Neurofibromatosis type 1 (NF1) is an autosomal dominant tumor predisposition syndrome that affects children and adults. Individuals with NF1 are at high risk for central nervous system neoplasms including gliomas. The purpose of this review is to discuss the spectrum of intracranial gliomas arising in individuals with NF1 with a focus on recent preclinical and clinical data. In this review, possible mechanisms of gliomagenesis are discussed, including the contribution of different signaling pathways and tumor microenvironment. Furthermore, we discuss the recent notable advances in the developing therapeutic landscape for NF1-associated gliomas including clinical trials and collaborative efforts.

Neurofibromatosis type 1 (NF1) is a genetic disorder characterized by a predisposition to develop multiple benign tumors. A major feature of NF1 is the development of localized cutaneous neurofibromas. Cutaneous neurofibromas manifest in > 99% of adults with NF1 and are responsible for major negative effects on quality of life. Previous reports have correlated increased burden of cutaneous neurofibromas with age and pregnancy, but longitudinal data are not available to establish a quantitative natural history of these lesions. The purpose of this study is to conduct a prospective natural history study of 22 adults with NF1 over an 8-year period to quantify cutaneous neurofibroma number and size. The average monthly increase in volume for cutaneous neurofibromas was 0.37 mm3 in the back region (95% CI (0.23, 0.51), p < 0.0001), 0.28 mm3 in the abdominal region (95% CI (0.16, 0.41), p < 0.0001), and 0.21 mm3 in the arm/leg region (95% CI (0.08, 0.34), p = 0.0022). The number of cutaneous neurofibromas significantly increased in the back (slope = 0.032, p = 0.011) and abdominal (slope = 0.018, p = 0.026) regions, while the leg/arm regions retained a positive trend (slope = 0.004, p = 0.055). The number and volume of cutaneous neurofibromas significantly increased over an 8-year timespan; however, the rate of increase is variable by individual and body region. These findings may provide insight into cutaneous neurofibroma development and benefit researchers considering clinical trials targeting cutaneous neurofibromas.

To meet current and expected future demand for genome sequencing in the neonatal intensive care unit (NICU), adjustments to traditional service delivery models are necessary. Effective programs for the training of non-genetics providers (NGPs) may address the known barriers to providing genetic services including limited genetics knowledge and lack of confidence. The SouthSeq project aims to use genome sequencing to make genomic diagnoses in the neonatal period and evaluate a scalable approach to delivering genome sequencing results to populations with limited access to genetics professionals. Thirty-three SouthSeq NGPs participated in a live, interactive training intervention and completed surveys before and after participation. Here, we describe the protocol for the provider training intervention utilized in the SouthSeq study and the associated impact on NGP knowledge and confidence in reviewing, interpreting, and using genome sequencing results. Participation in the live training intervention led to an increased level of confidence in critical skills needed for real-world implementation of genome sequencing. Providers reported a significant increase in confidence level in their ability to review, understand, and use genome sequencing result reports to guide patient care. Reported barriers to implementation of genome sequencing in a NICU setting included test cost, lack of insurance coverage, and turn around time. As implementation of genome sequencing in this setting progresses, effective education of NGPs is critical to provide access to high-quality and timely genomic medicine care.

Importance: Cutaneous neurofibromas (cNFs) can cause itching, disfigurement, pain, and emotional difficulties in people with neurofibromatosis type 1 (NF1).Objective: To determine the impact of the mitogen-activated protein kinase kinase inhibitor selumetinib on cNF including change in tumor volume and patient-reported outcome measures.Design, Setting, and Participants: Adults with NF1 and 9 or more measurable cNFs were enrolled in this nonrandomized pilot trial at the National Cancer Institute and the University of Alabama at Birmingham, which spanned from August 26, 2017, to August 21, 2023.Intervention: Participants received selumetinib for up to 24 cycles (1 cycle = 28 days) with restaging visits after every 4 cycles.Main Outcomes and Measures: Photography and volumetric measurements of cNFs using calipers were used to evaluate the number and volume of tumors. Participants completed the Skindex-29 Quality of Life assessment to quantify the effect of treatment on symptoms, functioning, emotions, itching, and pain.Results: Among the 11 participants who enrolled, the median (range) age was 54 (28-75) years, and 6 were female. The median (IQR) best response across all participants and tumors was a −28.5% (−40.9% to −12.5%) decrease in cNF volume from baseline. Some participants showed a visible improvement in cNF burden while receiving treatment in standardized photographs. The median (range) duration of treatment was 9 cycles (1-24), with only 4 participants completing the full 24 cycles of treatment. Two of these participants continued treatment beyond the original 24 cycles due to perceived clinical benefit. All participants experienced at least 1 reversible drug-related adverse event (AE), with cutaneous AEs such as dry skin and rash being the most common. Two participants were removed from treatment due to concern for drug reaction with eosinophilia and systemic symptoms. While the Skindex-29 assessment showed improvement in emotion scores after cycle 1, there were no other significant or durable changes in scores.Conclusions and Relevance: In this nonrandomized pilot trial, selumetinib resulted in some decrease in cNF volume; however, there was no sustained improvement in patient-reported outcome measures. Study enrollment was incomplete, in part due to the COVID-19 pandemic, and highlights the challenges of treating patients with cNF with a drug that often leads to dermatologic AEs. Future larger studies using other measurement techniques, such as 3-dimensional photography, could help to yield results that are more generalizable to the phenotypically diverse NF1 population.Trial Registration: ClinicalTrials.gov Identifier: NCT02839720

