Publications by authors named "Elizabeth Schorry"

51 Publications

NF106: A Neurofibromatosis Clinical Trials Consortium Phase II Trial of the MEK Inhibitor Mirdametinib (PD-0325901) in Adolescents and Adults With NF1-Related Plexiform Neurofibromas.

J Clin Oncol 2021 Mar 28;39(7):797-806. Epub 2021 Jan 28.

Children's Hospital of Philadelphia, Philadelphia, PA.

Purpose: Patients with neurofibromatosis type 1 (NF1) frequently develop plexiform neurofibromas (PNs), which can cause significant morbidity. We performed a phase II trial of the MAPK/ERK kinase inhibitor, mirdametinib (PD-0325901), in patients with NF1 and inoperable PNs. The primary objective was response rate based on volumetric magnetic resonance imaging analysis.

Methods: Inclusion criteria included age ≥ 16 years and a PN that was either progressive or causing significant morbidity. First-dose pharmacokinetics were performed. Patients completed patient-reported outcome measures. Patients received mirdametinib by mouth twice a day at 2 mg/m/dose (maximum dose = 4 mg twice a day) in a 3-week on/1-week off sequence. Each course was 4 weeks in duration. Evaluations were performed after four courses for the first year and then after every six courses. Patients could receive a maximum of 24 total courses.

Results: Nineteen patients were enrolled, and all 19 received mirdametinib. The median age was 24 years (range, 16-39 years); the median baseline tumor volume was 363.8 mL (range, 3.9-5,161 mL). Eight of the 19 patients (42%) achieved a partial response of the target PN by course 12, and 10 (53%) had stable disease. One patient (5%) developed progressive disease at course 8. Significant and durable decreases were observed in pain ratings.

Conclusion: To our knowledge, this analysis represents the first characterization of the activity and pharmacokinetics of mirdametinib in patients with NF1 and PNs and is the first published response study for MAPK/ERK kinase inhibitors in adults with NF1 and PNs. Mirdametinib given at 2 mg/m/dose (maximum dose, 4 mg) twice daily in a 3-week on/1-week off sequence resulted in a 42% partial response rate with preliminary evidence of reduction in pain.
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http://dx.doi.org/10.1200/JCO.20.02220DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8078274PMC
March 2021

Neurofibromatosis Type 2 (NF2) and the Implications for Vestibular Schwannoma and Meningioma Pathogenesis.

Int J Mol Sci 2021 Jan 12;22(2). Epub 2021 Jan 12.

Department of Neurology, University of Cincinnati, Cincinnati, OH 45267, USA.

Patients diagnosed with neurofibromatosis type 2 (NF2) are extremely likely to develop meningiomas, in addition to vestibular schwannomas. Meningiomas are a common primary brain tumor; many NF2 patients suffer from multiple meningiomas. In NF2, patients have mutations in the gene, specifically with loss of function in a tumor-suppressor protein that has a number of synonymous names, including: Merlin, Neurofibromin 2, and schwannomin. Merlin is a 70 kDa protein that has 10 different isoforms. The Hippo Tumor Suppressor pathway is regulated upstream by Merlin. This pathway is critical in regulating cell proliferation and apoptosis, characteristics that are important for tumor progression. Mutations of the NF2 gene are strongly associated with NF2 diagnosis, leading to benign proliferative conditions such as vestibular schwannomas and meningiomas. Unfortunately, even though these tumors are benign, they are associated with significant morbidity and the potential for early mortality. In this review, we aim to encompass meningiomas and vestibular schwannomas as they pertain to NF2 by assessing molecular genetics, common tumor types, and tumor pathogenesis.
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http://dx.doi.org/10.3390/ijms22020690DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7828193PMC
January 2021

Are Some Randomized Clinical Trials Impossible?

J Pediatr Orthop 2021 Jan;41(1):e90-e93

Human Genetics, Cincinnati Children's Hospital, Cincinnati, OH.

Congenital tibial pseudarthrosis is a rare condition seen in neurofibromatosis type 1 (NF1), and treatment is complex. A randomized, placebo-controlled trial of bone morphogenetic protein (rhBMP-2; INFUSE bone graft) at time of tibial surgery was developed by the Neurofibromatosis Clinical Trials Consortium. Patients were randomized to receive rhBMP-2 that would, or would not, be added to the standard surgical procedure consisting of resection of pseudarthrosis tissue, insertion of a rigid intramedullary rod, and placement of autogenous iliac crest bone graft. Despite involvement of 16 centers with wide experience with NF1 orthopaedic management, only 5 patients (of 54 required) were able to be enrolled in the study during a 3-year time period. Because of the inability to recruit sufficient patients, this study was closed in June 2019, with plans to terminate. The obstacles that were encountered during the study are summarized. The authors question whether a randomized, placebo-controlled trial of a rare pediatric orthopaedic condition is possible to accomplish. Recommendations are provided to guide future studies of orthopaedic manifestations of NF1.Level of Evidence: Level V.
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http://dx.doi.org/10.1097/BPO.0000000000001650DOI Listing
January 2021

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

Oncologist 2020 07 22;25(7):e1109-e1116. Epub 2020 Apr 22.

NYU Langone Health, New York, New York, USA.

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.
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http://dx.doi.org/10.1634/theoncologist.2020-0069DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7356675PMC
July 2020

Examination of the genetic factors underlying the cognitive variability associated with neurofibromatosis type 1.

Genet Med 2020 05 4;22(5):889-897. Epub 2020 Feb 4.

Department of Neuroscience, Erasmus Medical Center, Rotterdam, The Netherlands.

Purpose: Neurofibromatosis type 1 (NF1) is an autosomal dominant disorder associated with cognitive deficits. The NF1 cognitive phenotype is generally considered to be highly variable, possibly due to the observed T2-weighted hyperintensities, loss of heterozygosity, NF1-specific genetic modifiers, or allelic imbalance.

Methods: We investigated cognitive variability and assessed the contribution of genetic factors by performing a retrospective cohort study and a monozygotic twin case series. We included data of 497 children with genetically confirmed NF1 and an IQ assessment, including 12 monozygotic twin and 17 sibling sets.

Results: Individuals carrying an NF1 chromosomal microdeletion showed significant lower full-scale IQ (FSIQ) scores than individuals carrying intragenic pathogenic NF1 variants. For the intragenic subgroup, the variability in cognitive ability and the correlation of IQ between monozygotic NF1 twin pairs or between NF1 siblings is similar to the general population.

