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Juvenile xanthogranuloma is the most frequent form of non-Langerhans cell histiocytosis in children. Clinically, it presents as well defined, yellowish papules that are typically located on the head, neck, upper trunk, and proximal region of the extremities. Although solitary lesions are the most common presentation, few cases of multiple juvenile xanthogranuloma have been described, more frequently associated with extracutaneous involvement. We report a 2-month-old girl with 22 cutaneous papules, clinically and histologically compatible with juvenile xanthogranulomas. Screening of visceral involvement was performed with no evidence of systemic disease. Identifying high-risk factors of systemic disease in patients with multiple juvenile xanthogranuloma is essential to perform an appropriate management of this entity.

Purpose: Although ophthalmic manifestations of neurofibromatosis Type 1 (NF1), including iris Lisch nodules and optic gliomas, have been well described, retinal involvement in these patients has yet to be established. Characterizing the relationship between NF1 and the retina is necessary to optimize outcomes for these patients. Methods: Independent chart review of NF1 patients was conducted. Results: Chart review yielded four patients, with a history of NF1, with subsequent retinal dialysis and rhegmatogenous retinal detachment. These four patients presented to our institution with a rhegmatogenous retinal detachment secondary to a retinal dialysis with no history of trauma. These patients also demonstrated hyperreflective choroidal abnormalities on near-infrared reflectance imaging and optical coherence tomography. Conclusion: Seeing that patients diagnosed with NF1 are susceptible to various ocular manifestations and pathological abnormalities, routine ophthalmic examinations are essential in maintaining their ocular health and minimizing morbidity. [ABSTRACT FROM AUTHOR]

Objective: To evaluate the literature and summarize cochlear implantation (CI) outcomes after intralabyrinthine schwannoma (ILS) excision and tumor observation with CI. Data Sources: OVID Medline, Embase, Web of Science; conception to 2024. Review Methods: A literature review was performed using subject headings, MeSH terms, and keywords. Abstracts and full texts were reviewed by two independent reviewers and adjudicated by a third. Inclusion criteria included studies with ILS and CI with reported audiologic outcomes. Subjects were analyzed into two groups, ILS resection with CI and in situ ILS with CI. Patients with NF2 were included. The main outcome of interest was CI audiometric performance level, with secondary outcomes of CI user status and open‐set speech attainment. Results: There were 29 articles with a total of 93 patients who met inclusion criteria. The resection group had 17% low performers, 44% intermediate performers, and 38% high performers. The in situ group had 40% low performers, 32% intermediate performers, 27% high performers. The resection group had 69 patients with 97% maintaining user status and 92% with open‐set speech recognition. The observation group had 24 patients, with 87% user rate and 86% achieving open‐set speech recognition. There was a greater percentage of NF2 diagnosis seen in the in situ group. Conclusion: There is a paucity of literature on CI and ILS. Patients are managed with both resection of tumor and implantation in situ. Early data are limited, with improvement in hearing outcomes and high user rates in both populations. Level of Evidence: N/A Laryngoscope, 134:3910–3920, 2024 [ABSTRACT FROM AUTHOR]

Objective: To integrate pharmacovigilance and network toxicology methods to explore the potential adverse drug events (ADEs) and toxic mechanisms of selumetinib, and to provide a reference for quickly understanding the safety and toxicological mechanisms of newly marketed drugs. Methods: Taking selumetinib as an example, this study integrated pharmacovigilance methods based on real-world data and network toxicology methods to analyze its ADE and its potential toxicological mechanism. First, the ADE reports of selumetinib were extracted from the US Food and Drug Administration (FDA) adverse event reporting system (FAERS), and the ADE signals were detected by reporting odds ratio (ROR) and UK medicines and healthcare products regulatory agency (MHRA) methods. The ADE signals were classified and described according to the preferred terms (PTs) and system organ class (SOC) derived from the Medical Dictionary for Regulatory Activities (MedDRA). The network toxicology method was used to analyze the toxicological mechanism of the interested SOCs. The specific steps included predicting the potential targets of selumetinib using TOXRIC, STITCH, ChEMBL, CTD, SwissTargetPreditcion, and Super-PRED databases, collecting the targets of SOC using GeneCards database, conducting protein-protein interaction (PPI) analysis through STRING database, conducting gene ontology (GO) and Kyoto encyclopedia of genes and genomes (KEGG) analysis through DAVID database, and testing the molecular affinity using AutoDock software. Results: A total of 1388 ADE reports related to selumetinib were extracted, and 53 positive signals were detected by ROR and MHRA methods, of which 20 signals were not mentioned in the package insert, including ingrowing nail, hyperphosphatemia, cardiac valve disease, hematuria, neutropenia, etc. Analysis of the toxicological mechanism of six SOCs involved in positive ADE signals revealed that the key targets included EGFR, STAT3, AKT1, IL6, BCL2, etc., and the key pathways included PI3K/Akt pathway, apoptosis, ErbB signaling pathway, and EGFR tyrosine kinase inhibitor resistance, etc. Molecular docking assays showed spontaneous binding of selumetinib to key targets in these pathways. Conclusion: The pharmacovigilance analysis identified some new potential ADEs of selumetinib, and the network toxicology analysis showed that the toxic effects of selumetinib may be related to PI3K/Akt pathway, apoptosis, ErbB signaling pathway, EGFR tyrosine kinase inhibitor resistance and other pathways. [ABSTRACT FROM AUTHOR]

Trametinib, an MEK inhibitor, may offer a new therapeutic option for patients with NF1-related GIST. [ABSTRACT FROM AUTHOR]

