Rosalie E. Ferner

Guidelines for the diagnosis and management of individuals with neurofibromatosis 1

Neurofibromatosis 1 (NF1) is a common neurocutaneous condition with an autosomal dominant pattern of inheritance. The complications are diverse and disease expression varies, even within families. Progress in molecular biology and neuroimaging and the development of mouse models have helped to elucidate the aetiology of NF1 and its clinical manifestations. Furthermore, these advances have raised the prospect of therapeutic intervention for this complex and distressing disease. Members of the United Kingdom Neurofibromatosis Association Clinical Advisory Board collaborated to produce a consensus statement on the current guidelines for diagnosis and management of NF1. The proposals are based on published clinical studies and on the pooled knowledge of experts in neurofibromatosis with experience of providing multidisciplinary clinical and molecular services for NF1 patients. The consensus statement discusses the diagnostic criteria, major differential diagnoses, clinical manifestations and the present strategies for monitoring and management of NF1 complications.

Optic pathway gliomas in neurofibromatosis-1: controversies and recommendations.

Optic pathway glioma (OPG), seen in 15% to 20% of individuals with neurofibromatosis type 1 (NF1), account for significant morbidity in young children with NF1. Overwhelmingly a tumor of children younger than 7 years, OPG may present in individuals with NF1 at any age. Although many OPG may remain indolent and never cause signs or symptoms, others lead to vision loss, proptosis, or precocious puberty. Because the natural history and treatment of NF1‐associated OPG is different from that of sporadic OPG in individuals without NF1, a task force composed of basic scientists and clinical researchers was assembled in 1997 to propose a set of guidelines for the diagnosis and management of NF1‐associated OPG. This new review highlights advances in our understanding of the pathophysiology and clinical behavior of these tumors made over the last 10 years. Controversies in both the diagnosis and management of these tumors are examined. Finally, specific evidence‐based recommendations are proposed for clinicians caring for children with NF1. Ann Neurol 2007;61:189–198

Neurofibromatosis 1 and neurofibromatosis 2: a twenty first century perspective

Historically, neurofibromatosis 1 (NF1) has been inextricably linked with neurofibromatosis 2 (NF2). Both are inherited autosomal-dominant neurocutaneous disorders that have high de novo mutation rates and carry a high risk of tumour formation. However, they are clinically and genetically distinct diseases and should be considered as seperate entities. NF1 is a common disease that mainly affects the skin and peripheral nervous system and causes characteristic bony dysplasia. By contrast, NF2 is a rare disorder with a relative paucity of skin manifestations and high-grade malignancy is unusual. Neurological symptoms are the predominant problem and the cardinal sign is bilateral vestibular schwannomas. In this Review, I discuss the pertinent diagnostic, clinical, and genetic symptoms of NF1 and NF2. I also examine the current views on the pathogenesis of these neurocutaneous disorders in the wake of advances in molecular genetics and the development of mouse models of disease.

Cognitive function and academic performance in neurofibromatosis. 1: consensus statement from the NF1 Cognitive Disorders Task Force.

Neurofibromatosis type 1 (NF1) is the most common single gene disorder to affect the human nervous system; it is inherited in an autosomal dominant manner with an estimated incidence of 1 in 3,500.l The physical features of NF1 are well characterized and include multiple cafe-au-lait spots, skinfold freckling, iris hamartomas (Lisch nodules), and benign and malignant neural tumors (e.g., neurofibromas, pheochromocytomas, and neurofibrosarcomas).’X2 CNS lesions include optic pathway gliomas, dural ectasia, and aqueduct stenosis. In addition to these specific pathologic lesions, cognitive impairment is common. Learning disabilities occur in at least 30 to 45% of children with NF1 and can be responsible for significant lifetime m~rb id i ty .~ ,~ The NF1 gene on human chromosome 17 has been ~ l o n e d ~ ~ and its protein product neurofibromin identified.*b9 The NF1 gene is usually classified as a tumor suppressor gene, as mutations in both NF1 alleles are detectable in malignant tumors associated with NF1lOJ1 and in benign tumors such as neurofibromas.12 The effects of the disorder on higher cortical function and the relationship between NF1 gene mutations, cognitive deficits, and intracranial pathology are less well understood. This consensus statement summarizes our current understanding of the frequency and nature of cognitive deficits and learning disability in children with NF1, provides recommendations for assessment and management, and examines the putative relationship between cognitive deficits and MRI signal abnormalities. We review possible pathogenetic mechanisms and future directions for research.