Conclusions: The variance and heritability of IQ in individuals with NF1 are similar to that of the general population, and hence mostly driven by genetic background differences. The only factor that significantly attenuates IQ in NF1 individuals is the NF1 chromosomal microdeletion genotype. Implications for clinical management are that individuals with intragenic NF1 variants that score <1.5-2 SD below the mean of the NF1 population should be screened for additional causes of cognitive disability.
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http://dx.doi.org/10.1038/s41436-020-0752-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7200599PMC
May 2020

KMT2C/D COMPASS complex-associated diseases [KCOM-ADs]: an emerging class of congenital regulopathies.

Clin Epigenetics 2020 01 10;12(1):10. Epub 2020 Jan 10.

Division of Allergy and Immunology, Cincinnati Children's Hospital Medical Center (CCHMC), 3333 Burnet Avenue, Cincinnati, OH, 45229-3026, USA.

The type 2 lysine methyltransferases KMT2C and KMT2D are large, enzymatically active scaffold proteins that form the core of nuclear regulatory structures known as KMT2C/D COMPASS complexes (complex of proteins associating with Set1). These evolutionarily conserved proteins regulate DNA promoter and enhancer elements, modulating the activity of diverse cell types critical for embryonic morphogenesis, central nervous system development, and post-natal survival. KMT2C/D COMPASS complexes and their binding partners enhance active gene expression of specific loci via the targeted modification of histone-3 tail residues, in general promoting active euchromatic conformations. Over the last 20 years, mutations in five key COMPASS complex genes have been linked to three human congenital syndromes: Kabuki syndrome (type 1 [KMT2D] and 2 [KDM6A]), Rubinstein-Taybi syndrome (type 1 [CBP] and 2 [EP300]), and Kleefstra syndrome type 2 (KMT2C). Here, we review the composition and biochemical function of the KMT2 complexes. The specific cellular and embryonic roles of the KMT2C/D COMPASS complex are highlight with a focus on clinically relevant mechanisms sensitive to haploinsufficiency. The phenotypic similarities and differences between the members of this new family of disorders are outlined and emerging therapeutic strategies are detailed.
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http://dx.doi.org/10.1186/s13148-019-0802-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6954584PMC
January 2020

Cognition, ADHD Symptoms, and Functional Impairment in Children and Adolescents With Neurofibromatosis Type 1.

J Atten Disord 2021 Jun 14;25(8):1177-1186. Epub 2019 Dec 14.

Murdoch Children's Research Institute, Royal Children's Hospital, Parkville, Victoria, Australia.

We examined the contribution of attention and executive cognitive processes to ADHD symptomatology in NF1, as well as the relationships between cognition and ADHD symptoms with functional outcomes. The study sample consisted of 141 children and adolescents with NF1. Children were administered neuropsychological tests that assessed attention and executive function, from which latent cognitive variables were derived. ADHD symptomatology, adaptive skills, and quality of life (QoL) were assessed using parent-rated questionnaires. Path analyses were conducted to test relationships among cognitive functioning, ADHD symptomatology, and functional outcomes. Significant deficits were observed on all outcome variables. Cognitive variables did not predict ADHD symptomatology. Neither did they predict functional outcomes. However, elevated ADHD symptomatology significantly predicted functional outcomes. Irrespective of cognitive deficits, elevated ADHD symptoms in children with NF1 negatively impact daily functioning and emphasize the importance of interventions aimed at minimizing ADHD symptoms in NF1.
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http://dx.doi.org/10.1177/1087054719894384DOI Listing
June 2021

Reproducibility of cognitive endpoints in clinical trials: lessons from neurofibromatosis type 1.

Ann Clin Transl Neurol 2019 12 3;6(12):2555-2565. Epub 2019 Dec 3.

Murdoch Children's Research Institute, Royal Children's Hospital, Parkville, Victoria, Australia.

Objective: Rapid developments in understanding the molecular mechanisms underlying cognitive deficits in neurodevelopmental disorders have increased expectations for targeted, mechanism-based treatments. However, translation from preclinical models to human clinical trials has proven challenging. Poor reproducibility of cognitive endpoints may provide one explanation for this finding. We examined the suitability of cognitive outcomes for clinical trials in children with neurofibromatosis type 1 (NF1) by examining test-retest reliability of the measures and the application of data reduction techniques to improve reproducibility.

Methods: Data were analyzed from the STARS clinical trial (n = 146), a multi-center double-blind placebo-controlled phase II trial of lovastatin, conducted by the NF Clinical Trials Consortium. Intra-class correlation coefficients were generated between pre- and post-performances (16-week interval) on neuropsychological endpoints in the placebo group to determine test-retest reliabilities. Confirmatory factor analysis was used to reduce data into cognitive domains and account for measurement error.

Results: Test-retest reliabilities were highly variable, with most endpoints demonstrating unacceptably low reproducibility. Data reduction confirmed four distinct neuropsychological domains: executive functioning/attention, visuospatial ability, memory, and behavior. Test-retest reliabilities of latent factors improved to acceptable levels for clinical trials. Applicability and utility of our model was demonstrated by homogeneous effect sizes in the reanalyzed efficacy data.

Interpretation: These data demonstrate that single observed endpoints are not appropriate to determine efficacy, partly accounting for the poor test-retest reliability of cognitive outcomes in clinical trials in neurodevelopmental disorders. Recommendations to improve reproducibility are outlined to guide future trial design.
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http://dx.doi.org/10.1002/acn3.50952DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6917317PMC
December 2019

Health Supervision for Children With Neurofibromatosis Type 1.

Pediatrics 2019 05;143(5)

Neurofibromatosis type 1 (NF1) is a multisystem disorder that primarily involves the skin and peripheral nervous system. Its population prevalence is approximately 1 in 3000. The condition is usually recognized in early childhood, when pigmentary manifestations emerge. Although NF1 is associated with marked clinical variability, most children affected follow patterns of growth and development within the normal range. Some features of NF1 can be present at birth, but most manifestations emerge with age, necessitating periodic monitoring to address ongoing health and developmental needs and minimize the risk of serious medical complications. In this report, we provide a review of the clinical criteria needed to establish a diagnosis, the inheritance pattern of NF1, its major clinical and developmental manifestations, and guidelines for monitoring and providing intervention to maximize the health and quality of life of a child affected.
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http://dx.doi.org/10.1542/peds.2019-0660DOI Listing
May 2019

Substantial pain burden in frequency, intensity, interference and chronicity among children and adults with neurofibromatosis Type 1.

Am J Med Genet A 2019 04 8;179(4):602-607. Epub 2019 Feb 8.

Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.

