Theoretical model of impact mitigation mechanisms inherent to the North American bison skull.

North American bison (Bovidae: Bison bison) incur blunt impacts to the interparietal and frontal bones when they engage in head-to-head fights. To investigate the impact mitigation of these bones, a finite element analysis (FEA) of the skull under loading conditions was performed. Based on anatomical and histological studies, the interparietal and frontal bones are both comprised of a combination of haversian and plexiform bone and are both underlain by bony septa. Additionally, the interparietal bone is thicker than the frontal bone. Data regarding the mechanical properties of bison bone are scarce, but the results of a phylogenetic analysis infer that the material properties of the closely related domestic cow bone are a suitable proxy for use in the FEA. Results of the FEA suggest that the thickness of the interparietal bone in conjunction with the bony septa may prevent fracture stresses by helping to absorb and disperse the blunt impact energy throughout the skull. Monotonic stress levels of 294 MPa, which are below the compressive strength of bone were exhibited in the simulated bison head impacts indicating no fracture of the bones.

The role of multimodality imaging in diffuse pelvicoabdominal plexiform neurofibroma: A rare case report.

Pelvicoabdominal plexiform neurofibroma is a rare and complicated form of type 1 neurofibromatosis (NF1), distinguished by developing benign nerve sheath tumors in the pelvis and abdomen. A male patient, aged 26, came to our center with dysuria, abdominal bloating, rectal mucosa prolapses, and trouble walking and moving legs. Physical examination revealed a palpable mass of solid consistency fixed in the pelvic cavity to the abdominal cavity. A large and extensive mass in the pelvic to the abdominal region can be evaluated with multimodality radiological imaging, including ultrasound, computed tomography, and magnetic resonance imaging. Imaging is crucial for diagnosis, evaluation of extension, and early detection of potential malignant transformation in these patients. The patient was scheduled for palliative surgical resection due to the extensive mass; however, he did not survive while waiting for the operation. Pathology examination and immunohistochemical staining revealed positive S-100 protein, indicating the neural crest originate lesion. We report the clinical and radiological features of plexiform neurofibroma in a young male patient, confirmed by pathology examination.

Interocular Symmetry and Intermachine Reproducibility of Optic Disc and Macular Parameters Measured by Two Different Models of Optical Coherence Tomography.

Purpose: To compare the interocular symmetry and investigate the intermachine reproducibility of optic disc and macular data measured by spectral-domain high-definition optical coherence tomography (HD-OCT) Cirrus HD-OCT 4000 and HD-OCT 5000 from healthy subjects. Patients and Methods: Forty-three volunteers were examined with both HD-OCT 4000 and HD-OCT 5000 at the same visit. Optic nerve head (ONH) and macular data were acquired using ONH Cube 200×200 scans and macular volume cube 512×128 scans, respectively. Results: The average age of the participants was 33 ± 8.6 years. Interocular OCT parameters of ONH and macula showed a high correlation between the right and left eyes regardless of HD-OCT models, displaying a low coefficient of variation (CV). However, the average retinal nerve fiber layer (RNFL) was thicker (96.67±11.19µm vs 95.3±10.89µm, p<0.01), and the average central subfield thickness (261.51±17.45µm vs 262.51±17.39 µm, p<0.01) and cube average thickness (283.91± 13.59µm vs 286.55±13.09µm, p<0.05) were thinner when measured by Cirrus 4000 compared to 5000. Intermachine reproducibility and reliability of RNFL and macular parameters exhibited a high intraclass correlation coefficient (ICC) (0.985) and low CV (2.4%). Ganglion cell-inner plexiform layer (GCIPL) measured by two OCT models showed similar values with an average thickness of 85 µm and had high intermachine reproducibility with high ICC (0.993) and low CV (1.2%). Conclusion: High interocular symmetry was observed across both HD-OCT models. Intermachine reproducibility for RNFL and all macular parameters was also high. GCIPL showed minimal intermachine differences with high reproducibility and reliability. Thus, the results imply that GCIPL values measured by two Cirrus OCT models may be used interchangeably.

Successful utilization of topical trametinib for neurofibromatosis type I-associated plexiform neurofibroma.

An 11-year-old female with neurofibromatosis type 1 (NF-1) and history of optic glioma presented with a progressive cutaneous plexiform neurofibroma of the breast. The lesion was treated with topical application of a mitogen-activated protein kinase inhibitor, trametinib, resulting in stable, non-progression cutaneous plexiform neurofibroma for greater than 2 years. This case demonstrates the potential application of topical trametinib for NF1-associated superficial cutaneous plexiform neurofibroma without the toxicities associated with systemic treatment.

