Faculty Bibliography

OBJECTIVE:Neurofibromatosis type 1 (NF1) dystrophic scoliosis is an early-onset, rapidly progressive multiplanar deformity. There are few studies on the surgical management of this patient population. Specifically, perioperative morbidity, instrument-related complications, and quality-of-life outcomes associated with surgical management have not been systematically evaluated. In this study, the authors aimed to perform a systematic review on the natural history, management options, and surgical outcomes in patients who underwent NF1 dystrophic scoliosis surgery. METHODS:A PubMed search for articles with "neurofibromatosis" and either "dystrophic" or "scoliosis" in the title or abstract was performed. Articles with 10 or more patients undergoing surgery for NF1 dystrophic scoliosis were included. Data regarding indications, treatment details, morbidity, and outcomes were summarized and analyzed with descriptive statistics. RESULTS:A total of 310 articles were identified, 48 of which were selected for full-text review; 30 studies describing 761 patients met the inclusion criteria. The mean age ranged from 7 to 22 years, and 99.7% of patients were younger than 18 years. The mean preoperative coronal Cobb angle was 75.2°, and the average correction achieved was 40.3°. The mean clinical follow-up in each study was at least 2 years (range 2.2-19 years). All patients underwent surgery with the intent of deformity correction. The scoliosis regions addressed were thoracic curves (69.6%) and thoracolumbar (11.1%) and lumbar (14.3%) regions. The authors reported on a variety of approaches: posterior-only, combined anterior-posterior, and growth-friendly surgery. For fixation techniques, 42.5% of patients were treated with hybrid constructs, 51.5% with pedicle screw-only constructs, and 6.0% with hook-based constructs. Only 0.9% of patients underwent a vertebral column resection. The nonneurological complication rate was 14.0%, primarily dural tears and wound infections. The immediate postoperative neurological deficit rate was 2.1%, and the permanent neurological deficit rate was 1.2%. Ultimately, 21.5% required revision surgery, most commonly for implant-related complications. Loss of correction in both the sagittal and coronal planes commonly occurred at follow-up. Five papers supplied validated patient-reported outcome measures, showing improvement in the mental health, self-image, and activity domains. CONCLUSIONS:Data on the surgical outcomes of dystrophic scoliosis correction are heterogeneous and sparse. The perioperative complication rate appears to be high, although reported rates of neurological deficits appear to be lower than clinically observed and may be underreported. The incidence of implant-related failures requiring revision surgery is high. There is a great need for multicenter prospective studies of this complex type of deformity.

INTRODUCTION/BACKGROUND: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.

OBJECTIVE:To determine a suitable outcome measure for assessing muscle strength in neurofibromatosis type 1 (NF1) and type 2 (NF2) clinical trials, we evaluated the intra-observer reliability of hand-held dynamometry (HHD) and developed consensus recommendations for its use in neurofibromatosis clinical trials. METHODS:Patients ≥5 years with weakness in at least 1 muscle group by manual muscle testing (MMT) were eligible. Maximal isometric muscle strength of a weak muscle group and the biceps of the dominant arm were measured by HHD. An average of 3 repetitions per session was used as an observation, and 3 sessions with rest period between each were performed on the same day by a single observer. Intra- and inter-session intraclass correlation (ICC) and coefficient of variation (CV) were calculated to assess reliability and measurement error. RESULTS:Twenty NF1 and 13 NF2 patients enrolled; median age was 12 years (interquartile range (IQR) 9-17) and 29 years (IQR 22-38) respectively. By MMT, weak muscle strength ranged from 2-/5 to 4+/5. Biceps strength was 5/5 in all patients. Inter-session ICC for the weak muscles were 0.98 and 0.99 in the NF1 and NF2 cohorts respectively and for biceps were 0.97 and 0.97 respectively. The median CV for average session strength were 5.4% (IQR 2.6%-7.3%) and 2.9% (IQR 2.0%-6.2%) for weak muscles and biceps respectively. CONCLUSION/CONCLUSIONS:HHD performed by a trained examiner with a well-defined protocol is a reliable technique to measure muscle strength in NF1 and NF2. Recommendations for strength testing in NF1 and NF2 trials are provided.

PURPOSE/OBJECTIVE:By incorporating major developments in genetics, ophthalmology, dermatology, and neuroimaging, to revise the diagnostic criteria for neurofibromatosis type 1 (NF1) and to establish diagnostic criteria for Legius syndrome (LGSS). METHODS:We used a multistep process, beginning with a Delphi method involving global experts and subsequently involving non-NF experts, patients, and foundations/patient advocacy groups. RESULTS:We reached consensus on the minimal clinical and genetic criteria for diagnosing and differentiating NF1 and LGSS, which have phenotypic overlap in young patients with pigmentary findings. Criteria for the mosaic forms of these conditions are also recommended. CONCLUSION/CONCLUSIONS:The revised criteria for NF1 incorporate new clinical features and genetic testing, whereas the criteria for LGSS were created to differentiate the two conditions. It is likely that continued refinement of these new criteria will be necessary as investigators (1) study the diagnostic properties of the revised criteria, (2) reconsider criteria not included in this process, and (3) identify new clinical and other features of these conditions. For this reason, we propose an initiative to update periodically the diagnostic criteria for NF1 and LGSS.

