Ocular ischemic syndrome in neurofibromatosis type 1 treated with corticosteroids.

Neurofibromatosis type 1 (NF-1) is an autosomal dominant condition characterized by café-au-lait spots, neurofibromas, and multisystem involvement, including vasculopathy that may lead to ischemic or hemorrhagic events. Cases of vascular occlusions involving the retinal or ophthalmic circulation have also been described. The majority of cases with reported outcomes describe poor visual acuity following resolution. We report a case of retinal and ophthalmic artery occlusion resulting in ocular ischemic syndrome in a patient with NF1 who had remarkable improvement in retinal perfusion and visual acuity following high-dose corticosteroid treatment.

Management of neurofibromatosis type 1-associated plexiform neurofibromas.

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.

Risk factors for treatment-refractory and relapsed optic pathway glioma in children with neurofibromatosis type 1.

BACKGROUND: Nearly one-third of patients with neurofibromatosis type 1-associated optic pathway glioma (NF1-OPG) fail frontline chemotherapy; however, little is known about risk factors for treatment failure. METHODS: We performed a retrospective multi-institutional cohort study to identify baseline risk factors for treatment-refractory/relapsed disease and poor visual outcome in children with NF1-OPG. Refractory/relapsed NF1-OPG was defined as a requirement of two or more treatment regimens due to progression or relapse. RESULTS: Of 111 subjects eligible for inclusion, adequate clinical and visual data were available for 103 subjects from 7 institutions. Median follow-up from the initiation of first chemotherapy regimen was 95 months (range 13-185). Eighty-four (82%) subjects received carboplatin-based frontline chemotherapy. Forty-five subjects (44%) experienced refractory/relapsed disease, with a median time of 21.5 months (range 2-149) from the initiation of first treatment to the start of second treatment. The proportion of patients without refractory/relapsed disease at 2 and 5 years was 78% and 60%. In multivariable analyses, age less than 24 months at initial treatment, posterior tumor location, and familial inheritance were associated with refractory/relapsed NF1-OPG by 2 years. Both age less than 24 months and posterior tumor location were associated with refractory/relapsed NF1-OPG by 5 years. Subjects with moderate to severe vision loss at last follow-up were more likely to have posterior tumor location, optic disc abnormalities, or abnormal visual acuity at initial treatment. CONCLUSION: Young age, posterior tumor location, and optic disc abnormalities may identify patients with the greatest likelihood of refractory/relapsed NF1-OPG and poor visual outcomes, and who may benefit from newer treatment strategies.

Neurofibromatosis Type 1-Associated Optic Pathway Glioma in Children: A Follow-Up of 10 Years or More.

PURPOSE: This study reports on neurofibromatosis type 1 (NF1)-associated optic pathway gliomas (OPGs) and a follow-up period of at least 10 years in a cohort of children. OPGs are a common manifestation of NF1 and can cause significant visual morbidity. Long-term follow-up in children with NF1-associated OPGs has not been reported previously. DESIGN: Retrospective observational case series. METHODS: This study included children with a documented follow-up of at least 10 years. Three final outcomes were evaluated: visual acuity (VA) per eye (i.e., in the more severely affected eye), VA per patient (i.e., VA when both eyes were open), and the presence of optic nerve head pallor. RESULTS: A total of 45 children were included, followed for a mean of 14 years (range, 10-21 years). At the end of follow-up, abnormal VA (considered moderate to severe impairment) in the more severely affected eye was present in 36% of the patients and in both eyes in 11%. Optic nerve head pallor of 1 or both nerves was present in 62%. In multivariate analysis, only initial VA and optic nerve head appearance at presentation were found to predict the final outcomes. All patients, except for 1, were asymptomatic at presentation and had normal VA and nerves that appeared normal, preserved their good vision in both eyes. Only 1 patient, who had normal VA and normal appearing nerves at presentation, had moderate to severe VA loss at long term follow-up. CONCLUSIONS: In this study, children with NF1-associated OPG whose examination signs and symptoms were normal had a normal initial examination and excellent long-term visual and anatomical outcomes. VA and the appearance of the optic nerve head at presentation predict long-term outcome.

Visual field outcomes in children treated for neurofibromatosis type 1-associated optic pathway gliomas: a multicenter retrospective study.