Consensus recommendations on management of selumetinib-associated adverse events in pediatric patients with neurofibromatosis type 1 and plexiform neurofibromas.

Background: Selumetinib is the first approved treatment for pediatric patients with neurofibromatosis type 1 (NF1) and symptomatic, inoperable plexiform neurofibromas (PN) in the EU and US, as well as in multiple other countries. Evidence for the management of selumetinib-associated adverse events (AEs) is mostly limited to clinical trials and expanded-access programs. We gathered a panel of European healthcare practitioners with clinical experience prescribing selumetinib and/or managing pediatric patients with NF1-PN to provide recommendations on the prevention and management of AEs. Methods: A modified Delphi approach was used to develop the recommendations among the group of experts. Initial statements were developed from a literature review of current management recommendations and regulatory reports. The panel refined the statements and rated the extent to which they agreed with them in 2 sessions and a follow-up survey. The panel comprised 2 pediatric neuro-oncologists, 1 pediatric oncologist, 1 pediatrician, 1 neuropediatrician, 1 oncologist, 1 neurologist, 2 psychologists, and 1 dermatologist. Results: The experts agreed on the relative frequency and impact of AEs potentially associated with selumetinib. Consensus-level agreement was reached for 36 statements regarding the prevention and management of AEs potentially associated with selumetinib. Experts recommended treatments for AEs based on their experience. Conclusions: The development of a variety of consensus statements indicates expert agreement on best practices for the prevention and management of AEs potentially associated with selumetinib in pediatric patients with NF1-PN. These events are generally manageable and should be considered alongside treatment benefit. Information sharing is warranted as further experience is gained.

Molecular insights into hybrid tumors: Exploring the heterogeneity in plexiform ameloblastoma.

For many years, odontogenic tumors have been known to present both clinical and histopathological challenges due to their origins in the epithelial, ectomesenchymal, and/or mesenchymal components of tooth-forming tissues. Gaining a comprehensive understanding of both common and rare odontogenic tumors is crucial for their effective study and clinical management. One particularly puzzling tumor is the "plexiform ameloblastoma," a variant of the solid multicystic ameloblastoma. This term describes a distinct pattern of epithelial proliferation within the cystic cavity. Numerous studies have emphasized the variability of the stromal component, further highlighting the enigmatic nature of ameloblastoma. The presence of unique and rare features, such as primitive, mature desmoplastic, hemangiomatous, or ghost cells within the stroma of plexiform ameloblastoma, underscores the differentiation potential of the neoplastic odontogenic epithelium and offers significant insights into the tissue reactions associated with this condition. This case review discusses four instances of plexiform ameloblastoma, illustrating various atypical stromal changes and their influence on patient prognosis. It also provides important criteria for analyzing stromal alterations related to this complex odontogenic tumor.

Murine Retina Outer Plexiform Layer Development and Transcriptome Analysis of Pre-Synapses in Photoreceptors.

Photoreceptors in the mammalian retina convert light signals into electrical and molecular signals through phototransduction and transfer the visual inputs to second-order neurons via specialized ribbon synapses. Two kinds of photoreceptors, rods and cones, possess distinct morphology and function. Currently, we have limited knowledge about rod versus (vs.) cone synapse development and the associated genes. The transcription factor neural retina leucine zipper (NRL) determines the rod vs. cone photoreceptor cell fate and is critical for rod differentiation. Nrl knockout mice fail to form rods, generating all cone or S-cone-like (SCL) photoreceptors in the retina, whereas ectopic expression of Nrl using a cone-rod homeobox (Crx) promoter (CrxpNrl) forms all rods. Here, we examined rod and cone pre-synapse development, including axonal elongation, terminal shaping, and synaptic lamination in the outer plexiform layer (OPL) in the presence or absence of Nrl. We show that NRL loss and knockdown result in delayed OPL maturation and plasticity with aberrant dendrites of bipolar neurons. The integrated analyses of the transcriptome in developing rods and SCLs with NRL CUT&RUN and synaptic gene ontology analyses identified G protein subunit beta (Gnb) 1 and p21 (RAC1) activated kinase 5 (Pak5 or Pak7) transcripts were upregulated in developing rods and down-regulated in developing SCLs. Notably, Gnb1 and Gnb5 are rod dominant, and Gnb3 is enriched in cones. NRL binds to the genes of Gnb1, Gnb3, and Gnb5. NRL also regulates pre-synapse ribbon genes, and their expression is altered in rods and SCLs. Our study of histological and gene analyses provides new insights into the morphogenesis of photoreceptor pre-synapse development and regulation of associated genes in the developing retina.

