMed: 37809258
DOI: 10.7759/cureus.44679 -
Journal of Medical Genetics Jan 2024Differential diagnosis between and ) is crucial as treatment and surveillance differ. We report the case of a girl with a clinical diagnosis of sporadic NF1 who...
Differential diagnosis between and ) is crucial as treatment and surveillance differ. We report the case of a girl with a clinical diagnosis of sporadic NF1 who developed a glioblastoma. Immunohistochemistry for MMR proteins identified PMS2 loss in tumour and normal cells and WES showed the tumour had an ultra-hypermutated phenotype, supporting the diagnosis of CMMRD. Germline analyses identified two variants (one pathogenic variant and one classified as variant(s) of unknown significance) in the gene and subsequent functional assays on blood lymphocytes confirmed the diagnosis of CMMRD. The large plexiform neurofibroma of the thigh and the freckling were however more compatible with NF1. Indeed, a PV (variant allele frequencies of 20%, 3% and 9% and in blood, skin and saliva samples, respectively) was identified confirming a mosaicism for NF1. Retrospective analysis of a French cohort identified NF1 mosaicism in blood DNA in 2 out of 22 patients with CMMRD, underlining the existence of early postzygotic PV of gene in patients with CMMRD whose tumours have been frequently reported to exhibit somatic mutations. It highlights the potential role of this pathway in the pathogenesis of CMMRD-associated gliomas and argues in favour of testing MEK inhibitors in this context.
Topics: Female; Humans; Neurofibromatosis 1; Mosaicism; Retrospective Studies; Mismatch Repair Endonuclease PMS2; Neoplastic Syndromes, Hereditary; Brain Neoplasms; Colorectal Neoplasms; DNA Mismatch Repair
PubMed: 37775264
DOI: 10.1136/jmg-2023-109235 -
Acta Neuropathologica Communications Sep 2023Plexiform neurofibroma (PN) is a leading cause of morbidity in children with the genetic condition Neurofibromatosis Type 1 (NF1), often disfiguring or threatening vital...
Plexiform neurofibroma (PN) is a leading cause of morbidity in children with the genetic condition Neurofibromatosis Type 1 (NF1), often disfiguring or threatening vital structures. During formation of PN, a complex tumor microenvironment (TME) develops, with recruitment of neoplastic and non-neoplastic cell types being critical for growth and progression. Due to the cohesive cellularity of PN, single-cell RNA-sequencing is difficult and may result in a loss of detection of critical cellular subpopulations. To bypass this barrier, we performed single-nuclei RNA-sequencing (snRNA-seq) on 8 frozen PN samples, and integrated this with spatial transcriptomics (ST) in 4 PN samples and immunohistochemistry to provide morphological context to transcriptomic data. SnRNA-seq analysis definitively charted the heterogeneous cellular subpopulations in the PN TME, with the predominant fraction being fibroblast subtypes. PN showed a remarkable amount of inter-sample homogeneity regarding cellular subpopulation proportions despite being resected from a variety of anatomical locations. ST analysis identified distinct cellular subpopulations which were annotated using snRNA-seq data and correlated with histological features. Schwann cell/fibroblast interactions were identified by receptor/ligand interaction analysis demonstrating a high probability of Neurexin 1/Neuroligin 1 (NRXN1/NLGN1) receptor-ligand cross-talk predicted between fibroblasts and non-myelinated Schwann cells (NM-SC) and subtypes, respectively. We observed aberrant expression of NRXN1 and NLGN1 in our PN snRNA-seq data compared to a normal mouse sciatic nerve single-cell RNA-seq dataset. This pathway has never been described in PN and may indicate a clear and direct communication pathway between putative NM-SC cells of origin and surrounding fibroblasts, potentially driving disease progression. SnRNA-seq integrated with spatial transcriptomics advances our understanding of the complex cellular heterogeneity of PN TME and identify potential novel communication pathways that may drive disease progression, a finding that could provide translational therapy options for patients with these devastating tumors of childhood and early adulthood.
Topics: Child; Humans; Mice; Animals; Adult; Neurofibromatosis 1; Neurofibroma, Plexiform; Transcriptome; Ligands; RNA, Small Nuclear; Disease Progression; RNA; Tumor Microenvironment
PubMed: 37770931
DOI: 10.1186/s40478-023-01639-1 -
International Journal of Surgery Case... Oct 2023Plexiform neurofibromatosis is a relatively rare manifestation of Type 1 neurofibromatosis (NF-1). This condition leads to gross disfiguration along with functional...
INTRODUCTION
Plexiform neurofibromatosis is a relatively rare manifestation of Type 1 neurofibromatosis (NF-1). This condition leads to gross disfiguration along with functional disability. We are presenting a case of 49 year male with Plexiform neurofibromatosis of lower back. The aim of this rare case report is also to discuss the management difficulties encountered.
PRESENTATION OF CASE
A 49 year male presented to us with gradually increasing swelling over the lower back which was present since his 10 years of age. He had already undergone debulking surgery for the same swelling 10 years back. For the last 2 years the swelling had increased in significant amount. He gave history of similar swellings in his father and grandfather. Proper examination revealed multiple café au lait macules, giant plexiform neurofibroma over lower back and multiple nodular swellings all over the body (neuroma). Biopsy report from previous surgery showed neurofibroma. He underwent debulking surgery. The procedure went for 12 h continuous. Intraoperatively, the mass was highly vascular and excessive bleeding was encountered. About 3 L of blood loss was there and patient received 12 units of blood products.
DISCUSSION
Plexiform neurofibromas are uncommon and may occur in around 30 % patients with NF-1. The genetic defect lies in chromosome 17 that encodes a protein neurofibromin. It causes disfiguration and severe distress to patients. Debulking surgery is one of the treatments to decrease the difficulties occurred from the mass. The aim of this report is to discuss the difficulties occurred in surgical intervention of this rare condition like excessive blood loss.
CONCLUSION
Although timely intervention could limit the disfigurement and morbidity associated with large lesion, due to unpredictable natural course and growth pattern, it is difficult to decide best time to intervene surgically. Registration of such rare case facilitates patient monitoring and development of appropriate treatment protocols.
PubMed: 37716061
DOI: 10.1016/j.ijscr.2023.108812 -
Cureus Aug 2023Plexiform neurofibromas are benign tumors that arise from neuronal cells and are commonly associated with neurofibromatosis type 1 (NF1) patients. However, the...
Plexiform neurofibromas are benign tumors that arise from neuronal cells and are commonly associated with neurofibromatosis type 1 (NF1) patients. However, the occurrence of plexiform neurofibromas in the pharyngeal region is extremely rare. In this particular case, we report the successful diagnosis of a retropharyngeal plexiform neurofibroma in an adult male patient without a history of neurofibromatosis. The diagnosis was made using magnetic resonance imaging (MRI) and confirmed by a biopsy. Following the diagnosis, the tumor was surgically excised, resulting in a successful removal of the neurofibroma.
PubMed: 37711936
DOI: 10.7759/cureus.43480