Malignant peripheral nerve sheath tumor on a patient with a maternally inherited novel NF1 gene pathogenic germline variant: Case report.

INTRODUCTION: Neurofibromatosis type 1 (NF1) is an autosomal dominant cancer predisposition syndrome caused by pathogenic variants in NF1, which negatively regulates the RAS pathway. Knowledge of the genotype-phenotype correlation in this disease is an important tool for prognostic evaluation and early detection of malignant peripheral nerve sheath tumors (MPNST), present in approximately 10% of these patients. We present the case of a teenager with a left jaw MPNST and a previously unreported germline pathogenic variant on NF1. CASE PRESENTATION: An 11-year-old female with a NF1 clinical diagnosis was referred to our hospital with a MPNST in an advanced state. A previously unreported NF1 pathogenic variant was obtained (GRCh37: NM_182493.2 c.3299C>G, p.Ser1100*). Despite great efforts from the surgical and medical teams, the tumor progression couldn't be halted, resulting in the patient's death. DISCUSSION: As MPNSTs are refractory to current treatment regimens, early diagnosis, and development of new therapies, such as MEK inhibitors, is necessary for reducing morbidity and mortality within NF1 patients. This increases the importance of a more widespread genetic testing strategy. CONCLUSION: The report of a novel NF1 pathogenic variant in a patient with maternally inherited neurofibromatosis type 1 and a MPNST increases the knowledge of the genotype-phenotype correlation in the disease.

Analysis of the current Covid-19 infection and vaccination status in patients with neurofibromatosis type 1

Background: To investigate the common symptoms after Covid-19 infection, characteristics of adverse events after vaccination, changes in clinical manifestations related to Neurofibromatosis type 1 (NF1), as well as the current vaccination status and factors related to vaccine hesitation among NF1 patients, in order to provide a basis for scientific protection and vaccine acceptance in NF1 individuals in the new phase of pandemic management. Method(s): From December 29, 2022, to January 10, 2023, we conducted a self-assessment questionnaire survey among diagnosed NF1 patients. General data were provided including sex, age, main clinical presentations, and current treatment. This study mainly focused on the infection and vaccination status of Covid-19 among these patients with NF1. The data were statistically analyzed using SPSS26.0 software. Result(s): Of the 250 questionnaires distributed, 226 were valid. Among the 164 patients (72.6%) with Covid-19 infection, the most common infection symptoms and incidence of patients were not significantly different from those in the normal population (P>0.05), but the incidence of symptoms such as nasal congestion, headache, myalgia, sore throat, abdominal pain, diarrhea, and eye discomfort was higher than that in the normal population (P<0.05), and no severe infection was observed;186 patients (82.3%) had completed the Covid-19 vaccination, and more than half of those who were not vaccinated had no plans for vaccination. Among the vaccinated patients, there was no significant difference in the incidence of adverse events, such as fever, pain, redness, and swelling at the injection site after vaccination, compared to the normal population (P>0.05), but the incidence of fatigue and headache was higher in NF1 patients (P<0.001). Most patients with NF1 believe that there is no significant progressive change in NF1-related clinical manifestations after Covid-19 infection and vaccination. Conclusion(s): Currently, some NF1 patients appear to be worried about the evolution of their disease after Covid-19 infection in the face of large fluctuations in the pandemic situation, and some patients hesitate to receive the vaccine due to their special disease condition. Thus, clinical trials should be conducted to develop a refined pandemic response and vaccination program for this special group.Copyright © 2023 China Medical Cosmetology Press Co. Ltd.

Evaluation of the Sense of Taste and Smell in Patients with Neurofibromatosis Type 1.