Giant sciatic nerve schwannoma: a rare case report and literature review.

Introduction and importance: Schwannomas are benign tumors that arise from Schwann cells commonly located in peripheral nerves. Depending on the size and location of sciatic nerve Schwannoma clinical manifestations can either varies from symptoms simulating radiculopathies such as positive Lasegue sign on the affected side, gait weakness and paresthesia or just present with pain and an associated palpable mass. Case presentation: The authors present a case of a 34-year-old female patient suffering from pain, gait weakness, and a palpable mass since many months. The palpable mass was present in the posterior region of the left lower limb. Imaging studies reveal an extensive lesion measuring 35 cm×8 cm that extends from the gluteal region to the left popliteal fossa. Clinical discussion: The finding of a palpable mass during physical examination guided us towards the diagnostic suspicion and thus necessitating the direct imaging studies. When approaching such type of patients, a history of neurofibromatosis must be ruled out due to its frequent association. Surgical resection should focus on the preservation of neurovascular structures, which offers improvement of the symptoms and the quality of life of patients. Conclusion: Giant sciatic nerve schwannoma if excised completely can lead to relieve of symptoms. Although recurrences are uncommon follow-up for years is necessary.

Myxoid variant of plexiform fibrohistiocytic tumor: case report.

Background: Plexiform fibrohistiocytic tumor (PFH) is a rarely metastasizing slowly growing neoplasm usually affecting children and young adults. The tumor usually has a dermal-subcutaneous location, is poorly circumscribed, and is comprised of a plexiform or multinodular proliferation of a variable admixture of fibroblasts and histiocytoid cells with a distinctive biphasic morphology. Myxoid change in PFH is extremely rare with only five cases of myxoid variant of PFH reported to date in the English literature. Case Description: In this case report, the author describes a rare case in a 39-year-old man who had presented with a newly developed right forearm mass. Given the tumor's unusual morphology an extensive immunohistochemical and molecular workup was performed to rule out common superficial myxoid neoplasms and potential mimickers. The overall ancillary findings along with the histomorphologic features and immunoprofile of the entirely excised mass were eventually compatible with myxoid PFH. Conclusions: Myxoid PFH is a rare or underrecognized entity that can present as a diagnostic pitfall and can lead to an erroneous diagnosis especially if the pathologist is unaware of such entity. In this case report the author sheds light on this unique tumor, myxoid PFH, discusses the pitfalls inherent to its differential diagnosis, and reviews the literature on such a rare phenomenon.

Plexiform's perplexities: a tale of two plexiform neurofibromas.

Plexiform neurofibroma (PF) is a rare benign variant belonging to a subtype of neurofibromatosis type 1 that forms bulging or deforming masses arising from the peripheral nerve sheath. These masses involve surrounding connective tissue or dermal layers, leading to multiple cutaneous changes and certain characteristic appearances. It is these appearances that aid in the diagnosis of PF. We have encountered two distinct patients diagnosed with this disorder. While one patient was clinically and pathologically confirmed for PF, the other had no characteristic cutaneous changes. The diagnosis was made with postoperative histopathology and confirmed with an immunohistochemical examination. There are various modalities in the management of PFs, with surgery being a mainstay in the treatment of disfiguring large PFs, especially in resource-restrained settings. In view of high recurrence rates, postoperative clinical follow-up is a must. This paper describes these patients' typical and atypical clinical presentation and subsequent management.

Plexiform Neurofibroma: A Case Report.

Neurofibromatosis is a group of genetic disorders that primarily impact the growth of neural tissues, leading to multiple tumors on nerve tissues in the brain, spinal cord, and peripheral nerves. As an autosomal dominant condition, it involves mutations in the neurofibromatosis type 1 (NF1) tumor-suppressor gene, inherited in a recessive manner. Plexiform neurofibroma is a rare manifestation. It is a benign peripheral nerve sheath tumor that grows beneath the skin or deeper within tissues without clear boundaries. The diverse presentations of NF1 necessitate careful, personalized medical management to address the disorder's effects on various organs. Due to its progressive nature, early diagnosis is crucial to prevent complications. Comprehensive care, including psychological support and long-term monitoring, is essential for enhancing the quality of life of NF1 patients. By adopting a proactive and holistic approach, healthcare providers can better assist patients in managing this complex condition.