Tumor growths, migraine headaches, and other health-related complications reported in patients with neurofibromatosis type 1 (NF1) are often associated with pain. Thus, this study sought to describe and quantify the pain experience in children and young adults with NF1. Surveys were administered to 49 participants (28 children and 21 adults), ages 8 through 40 years. The survey included the Numeric Rating Scale 11 (NRS11) to assess pain intensity and the Patient Reported Outcomes Measurement Information System (PROMIS) to assess pain interference. A supplemental survey was created to measure pain frequency, chronicity, quality, and location. Results suggest pain is not only present in 55% of the cohort, but that it can begin at early ages. Pain was chronic in 35% of participants, with 41% reporting the use of medication to manage pain symptoms. Common sources of pain included migraine headaches and NF-related tumors. Pain was described as having neuropathic features (i.e., burning, tingling, numbness, or itching), and was localized to the head, back, and extremities. Further, subsets of participants reported moderate-to-severe pain intensity, high frequency of pain, and interference of pain in daily activities. Continued investigation of the pain experience in a multisystem disorder, such as NF1, remains essential to providing guidance in the setting of complex pain management.
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http://dx.doi.org/10.1002/ajmg.a.61069DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6451830PMC
April 2019

Expanding the clinical phenotype of individuals with a 3-bp in-frame deletion of the NF1 gene (c.2970_2972del): an update of genotype-phenotype correlation.

Genet Med 2019 04 7;21(4):867-876. Epub 2018 Sep 7.

Department of Genetics, University of Alabama at Birmingham, Birmingham, Alabama, USA.

Purpose: Neurofibromatosis type 1 (NF1) is characterized by a highly variable clinical presentation, but almost all NF1-affected adults present with cutaneous and/or subcutaneous neurofibromas. Exceptions are individuals heterozygous for the NF1 in-frame deletion, c.2970_2972del (p.Met992del), associated with a mild phenotype without any externally visible tumors.

Methods: A total of 135 individuals from 103 unrelated families, all carrying the constitutional NF1 p.Met992del pathogenic variant and clinically assessed using the same standardized phenotypic checklist form, were included in this study.

Results: None of the individuals had externally visible plexiform or histopathologically confirmed cutaneous or subcutaneous neurofibromas. We did not identify any complications, such as symptomatic optic pathway gliomas (OPGs) or symptomatic spinal neurofibromas; however, 4.8% of individuals had nonoptic brain tumors, mostly low-grade and asymptomatic, and 38.8% had cognitive impairment/learning disabilities. In an individual with the NF1 constitutional c.2970_2972del and three astrocytomas, we provided proof that all were NF1-associated tumors given loss of heterozygosity at three intragenic NF1 microsatellite markers and c.2970_2972del.

Conclusion: We demonstrate that individuals with the NF1 p.Met992del pathogenic variant have a mild NF1 phenotype lacking clinically suspected plexiform, cutaneous, or subcutaneous neurofibromas. However, learning difficulties are clearly part of the phenotypic presentation in these individuals and will require specialized care.
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http://dx.doi.org/10.1038/s41436-018-0269-0DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6752285PMC
April 2019

Copb2 is essential for embryogenesis and hypomorphic mutations cause human microcephaly.

Hum Mol Genet 2017 12;26(24):4836-4848

Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.

Primary microcephaly is a congenital brain malformation characterized by a head circumference less than three standard deviations below the mean for age and sex and results in moderate to severe mental deficiencies and decreased lifespan. We recently studied two children with primary microcephaly in an otherwise unaffected family. Exome sequencing identified an autosomal recessive mutation leading to an amino acid substitution in a WD40 domain of the highly conserved Coatomer Protein Complex, Subunit Beta 2 (COPB2). To study the role of Copb2 in neural development, we utilized genome-editing technology to generate an allelic series in the mouse. Two independent null alleles revealed that Copb2 is essential for early stages of embryogenesis. Mice homozygous for the patient variant (Copb2R254C/R254C) appear to have a grossly normal phenotype, likely due to differences in corticogenesis between the two species. Strikingly, mice heterozygous for the patient mutation and a null allele (Copb2R254C/Zfn) show a severe perinatal phenotype including low neonatal weight, significantly increased apoptosis in the brain, and death within the first week of life. Immunostaining of the Copb2R254C/Zfnbrain revealed a reduction in layer V (CTIP2+) neurons, while the overall cell density of the cortex is unchanged. Moreover, neurospheres derived from animals with Copb2 variants grew less than control. These results identify a general requirement for COPB2 in embryogenesis and a specific role in corticogenesis. We further demonstrate the utility of CRISPR-Cas9 generated mouse models in the study of potential pathogenicity of variants of potential clinical interest.
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http://dx.doi.org/10.1093/hmg/ddx362DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5886270PMC
December 2017

Activity of Selumetinib in Neurofibromatosis Type 1-Related Plexiform Neurofibromas.

N Engl J Med 2016 12;375(26):2550-2560

From the Center for Cancer Research, Pediatric Oncology Branch, Bethesda (E.D., A. Baldwin, L.J.M., P. Whitcomb, S.M., R.E., P. Wolters, J.T., J.G., A.J.S., A.G., B.C.W.) and the Cancer Therapy Evaluation Program, Shady Grove (A.L.D.), National Cancer Institute, and the National Heart, Lung, and Blood Institute (A. Brofferio), Bethesda, National Institutes of Health, and the Food and Drug Administration, Silver Spring (L.J.M., R.E.) - all in Maryland; the Division of Oncology, Children's Hospital of Philadelphia, and the Department of Pediatrics, Perelman School of Medicine at the University of Pennsylvania, Philadelphia (M.J.F., J.B.B.); Children's National Health System, Washington, DC (A.K.); and Cincinnati Children's Hospital, Cincinnati (B.W., L.E.A.-S., T.A.R., J.W., E.S., N.R.).

Background: Effective medical therapies are lacking for the treatment of neurofibromatosis type 1-related plexiform neurofibromas, which are characterized by elevated RAS-mitogen-activated protein kinase (MAPK) signaling.

Methods: We conducted a phase 1 trial of selumetinib (AZD6244 or ARRY-142886), an oral selective inhibitor of MAPK kinase (MEK) 1 and 2, in children who had neurofibromatosis type 1 and inoperable plexiform neurofibromas to determine the maximum tolerated dose and to evaluate plasma pharmacokinetics. Selumetinib was administered twice daily at a dose of 20 to 30 mg per square meter of body-surface area on a continuous dosing schedule (in 28-day cycles). We also tested selumetinib using a mouse model of neurofibromatosis type 1-related neurofibroma. Response to treatment (i.e., an increase or decrease from baseline in the volume of plexiform neurofibromas) was monitored by using volumetric magnetic resonance imaging analysis to measure the change in size of the plexiform neurofibroma.