Background: Neurofibromatosis 1 is a form of phacomatosis or neurocutaneous disease inherited as an autosomal dominant disease. Thoracic involvement is rare and involves the lung parenchyma, mediastinum, and thoracic cage, including ribs and the spine. Lung parenchymal involvement includes airspace abnormalities like cysts, bullae, and emphysema with an upper lobe predominance and interstitial abnormality in the form of reticulations and fibrosis in the lower lobes. The structural abnormality of the lung resembles numerous other diseases. Hence, properly identifying and recognizing neurofibromatosis 1-associated diffuse lung disease (NF-1 DLD) is crucial in avoiding misdiagnosis. NF1-DLD is associated with many complications like pulmonary hypertension, lung malignancy, aspergilloma, secondary bacterial infections, and pneumothorax. Case presentation: An elderly male with neurofibromatosis type-1 presented with breathlessness, cough, and mucopurulent expectoration and was found to have diffuse involvement of the lung parenchyma involving cysts, bullae, emphysema, fibrosis, and traction bronchiectasis. He was managed conservatively, controlling infection and optimizing respiratory symptoms. Conclusion: Neurofibromatosis-associated diffuse lung disease is a rare disorder. There is no definitive treatment that can reverse the pulmonary lesions. However, early diagnosis will help plan effective preventive measures and avoid complications. We present this case to increase awareness regarding the various pulmonary manifestations of neurofibromatosis. [ABSTRACT FROM AUTHOR]

En bloc resection is required for treatment of intermediate-grade talar tumors with extraosseous extension (Enneking stage 3) and malignant talar tumors without intra-articular invasion (Enneking stages IA and IIA). After resection, reconstruction options include tibiocalcaneal fusion, frozen autograft, and talar prosthesis; however, a talar prosthesis is preferable because it preserves ankle range of motion, does not cause leg length discrepancy, and is associated with good long-term outcomes. To the best of our knowledge, en bloc resection and reconstruction of a malignant talar tumor has not been previously reported in detail. We report a detailed surgical technique for en bloc resection of a malignant talar bone tumor using combined anterior and lateral approaches followed by reconstruction using a talar prosthesis. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Background: Non-melanocytic benign skin tumours encompass a diverse group of lesions, classified based on their cellular origin, such as epidermal, vascular, fibrous, neural, muscle, and adnexal tumours. Though they often reveal solitary lesions, multiple skin tumours focus on genodermatoses. Each syndrome exhibits distinct clinical characteristics and potential complications, including cutaneous and extra-cutaneous malignancies, some of which are potentially life-threatening. Diagnosing genetic syndromes is complex and requires numerous histopathological and immunohistochemistry tests due to similarities between the adnexal tumours and basal cell carcinoma upon pathology. Methods: To illustrate the clinical practice, we conducted a retrospective case study that included eleven patients with genodermatoses referred to a tertiary dermatology clinic from September 2018 to April 2024. We have also conducted a research study on available treatment modalities in this setting. Results: Five patients with excellent aesthetic results were treated using a recently approved FDA plasma device. After searching SCOPUS and PubMed database records, we assessed 96 original articles to present current knowledge regarding the dermato-surgical approach. Conclusions: Multiple skin tumours, especially on the face, may significantly affect patients' quality of life and have psychological consequences. An appropriate treatment selection tailored to the patient's needs should be provided. There is no standardised treatment for multiple benign tumours in genodermatoses, and selected methods with varying efficacy are employed. We presented the utility of a new plasma device in these settings. [ABSTRACT FROM AUTHOR]

Background Neurofibromatosis type 1, NF2 -related schwannomatosis and non- NF2 -related schwannomatosis (grouped under the abbreviation "NF") are rare hereditary tumor predisposition syndromes. Due to the low prevalence, variability in the range, and severity of manifestations, as well as limited treatment options, these conditions require innovative trial designs to accelerate the development of new treatments. Methods Within European Patient-Centric Clinical Trial Platforms (EU-PEARL), we designed 2 platform-basket trials in NF. The trials were designed by a team of multidisciplinary NF experts and trial methodology experts. Results The trial will consist of an observational and a treatment period. The observational period will serve as a longitudinal natural history study. The platform trial design and randomization to a sequence of available interventions allow for the addition of interventions during the trial. If a drug does not meet the predetermined efficacy endpoint or reveals unacceptable toxicities, participants may stop treatment on that arm and re-enter the observational period, where they can be re-randomized to a different treatment arm if eligible. Intervention-specific eligibility criteria and endpoints are listed in intervention-specific-appendices, allowing the flexibility and adaptability needed for highly variable and rare conditions like NF. Conclusions These innovative platform-basket trials for NF may serve as a model for other rare diseases, as they will enhance the chance of identifying beneficial treatments through optimal learning from a small number of patients. The goal of these trials is to identify beneficial treatments for NF more rapidly and at a lower cost than traditional, single-agent clinical trials. [ABSTRACT FROM AUTHOR]

Objectives: To determine the natural history of hearing loss and tumor volume in patients with untreated neurofibromatosis type 2 (NF2)-related schwannomatosis. Moreover, we statistically examined the factors affecting hearing prognosis. Methods: This retrospective cohort study was conducted on 37 ears of 24 patients with NF2-related vestibular schwannomatosis followed up without treatment for more than 1 year. We obtained detailed chronological changes in the PTA and tumor volume in each case over time, and the rate of change per year was obtained. Multivariate analysis was also conducted to investigate factors associated with changes in hearing. Results: The average follow-up period was approximately 9 years, and hearing deteriorated at an average rate of approximately 4 dB/year. The rate of maintaining effective hearing decreased from 30 ears (81%) at the first visit to 19 ears (51%) at the final follow-up. The average rate of change in tumor growth for volume was approximately 686.0 mm3/year. This study revealed that most patients with NF2 experienced deterioration in hearing acuity and tumor growth during the natural course. A correlation was observed between an increase in tumor volume and hearing loss (r = 0.686; p < 0.001). Conclusions: Although the hearing preservation rate in NF2 cases is poor with the current treatment methods, many cases exist in which hearing acuity deteriorates, even during the natural course. Patients with an increased tumor volume during the follow-up period were more likely to experience hearing deterioration. Trial registration number 20140242 (date of registration: 27 October 2014). [ABSTRACT FROM AUTHOR]