Reduced PTPRS expression promotes epithelial-mesenchymal transition of Schwann cells in NF1-related plexiform neurofibromas.

Plexiform neurofibromas (PNFs) are a prevalent and severe phenotype associated with NF1, characterized by a high teratogenic rate and potential for malignant transformation. The growth and recurrence of PNFs are attributed to aberrant proliferation and migration of Nf1-deficient Schwann cells. Protein tyrosine phosphatase receptor S (PTPRS) is believed to modulate cell migration and invasion by inhibiting the EMT process in NF1-derived malignant peripheral nerve sheath tumors. Nevertheless, the specific role of PTPRS in NF1-derived PNFs remains to be elucidated. The study utilized the GEO database and tissue microarray to illustrate a decrease in PTPRS expression in PNF tissues, linked to tumor recurrence. Furthermore, the down- and over-expression of PTPRS in Nf1-deficient Schwann cell lines resulted in the changes of cell migration and EMT processes. Additionally, RTK assay and WB showed that PTPRS knockdown can promote EGFR expression and phosphorylation. The restoration of EMT processes disrupted by alterations in PTPRS levels in Schwann cells can be achieved through EGFR knockdown and EGFR inhibitor. Moreover, high EGFR expression has been significantly correlated with poor prognosis. These findings underscore the potential role of PTPRS as a tumor suppressor in the recurrence of PNF via the regulation of EGFR-mediated EMT processes, suggesting potential targets for future clinical interventions.

Correlation of Macular Ganglion Cell Layer + Inner Plexiform Layer (GCL + IPL) and Circumpapillary Retinal Nerve Fiber Layer (cRNFL) Thickness in Glaucoma Suspects and Glaucomatous Eyes.

Purpose: The study aimed to correlate macular ganglion cell layer + inner plexiform layer (GCL + IPL) thickness and circumpapillary retinal nerve fiber layer (cRNFL) thickness and to determine the validity of GCL + IPL in the evaluation of glaucoma across different stages using the area under the curve (AUC) analysis in comparison to cRNFL. Patients and Methods: The charts of 260 adult glaucoma suspect and glaucoma patients having macular ganglion cell analysis, optical coherence tomography (OCT) of the cRNFL and automated visual field (AVF) were reviewed. GCL + IPL thickness (average, minimum and sectoral) and sectoral cRNFL thickness were obtained. Glaucomatous eyes were further classified into stages based on the Hodapp-Anderson-Parrish Visual Field Criteria of Glaucoma Severity. AUC analysis was used to compare GCL + IPL parameters with cRNFL in glaucoma suspects and glaucoma patients. Results: A total of 122 eyes were included in the study and were grouped into glaucoma suspects (n = 43), early or mild glaucoma (n = 40), and moderate-to-severe glaucoma (n = 39). Both GCL + IPL and cRNFL thickness parameters showed a significant decline with greater glaucoma severity. In the determination of visual field defects across all glaucoma stages, the highest AUC was obtained by minimum GCL + IPL (AUC = 0.859) with cut-off value at ≤70 µm. Average GCL + IPL had the highest AUC (0.835) in detecting progression from glaucoma suspect to mild glaucoma, while the inferior sector of the cRNFL had the highest AUC (0.937) in discerning mild from moderate-to-severe glaucoma. Conclusion: The results of this study highlight the significance of macular ganglion cell analysis in the screening, detection and staging of glaucoma. Compared to cRNFL, macular ganglion analysis may be more beneficial in glaucoma screening and detecting progression from glaucoma suspect to mild glaucoma.

Assessment of ganglion cell complex thickness and its correlation with retinal sensitivity using microperimetry 6 months after epiretinal membrane surgery.

