Plexiform Neurofibromas (PN) are a common manifestation of the genetic disorder neurofibromatosis type 1 (NF1). These benign nerve sheath tumors often cause significant morbidity, with treatment options limited historically to surgery.... more
Plexiform Neurofibromas (PN) are a common manifestation of the genetic disorder neurofibromatosis type 1 (NF1). These benign nerve sheath tumors often cause significant morbidity, with treatment options limited historically to surgery. There have been tremendous advances over the past two decades in our understanding of PN, and the recent regulatory approvals of the MEK inhibitor selumetinib are reshaping the landscape for PN management. At present, there is no agreed upon PN definition, diagnostic evaluation, surveillance strategy, or clear indications for when to initiate treatment and selection of treatment modality. In this review, we address these questions via consensus recommendations from a panel of multidisciplinary NF1 experts.
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Purpose: Malignant peripheral nerve sheath tumors (MPNSTs) are highly aggressive soft-tissue sarcomas that lack effective treatments, underscoring the urgent need to uncover novel mediators of MPNST pathogenesis that may serve as... more
Purpose: Malignant peripheral nerve sheath tumors (MPNSTs) are highly aggressive soft-tissue sarcomas that lack effective treatments, underscoring the urgent need to uncover novel mediators of MPNST pathogenesis that may serve as potential therapeutic targets. Tumor angiogenesis is considered a critical event in MPNST transformation and progression. Here, we have investigated whether endoglin (ENG), a TGF-β coreceptor with a crucial role in angiogenesis, could be a novel therapeutic target in MPNSTs. Experimental Design: ENG expression was evaluated in human peripheral nerve sheath tumor tissues and plasma samples. Effects of tumor cell-specific ENG expression on gene expression, signaling pathways and in vivo MPNST growth and metastasis were investigated. The efficacy of ENG targeting in monotherapy or in combination with MEK inhibition was analyzed in xenograft models. Results: ENG expression was found to be upregulated in both human MPNST tumor tissues and plasma circulating smal...
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Treatment of high-grade gliomas with selective intra-arterial (IA) administration of chemotherapies has been proposed, and utilized as a therapeutic modality. This approach offers the conceptual benefit of providing maximal delivery of... more
Treatment of high-grade gliomas with selective intra-arterial (IA) administration of chemotherapies has been proposed, and utilized as a therapeutic modality. This approach offers the conceptual benefit of providing maximal delivery of the agent to the tumor bed, while potentially reducing systemic exposure to the agent. This retrospective study was designed to determine the vascular distribution of glioblastoma multiforme (GBM) at the time of diagnosis in an effort to determine what proportion of patients would likely be candidates for this approach. The preoperative MRI scans of 50 patients with GBM were analyzed and compared to published normative data of intracranial vascular distribution. Vascular distribution was determined by analyzing post-gadolinium axial and coronal T1 images, axial T2 images, and axial T2 images with an additional 1 cm margin (T2 + 1 cm) added in all dimensions. T1 analysis demonstrated 60% of tumors in a single vascular distribution. T2 analysis of these...
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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... more
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 ...
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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... more
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) respectivel...
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Object The poor outcome of malignant gliomas is largely due to local invasiveness. Previous studies suggest that gliomas secrete excess glutamate and destroy surrounding normal peritumoral brain by means of excitotoxic mechanisms. In this... more
Object The poor outcome of malignant gliomas is largely due to local invasiveness. Previous studies suggest that gliomas secrete excess glutamate and destroy surrounding normal peritumoral brain by means of excitotoxic mechanisms. In this study the authors assessed the effect on survival of 2 glutamate modulators (riluzole and memantine) in rodent glioma models. Methods In an in vitro growth inhibition assay, F98 and 9L cells were exposed to riluzole and memantine. Mouse cerebellar organotypic cultures were implanted with F98 glioma cells and treated with radiation, radiation + riluzole, or vehicle and assessed for tumor growth. Safety and tolerability of intracranially implanted riluzole and memantine CPP:SA polymers were tested in F344 rats. The efficacy of these drugs was tested against the 9L model and riluzole was further tested with and without radiation therapy (RT). Results In vitro assays showed effective growth inhibition of both drugs on F98 and 9L cell lines. F98 organot...