Results: A total of 24 children (median age, 10.9 years; range, 3.0 to 18.5) with a median tumor volume of 1205 ml (range, 29 to 8744) received selumetinib. Patients were able to receive selumetinib on a long-term basis; the median number of cycles was 30 (range, 6 to 56). The maximum tolerated dose was 25 mg per square meter (approximately 60% of the recommended adult dose). The most common toxic effects associated with selumetinib included acneiform rash, gastrointestinal effects, and asymptomatic creatine kinase elevation. The results of pharmacokinetic evaluations of selumetinib among the children in this trial were similar to those published for adults. Treatment with selumetinib resulted in confirmed partial responses (tumor volume decreases from baseline of ≥20%) in 17 of the 24 children (71%) and decreases from baseline in neurofibroma volume in 12 of 18 mice (67%). Disease progression (tumor volume increase from baseline of ≥20%) has not been observed to date. Anecdotal evidence of decreases in tumor-related pain, disfigurement, and functional impairment was observed.

Conclusions: Our early-phase data suggested that children with neurofibromatosis type 1 and inoperable plexiform neurofibromas benefited from long-term dose-adjusted treatment with selumetinib without having excess toxic effects. (Funded by the National Institutes of Health and others; ClinicalTrials.gov number, NCT01362803 .).
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http://dx.doi.org/10.1056/NEJMoa1605943DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5508592PMC
December 2016

Randomized placebo-controlled study of lovastatin in children with neurofibromatosis type 1.

Neurology 2016 Dec 9;87(24):2575-2584. Epub 2016 Nov 9.

From the Murdoch Children's Research Institute (J.M.P., S.J.C.H., K.N.N.), Royal Children's Hospital; Department of Paediatrics (J.M.P., K.N.N.), Faculty of Medicine, Dentistry and Health Sciences, University of Melbourne; Children's Hospital Education Research Institute (B.B.), Children's Hospital at Westmead; Discipline of Paediatrics and Child Health (B.B.), University of Sydney, Australia; Department of Neurology (N.J.U., C.R.-C.), Boston Children's Hospital, MA; Department of Preventative Medicine (A.C.), School of Public Health (G.C.), Department of Psychology (J.D.A.), and Department of Genetics (B.K.), University of Alabama at Birmingham; Department of Neurology (T.R., S.H.O.), Children's Hospital of Los Angeles, CA; Center for Neuroscience and Behavioral Medicine (K.S.W., G.A.G., R.J.P., M.T.A.), Children's National Health System, Washington, DC; Pediatric Oncology Branch Center for Cancer Research (P.L.W.), National Cancer Institute, Bethesda, MD; Division of Neurology (J.T., S.J.H.), University of Chicago Medicine Comer Children's Hospital, IL; Human Genetics (E.S.) and Division of Neurology (A.W.B.), Cincinnati Children's Hospital Medical Center, OH; Department of Genetics (D.V.), University of Utah, Salt Lake City; Department of Pediatrics (L.K.), University of Texas Southwestern Medical Center, Dallas; Division of Oncology (M.F., C.L.A.), Children's Hospital of Philadelphia, PA; Department of Neurology (D.H.G., J.I.), Washington University School of Medicine in St Louis, MO; Gonda Neuroscience and Genetics Center (A.J.S.), University of California Los Angeles; Primary Children's Hospital (N.L.C.), Salt Lake City, UT; and University of Texas MD Anderson Cancer Center (P.L.S.), Houston.

Objective: To assess the efficacy of lovastatin on visuospatial learning and attention for treating cognitive and behavioral deficits in children with neurofibromatosis type 1 (NF1).

Methods: A multicenter, international, randomized, double-blind, placebo-controlled trial was conducted between July 2009 and May 2014 as part of the NF Clinical Trials Consortium. Children with NF1 aged 8-15 years were screened for visuospatial learning or attention deficits (n = 272); 146 children demonstrated deficits at baseline and were randomly assigned to lovastatin (n = 74; 40 mg/d) or placebo (n = 70). Treatment was administered once daily for 16 weeks. Primary outcomes were total errors on the Cambridge Neuropsychological Test Automated Battery Paired Associate Learning task (visuospatial learning) and the Score subtest from the Test of Everyday Attention for Children (sustained attention). Secondary outcomes measured executive function, attention, visuospatial skills, behavior, and quality of life. Primary analyses were performed on the intention-to-treat population.

Results: Lovastatin had no significant effect on primary outcomes after 16 weeks of treatment: visuospatial learning (Cohen d = -0.15, 95% confidence interval -0.47 to 0.18) or sustained attention (Cohen d = 0.19, 95% confidence interval -0.14 to 0.53). Lovastatin was well tolerated, with no increase in reported adverse events compared to placebo.

Conclusions: Lovastatin administered once daily for 16 weeks did not improve visuospatial learning or attention in children with NF1 and is not recommended for amelioration of cognitive deficits in this population.

Clinicaltrialsgov Identifier: This study was registered at ClinicalTrials.gov (NCT00853580) and Australian New Zealand Clinical Trials Registry (ACTRN12607000560493).

Classification Of Evidence: This study provides Class I evidence that for children with NF1, lovastatin does not improve visuospatial learning or attention deficits.
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http://dx.doi.org/10.1212/WNL.0000000000003435DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5207004PMC
December 2016

Analysis of copy number variants in 11 pairs of monozygotic twins with neurofibromatosis type 1.

Am J Med Genet A 2017 Mar 14;173(3):647-653. Epub 2016 Nov 14.

Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.

Phenotypic variability among individuals with neurofibromatosis type 1 (NF1) has long been a challenge for clinicians and an enigma for researchers. Members of the same family and even identical twins with NF1 often demonstrate variable disease expression. Many mechanisms for this variability have been proposed. We have performed an exploratory study of copy number variants (CNVs) as a possible source of phenotypic variability in NF1. We enrolled 11 pairs of monozygotic (MZ) twins with NF1 and their parents, catalogued their clinical characteristics, and utilized a single nucleotide polymorphism (SNP) microarray to identify CNVs in blood and saliva. The 11 twin pairs showed high concordance for presence and number of café-au-lait spots, cutaneous neurofibromas, IQ, and ADHD. They were more likely to be discordant for optic pathway glioma, plexiform neurofibromas, skeletal manifestations, and malignancy. Microarray analysis identified a total of 81 CNVs meeting our conservative criteria, 37 of which overlap known genes. Of interest, three CNVs were previously unreported. Microarray analysis failed to ascertain any CNV differences within twin pairs, between twins and parents, or between tissues in any one individual. Results of this small pilot study did not demonstrate any de novo CNV events in our MZ twin pairs, nor were de novo CNVs overrepresented in these individuals with NF1. A much larger sample size would be needed to form any conclusions about the role of CNVs in NF1 variable expressivity. Alternative explanations for discordant phenotypes include epigenetic changes, smaller genetic alterations, or environmental factors. © 2016 Wiley Periodicals, Inc.
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http://dx.doi.org/10.1002/ajmg.a.38058DOI Listing
March 2017

Patient-reported outcomes of pain and physical functioning in neurofibromatosis clinical trials.