BACKGROUND: Optic pathway gliomas associated with neurofibromatosis type 1 (NF1-OPGs) may adversely affect visual acuity, but data regarding visual field (VF) outcomes after treatment in children are limited. The purpose of this study was to investigate the effects of NF1-OPGs on VF function in a large cohort of children after treatment with chemotherapy. METHODS: We performed a retrospective, international, multicenter study of VF outcomes in patients treated with chemotherapy for NF1-OPGs. RESULTS: A total of 25 participants underwent VF testing using formal perimetric techniques. At the end of treatment, 19 participants (76%) had persistent VF deficits. Formal VF testing was available for 16 participants (64%) at initiation and completion of treatment. Of the 16 children who underwent VF testing at initiation and completion of treatment, 7 (44%) showed stability of VF changes, 3 (19%) showed improvement of VF function, and 6 (38%) had worsening of VFs. Improvement or worsening of VF outcome did not always correlate with visual acuity outcome. Posterior tumor location involving the optic tracts and radiations was associated with more frequent and more profound VF defects. CONCLUSIONS: In our study cohort, children undergoing initial chemotherapy for NF1-OPGs had a high prevalence of VF loss, which could be independent of visual acuity loss. A larger, prospective study is necessary to fully determine the prevalence of VF loss and the effects of chemotherapy on VF outcomes in children with NF1-OPGs.

Neurofibromatosis 2 in children presenting during the first decade of life.

OBJECTIVE: To educate providers to recognize the clinical presentation of neurofibromatosis 2 (NF2) in young children. METHODS: A retrospective analysis of 22 children with NF2 from 4 tertiary care NF referral centers was performed. Age and signs/symptoms at initial presentation, age at NF2 diagnosis, family history, clinical/radiographic NF2 features, NF2 genetic testing results, and treatments were assessed. RESULTS: The average age at initial clinical presentation was 48.1 months, while the average age at NF2 diagnosis was 77.2 months. Children with a family history of NF2 (23%) tended to present earlier (mean 39.2 vs 50.7 months) and have shorter times to NF2 diagnosis (mean 1.6 vs 37.2 months). Vision/eye complaints (n = 9; 41%) were the most commonly reported presenting signs/symptoms. Meningiomas (n = 7; 32%) and ocular abnormalities (n = 5; 23%) were the most frequently identified initial NF2 features. Vestibular (n = 17; 77%) and peripheral (n = 15; 68%) schwannomas were the most common abnormalities encountered over the study period. Seventeen (77%) children required treatment, most frequently for vestibular schwannomas (n = 9; 41%), peripheral schwannomas (n = 7; 32%), and meningiomas (n = 7; 32%). Genetic testing was available for 13 individuals, in whom nonsense mutations were most commonly identified (n = 7; 54%). CONCLUSIONS: Although uncommon, a substantial number of individuals with NF2 come to medical attention in early childhood. The finding of meningioma or characteristic ocular abnormalities (retinal hamartomas and epiretinal membranes) in young children should raise clinical suspicion for NF2 and prompt immediate referral to appropriate specialists for diagnosis and management.

Lifespan Development: Symptoms Experienced by Individuals with Neurofibromatosis Type 1 Associated Plexiform Neurofibromas from Childhood into Adulthood.

This secondary data analysis qualitatively identified salient concerns reported by individuals with Neurofibromatosis Type 1 (NF1)-associated plexiform neurofibromas (pNFs) at different stages of development. Past literature has focused on overall symptomatology, but has not examined nuances in how these symptoms are experienced across developmental phases. Therefore, we aimed to identify commonalities and differences in symptom experiences across age groups to better assist individuals to adjust to symptoms across the lifespan. Thirty-one children, adolescents, and adults (age ≥ 5 years old) and 15 parents participated in semi-structured interviews. Analyses focused on the following symptom categories: pain, social functioning, physical function impact, and stigma. Aspects of pain endorsed by all age groups included localized brief pain on contact with pNF and abnormal sensations; however, only adolescents and adults reported chronic pain and change in pain over time. Social functioning themes of limited activity participation, role limitations, and relationship impact were endorsed by all age groups, but differences emerged across age groups in the types of activity and role limitations, the type of relationship impact, and family planning concerns. All age groups described difficulty with mobility, but only parents reported problems with coordination and physical developmental milestones. While all age groups reported external stigma, internalized stigma was predominately endorsed by adults. While individuals in all age groups described pNF concerns related to pain, social function, physical function, and stigma, specific aspects of these symptoms differed across the developmental continuum. These findings can help assist individuals with pNF better transition to the next developmental phases.

Correction: 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.

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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.

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.

Patient Reported Outcomes Measurement Information System and Quality of Life in Neurological Disorders Measurement System to Evaluate Quality of Life for Children and Adolescents with Neurofibromatosis Type 1 Associated Plexiform Neurofibroma.