OBJECTIVE: The objective of this study was to determine if patients with Neurofibromatosis Type 1 (NF1) have an impaired sense of smell or taste. Neurofibromin, the NF1gene protein product is ubiquitous in the body and is especially associated with the development of neurogenetic structures. Lately enlarged olfactory bulbs have been described in patients with NF1. Until now, there is no study to evaluate the sense of smell and taste in patients with NF1. METHOD: This study has been approved by the Hamburg Ethics committee. An evaluation of the sense of smell and taste was undertaken in 26 patients with NF1 using the Burghart Sniffin' Sticks. Three patients were excluded due to a prior infection with the Corona virus. As a control group the same examination was performed in healthy individuals (same sex/ same age as the NF1 patients) by the same examiner. RESULTS: The results show a normal sense of smell in patients with NF1. The morphologic finding of enlarged olfactory bulbs seem to have no functional equivalent. However, 8 out of 23 patients with NF1 had difficulties identifying at least one taste flavor. In total 9.8% of possible taste qualities were misidentified. In the healthy control group, all taste qualities were identified correctly. Considering each taste quality as separate case, a significant difference in the taste function was identified based on Fisher's exact test (p=0.003). CONCLUSION: The current study does not show a correlation between NF1 and an impaired sense of smell. Yet significant reduction in the sense of taste was found in the patients with NF1. Further research will have to be conducted to find the underlying causal pathways. CLINICAL RELEVANCE: NF1 is recently being acknowledged not only for its' macroscopic aesthetic and functional impairments, but also as a neurodevelopmental disorder. Evaluating the neural structures in regard to their function is a first step in understanding more about the disease.

COVID-19 in people with neurofibromatosis 1, neurofibromatosis 2, or schwannomatosis.

PURPOSE: People with pre-existing conditions may be more susceptible to severe COVID-19 when infected by SARS-CoV-2. The relative risk and severity of SARS-CoV-2 infection in people with rare diseases such as neurofibromatosis type 1 (NF1), neurofibromatosis type 2 (NF2), or schwannomatosis (SWN) is unknown. METHODS: We investigated the proportions of people with NF1, NF2, or SWN in the National COVID Cohort Collaborative (N3C) electronic health record data set who had a positive test result for SARS-CoV-2 or COVID-19. RESULTS: The cohort sizes in N3C were 2501 (NF1), 665 (NF2), and 762 (SWN). We compared these with N3C cohorts of patients with other rare diseases (98-9844 individuals) and the general non-NF population of 5.6 million. The site- and age-adjusted proportion of people with NF1, NF2, or SWN who had a positive test result for SARS-CoV-2 or COVID-19 (collectively termed positive cases) was not significantly higher than in individuals without NF or other selected rare diseases. There were no severe outcomes reported in the NF2 or SWN cohorts. The proportion of patients experiencing severe outcomes was no greater for people with NF1 than in cohorts with other rare diseases or the general population. CONCLUSION: Having NF1, NF2, or SWN does not appear to increase the risk of being SARS-CoV-2 positive or of being a patient with COVID-19 or of developing severe complications from SARS-CoV-2.

Ultrasound-guided and Peripheral Nerve Stimulator-guided Interscalene Brachial Plexus Block in a Patient with Neurofibromatosis during the COVID-19 Pandemic

An 18-year-old female with neurofibromatosis presented for enucleation biopsy of a slow-growing soft tissue mass on her right anteromedial arm during the COVID-19 pandemic. Ultrasonography was used in the mapping of the brachial plexus and the identification of possible neurofibroma along peripheral nerves. An interscalene brachial plexus nerve block was successfully and safely achieved with ultrasonographic and peripheral nerve stimulator guidance. Ultrasound-guided and nerve stimulator-guided peripheral nerve blocks are safe and viable anesthetic management options for patients with neurofibromatosis, especially in this time of the COVID-19 global pandemic. © 2022 University of the Philippines Manila. All rights reserved.

Primary pilocytic astrocytoma of the cerebellopontine angle in pediatric patient with neurofibromatosis type 1: a case report.