Neurology 2016 Aug;87(7 Suppl 1):S4-S12

From the Pediatric Oncology Branch (P.L.W., S.M., A.B.), National Cancer Institute, National Institutes of Health, Bethesda, MD; Department of Neurology and Cancer Center (V.L.M.), Massachusetts General Hospital, Boston; University of Chicago Pritzker School of Medicine (J.H.T.), IL; Department of Psychological Sciences (S.E.S.), University of Vermont, Burlington; Departments of Neurology and Genetics (A.L.B.), Johns Hopkins University, Baltimore, MD; Children's National Health System & The George Washington School of Medicine (K.W.), Washington, DC; Department of Speech Pathology & Audiology (H.L.T.), California State University, Sacramento; Veteran's Administration Pittsburgh Healthcare System and University of Pittsburgh (K.L.G.), PA; Department of Clinical Neurosciences (C.M.H.), Spectrum Health Medical Group and College of Human Medicine, Michigan State University, East Lansing; Division of Human Genetics (E.S.), Cincinnati Children's Hospital, OH; Department of Public Health Education (W.N.D.), School of Health and Human Sciences, University of North Carolina at Greensboro; and Advocure NF2 Inc. (B.F.), Los Angeles, CA.

Objective: Tumors and other disease complications of neurofibromatosis (NF) can cause pain and negatively affect physical functioning. To document the clinical benefit of treatment in NF trials targeting these manifestations, patient-reported outcomes (PROs) assessing pain and physical functioning should be included as study endpoints. Currently, there is no consensus on the selection and use of such measures in the NF population. This article presents the recommendations of the PRO group of the Response Evaluation in Neurofibromatosis and Schwannomatosis (REiNS) International Collaboration for assessing the domains of pain and physical functioning for NF clinical trials.

Methods: The REiNS PRO group reviewed and rated existing PRO measures assessing pain intensity, pain interference, and physical functioning using their systematic method. Final recommendations are based primarily on 4 main criteria: patient characteristics, item content, psychometric properties, and feasibility for clinical trials.

Results: The REiNS PRO group chose the Numeric Rating Scale-11 (≥8 years) to assess pain intensity, the Pain Interference Index (6-24 years) and the Patient-Reported Outcome Measurement Information System (PROMIS) Pain Interference Scale (≥18 years) to evaluate pain interference, and the PROMIS Physical Functioning Scale to measure upper extremity function and mobility (≥5 years) for NF clinical trials.

Conclusions: The REiNS Collaboration currently recommends these PRO measures to assess the domains of pain and physical functioning for NF clinical trials; however, further research is needed to evaluate their use in individuals with NF. A final consensus recommendation for the pain interference measure will be disseminated in a future publication based on findings from additional published research.
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http://dx.doi.org/10.1212/WNL.0000000000002927DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5578357PMC
August 2016

Clinical Impact and Cost-Effectiveness of Whole Exome Sequencing as a Diagnostic Tool: A Pediatric Center's Experience.

Front Pediatr 2015 3;3:67. Epub 2015 Aug 3.

Division of Human Genetics, Cincinnati Children's Hospital Medical Center and Department of Pediatrics, University of Cincinnati College of Medicine , Cincinnati, OH , USA.

Background: There are limited reports of the use of whole exome sequencing (WES) as a clinical diagnostic tool. Moreover, there are no reports addressing the cost burden associated with genetic tests performed prior to WES.

Objective: We demonstrate the performance characteristics of WES in a pediatric setting by describing our patient cohort, calculating the diagnostic yield, and detailing the patients for whom clinical management was altered. Moreover, we examined the potential cost-effectiveness of WES by examining the cost burden of diagnostic workups.

Methods: To determine the clinical utility of our hospital's clinical WES, we performed a retrospective review of the first 40 cases. We utilized dual bioinformatics analyses pipelines based on commercially available software and in-house tools.

Results: Of the first 40 clinical cases, we identified genetic defects in 12 (30%) patients, of which 47% of the mutations were previously unreported in the literature. Among the 12 patients with positive findings, seven have autosomal dominant disease and five have autosomal recessive disease. Ninety percent of the cohort opted to receive secondary findings and of those, secondary medical actionable results were returned in three cases. Among these positive cases, there are a number of novel mutations that are being reported here. The diagnostic workup included a significant number of genetic tests with microarray and single-gene sequencing being the most popular tests. Significantly, genetic diagnosis from WES led to altered patient medical management in positive cases.

Conclusion: We demonstrate the clinical utility of WES by establishing the clinical diagnostic rate and its impact on medical management in a large pediatric center. The cost-effectiveness of WES was demonstrated by ending the diagnostic odyssey in positive cases. Also, in some cases it may be most cost-effective to directly perform WES. WES provides a unique glimpse into the complexity of genetic disorders.
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http://dx.doi.org/10.3389/fped.2015.00067DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4522872PMC
August 2015

The Use of Magnetic Resonance Imaging Screening for Optic Pathway Gliomas in Children with Neurofibromatosis Type 1.

J Pediatr 2015 Oct 29;167(4):851-856.e1. Epub 2015 Jul 29.

Division of Human Genetics, Department of Pediatrics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH; University of Cincinnati College of Medicine, Cincinnati, OH.

Objective: To evaluate the utility of screening brain/orbital magnetic resonance imaging (MRI) in a large population of children with neurofibromatosis type 1 (NF1) over a 20-year period.

Study Design: A retrospective analysis of clinical and imaging data from children with NF1 seen at a single center between 1990 and 2010 was performed.

Results: During the 20-year study period, 826 individuals with NF1 (402 females, 424 males) ages 1-9 years were screened for optic pathway gliomas (OPGs) using brain/orbital MRI; 18% were identified with OPGs with a median age at detection of 3 years. Fifteen percent of patients with OPGs had radiologic or clinical progression requiring therapy. Children with chiasmatic and postchiasmatic tumors were more likely to require therapy compared with patients with prechiasmatic OPGs (P < .0001). Patients with visual deficits at the time of diagnosis were more likely to experience visual decline despite therapy when compared with patients treated based on radiologic progression (P < .012).

Conclusions: Our findings confirm that chiasmatic and postchiasmatic OPG in children with NF1 have the highest risk for progression and vision loss. Early identification of OPG by screening MRI prior to the development of vision loss may lead to improved visual outcomes. Children with negative brain and orbital MRI screening at age 15 months or later did not develop symptomatic OPGs.
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http://dx.doi.org/10.1016/j.jpeds.2015.07.001DOI Listing
October 2015

High Incidence of Noonan Syndrome Features Including Short Stature and Pulmonic Stenosis in Patients carrying NF1 Missense Mutations Affecting p.Arg1809: Genotype-Phenotype Correlation.