OBJECTIVE: To assess the health-related quality of life of children with neurofibromatosis type 1-related plexiform neurofibromas (pNF) using a battery of patient-reported outcome measures selected based on a conceptual framework derived from input by patients, parents, and clinicians regarding the most important pNF symptoms and concerns. STUDY DESIGN: There were 140 children with pNF ages 8-17 years who completed the Patient-Reported Outcomes Measurement Information System (including domains anxiety, depressive symptom, psychosocial stress experiences, fatigue, pain interference, meaning and purpose, positive affect, peer relationships, physical function-mobility) and Quality of Life in Neurological Disorders measurement system (stigma) via an online platform. T-scores for each measure were compared with US population norms. RESULTS: Children with pNF reported significantly worse scores than the population norms on 8 of 10 domains. Children with at least 1 family member having a diagnosis of neurofibromatosis type 1 and those having pain reported significantly worse symptoms and functioning on all domains. Boys reported significantly worse pain interference, stigma, meaning and purpose, mobility function, and upper extremity function than girls. CONCLUSIONS: Children with pNF experience significantly worse health-related quality of life on all but 1 domain, highlighting the importance of monitoring children's quality of life over time in clinical research and practice. Future research should evaluate the replicability of these findings and evaluate the validity of the Patient-Reported Outcomes Measurement Information System and Quality of Life in Neurological Disorders measurement system in relation to clinical characteristics among children with pNF.

2016 Children's Tumor Foundation conference on neurofibromatosis type 1, neurofibromatosis type 2, and schwannomatosis.

Organized and hosted by the Children's Tumor Foundation (CTF), the Neurofibromatosis (NF) conference is the premier annual gathering for clinicians and researchers interested in neurofibromatosis type 1 (NF1), neurofibromatosis type 2 (NF2), and schwannomatosis (SWN). The 2016 edition constituted a blend of clinical and basic aspects of NF research that helped in clarifying different advances in the field. The incorporation of next generation sequencing is changing the way genetic diagnostics is performed for NF and related disorders, providing solutions to problems like genetic heterogeneity, overlapping clinical manifestations, or the presence of mosaicism. The transformation from plexiform neurofibroma (PNF) to malignant peripheral nerve sheath tumor (MPNST) is being clarified, along with new management and treatments for benign and premalignant tumors. Promising new cellular and in vivo models for understanding the musculoskeletal abnormalities in NF1, the development of NF2 or SWN associated schwannomas, and clarifying the cells that give rise to NF1-associated optic pathway glioma were presented. The interaction of neurofibromin and SPRED1 was described comprehensively, providing functional insight that will help in the interpretation of pathogenicity of certain missense variants identified in NF1 and Legius syndrome patients. Novel promising imaging techniques are being developed, as well as new integrative and holistic management models for patients that take into account psychological, social, and biological factors. Importantly, new therapeutic approaches for schwannomas, meningiomas, ependymomas, PNF, and MPNST are being pursued. This report highlights the major advances that were presented at the 2016 CTF NF conference.

Optic Pathway Gliomas in Neurofibromatosis Type 1: An Update: Surveillance, Treatment Indications, and Biomarkers of Vision.

Optic pathway gliomas (OPGs) occur in 15%-20% of children with neurofibromatosis type 1 (NF1), leading to visual deficits in fewer than half of these individuals. The goal of chemotherapy is to preserve vision, but vision loss in NF1-associated OPG can be unpredictable. Determining which child would benefit from chemotherapy and, equally important, which child is better observed without treatment can be difficult. Unfortunately, despite frequent imaging and ophthalmologic evaluations, some children experience progressive vision loss before treatment. Indications for chemotherapy usually are based on a comprehensive, quantitative assessment of vision, but reliable vision evaluation can be challenging in young children with NF1-OPG. The ability to identify and predict impending vision loss could potentially improve management decisions and visual outcomes. To address this challenge, ophthalmologic, electrophysiologic, and imaging biomarkers of vision in NF1-OPG have been proposed. We review current recommendations for the surveillance of children at risk for NF1-OPG, outline guidelines for initiating therapy, and describe the utility of proposed biomarkers for vision.

A multi-institutional study of brainstem gliomas in children with neurofibromatosis type 1.

OBJECTIVE: To define the clinical and radiologic features of brainstem gliomas (BSGs) in children with neurofibromatosis type 1 (NF1). METHODS: We performed a retrospective cross-sectional study of 133 children with NF1 and concurrent BSGs cared for at 4 NF1 referral centers. BSG was determined using radiographic criteria. Age at diagnosis, tumor location and appearance, clinical symptoms, treatment, and presence of a concurrent optic pathway glioma were assessed. RESULTS: The average age at BSG diagnosis was 7.2 years, and tumors occurred most often in the midbrain and medulla (66%). The majority of children with NF1-BSGs were asymptomatic (54%) and were not treated (88%). Only 9 of the 72 asymptomatic children received treatment because of progressive tumor enlargement. In contrast, 61 children presented with clinical signs/symptoms attributable to their BSG; these individuals were older and more often had focal lesions. Thirty-one patients underwent treatment for their tumor, and 14 received CSF diversion only. Progression-free survival was ∼3 years shorter for children receiving tumor-directed therapy relative to those who had either no treatment or CSF diversion only. Overall survival was 85% for the tumor-directed therapy group, whereas no deaths were reported in the untreated or CSF diversion groups. CONCLUSIONS: Unlike children with sporadically occurring BSGs, most children with NF1-BSGs were asymptomatic, and few individuals died from complications of their tumor. Those requiring tumor-directed treatment tended to be older children with focal lesions, and had clinically more aggressive disease relative to those who were not treated or underwent CSF diversion only.