Background: Cerebellopontine angle tumor (CPA) in pediatrics is rare as compared to adults. We describe a case of pediatric pilocytic astrocytoma presented as a right CPA mass with a concurrent clinical diagnosis of neurofibromatosis type 1 (NF1). Case presentation: A 14-year-old boy with a newly diagnosed hypertension presented with a short history of headache and blurring vision. Neurological examination revealed bilateral papilloedema, partial right third nerve palsy and mild sensorineuronal hearing deficits. Skin examination identified multiple café au lait spots with cutaneous neurofibromas. Preoperative neuroimaging suggested the diagnosis of an extraaxial CPA mass consistent with meningioma, with obstructive hydrocephalus. A left ventriculoperitoneal shunt was inserted and the child was subjected for a suboccipital retrosigmoid approach for tumor resection. The histopathological features, however, were typical for pilocytic astrocytoma. Conclusions: A careful evaluation of the clinical presentation and radiological images of CPA lesions is necessary prior to surgical embarkment. To the best of our knowledge, this case is the first report of pilocytic astrocytoma in the CPA in pediatric with NF1.

Evaluation of the sense of smell and taste in patients with Neurofibromatosis Type 1

Objective The objective of this study was to determine if patients with Neurofibromatosis Type 1 (NF1) have an impaired sense of smell or taste. Neurofibromin, the NF1gene protein product is ubiquitous in the body and is especially associated with the development of neurogenetic structures. Lately enlarged olfactory bulbs have been described in patients with NF1. Until now, there is no study to evaluate the sense of smell and taste in patients with NF1. Method This study has been approved by the Hamburg Ethics committee. An evaluation of the sense of smell and taste was undertaken in 26 patients with NF1 using the Burghart Sniffin' Sticks. Three patients were excluded due to a prior infection with the Corona virus. As a control group the same examination was performed in healthy individuals (same sex/ same age as the NF1 patients) by the same examiner. Results Preliminary results show a normal sense of smell in patients with NF1. The morphologic finding of enlarged olfactory bulbs seem to have no functional equivalent. However, 8 out of 23 patients with NF1 had difficulties identifying at least one taste flavor. The data collection of the control group is still ongoing, thus far none of the study participants misidentified a taste flavor. A statistical significance is aimed at by increasing the case numbers.

NEUROFIBROMATOSIS THERAPEUTICS PROGRAM: DEVELOPMENT OF A PROGRAM

Neurofibromatosis (NF) therapeutics is a vital field in the care of children with NF. Recent developments in the treatment of plexiform neurofibromas (PN) have increased the numbers of patients seen for therapy. The Neurofibromatosis Therapeutics Program (NTP) provides high quality care to patients receiving therapy for brain tumors and PNs, as well as tumors related to NF2. The program at Children's Hospital Colorado (CHCO) includes a physician, nurse practitioner, and nurse care coordinator. The team collaborates with other disciplines in the care of the NF patient with plexiform neurofibromas and/or CNS tumors. As the program grew, key players were identified in each subspecialty and educated about the NTP. We have ongoing regular communication with a large number of subspecialists regarding protocols, clinical care pathways, and mutual patients. In addition, an extensive tissue collection study of plexiform neurofibromas and brain tumors enhances NTPs devotion to both clinical and lab research. Weekly clinical care meetings ensure continuity in the care of the nearly 140 patients with NF1 and NF2 under our program. Monthly strategy and vision meetings focus on grant applications, education of primary care providers and subspecialists in our large catchment area, development of new clinical pathways, treatment roadmaps, and growth of our program. Over the last two years of being a formalized program, we have increased research on the epigenetics of plexiform neurofibromas, opened a Phase 2 clinical trial for a Mek inhibitor, and increased our patient volume. The Covid pandemic has increased our ability to manage treatment side effects virtually through telehealth and online patient portals. Future goals of the NTP include completion of a program website, quarterly patient and provider newsletters, educational offerings, collaboration with other centers on Mek inhibitor side effects, adolescent and young adult education on tumor risk, and transition to adult care.