Hum Mutat 2015 Nov 21;36(11):1052-63. Epub 2015 Aug 21.

Chaim Sheba Medical Center, Tel Hashomer, Israel.

Neurofibromatosis type 1 (NF1) is one of the most frequent genetic disorders, affecting 1:3,000 worldwide. Identification of genotype-phenotype correlations is challenging because of the wide range clinical variability, the progressive nature of the disorder, and extreme diversity of the mutational spectrum. We report 136 individuals with a distinct phenotype carrying one of five different NF1 missense mutations affecting p.Arg1809. Patients presented with multiple café-au-lait macules (CALM) with or without freckling and Lisch nodules, but no externally visible plexiform neurofibromas or clear cutaneous neurofibromas were found. About 25% of the individuals had Noonan-like features. Pulmonic stenosis and short stature were significantly more prevalent compared with classic cohorts (P < 0.0001). Developmental delays and/or learning disabilities were reported in over 50% of patients. Melanocytes cultured from a CALM in a segmental NF1-patient showed two different somatic NF1 mutations, p.Arg1809Cys and a multi-exon deletion, providing genetic evidence that p.Arg1809Cys is a loss-of-function mutation in the melanocytes and causes a pigmentary phenotype. Constitutional missense mutations at p.Arg1809 affect 1.23% of unrelated NF1 probands in the UAB cohort, therefore this specific NF1 genotype-phenotype correlation will affect counseling and management of a significant number of patients.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5049609PMC
http://dx.doi.org/10.1002/humu.22832DOI Listing
November 2015

Mutations in SLC25A46, encoding a UGO1-like protein, cause an optic atrophy spectrum disorder.

Nat Genet 2015 Aug 13;47(8):926-32. Epub 2015 Jul 13.

Department of Pediatrics, Division of Medical Genetics, University of Mississippi Medical Center, Jackson, Mississippi, USA.

Dominant optic atrophy (DOA) and axonal peripheral neuropathy (Charcot-Marie-Tooth type 2, or CMT2) are hereditary neurodegenerative disorders most commonly caused by mutations in the canonical mitochondrial fusion genes OPA1 and MFN2, respectively. In yeast, homologs of OPA1 (Mgm1) and MFN2 (Fzo1) work in concert with Ugo1, for which no human equivalent has been identified thus far. By whole-exome sequencing of patients with optic atrophy and CMT2, we identified four families with recessive mutations in SLC25A46. We demonstrate that SLC25A46, like Ugo1, is a modified carrier protein that has been recruited to the outer mitochondrial membrane and interacts with the inner membrane remodeling protein mitofilin (Fcj1). Loss of function in cultured cells and in zebrafish unexpectedly leads to increased mitochondrial connectivity, while severely affecting the development and maintenance of neurons in the fish. The discovery of SLC25A46 strengthens the genetic overlap between optic atrophy and CMT2 while exemplifying a new class of modified solute transporters linked to mitochondrial dynamics.
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http://dx.doi.org/10.1038/ng.3354DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4520737PMC
August 2015

Sirolimus for progressive neurofibromatosis type 1-associated plexiform neurofibromas: a neurofibromatosis Clinical Trials Consortium phase II study.

Neuro Oncol 2015 Apr 14;17(4):596-603. Epub 2014 Oct 14.

Division of Oncology, Cincinnati Children's Hospital Medical Center, Cancer and Blood Diseases Institute, Cincinnati, Ohio (B.W., J.P.); Division of Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio (E.S.); Division of Clinical Pharmacology, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio (A.V.); National Cancer Institute, Pediatric Oncology Branch, Bethesda, Maryland (B.C.W, E.D., P.W.); Department of Genetics, University of Alabama at Birmingham, Birmingham, Alabama (B.K.); Department of Preventitive Medicine, University of Alabama at Birmingham, Birmingham, Alabama (A.C.); Department of Neurology, Boston Children's Hospital, Boston, Massachusetts (N.U.); Department of Neurology, Washington University, St. Louis, Missouri (D.H.G.); Children's National Health System, Center for Neuroscience and Behavioral Medicine, Washington, DC (R.J.P.); Division of Oncology, The Children's Hospital of Philadelphia, Philadelphia, Pennsylvania (M.J.F.); Division of Genetics, Primary Children's Hospital, Salt Lake City, Utah (D.V.); Division of Neurology, The University of Chicago Medicine Comer Children's Hospital, Chicago, Illinois (J.T.).

Background: Plexiform neurofibromas (PNs) are benign peripheral nerve sheath tumors that arise in one-third of individuals with neurofibromatosis type 1 (NF1). They may cause significant disfigurement, compression of vital structures, neurologic dysfunction, and/or pain. Currently, the only effective management strategy is surgical resection. Converging evidence has demonstrated that the NF1 tumor suppressor protein, neurofibromin, negatively regulates activity in the mammalian Target of Rapamycin pathway.

Methods: We employed a 2-strata clinical trial design. Stratum 1 included subjects with inoperable, NF1-associated progressive PN and sought to determine whether sirolimus safely and tolerably increases time to progression (TTP). Volumetric MRI analysis conducted at regular intervals was used to determine TTP relative to baseline imaging.

Results: The estimated median TTP of subjects receiving sirolimus was 15.4 months (95% CI: 14.3-23.7 mo), which was significantly longer than 11.9 months (P < .001), the median TTP of the placebo arm of a previous PN clinical trial with similar eligibility criteria.

Conclusions: This study demonstrated that sirolimus prolongs TTP by almost 4 months in patients with NF1-associated progressive PN. Although the improvement in TTP is modest, given the lack of significant or frequent toxicity and the availability of few other treatment options, the use of sirolimus to slow the growth of progressive PN could be considered in select patients.
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http://dx.doi.org/10.1093/neuonc/nou235DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4483073PMC
April 2015

A novel dominant COL11A1 mutation resulting in a severe skeletal dysplasia.

Am J Med Genet A 2014 Oct 4;164A(10):2607-12. Epub 2014 Aug 4.

Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio.

