Faculty Bibliography

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.

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.

Rapidly enlarging, painful plexiform neurofibromas (PN) in neurofibromatosis type 1 (NF1) patients are at higher risk for harboring a malignant peripheral nerve sheath tumor (MPNST). Fludeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) has been used to support more invasive diagnostic and therapeutic interventions. However, PET/CT imparts an untoward radiation hazard to this population with tumor suppressor gene impairment. The use of FDG PET coupled with magnetic resonance imaging (MRI) rather than CT is a safer alternative but its relative diagnostic sensitivity requires verification. Ten patients (6 females, 4 males, mean age 27 years, range 8-54) with NF1 and progressive PN were accrued from our institutional NF Clinic. Indications for PET scanning included increasing pain and/or progressive disability associated with an enlarging PN on serial MRIs. Following a clinically indicated whole-body FDG PET/CT, a contemporaneous PET/MRI was obtained using residual FDG activity with an average time interval of 3-4 h FDG-avid lesions were assessed for both maximum standardized uptake value (SUVmax) from PET/CT and SUVmax from PET/MR and correlation was made between the two parameters. 26 FDG avid lesions were detected on both PET/CT and PET/MR with an accuracy of 100%. SUVmax values ranged from 1.4-10.8 for PET/CT and from 0.2-5.9 for PET/MRI. SUVmax values from both modalities demonstrated positive correlation (r = 0.45, P < 0.001). PET/MRI radiation dose was significantly lower (53.35% ± 14.37% [P = 0.006]). In conclusion, PET/MRI is a feasible alternative to PET/CT in patients with NF1 when screening for the potential occurrence of MPNST. Reduction in radiation exposure approaches 50% compared to PET/CT.

BACKGROUND:Late-infantile neuronal ceroid lipofuscinosis type 2 (CLN2) disease, characterised by rapid psychomotor decline and epilepsy, is caused by deficiency of the lysosomal enzyme tripeptidyl peptidase 1. We aimed to analyse the characteristics and rate of progression of CLN2 disease in an international cohort of patients. METHODS:We did an observational cohort study using data from two independent, international datasets of patients with untreated genotypically confirmed CLN2 disease: the DEM-CHILD dataset (n=74) and the Weill Cornell Medical College (WCMC) dataset (n=66). Both datasets included quantitative rating assessments with disease-specific clinical domain scores, and disease course was measured longitudinally in 67 patients in the DEM-CHILD cohort. We analysed these data to determine age of disease onset and diagnosis, as well as disease progression-measured by the rate of decline in motor and language summary scores (on a scale of 0-6 points)-and time from first symptom to death. FINDINGS/RESULTS:In the combined DEM-CHILD and WCMC dataset, median age was 35·0 months (IQR 24·0-38·5) at first clinical symptom, 37·0 months (IQR 35·0 -42·0) at first seizure, and 54·0 months (IQR 47·5-60·0) at diagnosis. Of 74 patients in the DEM-CHILD dataset, the most common first symptoms of disease were seizures (52 [70%]), language difficulty (42 [57%]), motor difficulty (30 [41%]), behavioural abnormality (12 [16%]), and dementia (seven [9%]). Among the 41 patients in the DEM-CHILD dataset for whom longitudinal assessments spanning the entire disease course were available, a rapid annual decline of 1·81 score units (95% CI 1·50-2·12) was seen in motor-language summary scores from normal (score of 6) to no function (score of 0), which occurred over approximately 30 months. Among 53 patients in the DEM-CHILD cohort with available data, the median time between onset of first disease symptom and death was 7·8 years (SE 0·9) years. INTERPRETATION/CONCLUSIONS:In view of its natural history, late-infantile CLN2 disease should be considered in young children with delayed language acquisition and new onset of seizures. CLN2 disease has a largely predictable time course with regard to the loss of language and motor function, and these data might serve as historical controls for the assessment of current and future therapies. FUNDING/BACKGROUND:EU Seventh Framework Program, German Ministry of Education and Research, EU Horizon2020 Program, National Institutes of Health, Nathan's Battle Foundation, Cures Within Reach Foundation, Noah's Hope Foundation, Hope4Bridget Foundation.