“COGNITIVE IMPAIRMENTS IN CHILDREN AND ADOLESCENTS WITH NEUROFIBROMATOSIS”

BACKGROUND: Cognitive, learning and/or behavioral disorders are common (up to 70%) complications of neurofibromatosis (NF). The first multidisciplinary-clinic for neurocutaneous-disorders was established at the Aghia Sophia Children's Hospital in Athens, Greece, in 2016. Since then, more than 200 children and adolescents with NF have been examined. SCOPE: Acknowledging and indicating awareness on the devastating life-long consequences (poor academic performance, behavioral problems, and limited career prospectives) that can result from cognitive impairment, a research collaboration with educational specialists was recently implemented to examine the neurocognitive functions of children and adolescents with NF. MATERIALS: Children and adolescents aged 7-14 years who suffer from NF type I or type II, were eligible for study entry. The third edition of the Wechsler Intelligence Scale (WISC-III) was used to measure participants' cognitive function. RESULTS: Preliminary results of this ongoing study are presented. Patients' recruitment was limited by the coronavirus disease 2019 (COVID-19) restrictions. At this stage, the research involved 10 participants suffering from NF, with mean (± SD) age of 11.55 (± 1.80) years and a male-to-female ratio of 1. The mean (± SD) full-scale intelligence quotient (IQ) was 85.50 (± 18.80), corresponding to the 0.3rd to 73th percentile range. The mean (± SD) scores of performance IQ and verbal IQ were 84.90 (± 17.43) and 89.40 (± 17.23) respectively, corresponding to the 1st to 73rd percentile range for both subscales. CONCLUSION: Significant cognitive deficits, according to the percentile scores of WISC-III, were demonstrated in the small number of children and adolescents suffering from NF (type I or type II). Cognitive assessment, as part of the multidisciplinary approach of these patients is warranted, to aid timely educational interventions and improve patient learning outcomes.

Neurofibromatosis: New Clinical Challenges in the Era of COVID-19.

Rare diseases constitute a wide range of disorders thus defined for their low prevalence. However, taken together, rare diseases impact a considerable percentage of the world population, thus representing a public healthcare problem. In particular, neurofibromatoses are autosomal-dominant genetic disorders that include type 1 neurofibromatosis (NF1), type 2 neurofibromatosis (NF2) and schwannomatosis. Each of the three types is a genetically distinct disease with an unpredictable clinical course and for which there is still no resolutive cure. Therefore, a personalized therapeutic approach directed at improving the symptomatology as well as the search for new pharmacological strategies for the management of neurofibromatosis represents a priority for positive outcomes for affected patients. The coronavirus disease 2019 (COVID-19) pandemic has severely affected health systems around the world, impacting the provision of medical care and modifying clinical surveillance along with scientific research procedures. COVID-19 significantly worsened exchanges between healthcare personnel and neurofibromatosis patients, precluding continuous clinical monitoring in specialized clinic centers. In this new scenario, our article presents, for the first time, a comprehensive literature review on the clinical challenges for neurofibromatosis clinical care and research during the COVID-19 pandemic health emergency. The review was performed through PubMed (Medline) and Google Scholar databases until December 2021.

Characterization of a Novel Humanized Mouse Model of Neurofibromatosis

The purpose of this study was to characterize a mutant mouse that bears an NF1 mutation that is identical to one found in humans. No human samples exist to determine the nature of how this particular mutation affects the NF1 gene and protein. This mutation is particularly important to understand as it does not lead to the neurofibroma formation found in most patients, but it can lead to learning challenges, developmental delay and in some cases epilepsy. This study was able to determine that this particular mutant NF1 protein neither affects the most common pathways associated with the function of the NF1 protein nor leads to some inflammatory aspects of the disease. These are critical findings as they reveal that the protein has additional functions that are linked to a very specific region of the protein and that this mutation may be acting in very distinct ways from the effects of complete loss of the NF1 protein. This study also found a link between this mutation and programmed cell death in a region of the brain critical for learning and memory. This information will allow new studies to more clearly define the molecular basis for the neurological aspects of Neurofibromatosis with this new understanding bringing the potential for new therapeutic targets.

