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Pediatric Dermatology Apr 2024A 4-month-old male presented for a large, hypertrichotic brown patch on the upper back with several scattered 0.5-1.5 cm, round to oval, brown macules and patches on...
A 4-month-old male presented for a large, hypertrichotic brown patch on the upper back with several scattered 0.5-1.5 cm, round to oval, brown macules and patches on the trunk and extremities. The lesion was initially diagnosed as a giant congenital melanocytic nevus based on clinical exam and histopathology with immunohistochemical stains. The patient was later diagnosed with neurofibromatosis type 1, and the lesion on the back developed a "bag of worms" texture consistent with a plexiform neurofibroma and found to harbor a pathogenic variant in the NF1 gene. This case highlights the diagnostic challenge of differentiating these lesions and their overlapping clinical and histopathological features.
PubMed: 38561464
DOI: 10.1111/pde.15611 -
Journal of Maxillofacial and Oral... Sep 2023Facial plexiform neurofibromas (FPNF) are rare tumors frequently diagnosed in patients with neurofibromatosis type 1 (NF1), a tumor predisposition syndrome. FPNF often...
INTRODUCTION
Facial plexiform neurofibromas (FPNF) are rare tumors frequently diagnosed in patients with neurofibromatosis type 1 (NF1), a tumor predisposition syndrome. FPNF often grows invasively and destructively, which may complicate surgical treatment. Data on the frequency, location, and surgical procedures of patients with NF1-associated FPNF are scarce. This study provides treatment data from a nationally networked reference center for the treatment of NF1 patients.
MATERIAL AND METHODS
The localization and treatment data of 179 NF1 patients with FPNF were analyzed. Photographically documented tumors of the study area, further determined by imaging, were manually transferred to a facial scheme and digitized. The digitized registrations of the facial extensions of the tumors of each patient were overlaid in a single image (Photoshop™), so that the file of the facial scheme contained the sum of the tumor localization. Finally, the frequency of tumor localization was indicated with a color code. The frequency of tumor extension-related coded colors was applied to outline the lesions' topography on schematic face drawings (heat map).
RESULTS
The distribution of the tumors showed no side preference. The need for the treatment of patients with orbital/periorbital manifestations became evident in the graphic representations. Tumors do not respect anatomical units. However, the classification of the face according to dermatomes, especially the trigeminal nerve, offers indications of tumor spread and guides treatment planning. The mean number of surgical measures per patient was 2.21 (median: 1). Extensive swelling, hematoma, and delayed wound healing were all common postoperative complications.
CONCLUSION
The color-coded, schematic overview of the frequency distribution of cutaneous tumor spread in NF1 patients with FPNF illustrates the importance of orbital/periorbital and cheek tumor manifestations in patients' treatment needs. The imaging procedure is suitable for controlling natural tumor growth in the same way as the documentation of the post-surgical course. Repeated interventions in the region are included in surgical planning of the progressing tumor disease.
PubMed: 37534339
DOI: 10.1007/s12663-022-01838-8 -
International Journal of Oral and... Dec 2023Neurofibromas are frequently present in the skin, but are uncommon in the oral and maxillofacial region. There are three histological variants of neurofibroma:...
Neurofibromas are frequently present in the skin, but are uncommon in the oral and maxillofacial region. There are three histological variants of neurofibroma: localized, diffuse, and plexiform. The plexiform histological variant of neurofibroma is the least common and is a rare occurrence in the oral cavity. Furthermore, plexiform neurofibroma is usually pathognomonic of neurofibromatosis type 1. A case of solitary plexiform neurofibroma of the tongue with no evidence of neurofibromatosis in a 50-year-old female Chinese patient is reported here. The lesion presented as a single, large, well-circumscribed rounded mass in the left hemi-tongue. The tumour was completely excised. No recurrence was observed at the 6-month follow-up.