DISCLAIMER/UNASSIGNED:This practice resource is designed primarily as an educational resource for medical geneticists and other clinicians to help them provide quality medical services. Adherence to this practice resource is completely voluntary and does not necessarily assure a successful medical outcome. This practice resource should not be considered inclusive of all proper procedures and tests or exclusive of other procedures and tests that are reasonably directed to obtaining the same results. In determining the propriety of any specific procedure or test, the clinician should apply his or her own professional judgment to the specific clinical circumstances presented by the individual patient or specimen. Clinicians are encouraged to document the reasons for the use of a particular procedure or test, whether or not it is in conformance with this practice resource. Clinicians also are advised to take notice of the date this practice resource was adopted, and to consider other medical and scientific information that becomes available after that date. It also would be prudent to consider whether intellectual property interests may restrict the performance of certain tests and other procedures. PURPOSE/OBJECTIVE:Neurofibromatosis type 1 (NF1) is an autosomal dominant disorder that is caused by a heterozygous loss-of-function variant in the tumor suppressor gene NF1; it affects ~1/1,900-1/3,500 people worldwide. The disorder is associated with an 8-15-year reduction in average life expectancy in both men and women, primarily due to malignant neoplasms and cardiovascular causes. METHODS:A work group of experts sought to determine the prevalence, morbidity and mortality, and available treatments of common and emerging NF1-related clinical problems in adults. Work-group members identified peer-reviewed publications from PubMed. Publications derived from populations and multi-institution cohorts were prioritized. Recommendations for management arose by consensus from this literature and the collective expertise of the authors. RESULTS:Malignant peripheral nerve sheath tumor (MPNST), breast cancer, cutaneous neurofibromas, and significant psychiatric and neurologic diagnoses are common problems in patients with NF1. CONCLUSION/CONCLUSIONS:Patient education and sensitization to worrisome signs and symptoms such as progressive severe pain (MPNST), changes in tumor volume (MPNST), new, unexplained neurologic symptoms (MPNST, brain tumors), and diaphoresis/palpitations (pheochromocytoma) are important. Although many issues in adults with NF1 can be managed by an internist or family physician, we strongly encourage evaluation by, and care coordination with, a specialized NF1 clinic.

OBJECTIVES: The Response Evaluation in Neurofibromatosis and Schwannomatosis (REiNS) International Collaboration Whole-Body MRI (WB-MRI) Working Group reviewed the existing literature on WB-MRI, an emerging technology for assessing disease in patients with neurofibromatosis type 1 (NF1), neurofibromatosis type 2 (NF2), and schwannomatosis (SWN), to recommend optimal image acquisition and analysis methods to enable WB-MRI as an endpoint in NF clinical trials. METHODS: A systematic process was used to review all published data about WB-MRI in NF syndromes to assess diagnostic accuracy, feasibility and reproducibility, and data about specific techniques for assessment of tumor burden, characterization of neoplasms, and response to therapy. RESULTS: WB-MRI at 1.5T or 3.0T is feasible for image acquisition. Short tau inversion recovery (STIR) sequence is used in all investigations to date, suggesting consensus about the utility of this sequence for detection of WB tumor burden in people with NF. There are insufficient data to support a consensus statement about the optimal imaging planes (axial vs coronal) or 2D vs 3D approaches. Functional imaging, although used in some NF studies, has not been systematically applied or evaluated. There are no comparative studies between regional vs WB-MRI or evaluations of WB-MRI reproducibility. CONCLUSIONS: WB-MRI is feasible for identifying tumors using both 1.5T and 3.0T systems. The STIR sequence is a core sequence. Additional investigation is needed to define the optimal approach for volumetric analysis, the reproducibility of WB-MRI in NF, and the diagnostic performance of WB-MRI vs regional MRI.

BACKGROUND AND PURPOSE: Late infantile neuronal ceroid lipofuscinosis (CLN2 disease) is a uniformly fatal lysosomal storage disease resulting from mutations in the CLN2 gene. Our hypothesis was that regional analysis of cortical brain degeneration may identify brain regions that are affected earliest and most severely by the disease. MATERIALS AND METHODS: Fifty-two high-resolution 3T MR imaging datasets were prospectively acquired on 38 subjects with CLN2. A retrospective cohort of 52 disease-free children served as a control population. The FreeSurfer software suite was used for calculation of cortical thickness. RESULTS: An increased rate of global cortical thinning in CLN2 versus control subjects was the primary finding in this study. Three distinct patterns were observed across brain regions. In the first, subjects with CLN2 exhibited differing rates of cortical thinning versus age. This was true in 22 and 26 of 34 regions in the left and right hemispheres, respectively, and was also clearly discernable when considering brain lobes as a whole and Brodmann regions. The second pattern exhibited a difference in thickness from healthy controls but with no discernable change with age (9 left hemispheres, 5 right hemispheres). In the third pattern, there was no difference in either the rate of cortical thinning or the mean cortical thickness between groups (3 left hemispheres, 3 right hemispheres). CONCLUSIONS: This study demonstrates that CLN2 causes differential rates of degeneration across the brain. Anatomic and functional regions that degenerate sooner and more severely than others compared with those in healthy controls may offer targets for directed therapies. The information gained may also provide neurobiologic insights regarding the mechanisms underlying disease progression.