This Week in the Journal

The clinician must pay close attention to the patient history, aided by the development of molecular diagnostic tests, to distinguish infections from other causes. see Review Article, N Engl J Med 2022;386:463-477 Lisch Nodules A 40-year-old man with a history of neurofibromatosis type 1 presented for a routine eye examination. Six weeks before jaundice developed, he had been hospitalized with Covid-19. see Clinical Problem-Solving, N Engl J Med 2022;386:479-485 Using Economics to Inform Public Health Policy Although public health practitioners and researchers focus primarily on improving health, economists view health as but one important component of what people may value. [...]substantial neutralization of the omicron variant was detected in samples from participants who had received three doses. see Correspondence, N Engl J Med 2022;386:492-494 Preliminary Data on Vaccine Protection against Omicron Using a test-negative study design focused on the period of dominance of the B.1.1.529 (omicron) variant in South Africa, investigators found that two doses of the BNT162b2 vaccine had an efficacy of 50 to 70% against hospitalization caused by omicron in Gauteng province. see Correspondence, N Engl J Med 2022;386:494-496

A case of a patient with neurofibromatosis type I who developed pneumothorax and eosinophilic pleural effusion after suffering from COVID-19 pneumonia.

Coronavirus disease 2019 (COVID-19) has become a global pandemic since its discovery in December 2019, and as the disease continues to evolve, varying complications associated with it continue to arise. In this regard, computed tomography has played an extremely important role in the diagnosis and evaluation of COVID-19 pneumonia and its complications. We encountered a case of a male patient with neurofibromatosis (type I) who developed concurrent pneumothorax and pleural effusion during his recovery period from severe COVID-19 pneumonia. Pulmonary fibrosis and emphysema were also confirmed. Furthermore, an eosinophil pleural effusion appeared and was prolonged during the healing process of COVID-19. This clinical presentation suggests that fibrosis and emphysema formation due to neurofibromatosis may have caused pneumothorax and pleural effusion.

Impact of the coronavirus pandemic on mental health and health care in adults with neurofibromatosis: Patient perspectives from an online survey.

The coronavirus pandemic increased anxiety and stress and prevented access to health care worldwide; it is unclear how COVID-19 affected adults with a multisystem genetic disorder such as neurofibromatosis (NF). An anonymous online survey was distributed through an international registry and foundations to adults with NF (June-August 2020) to assess the impact of the pandemic on mental health and NF health care. Six hundred and thirteen adults (18-81 years; M = 45.7) with NF1 (77.8%), NF2 (14.2%), and schwannomatosis (7.8%) provided complete responses. Respondents rated moderate-to-high amounts of worry about the impact of COVID-19 on their emotional (46.3%) and physical health (46.7%), and 54.8% endorsed moderate-to-high pandemic-related stress. Adults with diagnosed/suspected mental health disorders or moderate-to-severe NF symptom impact as well as females endorsed higher COVID-19 stress (ps < 0.01). Less than half who missed a doctor's appointment for their NF care (43.4%) used telehealth. Of these, 33.3% and 46.2% reported that telehealth met their needs to a moderate or high degree, respectively. Results indicated that subgroups of adults with NF experience higher COVID-19-related worries and stress and may need additional support. Furthermore, telehealth is under-utilized and could help NF providers connect with patients, although improved delivery and patient training may facilitate expanded use of these services.

The impact of the COVID-19 pandemic on neurofibromatosis clinical care and research.

PURPOSE: The coronavirus disease 2019 (COVID-19) pandemic has had unprecedented impact on the provision of medical care for genetic disorders. The purpose of this study was to assess the effects of the pandemic on neurofibromatosis (NF) care and research. METHODS: Sixty-three United States NF clinics were surveyed to identify the impact of the pandemic on clinician role, patient volume, continuity of guideline-driven surveillance, research protocols, and use of (and satisfaction with) telehealth for the delivery of NF care. RESULTS: Fifty-two clinic directors or their representatives completed the survey (83% response rate). About 2/3 of the clinics reported a greater than 50% decrease in the number of available patient appointments, and modified clinical surveillance and research protocols. Fifty-one clinics (98%) newly instituted telehealth during the pandemic. Barriers to telehealth prior to the pandemic were insurance reimbursement concerns and lack of infrastructure. Since telehealth was initiated, high provider satisfaction was reported with ease of use. The most common area of concern was related to inability to perform a physical examination. CONCLUSION: Results show marked impacts on NF care and research since the beginning of the pandemic, with potential long-term changes related to the introduction (or adoption) of telehealth for clinical care.