Topics: Female; Humans; Middle Aged; Neurofibroma, Plexiform; Neurofibromatosis 1; Neurofibroma; Tongue; Head
PubMed: 37080888
DOI: 10.1016/j.ijom.2023.03.014 -
Journal of Neuro-oncology May 2024Neurofibromatosis type 1 (NF1) is an autosomal dominant disorder which commonly causes neoplasms leading to disfigurement or dysfunction. Mitogen-activated protein...
PURPOSE
Neurofibromatosis type 1 (NF1) is an autosomal dominant disorder which commonly causes neoplasms leading to disfigurement or dysfunction. Mitogen-activated protein kinase inhibitors (MEKi) are generally well-tolerated treatments which target neural tumor progression in patients with NF1. However, cutaneous adverse events (CAEs) are common and may hinder patients' abilities to remain on treatment, particularly in children. We aim to characterize CAEs secondary to MEKi treatment in pediatric and young adult patients with NF1.
METHODS
We reviewed institutional medical records of patients under 30 years with a diagnosis of "NF1," "NF2," or "other neurofibromatoses" on MEKi therapy between January 1, 2019 and June 1, 2022. We recorded the time-to-onset, type, and distribution of CAEs, non-cutaneous adverse events (AEs), AE management, and tumor response.
RESULTS
Our cohort consisted of 40 patients with NF1 (median age, 14 years). Tumor types included low-grade gliomas (51%) and plexiform neurofibromas (38%). MEKi used included selumetinib (69%), trametinib (25%), and mirdametinib (6%). A total of 74 CAEs occurred, with 28 cases of acneiform rash (38%). Other common CAEs were paronychia, seborrheic dermatitis, eczema, xerosis, and oral mucositis. The most common treatments included oral antibiotics and topical corticosteroids. Most patients had clinical (stable or improved) tumor response (71%) while 29% had tumor progression while on a MEKi. There was no significant association between CAE presence and tumor response (p = 0.39).
CONCLUSIONS
Improvement in characterization of MEKi toxicities and their management is important to develop treatment guidelines for pediatric and young adult patients with NF1 on MEKi therapy.
Topics: Humans; Neurofibromatosis 1; Female; Male; Adolescent; Child; Young Adult; Adult; Protein Kinase Inhibitors; Retrospective Studies; Child, Preschool; Neurofibroma, Plexiform; Follow-Up Studies; Drug Eruptions; Prognosis
PubMed: 38443692
DOI: 10.1007/s11060-024-04617-2 -
Clinical Cancer Research : An Official... May 2024
PubMed: 38690594
DOI: 10.1158/1078-0432.CCR-24-0635 -
Epilepsy Research May 2024Studies 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,...
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% (CI=6-18%) and point prevalence 7% (CI= 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% (CI=3-65) and specificity of 99% (CI=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; CI=2.2-674.7; p<0.01), learning disability (OR: 5.7; CI=1.0-31.5; p<0.05), and no plexiform neurofibroma (OR: 0.05; CI=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.
Topics: Humans; Neurofibromatosis 1; Epilepsy; Male; Female; Adult; Prevalence; Young Adult; Electroencephalography; Phenotype; Middle Aged; Genotype; Adolescent; Magnetic Resonance Imaging; Prospective Studies
PubMed: 38471245
DOI: 10.1016/j.eplepsyres.2024.107336 -
Neuro-oncology Sep 2023Plexiform neurofibromas can transform into atypical neurofibromas (ANF) and then further progress to aggressive malignant peripheral nerve sheath tumors (MPNST). ANF...
BACKGROUND
Plexiform neurofibromas can transform into atypical neurofibromas (ANF) and then further progress to aggressive malignant peripheral nerve sheath tumors (MPNST). ANF have been described to harbor distinct histological features and frequent loss of CDKN2A/B. However, histological evaluation may be rater-dependent, and detailed knowledge about the molecular mechanisms of malignant transformation is scarce. In general, malignant transformation can be accompanied by significant epigenetic changes, and global DNA methylation profiling is able to differentiate relevant tumor subgroups. Therefore, epigenetic profiling might provide a valuable tool to distinguish and characterize ANF with differing extent of histopathological atypia from neurofibromas and MPNST.