Neurofibromatosis type 1.

Neurofibromatosis type 1 is a complex autosomal dominant disorder caused by germline mutations in the NF1 tumour suppressor gene. Nearly all individuals with neurofibromatosis type 1 develop pigmentary lesions (café-au-lait macules, skinfold freckling and Lisch nodules) and dermal neurofibromas. Some individuals develop skeletal abnormalities (scoliosis, tibial pseudarthrosis and orbital dysplasia), brain tumours (optic pathway gliomas and glioblastoma), peripheral nerve tumours (spinal neurofibromas, plexiform neurofibromas and malignant peripheral nerve sheath tumours), learning disabilities, attention deficits, and social and behavioural problems, which can negatively affect quality of life. With the identification of NF1 and the generation of accurate preclinical mouse strains that model some of these clinical features, therapies that target the underlying molecular and cellular pathophysiology for neurofibromatosis type 1 are becoming available. Although no single treatment exists, current clinical management strategies include early detection of disease phenotypes (risk assessment) and biologically targeted therapies. Similarly, new medical and behavioural interventions are emerging to improve the quality of life of patients. Although considerable progress has been made in understanding this condition, numerous challenges remain; a collaborative and interdisciplinary approach is required to manage individuals with neurofibromatosis type1 and to develop effective treatments.

Using a qualitative approach to conceptualize concerns of patients with neurofibromatosis type 1 associated plexiform neurofibromas (pNF) across the lifespan.

Neurofibromatosis Type 1 (NF1) plexiform neurofibromas (pNFs) are associated with a variety of symptoms and concerns that affect patients' quality of life (QOL), highlighting the value of incorporating the patients' perspective when evaluating treatment outcomes. To better conceptualize the experience of patients with pNFs, this qualitative study sought to identify the most important outcomes to assess from the perspective of patients, families, and clinicians. Clinicians, patients age 5 years old and above, and parents of patients aged 5-17 years participated in semi-structured interviews to elicit the pNF symptoms/concerns considered most important to assess. The data were analyzed using an iterative coding procedure and the frequency with which symptoms/concerns emerged was tabulated. Eight clinicians, 31 patients, and 17 parents of patients participated in semi-structured interviews. The most frequently reported concerns raised by patients across all age groups included pain, appearance/disfigurement, social activity/role participation, stigma, and anxiety. For parents, physical functioning was the primary concern, followed by pain, social activity/role participation, appearance/disfigurement, and social relationships. The resulting conceptual framework included five domains to represent the most important identified symptoms/concerns: pain, social functioning, physical function impact, stigma, and emotional distress. This conceptual framework describing the symptoms/concerns of patients with pNF can help investigators create a measurement system to improve assessment of aspects of QOL only patients can report on. It may also provide the ability to identify symptoms/concerns that might warrant referrals to various clinical disciplines. © 2016 Wiley Periodicals, Inc.

Growth Hormone Excess in Children with Optic Pathway Tumors Is a Transient Phenomenon.

BACKGROUND/AIMS: Growth hormone (GH) excess in children with chiasmal optic pathway tumors (OPT), often associated with neurofibromatosis type 1 (NF1), is likely underrecognized. These children have elevated insulin-like growth factor 1 (IGF-1) levels, evidence of rapid growth despite treatment of precocious puberty, and failure to suppress GH levels following oral glucose challenge. The aim of this report is to describe the treatment course and natural history of this rare clinical condition in 7 patients. METHODS: This is a descriptive case series of 5 children previously described and 2 additional children more recently diagnosed at our institution. All 7 children had clinical and biochemical evidence of GH excess and received treatment with the somatostatin analog octreotide. RESULTS: Length of treatment varied among the patients. Five of the 7 patients have had resolution of GH excess and currently have normal IGF-1 levels without treatment. CONCLUSIONS: Unrestrained GH secretion occurs in a subset of children with OPT with potential adverse outcomes. Since GH excess appears to resolve over time, the benefit of treatment to alter outcomes or prevent tumor progression is unclear.