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Overt stroke, clinically “silent” cerebral infarct, and neurocognitive impairment are frequent complications of sickle cell anemia (SCA). Current imaging techniques have limited sensitivity and specificity to identify children at risk for... more
Overt stroke, clinically “silent” cerebral infarct, and neurocognitive impairment are frequent complications of sickle cell anemia (SCA). Current imaging techniques have limited sensitivity and specificity to identify children at risk for neurocognitive impairment. We prospectively evaluated 24 children with SCA with a neurologic exam, complete blood count, transcranial Doppler ultrasound (TCD), measurement of intelligence quotient (IQ), and magnetic resonance imaging (MRI) with measurement of cerebral blood flow (CBF) using continuous arterial spin-labeling (CASL) MRI. Average CBF to gray matter was 112 ± 36 mL/100 g/min. We identified a strong inverse relationship between performance IQ and CBF (-1.5 points per 10 mL/100 g/min increase in CBF, P = .013). Elevated steady-state white blood cell count (≥ 14 × 109/L [14 000/μL]) was associated with lower full scale IQ (86 ± 9 vs 99 ± 10, P = .005). CASL MRI may identify children with neurocognitive impairment, before damage is evident...
Research Interests: Sickle Cell Anemia, Magnetic Resonance Imaging, Linear models, Prospective studies, Humans, and 15 moreChild, Blood, Clinical Sciences, Cognitive Function, Intelligence quotient, Sensitivity and Specificity, Cerebral Blood Flow, Blood Flow Velocity, Gray Matter, Cognition disorders, Magnetic resonance image, Neuropsychological Tests, Cardiovascular medicine and haematology, Paediatrics and reproductive medicine, and cerebral arteries
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Purpose 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).... more
Purpose 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 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 properti...
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IntroductionGiven the wide range of neurofibromatoses (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 United States NF... more
IntroductionGiven the wide range of neurofibromatoses (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 United States NF specialists.MethodsAn anonymous, cross-sectional online survey was distributed to attendees of a large NF research conference. Respondents self-reported demographics, practice characteristics, awareness of seven NF guideline publications, and level of agreement with up to 40 individual guidelines using a 5-point Likert scale. We calculated the proportion of guidelines that each clinician rated “strongly agree”, and assessed for differences in guideline awareness and agreement by respondent characteristics.ResultsSixty-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 en...
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... more
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 dis...
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Background 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... more
Background 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 Pediatric and adult patients with NF1 and inoperable PN participating in phase 2 studies of selumetinib for PN were included in this analysis if they had SNF and serial spine magnetic resonance imaging (MRI). Selumetinib was administered orally at the recommended dose of 25 mg/m2/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 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. Twe...
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To compare community diagnoses of Autism Spectrum Disorder (ASD) reported by parents to consensus diagnoses made using standardized tools plus clinical observation. 87 participants (85% male, average age 7.4 years), with reported... more
To compare community diagnoses of Autism Spectrum Disorder (ASD) reported by parents to consensus diagnoses made using standardized tools plus clinical observation. 87 participants (85% male, average age 7.4 years), with reported community diagnosis of ASD were evaluated using the Autism Diagnostic Observation Schedule) (ADOS-2), Differential Ability Scale (DAS-II), and Vineland Adaptive Behavior Scales (VABS-II). Detailed developmental and medical history was obtained from all participants. Diagnosis was based on clinical consensus of at least two expert clinicians, using test results, clinical observations, and parent report. 23% of participants with a reported community diagnosis of ASD were classified as non-spectrum based on our consensus diagnosis. ASD and non-spectrum participants did not differ on age at evaluation and age of first community diagnosis. Non-verbal IQ scores and Adaptive Behavior Composite scores were significantly higher in the non-spectrum group compared to ...
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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... more
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 i...
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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... more
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. 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. In th...