METHODS
We investigated 40 tumors histologically diagnosed as ANF and compared their global methylation profile to other peripheral nerve sheath tumors.
RESULTS
Unsupervised class discovery and t-SNE analysis indicated that 36/40 ANF cluster with benign peripheral nerve sheath tumors with clear separation from MPNST. 21 ANF formed a molecularly distinct cluster in proximity to schwannomas. Tumors in this cluster had a frequent heterozygous or homozygous loss of CDKN2A/B and significantly more lymphocyte infiltration than MPNST, schwannomas, and NF. Few ANF clustered closely with neurofibromas, schwannomas, or MPNST, raising the question, whether diagnosis based on histological features alone might pose a risk to both over- and underestimate the aggressiveness of these lesions.
CONCLUSIONS
Our data suggest that ANF with varying histological morphology show distinct epigenetic similarities and cluster in proximity to benign peripheral nerve sheath tumor entities. Future investigations should pay special respect to correlating this methylation pattern to clinical outcomes.
Topics: Humans; Neurofibromatosis 1; Neurofibrosarcoma; Neurofibroma; Nerve Sheath Neoplasms; Neurofibromatoses; Neurilemmoma; Epigenesis, Genetic
PubMed: 36866403
DOI: 10.1093/neuonc/noad053 -
Future Oncology (London, England) May 2024This summary describes a publication about a study called SPRINT. The SPRINT study included 50 children with neurofibromatosis type 1 (NF1) and plexiform neurofibroma... (Clinical Trial)
Clinical Trial
WHAT IS THIS SUMMARY ABOUT?
This summary describes a publication about a study called SPRINT. The SPRINT study included 50 children with neurofibromatosis type 1 (NF1) and plexiform neurofibroma (PN) that could not be removed with surgery. PNs are tumors that grow along nerves and can cause various problems for children, such as pain, changes to appearance, and muscle weakness. In SPRINT, the study team wanted to learn whether a medication called selumetinib was able to shrink the PN caused by NF1 (also known as NF1-related PN), and if shrinking PNs helped relieve children of the problems caused by it. To assess how selumetinib might help, children had scans to measure the size of their PN, completed questionnaires, and had a variety of other tests done by their doctor. Their caregivers also completed questionnaires about their child. The children took selumetinib capsules twice a day on an empty stomach.
WHAT WERE THE RESULTS?
The results showed that selumetinib was able to shrink the PN for most children (68%). The results also showed that the problems caused by the children's PNs mostly improved while on selumetinib treatment. SPRINT also showed that the side effects of selumetinib were mainly mild and could be managed by doctors.
WHAT DO THE RESULTS MEAN?
Before SPRINT, there were not many treatment options for children with NF1 and PN as there were no medications that had been shown to shrink PN, and surgery was not always possible. SPRINT showed that this medication shrinks most PNs and could help children with NF1 and PN. In April 2020, selumetinib was approved by the US Food and Drug Administration (FDA) because of the results of SPRINT. Selumetinib was the first and, as of February 2024, is the only medicine that can be prescribed by doctors to help children with NF1-related PN. : NCT01362803 (SPRINT) (ClinicalTrials.gov).
Topics: Adolescent; Child; Child, Preschool; Female; Humans; Male; Benzimidazoles; Neurofibroma, Plexiform; Neurofibromatosis 1; Protein Kinase Inhibitors; Treatment Outcome
PubMed: 38869947
DOI: 10.2217/fon-2023-0565 -
Journal of Clinical and Experimental... Mar 2024Neurofibromatosis type 1 (NF1) is an autosomal dominant inherited tumor predisposition disease with a highly variable phenotype. The influence of the characteristic NF1...