Congenital pseudarthrosis of the forearm bones (CPFBs) is rare, with only 106 reported cases, and is frequently associated with neurofibromatosis (NF). Approximately 5% of patients with NF develop pseudarthrosis, and 50% of patients with pseudarthrosis have NF. Achieving bone union is difficult in congenital pseudarthrosis. Many methods have been attempted, including casting, internal fixation with or without grafting, and electrical stimulation, but failure is frequent. Free vascularized fibular flaps (FVFs) have been used to bridge long bone defects since 1975 and in tibial pseudarthrosis since 1979. In CPFB, FVF is more successful than other methods in achieving union and is the current treatment of choice. Here, we presented three cases of forearm pseudarthrosis treated with FVF, reviewed the literature on CPFB, and discussed some technical aspects of FVF treatment. Three cases of congenital pseudoarthrosis were treated with free fibula flaps, diagnosed at ages of 7 years (ulna), 15 months (radius), and 9 years (radius and ulna). Two flaps were stabilized with intramedullary wires and latterly, one with compression plates. One persistent nonunion received revision nonvascularized bone grafting and plating. All patients achieved union by 11 months after index surgery. Reconstruction with vascularized fibula is the treatment of choice because it offers the highest published union rates and good functional results. Complete resection of the affected bone and stable fixation, latterly with compression plates are critical to success. Surgery is technically demanding, and complications are common. Secondary surgery may be required, but outcomes are favorable. IV [ABSTRACT FROM AUTHOR]

Purpose: Selumetinib is an FDA-approved targeted therapy for plexiform neurofibromas in neurofibromatosis type 1(NF1) with durable response rates seen in most, but not all patients. In this proof-of-concept study, we demonstrate single-cell RNA sequencing(scRNAseq) as a technique for quantifying drug response to selumetinib at the single cell level. Methods: scRNAseq data from neurofibroma biopsies was obtained from a public genomics repository. Schwann cell populations were identified through standard clustering techniques and single-cell selumetinib sensitivity was quantified on a scale of 0(resistant) to 1(sensitive) based on the expression pattern of a 500 gene selumetinib sensitivity signature from the BeyondCell sensitivity library. Results: A total of seven plexiform neurofibromas were included in our final analysis. The median absolute number of Schwann cells across samples was 658 cells (IQR: 1,029 cells, Q1-Q3: 135 cells to 1,163 cells). There was a statistically significant difference in selumetinib sensitivity profiles across samples (p < 0.001). The tumor with the highest median selumetinib sensitivity score had a median selumetinib sensitivity score of 0.64(IQR: 0.14, Q1-Q3: 0.59–0.70, n = 112 cells) and the tumor with the lowest median selumetinib sensitivity score had a median score of 0.37 (IQR: 0.21, Q1-Q3: 0.27–0.48, n = 1,034 cells). Conclusions: scRNAseq of plexiform neurofibroma biopsies reveals differential susceptibilities to selumetinib on a single cell level. These findings may explain the partial responses seen in clinical trials of selumetinib for NF1 and demonstrate the value of collecting scRNAseq data for future NF1 trials. [ABSTRACT FROM AUTHOR]

The skin manifestations of neurofibromatosis 1 significantly reduce health‐related quality‐of‐life. However, data on the utility of existing surveys in capturing neurofibromatosis 1 skin treatment outcomes are lacking. This quantitative study examined the relationship between clinician‐rated severity and visibility and patient‐rated itch and quality‐of‐life (QoL) to (1) establish baseline levels of skin‐ and condition‐specific‐related QoL, itch, depression and anxiety; (2) identify patient concerns to inform the development and evaluation of skin interventions; and (3) compare the sensitivity of different QoL measures. Validated scales included Skindex‐29, Dermatology Life Quality Index (DLQI), Neurofibromatosis 1‐adult quality‐of‐life (NF1‐AdQOL) questionnaire, and the Hospital Anxiety and Depression Scale (HADS). We recruited 100 participants (response rate: 95%). Of these, 42% reported itch and 23% had probable clinical anxiety. Our cohort had higher levels of anxiety and total HADS scores compared to a control population. Using multivariate regression analysis, increasing visibility significantly predicted poorer QoL using the Skindex‐29, NF1‐AdQOL, and DLQI (p < 0.05); and itch significantly predicted worse QoL in Skindex‐29 and NF1‐AdQOL (p < 0.05). The highest mean scoring questions in Skindex‐29 and NF1‐AdQOL concerned worry about worsening skin disease and embarrassment. The highest mean scoring questions in DLQI were regarding itch, pain, and embarrassment. Items asking specifically about cutaneous neurofibromas (cNF) scored higher than comparable skin‐specific questions (t‐test p value <0.05). In summary, this study provides insights into the factors contributing to impaired QoL, anxiety, and mood in NF1 patients with cutaneous neurofibromas. Key factors identified for use in cNF measures include visibility, itch, anxiety, embarrassment, fears of worsening skin disease, and cNF‐specific questions. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Simple Summary: This study analyzes 61 rare tumors and lesions mimicking peripheral nerve tumors using data from the German Peripheral Nerve Tumor Registry. These cases exhibit significant heterogeneity with various morphological features and biological potentials, including malignant peripheral nerve tumors, perineuriomas, and hybrid nerve sheath tumors. This study underscores the challenges in preoperatively differentiating these rare entities from benign tumors using clinical and radiological methods alone. It highlights the importance of a multidisciplinary approach involving radiologists, neurologists, neuropathologists, and neurosurgeons for accurate diagnosis and effective treatment. The supplementary material offers valuable insights to help clinicians recognize these rare tumors early, improving patient outcomes. The most common peripheral nerve tumors are of a benign nature and include schwannoma or neurofibroma. In rare cases, other tumors or non-tumorous lesions can mimic peripheral nerve tumors clinically or radiologically. Based on data from the multicentric German Peripheral Nerve Tumor Registry (PNTR), which encompasses current information on 315 surgically treated patients from three high-volume centers, we present 61 cases of rare tumors and lesions that mimic tumors associated with peripheral nerves. This cohort displays considerable heterogeneity, featuring a broad spectrum of morphological features and biological potentials. Histopathological diagnoses include various intrinsic peripheral nerve tumors such as malignant peripheral nerve tumors (MPNSTs) (n = 13), perineurioma (n = 17), and hybrid nerve sheath tumors (HPNSTs, comprising schwannoma/perineurioma and schwannoma/neurofibroma) (n = 14), as well as atypical neurofibromatous neoplasm with unknown biological potential (ANNUBP) (n = 1). Additionally, the cohort encompasses extrinsic tumorous lesions like lymphoma (n = 3), lymphangioma (n = 2), hemangioma (n = 2), solitary fibrous tumor (n = 2), metastatic disease (n = 1), and single cases of other rare tumor entities (n = 6). An overview of the underlying pathology, imaging features, and clinical presentation is provided, with a brief description of each entity. A definitive preoperative differentiation between benign peripheral nerve tumors and rare intrinsic and extrinsic tumors is often not possible. Clinical examination and subtle imaging clues can at least indicate the possibility of a rare entity. The basic requirement is close cooperation between radiologists, neurologists, neuropathologists, and neurosurgeons at a specialized center to develop a multidisciplinary concept and offer the patient the best therapeutic approaches. [ABSTRACT FROM AUTHOR]