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We report a case of an 11-year-old girl with bilateral panuveitis in association with pseudotumor cerebri. The patient underwent complete ophthalmologic, neurologic, and laboratory evaluations and was treated with therapy for pseudotumor... more
We report a case of an 11-year-old girl with bilateral panuveitis in association with pseudotumor cerebri. The patient underwent complete ophthalmologic, neurologic, and laboratory evaluations and was treated with therapy for pseudotumor cerebri. The patient met the diagnostic criteria for pseudotumor cerebri and also had panuveitis. Symptoms and findings of pseudotumor cerebri and panuveitis improved significantly after combination therapy of oral acetazolamide and weight reduction. The index case illustrates that pseudotumor cerebri can be associated with panuveitis. Therapy for pseudotumor cerebri might also help with the resolution of uveitis.
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Schwannomatosis is a recently recognized disorder, with diagnostic criteria first published in 2005. Little is known about the natural history of schwannomatosis. It is thought to be a rare disorder with the incidence still to be... more
Schwannomatosis is a recently recognized disorder, with diagnostic criteria first published in 2005. Little is known about the natural history of schwannomatosis. It is thought to be a rare disorder with the incidence still to be determined. Better understanding of natural history will lay a foundation for future advances in patient care, including treatment trials. A robust database designed to address critical, hypothesis-driven research questions is a powerful mechanism for pooling data from multiple centers. The specific aims of this project were: (1) to coordinate national and international experts in schwannomatosis to formulate key research questions; (2) to translate key questions into specific data points; and (3) to design a web-based database to collect data across international treatment centers. Preliminary data would be gathered and analyzed to support an application for future funding to grow the project. The study period for this project is 24 months, ending in May 2...
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Late infantile neuronal ceroid lipofuscinosis (LINCL), a fatal, lysosomal storage disorder caused by mutations in the CLN2 gene, results in a deficiency of tripeptidyl-peptidase I (TPP-I) activity in neurons. Our prior studies showed that... more
Late infantile neuronal ceroid lipofuscinosis (LINCL), a fatal, lysosomal storage disorder caused by mutations in the CLN2 gene, results in a deficiency of tripeptidyl-peptidase I (TPP-I) activity in neurons. Our prior studies showed that delivery of the human CLN2 cDNA directly to the CNS, using an adeno-associated virus serotype 2 (AAV2) vector, is safe in children with LINCL. As a second-generation strategy, we have demonstrated that AAVrh.10hCLN2, a rhesus-derived AAV vector, mediates wide distribution of TPP-I through the CNS in a murine model. This study tests the hypothesis that direct administration of AAVrh.10hCLN2 to the CNS of rats and nonhuman primates at doses scalable to humans has an acceptable safety profile and mediates significant CLN2 expression in the CNS. A dose of 10(11) genome copies (GC) was administered bilaterally to the striatum of Sprague Dawley rats with sacrifice at 7 and 90 days with no significant impact except for mild vector-related histopathological changes at the site of vector administration. A dose of 1.8×10(12) GC of AAVrh.10hCLN2 was administered to the CNS of 8 African green monkeys. The vector-treated monkeys did not differ from controls in any safety parameter except for mild to moderate white matter edema and inflammation localized to the administration sites of the vector. There were no clinical sequelae to these localized findings. TPP-I activity was >2 SD over background in 31.7±8.1% of brain at 90 days. These findings establish the dose and safety profile for human clinical studies for the treatment of LINCL with AAVrh.10hCLN2.
Research Interests: Animal Behavior, Gene expression, Primates, Cell line, Brain, and 8 moreHumans, Female, Animals, Male, Serine Proteases, Rats, Time Factors, and Genetic Therapy
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Neurofibromatosis type 1 (NF1) is a common autosomal dominant neurocutaneous disorder with a predisposition to the development of benign and malignant tumors. Mutations in the NF1 gene result in loss of function of neurofibromin, a... more
Neurofibromatosis type 1 (NF1) is a common autosomal dominant neurocutaneous disorder with a predisposition to the development of benign and malignant tumors. Mutations in the NF1 gene result in loss of function of neurofibromin, a guanosine triphosphatase-activating protein that helps maintain the proto-oncogene Ras in its inactive form. Loss of neurofibromin results in increased proliferation and tumorigenesis. As a result, people with NF1 are at increased risk for the development of nervous and non-nervous system malignancies. Malignancy is a major source of morbidity and mortality in NF1. The natural history of NF1-associated malignancies is often different than that of their sporadic counterparts and, as such, management strategies need to be adjusted accordingly.