Mutations in the type XI collagen alpha-1 chain gene (COL11A1) cause a change in protein structure that alters its interactions with collagens II and V, resulting in abnormalities in cartilage and ocular vitreous. The most common type XI collagenopathies are dominantly inherited Stickler or Marshall syndromes, while severe recessive skeletal dysplasias, such as fibrochondrogenesis, occur less frequently. We describe a family with a severe skeletal dysplasia caused by a novel dominantly inherited COL11A1 mutation. The siblings each presented with severe myopia, hearing loss, micromelia, metaphyseal widening of the long bones, micrognathia, and airway compromise requiring tracheostomy. The first child lived for over 2 years, while the second succumbed at 5 months of age. Their mother has mild rhizomelic shortening of the limbs, brachydactyly, and severe myopia. Sequencing of COL11A1 revealed a novel deleterious heterozygous mutation in COL11A1 involving the triple helical domain in both siblings, and a mosaic mutation in their mother, indicating germline mosaicism with subsequent dominant inheritance. These are the first reported individuals with a dominantly inherited mutation in COL11A1 associated with a severe skeletal dysplasia. The skeletal involvement is similar to, yet milder than fibrochondrogenesis and allowed for survival beyond the perinatal period. These cases highlight both a novel dominant COL11A1 mutation causing a significant skeletal dysplasia and the phenotypic heterogeneity of collagenopathies.
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http://dx.doi.org/10.1002/ajmg.a.36688DOI Listing
October 2014

Sirolimus for non-progressive NF1-associated plexiform neurofibromas: an NF clinical trials consortium phase II study.

Pediatr Blood Cancer 2014 Jun;61(6):982-6

Background: Patients with Neurofibromatosis Type 1 (NF1) have an increased risk of developing tumors of the central and peripheral nervous system, including plexiform neurofibromas (PN), which are benign nerve sheath tumors that are among the most debilitating complications of NF1. There are no standard treatment options for PN other than surgery, which is often difficult due to the extensive growth and invasion of surrounding tissues. Mammalian Target of Rapamycin (mTOR) acts as a master switch of cellular catabolism and anabolism and controls protein translation, angiogenesis, cell motility, and proliferation. The NF1 tumor suppressor, neurofibromin, regulates the mTOR pathway activity. Sirolimus is a macrolide antibiotic that inhibits mTOR activity.

Procedure: We conducted a 2-stratum phase II clinical trial. In stratum 2, we sought to determine whether the mTOR inhibitor sirolimus in subjects with NF1 results in objective radiographic responses in inoperable PNs in the absence of documented radiographic progression at trial entry.

Results: No subjects had better than stable disease by the end of six courses. However, the children's self-report responses on health-related quality of life questionnaires indicated a significant improvement in the mean scores of the Emotional and School domains from baseline to 6 months of sirolimus.

Conclusions: This study efficiently documented that sirolimus does not cause shrinkage of non-progressive PNs, and thus should not be considered as a treatment option for these tumors. This study also supports the inclusion of patient-reported outcome measures in clinical trials to assess areas of benefit that are not addressed by the medical outcomes.
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http://dx.doi.org/10.1002/pbc.24873DOI Listing
June 2014

Mutations in PIEZO2 cause Gordon syndrome, Marden-Walker syndrome, and distal arthrogryposis type 5.

Am J Hum Genet 2014 May 10;94(5):734-44. Epub 2014 Apr 10.

Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.

Gordon syndrome (GS), or distal arthrogryposis type 3, is a rare, autosomal-dominant disorder characterized by cleft palate and congenital contractures of the hands and feet. Exome sequencing of five GS-affected families identified mutations in piezo-type mechanosensitive ion channel component 2 (PIEZO2) in each family. Sanger sequencing revealed PIEZO2 mutations in five of seven additional families studied (for a total of 10/12 [83%] individuals), and nine families had an identical c.8057G>A (p.Arg2686His) mutation. The phenotype of GS overlaps with distal arthrogryposis type 5 (DA5) and Marden-Walker syndrome (MWS). Using molecular inversion probes for targeted sequencing to screen PIEZO2, we found mutations in 24/29 (82%) DA5-affected families and one of two MWS-affected families. The presence of cleft palate was significantly associated with c.8057G>A (Fisher's exact test, adjusted p value < 0.0001). Collectively, although GS, DA5, and MWS have traditionally been considered separate disorders, our findings indicate that they are etiologically related and perhaps represent variable expressivity of the same condition.
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http://dx.doi.org/10.1016/j.ajhg.2014.03.015DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4067551PMC
May 2014

CTF meeting 2012: Translation of the basic understanding of the biology and genetics of NF1, NF2, and schwannomatosis toward the development of effective therapies.

Am J Med Genet A 2014 Mar 17;164A(3):563-78. Epub 2014 Jan 17.

Pediatric Oncology Branch, NIH-National Cancer Institute, Bethesda, Maryland.

The neurofibromatoses (NF) are autosomal dominant genetic disorders that encompass the rare diseases NF1, NF2, and schwannomatosis. The NFs affect more people worldwide than Duchenne muscular dystrophy and Huntington's disease combined. NF1 and NF2 are caused by mutations of known tumor suppressor genes (NF1 and NF2, respectively). For schwannomatosis, although mutations in SMARCB1 were identified in a subpopulation of schwannomatosis patients, additional causative gene mutations are still to be discovered. Individuals with NF1 may demonstrate manifestations in multiple organ systems, including tumors of the nervous system, learning disabilities, and physical disfigurement. NF2 ultimately can cause deafness, cranial nerve deficits, and additional severe morbidities caused by tumors of the nervous system. Unmanageable pain is a key finding in patients with schwannomatosis. Although today there is no marketed treatment for NF-related tumors, a significant number of clinical trials have become available. In addition, significant preclinical efforts have led to a more rational selection of potential drug candidates for NF trials. An important element in fueling this progress is the sharing of knowledge. For over 20 years the Children's Tumor Foundation has convened an annual NF Conference, bringing together NF professionals to share novel findings, ideas, and build collaborations. The 2012 NF Conference held in New Orleans hosted over 350 NF researchers and clinicians. This article provides a synthesis of the highlights presented at the conference and as such, is a "state-of-the-field" for NF research in 2012.
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http://dx.doi.org/10.1002/ajmg.a.36312DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4150212PMC
March 2014

Patient-reported outcomes in neurofibromatosis and schwannomatosis clinical trials.

Neurology 2013 Nov;81(21 Suppl 1):S6-14

From the Pediatric Oncology Branch (P.L.W., S.M., A.B.), National Cancer Institute; Department of Neurology and Cancer Center (V.L.M.), Massachusetts General Hospital; Veterans Administration Pittsburgh Healthcare System and University of Pittsburgh (K.L.G.); Department of Clinical Neurosciences (C.M.H.), Spectrum Health Medical Group and College of Human Medicine, Michigan State University; University of Chicago Pritzker School of Medicine (J.H.T.); and Division of Human Genetics (E.K.S.), Cincinnati Children's Hospital.

Objectives: Neurofibromatosis (NF) is a genetic disease with multiple clinical manifestations that can significantly impact quality of life (QOL). Clinical trials should include patient-reported outcomes (PROs) as endpoints to assess treatment effects on various aspects of QOL, but there is no consensus on the selection and use of such measures in NF. This article describes the PRO Working Group of the Response Evaluation in Neurofibromatosis and Schwannomatosis (REiNS) Collaboration, its main goals, methods for identifying appropriate PRO measures for NF clinical trials, and recommendations for assessing pain intensity.

