Neurofibromatosis- and schwannomatosis-associated tumors: Approaches to genetic testing and counseling considerations.

Neurofibromatosis (NF) and schwannomatosis (SWN) are genetic conditions characterized by the risk of developing nervous system tumors. Recently revised diagnostic criteria include the addition of genetic testing to confirm a pathogenic variant, as well as to detect the presence of mosaicism. Therefore, the use and interpretation of both germline and tumor-based testing have increasing importance in the diagnostic approach, treatment decisions, and risk stratification of these conditions. This focused review discusses approaches to genetic testing of NF- and SWN-related tumor types, which are somewhat rare and perhaps lesser known to non-specialized clinicians. These include gastrointestinal stromal tumors, breast cancer, plexiform neurofibromas with or without transformation to malignant peripheral nerve sheath tumors, gliomas, and schwannomas, and emphasizes the need for inclusion of genetic providers in patient care and appropriate pre- and post-test education, genetic counseling, and focused evaluation by a medical geneticist or other healthcare provider familiar with clinical manifestations of these disorders.

Parent perspectives on disclosing a pediatric neurofibromatosis type 1 diagnosis.

Neurofibromatosis 1 (NF1) is a common genetic disorder typically diagnosed in childhood and characterized by cutaneous findings, nerve sheath tumors, skeletal abnormalities, malignancies, and developmental differences. Due to its variability, NF1 is an unpredictable condition that parents have concerns about discussing with their children. While there are publications addressing the disclosure of genetic conditions in general, no NF1-specific disclosure literature exists. To fill this gap, this mixed methods study sought to evaluate the concerns, barriers, failures, or successes parents or guardians have experienced when they have or have not chosen to tell their child(ren) about an NF1 diagnosis. Parents of children between ages 0 and 17 with a diagnosis of NF1 completed a survey and some parents were selected for an interview invitation. A total of 258 surveys were completed, and 20 parents were interviewed. Interview transcripts were categorized into disclosure and non-disclosure groups. Themes were organized into five categories based on interview questions: disclosure concerns, factors affecting disclosure/non-disclosure, approaches to disclosure, desired resources, and recommendations for disclosure. Sentiment analysis was performed on responses about the disclosure discussion itself. Results indicated that most parents (70.5%) disclosed the NF1 diagnosis to their child and overall felt it was a positive experience. Almost one-third of parents (29.5%) had not disclosed the diagnosis. A strong significance was identified between disclosure and severe presentation of NF1 (p = 0.0008). Parents in both groups shared similar concerns about discussing the diagnosis and multiple factors influenced the disclosure decision. Most parents approached disclosure as a process and emphasized the need to be honest and supportive of their child. Parents highlighted the need for more educational resources for children and guidance on how to disclose. These findings indicate that additional resources and support for parents would facilitate disclosure and the involvement of genetic counselors in the process would be beneficial.

The Use of MEK Inhibitors in Neurofibromatosis Type 1-Associated Tumors and Management of Toxicities.

Early-phase clinical trials using oral inhibitors of MEK, the mitogen-activated protein kinase kinase, have demonstrated benefit for patients with neurofibromatosis type 1 (NF1)-associated tumors, particularly progressive low-grade gliomas and plexiform neurofibromas. Given this potential of MEK inhibition as an effective medical therapy, the use of targeted agents in the NF1 population is likely to increase substantially. For clinicians with limited experience prescribing MEK inhibitors, concern about managing these treatments may be a barrier to use. In this manuscript, the Clinical Care Advisory Board of the Children's Tumor Foundation reviews the published experience with MEK inhibitors in NF1 and outlines recommendations for side-effect management, as well as monitoring guidelines. These recommendations can serve as a beginning framework for NF providers seeking to provide the most effective treatments for their patients. IMPLICATIONS FOR PRACTICE: Neurofibromatosis type 1 (NF1) clinical care is on the cusp of a transformative shift. With the success of recent clinical trials using MEK inhibitors, an increasing number of NF1 patients are being treated with MEK inhibitors for both plexiform neurofibromas and low-grade gliomas. The use of MEK inhibitors is likely to increase substantially in NF1. Given these changes, the Clinical Care Advisory Board of the Children's Tumor Foundation has identified a need within the NF1 clinical community for guidance for the safe and effective use of MEK inhibitors for NF1-related tumors. This article provides a review of the published experience of MEK inhibitors in NF1 and provides recommendations for monitoring and management of side effects.

Genetic Counseling for Neurofibromatosis 1, Neurofibromatosis 2, and Schwannomatosis-Practice Resource of the National Society of Genetic Counselors.