Dermoscopy aids in the diagnosis and management of pigmented growths and disorders of pigmentation in children. However, there is limited literature on the dermoscopic appearance of café‐au‐lait macules (CALMs) and congenital melanocytic nevi in patients with dark skin. We report two cases of young children with dark skin and many hyperpigmented patches in whom dermoscopy was utilized to accurately diagnose CALMs and facilitate testing for neurofibromatosis. [ABSTRACT FROM AUTHOR]

Objectives: Currently, anterior‐only (AO), posterior‐only, and combined anterior–posterior spinal fusions are common strategies for treating cervical kyphosis in patients with neurofibromatosis‐1 NF‐1. Nevertheless, the choice of surgical strategy remains a topic of controversy. The aim of our study is to evaluate the safety and effectiveness of anterior decompression and spinal reconstruction for the treatment of cervical kyphosis in patients with NF‐1. Methods: Twelve patients with NF‐1‐associated cervical kyphotic deformity were reviewed retrospectively between January 2010 and April 2020. All patients underwent AO correction and reconstruction. The X‐ray was followed up in all these patients to assess the preoperative and postoperative local kyphosis angle (LKA), the global kyphosis angle (GKA), the sagittal vertical axis, and the T1 slope. The visual analog scale score, Japanese Orthopedic Association (JOA) score, and neck disability index (NDI) score were used to evaluate the improvement inclinical symptoms. The results of the difference in improvement from preoperatively to the final follow‐up assessment were assessed using a paired t‐test or Mann–Whitney U‐test. Results: The LKA and GKA decreased from the preoperative average of 64.42 (range, 38–86) and 35.50 (range, 10–81) to an average of 16.83 (range, −2 to 46) and 4.25 (range, −22 to 39) postoperatively, respectively. The average correction rates of the LKA and GKA were 76.11% and 111.97%, respectively. All patients had achieved satisfactory relief of neurological symptoms (p < 0.01). JOA scores were improved from 10.42 (range, 8–16) preoperatively to 15.25 (range, 11–18) at final follow‐up (p < 0.01). NDI scores were decreased from an average of 23.25 (range, 16–34) preoperatively to an average of 7.08 (range, 3–15) at the final follow‐up (p < 0.01). Conclusion: Anterior‐only correction and reconstruction is a safe and effective method for correcting cervical kyphosis in NF‐1 patients. In fixed cervical kyphosis cases, preoperative skull traction should also be considered. [ABSTRACT FROM AUTHOR]

Peripheral nerve sheath tumors known as neurofibromas are benign and can be a part of syndromes like neurofibromatosis Type-1 (NF1) or type-2. NF1 is linked to plexiform neurofibroma. They are primarily made up of fibroblasts and Schwann cells. It can involve any nerve. In our case, a branch of the superficial peroneal nerve gave rise to neurofibroma, which extrinsically compressed the deep peroneal nerve. The patient's symptoms resembled those of anterior tarsal tunnel syndrome. [ABSTRACT FROM AUTHOR]

Selumetinib is clinically used for pediatric patients with neurofibromatosis type 1 and symptomatic, inoperable plexiform neurofibromas. Until recently, selumetinib had to be taken twice daily, after 2 hours of fasting and followed by 1 hour of fasting, which could be inconvenient. This population analysis evaluated the effect of low‐ and high‐fat meals on the pharmacokinetic (PK) parameters of selumetinib and its active metabolite N‐desmethyl selumetinib. The dataset comprised 511 subjects from 15 clinical trials who received ≥1 dose of selumetinib and provided ≥1 measurable postdose concentration of selumetinib and N‐desmethyl selumetinib. A 2‐compartment model with sequential 0‐ and 1st‐order delayed absorption and 1st‐order elimination adequately described selumetinib PK characteristics. A 1‐compartment model reasonably described N‐desmethyl selumetinib PK characteristics over time simultaneously with selumetinib. Selumetinib geometric mean area under the concentration–time curve ratio (1‐sided 90% confidence interval [CI] lower bound) was 76.9% (73.3%) with a low‐fat meal and 79.3% (76.3%) with a high‐fat meal versus fasting. The lower bound of the 1‐sided 90% CI demonstrated a difference of <30% between fed and fasted states. Considering the flat exposure‐response relationship within the dose range (20‐30 mg/m2), the observed range of exposure, and the variability in the SPRINT trial, this was not considered clinically relevant. [ABSTRACT FROM AUTHOR]

