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Pediatric Neurology Dec 2023Neurofibromatosis type 1 (NF1) is the most common neurocutaneous disease and is caused by mutations in the NF1 gene. The most common clinical features of NF1 are...
BACKGROUND
Neurofibromatosis type 1 (NF1) is the most common neurocutaneous disease and is caused by mutations in the NF1 gene. The most common clinical features of NF1 are pigmentary abnormalities such as café-au-lait spots and inguinal or axillary freckling, cutaneous and plexiform neurofibromas, hamartomas of the iris, optic gliomas, and bone lesions. The aim of this retrospective study was to define the clinical and molecular characteristics of a pediatric sample of NF1, as well as the mutational spectrum and genotype-phenotype correlation.
METHODS
The study included 40 children with clinically suspected NF1. The patients were screened for NF1 mutations by DNA-based sequencing. In addition, all the patients were studied by multiplex ligation-dependent probe amplification (MLPA) to identify any duplications or deletions in NF1. The demographic, clinical, and genetic features of the children were characterized.
RESULTS
A total of 40 children with NF1 were included. Of those, 28 were female and 12 were male. The mean age was 8.91 years. An NF1 variant was discovered in 28 of 40 patients (70%). Among these mutations, intronic mutations were the most frequently detected mutations; 15 of these variants had not been previously reported. Only one patient had a whole NF1 gene deletion.
CONCLUSIONS
This study expands the spectrum of mutations in the NF1 gene. This study also showed that genetic screening using both next-generation sequencing and MLPA had a positive effect on diagnosis and genetic counseling in patients with suspected NF1.
Topics: Child; Female; Humans; Male; Hamartoma; Neurofibroma, Plexiform; Neurofibromatosis 1; Optic Nerve Glioma; Retrospective Studies
PubMed: 37806041
DOI: 10.1016/j.pediatrneurol.2023.08.036 -
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 -
Hand Surgery & Rehabilitation Dec 2023Plexiform neurofibroma is a benign peripheral nerve-sheath tumor, rarely involving major nerves of the extremities. In the literature, there are no clear treatment...
Plexiform neurofibroma is a benign peripheral nerve-sheath tumor, rarely involving major nerves of the extremities. In the literature, there are no clear treatment strategies for plexiform neurofibroma of major peripheral nerves. Our experience encountered two patients with plexiform neurofibroma of the median nerve, presenting with a palmar mass and symptoms of carpal tunnel compression. Preoperatively, plexiform neurofibroma was diagnosed on MRI and clinical examination. Both patients also experienced significant neurological deterioration, with finger numbness and increased nerve/tumor size. Potential malignant transformation was also considered. For these reasons, resection of the involved area of the nerve and repair were indicated. In both patients, intraoperative pathological diagnosis was plexiform neurofibroma. The 45-year-old male patient refused further surgery after carpal tunnel release, which was performed under axillary block. One year postoperatively, nerve compression symptoms decreased moderately. In the other patient, a 7-year-old boy, a significantly enlarged area of the median nerve was resected, and neurorrhaphy was performed. One year postoperatively, median nerve motor-sensory functions recovered completely. Four years postoperatively, no enlargement of the residual tumor was observed.
Topics: Male; Humans; Middle Aged; Child; Neurofibroma, Plexiform; Median Nerve; Hamartoma; Carpal Tunnel Syndrome; Peripheral Nervous System Neoplasms; Upper Extremity
PubMed: 37714515
DOI: 10.1016/j.hansur.2023.08.007 -
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 -
Pediatric Clinics of North America Oct 2023Neurofibromatosis type I (NF1) is a common dominantly inherited disorder, and one of the most common of the RASopathies. Most individuals with NF1 develop plexiform... (Review)
Review
Neurofibromatosis type I (NF1) is a common dominantly inherited disorder, and one of the most common of the RASopathies. Most individuals with NF1 develop plexiform neurofibromas and cutaneous neurofibromas, nerve tumors caused by NF1 loss of function in Schwann cells. Cell culture models and mouse models of NF1 are being used to test drug efficacy in preclinical trials, which led to Food and Drug Administration approval for use of MEK inhibitors to shrink most inoperable plexiform neurofibromas. This article details methods used for testing in preclinical models, and outlines newer models that may identify additional, curative, strategies.