Methods: The REiNS PRO group selected core endpoint domains important to assess in NF. The members developed criteria to rate PRO measures, including patient characteristics, psychometric properties, and feasibility, and utilized a systematic process to evaluate PROs for NF clinical trials. Within the subdomain of pain intensity, the group reviewed the Numerical Rating Scale-11 (NRS-11), the Visual Analogue Scale, and the Faces Pain Scale-Revised using this process.

Results: Based on the review criteria, each of these pain intensity scales is brief, reliable, valid, and widely used. However, the NRS-11 was given the highest rating for use in NF clinical trials due to recommendations from pain experts and other consensus groups, its extensive use in research, strong psychometric data including sensitivity to change, and excellent feasibility in ages ≥ 8 years.

Conclusions: The systematic review criteria and process are effective for identifying appropriate PRO measures and provide information utilized by the REiNS Collaboration to achieve consensus regarding PROs in NF clinical trials.
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http://dx.doi.org/10.1212/01.wnl.0000435747.02780.bfDOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3908341PMC
November 2013

Does the presence of dystrophic features in patients with type 1 neurofibromatosis and spinal deformities increase the risk of surgery?

Spine (Phila Pa 1976) 2013 Aug;38(18):1595-601

Cincinnati Children's Hospital Medical Center, Cincinnati, OH, USA.

Study Design: Retrospective chart and radiographical review.

Objective: To present the demographics of patients with scoliosis and neurofibromatosis type 1 (NF-1), to record the incidence of dystrophic features, and to determine whether the presence of dystrophic features increase the risk of surgery in patients with NF-1 and associated spinal pathology.

Summary Of Background Data: The most common of the osseous complications of NF-1 is spinal deformity, occurring in 10% to 30% of individuals with NF-1. Many of these patients will eventually require surgery for curve progression, which makes study of demographics and identification of features predicting the need for surgery essential in this patient population.

Methods: A retrospective review was performed in patients with NF-1 and spinal deformities, followed in a multidisciplinary neurofibromatosis center. A subset of 56 patients with complete radiographical evaluation was reviewed for identification of risk factors for spine surgery.

Results: One hundred thirty-one patients from a population of 694 patients with NF-1 (19%) had scoliosis. Mean age at diagnosis of scoliosis was 9 years (range; 1-17 yr). Scoliosis and need for surgery were equally distributed between males and females. In the group of 56 patients, 63% had 3 or more dystrophic features. The presence of 3 or more dystrophic features was the strongest predictor of the need for surgery (odds ratio = 14.34; P < 0.001). Individual features most predictive of need for surgery were the presence of vertebral scalloping (odds ratio = 13.19; P < 0.001) followed by the presence of dural ectasia (odds ratio = 6.38; P = 0.005). Patients with no dystrophic features were unlikely to progress to need for surgery.

Conclusion: Scoliosis and need for surgery were equally distributed between males and females. The presence of 3 or more dystrophic features was highly predictive of the need for surgery, with the most significant individual predictors being vertebral scalloping and dural ectasia. A combination of radiographical and MRI features can be used to predict need for spinal surgery.

Level Of Evidence: 3.
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http://dx.doi.org/10.1097/BRS.0b013e31829a7779DOI Listing
August 2013

Fractures in children with neurofibromatosis type 1 from two NF clinics.

Am J Med Genet A 2013 May 25;161A(5):921-6. Epub 2013 Mar 25.

Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, OH 45229, USA.

Neurofibromatosis type 1 (NF1) is an autosomal dominant genetic disorder with osseous abnormalities occurring in up to one-third of patients. Several studies have documented osteopenia in both children and adults with NF1; however, the significance of lower bone mineral density (BMD) in relationship to fracture incidence is not well elucidated in NF1, particularly in children. We undertook a retrospective study to determine prevalence and location of fractures in children and adolescents with NF1, ages 5-20 years, using a standardized questionnaire. We surveyed 256 individuals with NF1 from two multidisciplinary NF centers and 178 controls without NF1 of similar ages and sex. Participants with known long bone dysplasia (LBD) were analyzed separately. Data collected included numbers and location of fractures, dietary calcium intake, and physical activity levels. There was no difference in prevalence of ever having a fracture between the NF1 group without LBD (22%) and the control group (25%); median number of fractures also did not differ. There were significant differences in fracture location with a higher frequency of fractures of the lower extremities in NF1 individuals without LBD compared to controls. Both NF1 cohorts had lower rates of physical activity than controls (P < 0.0001). Our data demonstrate that the likelihood of having had a fracture is not higher in young NF1 individuals without LBD in comparison to healthy controls. The lower physical activity level may have a "protective effect" for those with NF1, thus keeping their fracture incidence lower than expected for their relative degree of osteopenia.
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http://dx.doi.org/10.1002/ajmg.a.35541DOI Listing
May 2013

Approaches to treating NF1 tibial pseudarthrosis: consensus from the Children's Tumor Foundation NF1 Bone Abnormalities Consortium.

J Pediatr Orthop 2013 Apr-May;33(3):269-75

Department of Pediatrics, Division of Medical Genetics, University of Utah, Salt Lake City, UT 84132, USA.

Background: Neurofibromatosis 1 (NF1) is an autosomal dominant disorder with various skeletal abnormalities occurring as part of a complex phenotype. Tibial dysplasia, which typically presents as anterolateral bowing of the leg with subsequent fracture and nonunion (pseudarthrosis), is a serious but infrequent osseous manifestation of NF1. Over the past several years, results from clinical and experimental studies have advanced our knowledge of the role of NF1 in bone. On the basis of current knowledge, we propose a number of concepts to consider as a theoretical approach to the optimal management of tibial pseudarthrosis.

Methods: A literature review for both clinical treatment and preclinical models for tibial dysplasia in NF1 was performed. Concepts were discussed and developed by experts who participated in the Children's Tumor Foundation sponsored International Bone Abnormalities Consortium meeting in 2011.

Results: Concepts for a theoretical approach to treating tibial pseudarthrosis include: bone fixation appropriate to achieve stability in any given case; debridement of the "fibrous pseudarthrosis tissue" between the bone segments associated with the pseudarthrosis; creating a healthy vascular bed for bone repair; promoting osteogenesis; controlling overactive bone resorption (catabolism); prevention of recurrence of the "fibrous pseudarthrosis tissue"; and achievement of long-term bone health to prevent recurrence.

Conclusions: Clinical trials are needed to assess effectiveness of the wide variation of surgical and pharmacologic approaches currently in practice for the treatment of tibial pseudarthrosis in NF1.

Level Of Evidence: Level V, expert opinion.
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http://dx.doi.org/10.1097/BPO.0b013e31828121b8DOI Listing
September 2013