The goal of this practice resource is to provide genetic counselors and other healthcare professionals with a resource to reference when providing genetic counseling services to individuals and families undergoing evaluation for neurofibromatosis (NF) or who have received a diagnosis of NF, including NF1, NF2, and schwannomatosis. This resource represents the opinions of a multi-center working group of Certified Genetic Counselors with experience in the care of individuals with NF, providing topics to be considered for the incorporation into a clinical genetic counseling session.

Increasing access to specialty care for rare diseases: a case study using a foundation sponsored clinic network for patients with neurofibromatosis 1, neurofibromatosis 2, and schwannomatosis.

BACKGROUND: Our primary aim was to assess the ability of a non-profit foundation-sponsored clinic network to facilitate access to specialized care for patients with neurofibromatoses (NF), a group of neurogenetic disorders including NF1, NF2, and schwannomatosis (SWN). Our secondary aim was to identify how our findings in NF could be applied more broadly to other rare diseases. METHODS: We retrospectively reviewed aggregate data on patient volume reported by specialty NF clinics in a nonprofit network from 2008 to 2015. We classified clinics as high or low volume for disease type (NF1 and NF2/schwannomatosis) and pediatric/adult care. We compared clinic-level data to self-reported patient-level data from a large online patient registry. RESULTS: Between 2008 and 2015, the number of certified NF clinics grew from 32 to 50, and annual patient volume rose from 6776 to 10,245 patients (13% of the total estimated U.S. NF patient population). For patient registry participants (n = 4476), the median driving distance to the nearest network clinic was 51.3 miles. Driving distances to reach high-volume centers were elevated for adults compared to children (295.8 vs. 67.9 miles), and schwannomatosis and NF2 patients compared to NF1 patients (310.9 vs. 368.1 vs. 161.7 miles). Of registry participants reporting their location of care (n = 2271), only 43.2% received care in a network specialty clinic, with especially low rates of attendance in the Southwest and Far West. CONCLUSIONS: While the number of certified NF clinics and volume of patients seen in these clinics has increased, many NF patients still do not attend specialty clinics and/or travel a significant distance for care. Geographic access to care is more limited for adults, patients with rarer conditions, and patients in the Western U.S. Potential measures to improve access to specialty care for people living with NF and other rare diseases are discussed.

Jaffe-Campanacci syndrome, revisited: detailed clinical and molecular analyses determine whether patients have neurofibromatosis type 1, coincidental manifestations, or a distinct disorder.

PURPOSE: "Jaffe-Campanacci syndrome" describes the complex of multiple nonossifying fibromas of the long bones, mandibular giant cell lesions, and café-au-lait macules in individuals without neurofibromas. We sought to determine whether Jaffe-Campanacci syndrome is a distinct genetic entity or a variant of neurofibromatosis type 1. METHODS: We performed germline NF1, SPRED1, and GNAS1 (exon 8) mutation testing on patients with Jaffe-Campanacci syndrome or Jaffe-Campanacci syndrome-related features. We also performed somatic NF1 mutation testing on nonossifying fibromas and giant cell lesions. RESULTS: Pathogenic germline NF1 mutations were identified in 13 of 14 patients with multiple café-au-lait macules and multiple nonossifying fibromas or giant cell lesions ("classical" Jaffe-Campanacci syndrome); all 13 also fulfilled the National Institutes of Health diagnostic criteria for neurofibromatosis type 1. Somatic NF1 mutations were detected in two giant cell lesions but not in two nonossifying fibromas. No SPRED1 or GNAS1 (exon 8) mutations were detected in the seven NF1-negative patients with Jaffe-Campanacci syndrome, nonossifying fibromas, or giant cell lesions. CONCLUSION: In this study, the majority of patients with café-au-lait macules and nonossifying fibromas or giant cell lesions harbored a pathogenic germline NF1 mutation, suggesting that many Jaffe-Campanacci syndrome cases may actually have neurofibromatosis type 1. We provide the first proof of specific somatic second-hit mutations affecting NF1 in two giant cell lesions from two unrelated patients, establishing these as neurofibromatosis type 1-associated tumors.

Neurofibromatosis Type 1 (NF1): Addressing the Transition from Pediatric to Adult Care.

Health care transition, or HCT, is the process of adolescents and young adults moving from a child/family-centered model of health care to an adult/patient-centered model of health care. Healthcare providers have an essential role in this process which can be especially challenging for individuals with medical or special healthcare needs. Neurofibromatosis type 1 (NF1) is a complex multisystem disorder requiring lifelong medical surveillance, education, and psychosocial support. This review highlights the transition needs of NF1 patients and provides resources for both clinicians and families to facilitate HCT in this population. The authors propose a framework for the development of an effective NF1 transition program by using the Six Core Elements model of the Got Transition program, reviewing existing literature, and incorporating author experiences in the care and transition of NF1 patients.