NF2-related schwannomatosis (NF2) is a rare autosomal-dominant genetic disorder characterized by bilateral vestibular schwannomas and multiple meningiomas. This case report presents the extremely rare occurrence of an anaplastic meningioma in a 12-year-old male with previously undiagnosed NF2. The patient presented with a history of abdominal pain and episodic emesis, gait unsteadiness, right upper and lower extremity weakness, and facial weakness. He had sensorineural hearing loss and wore bilateral hearing aids. MR imaging revealed a sizable left frontoparietal, dural-based meningioma with heterogeneous enhancement with mass effect on the brain and midline shift. Multiple additional CNS lesions were noted including a homogenous lesion at the level of T5 indicative of compression of the spinal cord. The patient underwent a frontotemporoparietal craniotomy for the removal of his large dural-based meningioma, utilizing neuronavigation and transdural ultrasonography for precise en bloc resection of the mass. Histopathology revealed an anaplastic meningioma, WHO grade 3, characterized by brisk mitotic activity, small-cell changes, high Ki-67 proliferation rate, and significant loss of P16. We report an anaplastic meningioma associated with an underlying diagnosis of NF2 for which we describe clinical and histopathological features. [ABSTRACT FROM AUTHOR]

Background and Objective: The psychological experience of mental pain can lead to distress similar to that caused by actual injury or trauma. As such, it poses a life-threatening consequence for chronic patients, although it is rarely assessed and treated in clinical settings. One of the diseases associated with high levels of physical and mental pain is the rare disorder neurofibromatosis. This study aimed to evaluate mental pain in patients with neurofibromatosis and its association with disease severity. Methods: This descriptive-analytical study was conducted on 207 patients with neurofibromatosis who were members of the Iranian Neurofibromatosis Support Association during 2023. Data collection tools included a demographic and clinical information registration form and the Orbach and Mikulincer Mental Pain Scale (OMMP), which comprises 44 items and 6 subscales, with a scoring range from 44 to 220. Results: The total mental pain score was 121.15±42.41, with a range of 44 to 206. The total mental pain scores for men and women were 123.67±38.98 and 120.31±43.58, respectively. The "confusion" subscale had the highest average score, while the "fear of loneliness" subscale had the lowest average score. There was a statistically significant association between the total mental pain score and its subscales with the severity of the disease and the patient's educational level (P<0.05). Conclusion: The mental pain scores of patients with neurofibromatosis were evaluated to be relatively unfavorable. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Purpose: Severe cervical kyphosis (CK) in neurofibromatosis type 1 (NF-1) is associated with a high risk for progression and neurologic impairment in children. We present our surgical technique and mid-term outcomes of uninstrumented anterior tibial strut grafting for severe CK secondary to NF-1. Methods: Case report. The Consensus-based Clinical Case Reporting Guideline Development (CARE) guidelines were followed. Results: Two paediatric patients (8- and 3-year-old) presented with severe CK secondary to NF-1. A halo body jacket (HV) allowed the progressive distraction of the cervical spine, avoiding neurological compromise and deformity progression. Circumferential fusion was obtained with anterior tibial strut autograft and posterior onlay bone graft. Cervical spine fusion was successfully maintained at a minimum 4-year follow-up in both patients. Conclusion: In children with severe CK secondary to NF-1, cervical distraction and immobilisation with a HV followed by uninstrumented anterior tibial strut grafting and posterior bone grafting, provided spinal fusion and stability without increasing the risk of neurological injury and donor site morbidity. The reported surgical technique appears to be a valuable tool in the armamentarium of the spinal surgeon. [ABSTRACT FROM AUTHOR]

Neurofibromatosis type 1 (NF1) is a multisystem neurocutaneous disorder. Scoliosis and dural ectasia are features of the associated mesodermal dysplasia. Lateral thoracic meningoceles can develop in NF1 and progressively enlarge due to cerebrospinal fluid (CSF) pulsations. Large meningoceles can cause compressive symptoms in the thorax. We are reporting a case of a NF1 presenting with acute onset respiratory distress, who also had chronic orthostatic headaches. CT chest showed unruptured enlarging bilateral lateral thoracic meningoceles causing lung compression. MRI of the brain and spine showed features of CSF hypotension, explaining the headaches. CSF hypotension with unruptured meningoceles is extremely rare. Management of the condition is challenging since surgical removal is prone to complications due to underlying mesodermal abnormalities. Cystoperitoneal shunting to relieve lung compression may worsen CSF hypotension. A shunt with a programmable valve allowed controlled drainage and successfully relieved lung compression without worsening of orthostatic headaches in our case. [ABSTRACT FROM AUTHOR]

Neurofibromatosis is one of the most common genetic diseases. It is inherited in an autosomal dominant manner. It is divided into two genetically distinct subtypes, characterized by multiple skin lesions and tumors of the peripheral and central nervous system. Neurofibromatosis type 1, or Recklinghausen's disease, is the most common phakomatosis. The disease is genetically determined by a mutation of the neurofibromin-1 gene on chromosome 17. Neurofibromatosis type 2 accounts for 3% of all cases. The disease is genetically determined - caused by a mutation of the neurofibromin-2 gene on chromosome 22. The diagnostic and therapeutic process of neurofibromatosis is a major challenge for clinicians. Given the complexity of the problem, we have reviewed the literature on the diagnostic and therapeutic possibilities of the disease. [ABSTRACT FROM AUTHOR]