PURPOSE: To verify the correlation between the full-macular and the ganglion cell complex (GCC) thickness measurements and retinal sensitivity (RS) assessed by microperimetry (MP) 6 months after surgical peeling for idiopathic epiretinal membrane (ERM). METHODS: Forty-three were submitted to pars-plana posterior vitrectomy (PPV) with concomitant peeling of internal limiting membrane (ILM) for idiopathic ERM treatment. Best-corrected visual acuity (BCVA) and 3D volumetric high-definition optical coherence tomography (OCT) imaging were preoperatively acquired. Six months after the surgery, BCVA, OCT imaging, and RS measured by MP were assessed. For the OCT parameters, we analyzed both the full-macular and the ganglion cell layer complex (GCC) thicknesses. The MP parameters tested were 44 points covering 20 central degrees (6 mm), with direct correspondence with the nine sectors of the OCT-ETDRS map. This approach enables the direct topographic correlation between the structure and functional measurements. The OCT and MP exam measurements were also performed in 43 eyes of age-matched healthy controls. Correlations between BCVA, RS, and OCT parameters were examined. RESULTS:  All patients exhibited a substantial improvement in visual acuity following surgery. The RS parameters were significantly lower in patients compared to the controls. The full-macular thickness measurements were thicker than controls preoperatively and significantly reduced postoperatively; however, remaining significantly higher than controls, in the 4 inner sectors, at the fovea and for the average macular thickness. Preoperative GCC measurements were higher than those in controls. There was a significant reduction in GCC thickness in all sectors postoperatively, especially in the outer sectors, as well as in the average macular thickness. A positive correlation was found between full-macular and GCC thickness and RS postoperatively in several sectors. CONCLUSIONS: Our results demonstrate that ERM peeling can improve visual acuity in the postoperative period. However, RS may not fully restore, remaining significantly lower when compared to the controls. Both full-macular and GCC thickness measurements were reduced 6 months after surgery. However, significant thinning of the GCC thickness was observed when compared to the normal control eyes, indicating the occurrence of some degree of ganglion cell layer atrophy. We have demonstrated significant correlations among various OCT thickness parameters, particularly for GCC measurements. We believe that GCC integrity may play an important role in visual function after ERM surgery, and that MP may help better understand the correlations between structural and functional findings following ERM surgery.

Investigating therapeutic nonsense suppression in a neurofibromatosis mouse model.

Neurofibromatosis type 1 (NF1) is a human genetic disorder caused by variants in the NF1 gene. Plexiform neurofibromas, one of many NF1 manifestations, are benign peripheral nerve sheath tumors occurring in up to 50% of NF1 patients. A substantial fraction of NF1 pathogenetic variants are nonsense mutations, which result in the synthesis of truncated non-functional NF1 protein (neurofibromin). To date, no therapeutics have restored neurofibromin expression or addressed the consequences of this protein's absence in NF1 nonsense mutation patients, but nonsense suppression is a potential approach to the problem. Ataluren is a small molecule drug that has been shown to stimulate functional nonsense codon readthrough in several models of nonsense mutation diseases, as well as in Duchenne muscular dystrophy patients. To test ataluren's potential applicability in nonsense mutation NF1 patients, we evaluated its therapeutic effects using three treatment regimens in a previously established NF1 patient-derived (c.2041C > T; p.Arg681X) nonsense mutation mouse model. Collectively, our experiments indicate that: i) ataluren appeared to slow the growth of neurofibromas and alleviate some paralysis phenotypes, ii) female Nf1-nonsense mutation mice manifested more severe paralysis and neurofibroma phenotypes than male mice, iii) ataluren doses with apparent effectiveness were lower in female mice than in male mice, and iv) age factors also influenced ataluren's effectiveness.

A Fibroblast-Derived Secretome Stimulates the Growth and Invasiveness of 3D Plexiform Neurofibroma Spheroids.

Plexiform neurofibromas (PNs) occur in about a half of neurofibromatosis type 1 (NF1) patients and have garnered significant research attention due to their capacity for growth and potential for malignant transformation. NF1 plexiform neurofibroma (pNF1) is a complex tumor composed of Schwann cell-derived tumor cells (Nf1-/-) and the tumor microenvironment (TME). Although it has been widely demonstrated that the TME is involved in the formation of neurofibromas, little is known about the effects of the TME on the subsequent progression of human pNF1. Elucidating the molecular interactions between tumor cells and the TME may provide new therapeutic targets to reduce the progression of pNF1. In the present study, we focused on the contributions of fibroblasts, the most abundant cell types in the TME, to the growth of pNF1. To simulate the TME, we used a three-dimensional (3D) coculture model of immortalized pNF1 tumor cells (Nf1-/-) and primary fibroblasts (Nf1+/-) derived from pNF1 patients. We performed live-cell imaging of 3D/4D (3D in real-time) cultures through confocal microscopy followed by 3D quantitative analyses using advanced imaging software. The growth of pNF1 spheroids in 3D cocultures with fibroblasts was significantly greater than that of pNF1 spheroids in 3D monocultures. An increase in the growth of pNF1 spheroids also occurred when they were cultured with conditioned media (CM) from fibroblasts. Moreover, fibroblast-derived CM increased the invasive outgrowth and further local invasion of pNF1 spheroids. Interestingly, when small extracellular vesicles (sEVs) were depleted from the fibroblast-derived CM, the stimulation of the growth of pNF1 spheroids was lost. Our results suggest that fibroblast-derived sEVs are a therapeutic target for reducing the growth of pNF1.