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Neurofibromatosis types 1 and 2 (NF1 and NF2) are autosomal dominant phakomatoses. The NF1 and NF2 genes encode for neurofibromin and merlin, respectively. These 2 functionally unrelated proteins both act as tumor suppressor genes,... more
Neurofibromatosis types 1 and 2 (NF1 and NF2) are autosomal dominant phakomatoses. The NF1 and NF2 genes encode for neurofibromin and merlin, respectively. These 2 functionally unrelated proteins both act as tumor suppressor genes, possibly through modulation of the RAS/RAC oncogenic pathways. Improved understanding of the mechanisms by which these tumor suppressors act may allow for medical therapies for neurofibromatosis and may offer insights for cancer therapeutics.
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Neurofibromatosis types 1 and 2 (NF1 and NF2) are autosomal dominant neurocutaneous disorders with some similarities and many differences. They are frequently discussed together and often confused for one another by clinicians. Both... more
Neurofibromatosis types 1 and 2 (NF1 and NF2) are autosomal dominant neurocutaneous disorders with some similarities and many differences. They are frequently discussed together and often confused for one another by clinicians. Both disorders have widely variable presentations and degrees of severity. A thorough understanding of these complex disorders is essential for proper medical management, anticipatory care, and patient education. In this article, the clinical features, genetics, pathogenesis, and management of neurofibromatosis types 1 and 2 are reviewed and compared. NF1 and NF2 are complex genetic disorders with numerous manifestations and wide phenotypic variability. The complex nature of these disorders requires coordinated multidisciplinary care.
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Familial hemophagocytic lymphohistiocytosis is an inherited deficiency of natural killer cell function and excessive cytokine activity, which predominantly presents in early childhood. The initial symptoms of familial hemophagocytic... more
Familial hemophagocytic lymphohistiocytosis is an inherited deficiency of natural killer cell function and excessive cytokine activity, which predominantly presents in early childhood. The initial symptoms of familial hemophagocytic lymphohistiocytosis are often nonspecific but may be predominantly neurologic. The case presented here describes an 18-month-old boy who initially presented with fever, encephalopathy, and hemiparesis. He had innumerable brain lesions visualized on magnetic resonance imaging scans. An infectious etiology was excluded, and brain, liver, and bone marrow biopsies were nonspecific but consistent with hemophagocytic lymphohistiocytosis. Cells were sent for flow cytometry perforin analysis, which demonstrated defective natural killer cell function. A diagnosis of familial hemophagocytic lymphohistiocytosis was confirmed by mutation analysis and decreased expression of the perforin gene, in the patient and immediate family members. These results showed the pati...
Research Interests: Cognitive Science, Magnetic Resonance Imaging, Flow Cytometry, Early Childhood, Humans, and 15 moreChild, Male, Magnetic Resonance, Sepsis, Immunotherapy, Infant, Bone marrow, Differential Diagnosis, Child Neurology, Clinical Sciences, Bone Marrow Transplantation, Neurosciences, Perforin, Magnetic resonance image, and Mutation analysis
Neurofibromatosis type I (NF-1), affecting 1: 3000 people, is one of the most common disorders of the nervous system, and most pediatricians will care for a patient with this condition. It is imperative that careful attention be paid to... more
Neurofibromatosis type I (NF-1), affecting 1: 3000 people, is one of the most common disorders of the nervous system, and most pediatricians will care for a patient with this condition. It is imperative that careful attention be paid to screening for scoliosis and tibial dysplasia. Prompt referral to an orthopaedist at the time of diagnosis, as well as neurologist, ophthalmologist, and dermatologist, will provide a global spectrum of care for the individual. Patient care between surgical procedures will be inevitable, with 70% of patients with NF-1 undergoing hospitalization or surgery. This review provides a description of diagnosis, presurgical evaluation, and advances in understanding tibial dysplasia, scoliosis and malignant peripheral nerve sheath tumors. New pharmaceutical treatments such as lovastatin have improved bone healing in vivo and induced apoptosis in vitro. Multiple pharmaceuticals have shown neurofibroma arrest in vitro and are in phase II clinical trials. As animal models improve and clinical trials proceed, there is momentum toward eliminating the musculoskeletal morbidity associated with NF-1.