Both Neurofibromatosis type 1 (NF1) and Noonan syndrome (NS) are RASopathies. Characteristic cardiac phenotypes of NS, including specific electrocardiographic changes, pulmonary valve stenosis and hypertrophic cardiomyopathy have not been completely studied in NF1. Purpose: The aims of this study were to assess: (1) similarities in the prevalence and types of ECG and conventional echocardiographic findings described in NS in asymptomatic patients with NF1, and (2) the presence of discrete myocardial dysfunction in NF1 patients using myocardial strain imaging. Methods: Fifty-eight patients with NF1 (ages 0–18 years), and thirty-one age-matched healthy controls underwent cardiac assessment including blood pressure measurements, a 12-lead ECG, and detailed echocardiography. Quantification of cardiac chamber size, mass and function were measured using conventional echocardiography. Myocardial strain parameters were assessed using 2-Dimensional (2D) Speckle tracking echocardiography. Results: Asymptomatic patients with NF1 had normal electrocardiograms, none with the typical ECG patterns described in NS. However, patients with NF1 showed significantly decreased calculated Z scores of the left ventricular internal diameter in diastole and systole, reduced left ventricular mass index and a higher incidence of cardiac abnormal findings, mainly of the mitral valve, in contrast to the frequently described types of cardiac abnormalities in NS. Peak and end systolic global circumferential strain were the only significantly reduced speckle tracking derived myocardial strain parameter. Conclusions: Children with NF1 demonstrated more dissimilarities than similarities in the prevalence and types of ECG and conventional echocardiographic findings described in NS. The role of the abnormal myocardial strain parameter needs to be explored. [ABSTRACT FROM AUTHOR]

Schwannomatosis is a rare neurocutaneous syndrome characterized by the presence of multiple schwannomas along the peripheral nerves, distinctly excluding the vestibular nerves. It is recognized as the third principal form of neurofibromatosis, alongside neurofibromatosis types 1 and 2. In this report, we discuss the case of a 45-year-old woman who initially sought medical attention for low back pain and swelling in her left axilla. Her magnetic resonance imaging revealed multiple enhancing intradural extramedullary lesions, along with a mass in the right upper thoracic region and another in the left axilla, raising suspicions of metastasis. However, a comprehensive analysis that aligned imaging results with histopathological findings confirmed the diagnosis of schwannomatosis. This case highlights the importance of differentiating between various conditions that can cause multiple intradural extramedullary masses, such as nerve sheath tumors, meningiomas, and metastasis. The presence of multiple schwannomas suggests a diagnosis of either neurofibromatosis type 2 or schwannomatosis, making the distinction between these two conditions critical for appropriate management.

Abstract Background Neurofibromatosis 1 is a form of phacomatosis or neurocutaneous disease inherited as an autosomal dominant disease. Thoracic involvement is rare and involves the lung parenchyma, mediastinum, and thoracic cage, including ribs and the spine. Lung parenchymal involvement includes airspace abnormalities like cysts, bullae, and emphysema with an upper lobe predominance and interstitial abnormality in the form of reticulations and fibrosis in the lower lobes. The structural abnormality of the lung resembles numerous other diseases. Hence, properly identifying and recognizing neurofibromatosis 1-associated diffuse lung disease (NF-1 DLD) is crucial in avoiding misdiagnosis. NF1-DLD is associated with many complications like pulmonary hypertension, lung malignancy, aspergilloma, secondary bacterial infections, and pneumothorax. Case presentation An elderly male with neurofibromatosis type-1 presented with breathlessness, cough, and mucopurulent expectoration and was found to have diffuse involvement of the lung parenchyma involving cysts, bullae, emphysema, fibrosis, and traction bronchiectasis. He was managed conservatively, controlling infection and optimizing respiratory symptoms. Conclusion Neurofibromatosis-associated diffuse lung disease is a rare disorder. There is no definitive treatment that can reverse the pulmonary lesions. However, early diagnosis will help plan effective preventive measures and avoid complications. We present this case to increase awareness regarding the various pulmonary manifestations of neurofibromatosis.

Objectives Currently, anterior‐only (AO), posterior‐only, and combined anterior–posterior spinal fusions are common strategies for treating cervical kyphosis in patients with neurofibromatosis‐1 NF‐1. Nevertheless, the choice of surgical strategy remains a topic of controversy. The aim of our study is to evaluate the safety and effectiveness of anterior decompression and spinal reconstruction for the treatment of cervical kyphosis in patients with NF‐1. Methods Twelve patients with NF‐1‐associated cervical kyphotic deformity were reviewed retrospectively between January 2010 and April 2020. All patients underwent AO correction and reconstruction. The X‐ray was followed up in all these patients to assess the preoperative and postoperative local kyphosis angle (LKA), the global kyphosis angle (GKA), the sagittal vertical axis, and the T1 slope. The visual analog scale score, Japanese Orthopedic Association (JOA) score, and neck disability index (NDI) score were used to evaluate the improvement inclinical symptoms. The results of the difference in improvement from preoperatively to the final follow‐up assessment were assessed using a paired t‐test or Mann–Whitney U‐test. Results The LKA and GKA decreased from the preoperative average of 64.42 (range, 38–86) and 35.50 (range, 10–81) to an average of 16.83 (range, −2 to 46) and 4.25 (range, −22 to 39) postoperatively, respectively. The average correction rates of the LKA and GKA were 76.11% and 111.97%, respectively. All patients had achieved satisfactory relief of neurological symptoms (p

A consistent set of measurement techniques must be applied to reliably and reproducibly evaluate the efficacy of treatments for cutaneous neurofibromas (cNFs) in people with neurofibromatosis type 1 (NF1). cNFs are neurocutaneous tumors that are the most common tumor in people with NF1 and represent an area of unmet clinical need. This review presents the available data regarding approaches in use or development to identify, measure, and track cNFs, including calipers, digital imaging, and high-frequency ultrasound sonography. We also describe emerging technologies such as spatial frequency domain imaging and the application of imaging modalities such as optical coherence tomography that may enable the detection of early cNFs and prevention of tumor-associated morbidity.