The ABMG was founded in 1980. From 1984 to 1995, it accredited all medical genetics training programs and was also responsible for administering the certification exams to all graduates of training programs. At the outset, multiple training and accreditation categories were recognized, and certificates offered in clinical genetics, clinical biochemical genetics, clinical cytogenetics, and genetic counseling (Figure 1). Physicians could achieve certification as clinical geneticists, and either physicians or PhDs could achieve certification as clinical laboratory geneticists, with separate training and certification in clinical cytogenetics and clinical biochemical genetics. PhDs could also be certified as medical geneticists. The ABMG administered the certification examinations for genetic counselors through 1993; they did not accredit genetic counseling training programs, but did approve sites for clinical training. In 1990 clinical molecular genetics was approved as a new laboratory specialty; the first certification exam was given as a joint examination with clinical biochemical genetics, and then in 1993 clinical molecular genetics certification was offered as a third distinct laboratory specialty. PhD medical genetics certification was not offered after 2005 due to a dwindling number of trainees. The ABMG was accepted by the ABMS as the 24th member specialty board in 1991. Subsequently, the Accreditation Council for Graduate Medical Education (ACGME) assumed responsibility for the accreditation of medical genetics residency training programs by establishing a medical genetics residency review committee. The ABMG continued to be the certifying organization for all medical genetics specialties and continued to accredit medical genetics laboratory training programs. The American Board of Genetic Counseling was incorporated in 1993 and took on the role of independently certifying genetic counselors in 1996. Formal accreditation of genetic counseling graduate programs by this board began in 1995. In 1999, a new subspecialty in molecular genetic pathology, sponsored by the ABMG and the American Board of Pathology, was approved by the ABMS, with training programs accredited by the ACGME by a review committee comprised members drawn from the medical genetics and pathology residency review committee. A subspecialty in medical biochemical genetics, sponsored by the ABMG, was approved by the ABMS in 2007, with ACGME accreditation under the aegis of the medical genetics residency review committee. The ABMG, with formal approval from the ABMS, changed its name to the ABMGG in 2014. In the time since the initiation of formal medical genetics training, growth in the number of new medical geneticists has been relatively small, though with variability between specialties over time (Figure 2). This issue was the subject of previous Banbury meetings on medical genetics.1, 2 Numbers of clinical cytogeneticists have been stable but more and more are becoming dual-certified in both clinical cytogenetics and clinical molecular genetics. The numbers seeking clinical molecular genetics training have grown.Training programs have limited funding, so many applicants have difficulty finding a funded training position. The number of genetic counselors has steadily increased, though not necessarily in proportion to the opportunity to incorporate genetics and genomics into medical practice, perhaps in part due to challenges in billing for genetic counseling services and the expanded role of genetic counselors in industry. Participants in the meeting identified a set of guiding principles, which are discussed below. Given the principles stated above, the attendees at the meeting offered a set of recommendations for the evolution of medical genetics and genomics training. As noted above, the meeting participants did not embrace the idea of proliferating genetics subspecialty training into other medical specialties. This concept has been considered for some time, and might be viable in some areas where genetics has been adopted as an important approach, such as oncology, neurology, and cardiology. Indeed, some individuals have customized their own training to obtain expertise in more than one area. In other cases, individuals who were trained in one area of medicine have made the effort to self-learn how to incorporate genetics and genomics into their practice. Nonetheless, we believe that this will not be a sustainable model for all areas of medicine, and instead encourage medical geneticists to be broadly trained and to expect to collaborate with colleagues across all medical specialties. This will require that collaboration be incorporated into training, as well as into medical practice. Medical genetics trainees need to have opportunities to interact with colleagues in other areas of medicine, including through participation in multidisciplinary clinical programs and case conferences in various specialties. The use of innovative approaches, as noted previously, can also help fill gaps in specific training programs. Most importantly, trainees need to be able to look to their mentors as role models in interdisciplinary care. Even as medical geneticists must collaborate with other specialists, there remains a great need to educate non-geneticists on the use of genetics and genomics in their practice. Rather than convince them that they can practice genetics without formal training, this exposure is likely to convince them of the importance of genetics and genomics and of the need to engage experts in helping them to provide care to their patients. The medical genetics community should therefore be encouraged to reach out to other medical specialties to help educate their members about the application of genetics and genomics at all levels of training, including pre-graduate, residency, fellowship, and continuing education. As previously noted, the application of genomics raises a host of new challenges and...