BACKGROUND
Neurofibromatosis type 1 (NF1) is an autosomal dominant inherited tumor predisposition disease with a highly variable phenotype. The influence of the characteristic NF1 tumors (neurofibromas) on dentition has not yet been examined in detail. The aim of the study was to assess the dentition of NF1 children and adolescents, considering the symmetry of tooth development.
MATERIAL AND METHODS
The panoramic radiographs of 59 patients with a confirmed NF1 diagnosis were compared with 59 age-and-sex-matched controls. The stages of tooth development on the sides of the jaw, added to a score, were assessed. In addition, the number of filled or decayed teeth, and the number of retained or missing teeth were assessed.
RESULTS
The tooth development of both study groups is symmetrical for almost all parameters and in the same developmental stage according to the sum score of the tooth development stages. Discrete developmental delays of teeth, in particular in the oral area of facial plexiform neurofibroma (PNF) are noticeable. NF1 patients' teeth showed less decay and more restorations than that of the control group. The facial PNF (FPNF) does not impair emergence of deciduous teeth.
CONCLUSIONS
Development of dentition of NF1 patients does not differ from the general population. However, FPNF with oral tumor components often prevent mesial movement of permanent molars and premolars, so these teeth do not develop contact (spacing), hardly emerge or may stay retained in bone. Oral PNF may have a low-retarding effect on some tooth root development (e.g., wisdom teeth). This effect is negligible when comparing the affected and unaffected sides of the jaw and is probably non-specific. Neurofibromatosis type 1, plexiform neurofibroma, dentition, mixed dentition, symmetry, oral health, tooth development.
PubMed: 38600934
DOI: 10.4317/jced.61363 -
Clinical Neuropathology May 2024Expression patterns of key proteins involved in RAS signaling and connected pathways were determined and correlated to possibly provide information for therapeutic...
AIMS
Expression patterns of key proteins involved in RAS signaling and connected pathways were determined and correlated to possibly provide information for therapeutic application of RAS inhibitors in neurofibromatosis type 1 (NF1)-associated peripheral nerve sheath tumors (PNST).
MATERIALS AND METHODS
Clinical variables (age, sex), histological parameters (cell density, mitoses), and expression of immunohistochemically evaluated ligand and receptor proteins (neuregulin 1 (NRG1), ErbB2, ErbB3), RAS pathway proteins (mTor, Rho, phosphorylated MEK), transcription factors (Pax7, Sox9), and proliferation marker Ki-67, were correlated in cutaneous (CNF, n = 136), diffuse (DNF, n = 123)/diffuse plexiform (DPNF, n = 113), and plexiform neurofibroma (PNF, n = 126), and in malignant PNST (MPNST, n = 22).
RESULTS
In CNF, NRG1 correlated with Ki-67 and Pax7. Further, mTOR correlated with ErbB3, Sox9, Pax7, and Ki-67. In DNF/DPNF, expression of NRG1 correlated with pMEK and Pax7. mTOR correlated with pMEK, Sox9, and Pax7. Noteworthy, pMEK was weakly expressed in some DNF but not in DPNF. ErbB3 correlated with mTor and Ki-67. Furthermore, Rho correlated with Pax7 and Ki-67. In PNF, ErbB3 expression was associated with Sox9, mTOR, pMEK, and Pax7 as well as mTOR with Sox9 and Pax7, Rho with pMEK and Pax7, and pMEK with Pax7 and Sox9. In MPNST, only few correlations were observed, ErbB2 correlated with Ki-67, and Rho with pMEK.
CONCLUSION
Signaling networks of the RAS pathway could be retraced by correlation analysis of protein expression in subgroups of NF1 associated benign PNST. In regard to treatment of PNST, MEK inhibitors, which are presently evaluated for PNF, may possibly also be effective to some extent in DNF.
PubMed: 38818730
DOI: 10.5414/NP301624