Late infantile Batten disease (CLN2 disease) is an autosomal recessive, neurodegenerative lysosomal storage disease caused by mutations in the CLN2 gene encoding tripeptidyl peptidase 1 (TPP1). We tested intraparenchymal delivery of AAVrh.10hCLN2, a nonhuman serotype rh.10 adeno-associated virus vector encoding human CLN2, in a nonrandomized trial consisting of two arms assessed over 18 months: AAVrh.10hCLN2-treated cohort of 8 children with mild to moderate disease and an untreated, Weill Cornell natural history cohort consisting of 12 children. The treated cohort was also compared to an untreated European natural history cohort of CLN2 disease. The vector was administered through six burr holes directly to 12 sites in the brain without immunosuppression. In an additional safety assessment under a separate protocol, five children with severe CLN2 disease were treated with AAVrh.10hCLN2. The therapy was associated with a variety of expected adverse events, none causing long-term disability. Induction of systemic anti-AAVrh.10 immunity was mild. After therapy, the treated cohort had a 1.3- to 2.6-fold increase in cerebral spinal fluid TPP1. There was a slower loss of gray matter volume in four of seven children by MRI and a 42.4 and 47.5% reduction in the rate of decline of motor and language function, compared to Weill Cornell natural history cohort (P < 0.04) and European natural history cohort (P < 0.0001), respectively. Intraparenchymal brain administration of AAVrh.10hCLN2 slowed the progression of disease in children with CLN2 disease. However, improvements in vector design and delivery strategies will be necessary to halt disease progression using gene therapy.

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 with the expected upcoming approval of selumetinib for a specific indication for treatment of plexiform neurofibromas 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.

Background/UNASSIGNED:Spinal neurofibromas (SNFs) in neurofibromatosis type 1 (NF1) can cause progressive spinal cord compression and neurological dysfunction. The MEK inhibitor selumetinib shrinks the majority of plexiform neurofibromas (PNs) in patients with NF1. We assessed the effect of selumetinib on SNF. Methods/UNASSIGNED:/dose twice daily (max 50 mg b.i.d.; 1 cycle = 28 days). We qualitatively assessed the effect of selumetinib on SNF-related spinal canal distortion, cerebrospinal fluid distribution, and spinal cord deformity on MRI. Results/UNASSIGNED:Twenty-four patients (18 male), median age 16.9 years (range, 6.2-60.3), had SNF, 22 of which were associated with the same nerves as the target PN assessed on the clinical trial. Twenty patients had spinal cord deformity. Twenty-three patients completed at least 12 treatment cycles to date. Eighteen patients showed subtle to a marked improvement in SNF burden, 5 remained stable, and no worsening was observed during treatment. Conclusions/UNASSIGNED:This is the first study describing the effect of selumetinib on SNF. Of 24 patients, 18 exhibited some improvement of SNF burden on imaging. These findings suggest that selumetinib may prevent the worsening of cord compression, potentially reducing the need for surgical interventions in select patients or benefitting patients who do not have a surgical option. Prospective evaluation of the clinical benefit of selumetinib for SNF is warranted.

We report 281 individuals carrying a pathogenic recurrent NF1 missense variants at p.Met1149, p.Arg1276 or p.Lys1423, representing three non-truncating NF1 hotspots in the University of Alabama at Birmingham (UAB) cohort, together identified in 1.8% of unrelated NF1 individuals. About 25% (95% CI, 20.5%-31.2%) of individuals heterozygous for a pathogenic NF1 p.Met1149, p.Arg1276 or p.Lys1423 missense variant had a Noonan-like phenotype, which is significantly more compared to the "classic" NF1-affected cohorts (all P<0.0001). Furthermore, p.Arg1276 and p.Lys1423 pathogenic missense variants were associated with a high prevalence of cardiovascular abnormalities, including pulmonic stenosis (all P<0.0001), while p.Arg1276 variants had a high prevalence of symptomatic spinal neurofibromas (P<0.0001) compared with "classic" NF1-affected cohorts. However, p.Met1149-positive individuals had a mild phenotype, characterized mainly by pigmentary manifestations without externally visible plexiform neurofibromas, symptomatic spinal neurofibromas or symptomatic optic pathway gliomas. As up to 0.4% of unrelated individuals in the UAB cohort carries a p.Met1149 missense variant, this finding will contribute to more accurate stratification of a significant number of NF1 individuals. Although clinically relevant genotype-phenotype correlations are rare in NF1, each affecting only a small percentage of individuals, together they impact counseling and management of a significant number of the NF1 population. This article is protected by copyright. All rights reserved.