Prediction of the Cause of Glaucoma Disease Identified by Glaucoma Optical Coherence Tomography Test in Relation to Diabetes and Hypertension at a National Hospital in Seoul: A Retrospective Study.

Glaucoma remains the primary cause of long-term blindness. While diabetes mellitus (DM) and hypertension (HTN) are known to influence glaucoma, other factors such as age and sex may be involved. In this retrospective study, we aimed to investigate the associations between age, sex, DM, HTN, and glaucoma risk. We employed optical coherence tomography (OCT) conducted using a 200 × 200-pixel optic cube (Cirrus HD OCT 6000, version 10.0; Carl Zeiss Meditec, Dublin, CA, USA). Effects obscured by low-test signals were disregarded. Data were amassed from 1337 patients. Among them, 218 and 402 patients had DM and HTN, respectively, with 133 (10%) exhibiting both. A sex-based comparison revealed slightly greater retinal nerve fiber layer (RNFL) and ganglion cell-inner plexiform layer (GCIPL) thickness in females. Patients without DM and HTN were predominantly in their 50 s and 60 s, whereas DM and HTN were most prevalent in those in their 60 s and 70 s. Both RNFL and GCIPL thicknesses decreased with advancing age in most patients. The study revealed that older individuals were more prone to glaucoma than younger individuals, with a higher incidence among patients with DM and HTN and reduced RNFL and GCIPL thicknesses. Furthermore, early detection before advancing age could furnish valuable preventive insights.

Ameloblastoma With the Hybrid Desmoplastic and Plexiform Pattern: A Case Report.

Ameloblastoma is an epithelial odontogenic tumor with a benign nature and demonstrates local aggressiveness. It frequently occurs between the third and fifth decades of life, showing significant gender predilection. While typically displaying a benign growth pattern, it tends to invade and sporadically metastasize locally. Ameloblastoma is predominantly found in the posterior regions. Periodic recur commonly follows insufficient treatment. Hence, conducting thorough identification of tumors and management is crucial to prevent relapse. Complications and improved prognosis are associated with meticulous surgical techniques, regular follow-up care, and early detection of recurrence. This study presented a report of a 19-year-old male with swelling in the left lower jaw, detailing its area of complaint, radiographic findings, histopathologic characteristics, and different treatment approaches. The uniqueness of the case is the hybrid histopathology of ameloblastoma composed of plexiform and desmoplastic variants.

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.

Safety and efficacy of selumetinib in pediatric and adult patients with neurofibromatosis type 1 and plexiform neurofibroma.

BACKGROUND: The MEK inhibitor, selumetinib, reduces plexiform neurofibroma (PN) in pediatric patients with neurofibromatosis type 1 (NF1). Its safety and efficacy in adults with PN and effectiveness in other NF1manifestations (e.g., neurocognitive function, growth reduction, and café-au-lait spots) are unknown. METHODS: This open-label, phase 2 trial enrolled 90 pediatric or adult NF1 patients with inoperable, symptomatic, or potentially morbid, measurable PN (≥ 3 cm). Selumetinib was administered at doses of 20 or 25 mg/m2 or 50 mg q 12 hrs for 2 years. Pharmacokinetics, PN volume, growth parameters, neurocognitive function, café-au-lait spots, and quality of life (QoL) were evaluated. RESULTS: Fifty-nine children and 30 adults (median age, 16 years; range, 3-47) received an average of 22±5 (4-26) cycles of selumetinib. Eighty-eight (98.9%) out of 89 per-protocol patients showed volume reduction in the target PN (median, 40.8%; 4.2%-92.2%), and 81 (91%) patients showed partial response (≥ 20% volume reduction). The response lasted until cycle 26. Scores of neurocognitive functions (verbal comprehension, perceptual reasoning, processing speed, and full-scale IQ) significantly improved in both pediatric and adult patients (P <0.05). Prepubertal patients showed increases in height score and growth velocity (P <0.05). Café-au-lait spot intensity decreased significantly (P <0.05). Improvements in QoL and pain scores were observed in both children and adults. All adverse events were CTCAE grade 1 or 2 and were successfully managed without drug discontinuation. CONCLUSION: Selumetinib decrease PN volume in the majority of pediatric and adult NF1 patients while also showing efficacy in non-malignant diverse NF1 manifestations.