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.

Hearing loss has not been thoroughly investigated as a comorbidity in larger cohorts with neurofibromatosis type 1 (NF1). Available audiometric data were reviewed from patients with NF1 seen at a tertiary pediatric hospital to assess prevalence and risk factors for hearing loss. Of 1172 patients with NF1 seen between 2010 and 2022, 90 had available audiometric data and 48 of 90 patients (53%) had one or more audiogram revealing hearing loss. Those not referred to audiology were presumed to have normal hearing, resulting in a conservative hearing loss estimate of 4% for children and young adults with NF1. Of 90 patients with audiograms, 29 (32%) had conductive loss (CHL), 15 (17%) had sensorineural loss (SNHL), and 3 (3%) had mixed hearing loss. Hearing loss type was undetermined for one patient. For children with CHL, six had permanent CHL secondary to plexiform neurofibroma, 19 CHL were transient due to active middle ear dysfunction, and four CHL cases were indeterminate in etiology. For three children with SNHL or mixed hearing loss, etiology included history of ototoxic chemotherapy and/or family history of SNHL. In the 16 patients with SNHL or mixed hearing loss with more than one audiogram over time, progressive hearing decline was noted in eight of 16, and 26 of 178 hearing thresholds (15%) progressed. Our findings suggest that audiometric evaluations should be considered for at least a subset of children with NF1, given the higher-than-expected rate of hearing loss in patients with NF1 compared with the general population. [ABSTRACT FROM AUTHOR]

Background and Objective: The psychological experience of mental pain can lead to distress similar to that caused by actual injury or trauma. As such, it poses a life-threatening consequence for chronic patients, although it is rarely assessed and treated in clinical settings. One of the diseases associated with high levels of physical and mental pain is the rare disorder neurofibromatosis. This study aimed to evaluate mental pain in patients with neurofibromatosis and its association with disease severity. Methods: This descriptive-analytical study was conducted on 207 patients with neurofibromatosis who were members of the Iranian Neurofibromatosis Support Association during 2023. Data collection tools included a demographic and clinical information registration form and the Orbach and Mikulincer Mental Pain Scale (OMMP), which comprises 44 items and 6 subscales, with a scoring range from 44 to 220. Results: The total mental pain score was 121.15±42.41, with a range of 44 to 206. The total mental pain scores for men and women were 123.67±38.98 and 120.31±43.58, respectively. The "confusion" subscale had the highest average score, while the "fear of loneliness" subscale had the lowest average score. There was a statistically significant association between the total mental pain score and its subscales with the severity of the disease and the patient's educational level (P

Abstract Neurofibromatosis Type 1 (NF1) is caused by loss of function variants in the NF1 gene. Most patients with NF1 develop skin lesions called cutaneous neurofibromas (cNFs). Currently the only approved therapeutic for NF1 is selumetinib, a mitogen -activated protein kinase (MEK) inhibitor. The purpose of this study was to analyze the transcriptome of cNF tumors before and on selumetinib treatment to understand both tumor composition and response. We obtained biopsy sets of tumors both pre- and on- selumetinib treatment from the same individuals and were able to collect sets from four separate individuals. We sequenced mRNA from 5844 nuclei and identified 30,442 genes in the untreated group and sequenced 5701 nuclei and identified 30,127 genes in the selumetinib treated group. We identified and quantified distinct populations of cells (Schwann cells, fibroblasts, pericytes, myeloid cells, melanocytes, keratinocytes, and two populations of endothelial cells). While we anticipated that cell proportions might change with treatment, we did not identify any one cell population that changed significantly, likely due to an inherent level of variability between tumors. We also evaluated differential gene expression based on drug treatment in each cell type. Ingenuity pathway analysis (IPA) was also used to identify pathways that differ on treatment. As anticipated, we identified a significant decrease in ERK/MAPK signaling in cells including Schwann cells but most specifically in myeloid cells. Interestingly, there is a significant decrease in opioid signaling in myeloid and endothelial cells; this downward trend is also observed in Schwann cells and fibroblasts. Cell communication was assessed by RNA velocity, Scriabin, and CellChat analyses which indicated that Schwann cells and fibroblasts have dramatically altered cell states defined by specific gene expression signatures following treatment (RNA velocity). There are dramatic changes in receptor-ligand pairs following treatment (Scriabin), and robust intercellular signaling between virtually all cell types associated with extracellular matrix (ECM) pathways (Collagen, Laminin, Fibronectin, and Nectin) is downregulated after treatment. These response specific gene signatures and interaction pathways could provide clues for understanding treatment outcomes or inform future therapies.