Transition Readiness Assessment in Adolescents and Young Adults with Neurofibromatosis Type 1 (NF1).

Neurofibromatosis type 1 (NF1) conveys significant disease morbidity and lower quality of life compared to the general population. Research has shown that decreased positive health outcomes are directly correlated with inadequate development of health-related self-management skills among similar patient populations, and among these populations a healthcare transition (HCT) intervention improves provision of care and health outcomes. Thus, HCT intervention may improve care and outcomes in NF1. To design a future informed NF1 HCT intervention, baseline transition readiness must be assessed. A survey distributed by Children's Tumor Foundation (CTF) was developed to assess transition readiness and the impact of NF1 on factors of young adult life. A total of 101 participants aged 14-26 years living in the United States completed the survey with a median [IQR] age of 18 [16, 21]. The majority of participants reported that NF1 had significant or some impact on all factors of young adult life including education, career, relationships, and family planning. The median Transition Readiness Assessment Questionnaire (TRAQ) score in this study (3.50/5.00) was significantly lower than the previously published score of healthy peers (3.93/5.00) (p< .001). Higher TRAQ scores correlated with higher NF1-specific transition knowledge and skills (NF1-TRAQ) (r = 0.632). Participants self-report adequate knowledge of NF1 and comfort in talking to medical providers. They report discomfort with appointment keeping, insurance related tasks, addressing NF1 emergencies, and discussing NF1 with non-medical providers and peers. Further, TRAQ and NF1-TRAQ scores were lower in individuals who reported that their diagnosis of NF1 had some or significant impact on education, career, and relationships. Findings demonstrate that among individuals with NF1 in this study, decreased transition readiness is associated with a negative impact on young adult life. Data from this study supports the need to develop NF1-specific HCT intervention tools, with an effort to improve quality of life and standardize NF1 care.

Awareness and agreement with neurofibromatosis care guidelines among U.S. neurofibromatosis specialists.

INTRODUCTION: The neurofibromatoses (NF) are a group of rare, genetic diseases sharing a predisposition to develop multiple benign nervous system tumors. Given the wide range of NF symptoms and medical specialties involved in NF care, we sought to evaluate the level of awareness of, and agreement with, published NF clinical guidelines among NF specialists in the United States. METHODS: An anonymous, cross-sectional, online survey was distributed to U.S.-based NF clinicians. Respondents self-reported demographics, practice characteristics, awareness of seven NF guideline publications, and level of agreement with up to 40 individual recommendations using a 5-point Likert scale. We calculated the proportion of recommendations that each clinician rated "strongly agree", and assessed for differences in guideline awareness and agreement by respondent characteristics. RESULTS: Sixty-three clinicians (49% female; 80% academic practice) across > 8 medical specialties completed the survey. Awareness of each guideline publication ranged from 53%-79% of respondents; specialists had higher awareness of publications endorsed by their medical professional organization (p < 0.05). The proportion of respondents who "strongly agree" with individual recommendations ranged from 17%-83%; for 16 guidelines, less than 50% of respondents "strongly agree". There were no significant differences in overall agreement with recommendations based on clinicians' gender, race, specialty, years in practice, practice type (academic/private practice/other), practice location (urban/suburban/rural), or involvement in NF research (p > 0.05 for all). CONCLUSIONS: We identified wide variability in both awareness of, and agreement with, published NF care guidelines among NF experts. Future quality improvement efforts should focus on evidence-based, consensus-driven methods to update and disseminate guidelines across this multi-specialty group of providers. Patients and caregivers should also be consulted to proactively anticipate barriers to accessing and implementing guideline-driven care. These recommendations for improving guideline knowledge and adoption may also be useful for other rare diseases requiring multi-specialty care coordination.

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.

Neurofibromatosis type 1 in genetic counseling practice: recommendations of the National Society of Genetic Counselors.

The objective of this document is to provide recommendations for the genetic counseling of patients and families undergoing evaluation for neurofibromatosis type 1 (NF1) or who have received a diagnosis of NF1. These recommendations are the opinions of a multi-center working group of genetic counselors with expertise in the care of individuals with NF1. These recommendations are based on the committee's clinical experiences, a review of pertinent English language medical articles, and reports of expert committees. These recommendations are not intended to dictate an exclusive course of management, nor does the use of such recommendations guarantee a particular outcome. These recommendations do not displace a health care provider's professional judgment based on the clinical circumstances of an individual patient.