Topics: United States; Humans; Animals; Mice; Child; Neurofibromatosis 1; Neurofibroma, Plexiform
PubMed: 37704352
DOI: 10.1016/j.pcl.2023.05.007 -
Urology Annals 2023Neurofibromatosis of the genitourinary tract is rare, with a prevalence of 0.65%, and it is exceedingly rare to involve the external genitalia. Involvement of the...
Neurofibromatosis of the genitourinary tract is rare, with a prevalence of 0.65%, and it is exceedingly rare to involve the external genitalia. Involvement of the clitoris, labia majora, and prepuce was reported with clitoromegaly being the most frequently occurring. Herein, we are reporting the case of a 6-year-old girl who was diagnosed with a neurofibroma of the clitoris; measuring 9.4 cm in its largest dimension. To the best of our knowledge, this is the largest clitoral neurofibroma reported in the literature. Due to the rarity of such cases and reports limitations in the literature, the diagnosis of neurofibroma of the external genitalia requires a high index of suspicion by health-care providers. Surgical excision and postoperative follow-up for possible recurrence remain the gold standard of management.
PubMed: 37664088
DOI: 10.4103/ua.ua_86_22 -
Indian Journal of Otolaryngology and... Sep 2023Ganglioneuromas (GNs) are slow-growing, benign tumors arising from Schwann cells, gangliocytes, and neuronal tissues. We report a rare intraparotid ganglioneuroma in a...
Ganglioneuromas (GNs) are slow-growing, benign tumors arising from Schwann cells, gangliocytes, and neuronal tissues. We report a rare intraparotid ganglioneuroma in a 42-year-old female presented with a parotid mass. The onset of the lesion dated back to 2021, but the growth was remarkable only in November 2022. The FNA suggested a plexiform neurofibroma. The post-surgical microscopic examination of the excised lesion revealed neoplastic large, rounded cells with abundant, finely granular eosinophilic cytoplasm and a large, eccentric nucleus with a prominent nucleolus as well as fasciculated, with an elongated cytoplasm with fine fibrillar extensions. No mitosis or tumor necrosis was observed. The periphery of the tumor showed perineural entrapment. The immunohistochemical staining for S100 protein, synaptophysin, and chromogranin A were positive. However, the neoplastic cells showed no immunoreactivity for cytokeratin (CK5/6, CK7, AE1/AE3), epithelial membrane antigen, HMB45, Melan A, CD30, CD117 and p40. The case was signed out as mature intraparotid ganglioneuroma. The treatment of choice was surgical resection without adjuvant radiotherapy. No recurrence or post-surgical complications were hitherto reported. To the best of our knowledge, this is the first reported case of intraparotid ganglioneuroma. Caution should be taken not to diagnose this benign neoplasm as a metastasis (e.g. metastatic neuroblastoma) or to request unnecessary overtreatment (e.g., postoperative chemotherapy and radiotherapy).
PubMed: 37636636
DOI: 10.1007/s12070-023-03800-7 -
The Keio Journal of Medicine Aug 2023Neurofibromatosis 1 (NF1), also known as von Recklinghausen disease, is one of the most common neurocutaneous genetic disorders. Loss of function of the NF1 gene results...
Neurofibromatosis 1 (NF1), also known as von Recklinghausen disease, is one of the most common neurocutaneous genetic disorders. Loss of function of the NF1 gene results in overactivation of the RAS/MAPK pathway, leading to neurocutaneous manifestations and osseous abnormalities. Because of medical progress, molecular testing for NF1 after genetic counseling is now available in Japan. In addition, revised diagnostic criteria for NF1 were proposed by NF1 experts of an international panel in 2021. Because the overall degree of severity and manifestations in each patient are not predictable, age-specific annual monitoring and patient education by a multidisciplinary team are important for the management of NF1. Although treatment of plexiform neurofibroma has been challenging, selumetinib (an oral selective MEK1/2 inhibitor), which targets a pathway downstream of RAS, was approved in 2022 for use in children with inoperable, symptomatic plexiform neurofibromas in Japan. This article summarizes recent progress in diagnosis, clinical characteristics, and treatment of various manifestations of NF1 and proposes the future direction required to resolve unmet needs in patients with NF1 in Japan.
PubMed: 37635082
DOI: 10.2302/kjm.2023-0013-IR