Background: Congenital pseudoarthrosis of the tibia (CPT) is a rare pathological disease associated with neurofibromatosis type 1 (NF1). It presents with tibial bowing and can progress into a nonhealing fracture. Treatment options include conservative approaches such as serial bracing or various surgical options.Surgically, the aims are to achieve long-term bone union, prevent limb length discrepancies (LLDs), and avoid mechanical axis deviation, soft tissue lesions, nearby joint stiffness, and pathological fracture.The purpose of our study is to highlight our experience with both the conservative approach and the use of vascularized free fibula reconstruction of these deformities, including the challenges encountered with a long-term follow-up until skeletal maturity. Methods: We present a retrospective analysis of a total of nine (9) patients consisting of three (3) girls and six (6) boys. Six (6) children were treated with a vascularized fibula flap, and the other three (3) were treated conservatively. Outcomes measured included fractures, LLD, ankle valgus deformity, donor site morbidity, and number of surgical corrections. Results: All patients had flap survival. Three (3) of six children had a previous failed surgery with intramedullary nail and bone graft prior to performing a vascularized free fibula reconstruction. The follow-up period ranged from 8 months to 200 months. The complications included stress fractures (50%), LLD (66.6%), and ankle valgus (33.3%). During growth phases, these children required multiple corrective surgeries. Conclusions: Fibula free flap is a good treatment option for CPT even in patients with prior surgical failures with variable results.Level of Evidence - Level 4 - Case series Therapeutic Studies—Investigating the Results of Treatment.

Abstract Background Benign peripheral nerve sheath tumors (BPNSTs) include schwannomas and neurofibromas. About 10% of soft tissue sarcomas are malignant peripheral nerve sheath tumors (MPNSTs), which are invasive and aggressive tumors. These can happen occasionally or after radiation exposure. Up to 90% of schwannomas are made up of differentiated neoplastic Schwann cells. Malignant transformation of schwannomas is rare. Methods We collected the medical records of all patients (including their family histories), performed comprehensive physical and neurological assessments, and checked for the presence of a Tinel-like sign, as well as screening for neurofibromatosis (NF) signs. Magnetic resonance imaging (MRI), nerve conduction studies, and ultrasound were done for all cases. Results We have operated on 21 patients with age range 29–52 years. The mean age was 39.4 years. 14 of these patients were females and 7 were males. The presenting symptoms were just swelling at nerve site in 14 patients, spontaneous pain at the nerve sites in 7 patients, and sensory deficit at the nerve distribution sites in 9 patients. The other 12 patients were sensory intact and only 7 patients had motor deficit. Postoperatively all patients had improved motor and sensory deficit and none of intact patients were worsened. Preoperatively we did MRI to show important nearby vascular structure anatomical abnormalities and we ordered nerve studies to all patients that showed abnormalities, which was only in 9 patients. Gross total resection was done in 18 patients and other 3 cases had partial resection to avoid sensory and motor deficits. The pathological analysis revealed 11 schwannomas and 10 neurofibromas. With 1 year follow up there was no recurrence in any patients. Conclusion Benign pheripheral nerve sheath tumours are safely resected without increased sensory and motor deficits after surgery and with improve clinical outcome with no recurrence on follow up.

MEK inhibitors (MEKi) represent innovative and promising treatments for managing manifestations of neurofibromatosis type 1 (NF1). To mitigate potential ophthalmic side effects, such as MEKi-associated retinopathy (MEKAR), patients undergoing MEKi therapy routinely receive ophthalmology evaluations. Our study aims to assess the necessity of this regular screening within a predominantly pediatric NF1 population by examining the occurrence of ocular adverse events (OAE). A retrospective study evaluated 45 NF1 patients receiving MEKi. Inclusion criteria included baseline and follow-up examinations following the initiation of MEKi therapy. At each assessment, a comprehensive eye evaluation was performed, comprising a dilated fundus examination, ocular coherence tomography of the macula and nerve fiber layer, and Humphrey visual field testing. Twenty-six patients, with an average age of 13 years (range 2–23 years) and an average follow-up duration of 413 days were included in the analysis. Three different MEKi were used: selumetinib (77%), trametinib (23%), and mirdametinib (4%). None of the patients experienced retinopathy at any point during the study. Some patients had pre-existing optic neuropathies (27%), but no instances of nerve changes occurred after commencing MEKi therapy. Four patients (15%) exhibited symptoms of dry eye, all of which were effectively managed with topical lubrication.

ABSTRACT: Neurofibromatosis type 1 (NF1) is an autosomal dominant genetic disorder that primarily causes the growth of tumors alongnerves. Additionally, the germline mutations involved in NF1 predispose patients to develop further malignancies. The mainstay initial treatment for these malignancies is surgical removal at diagnosis, although targeted therapies are under evaluation in the relapsed setting. We report a case of malignant peripheral nerve sheath tumor (MPNST), gastrointestinal stromal tumor (GIST), and pheochromocytoma in a patient with NF1 who presented with an infected right shoulder lesion that was confirmed to be spindle cell sarcoma via biopsy. She was treated with antibiotics; however, she rapidly deteriorated and opted for hospice care. NF1 germline mutations increase the risk of patients developing various types of cancer. Recent studies have shown that there is a rolefor using MEK inhibitors such as selumetinib for treating patients with NF1.

Abstract Background Neurofibromatosis type I (NF1) is a genetic disorder characterized by the tumor’s development in nerve tissue. Complications of NF1 can include pigmented lesions, skin neurofibromas, and heart problems such as cardiomyopathy. In this study, we performed whole-exome sequencing (WES) on an Iranian patient with NF1 to identify the genetic cause of the disease. Methods Following clinical assessment, WES was used to identify genetic variants in a family with a son suffering from NF1. No symptomatic manifestations were observed in other family members. In the studied family, in silico and segregation analysis were applied to survey candidate variants. Results Clinical manifestations were consistent with arrhythmogenic cardiomyopathy (ACM). WES detected a likely pathogenic heterozygous missense variant, c.3277G > A:p.Val1093Met, in the NF1 gene, confirmed by PCR and Sanger sequencing. The patient’s parents and brother had a normal sequence at this locus. Conclusions Although there is no cure for NF1, genetic tests, such as WES, can detect at-risk asymptomatic family members. Furthermore, cardiac evaluation could also help these patients before heart disease development.