Second Primary Tumors in Neurofibromatosis 1 Patients Treated for Optic Glioma: Substantial Risks After Radiotherapy

PURPOSE Optic pathway gliomas (OPGs) are the most common CNS tumor in neurofibromatosis 1 (NF1) patients. We evaluated the long-term risk of second tumors in NF1-related OPGs after radiotherapy. PATIENTS AND METHODS We reviewed 80 NF1 OPG patients from two NF1 clinics to evaluate the long-term risk of developing subsequent nervous system tumors, with or without radiotherapy. RESULTS Fifty-eight patients were assessable for second tumors. Nine (50%) of 18 patients who received radiotherapy after their OPGs developed 12 second tumors in 308 person-years of follow-up after radiotherapy. Eight (20%) of 40 patients who were not treated with radiotherapy developed nine tumors in 721 person-years of follow-up after diagnosis of their OPGs. The relative risk of second nervous system tumor after radiotherapy was 3.04 (95% CI, 1.29 to 7.15). CONCLUSION There is a significantly increased risk of second nervous system tumors in those NF1 patients who received radiotherapy for their OPGs, especially when treated in childhood. Thus radiotherapy should only be used if absolutely essential in children with NF1.

Management of the patient and family with neurofibromatosis 2: a consensus conference statement.

A consensus conference on neurofibromatosis 2 (NF2) was held in 2002 at the request of the United Kingdom (UK) Neurofibromatosis Association, with particular emphasis on vestibular schwannoma (VS) surgery. NF2 patients should be managed at specialty treatment centres, whose staff has extensive experience with the disease. All NF2 patients and their families should have access to genetic testing because presymptomatic diagnosis improves the clinical management of the disease. Some clinical manifestations of NF2, such as ocular abnormalities, can be detected in infancy; therefore, clinical screening for at-risk members of NF2 families can start at birth, with the first magnetic resonance (MRI) scan at 10 – 12 years of age. Minimal interference, maintenance of quality of life, and conservation of function or auditory rehabilitation are the cornerstones of NF2 management, and the decision points to achieve these goals for patients with different clinical presentations are discussed.

Evaluation of (18)fluorodeoxyglucose positron emission tomography ((18)FDG PET) in the detection of malignant peripheral nerve sheath tumours arising from within plexiform neurofibromas in neurofibromatosis 1

OBJECTIVES The ability of 18fluorodeoxyglucose positron emission tomography (18FDG PET) to detect malignant change in plexiform neurofibromas from patients with neurofibromatosis 1 (NF1) was evaluated. METHODS Eighteen NF1 patients who presented with pain, increase in size, or neurological deficit associated with a plexiform neurofibroma were assessed. Magnetic resonance imaging determined the site and extent of the lesion. Qualitative18FDG PET was performed and the standard uptake value (SUV) measured the regional glucose metabolism. Histological confirmation of the diagnosis was obtained in 10 patients. RESULTS Twenty three plexiform neurofibromas were detected in 18 patients. Seven malignant peripheral nerve sheath tumours, four high grade and three low grade tumours, occurred in five patients. In one patient the clinical and radiological characteristics of the tumour suggested malignancy, but histology was inconclusive. Fifteen benign plexiform neurofibromas were identified in 12 patients and these findings were confirmed histologically in five lesions from four patients. Ten plexiform neurofibromas occurring in eight patients were considered benign on18FDG PET and the patients did not undergo surgery. They remained stable or their symptoms improved on clinical follow up (median 9 months). The results of qualitative 18FDG PET were interpreted as indicating that 13 plexiform neurofibromas were benign and 10 were malignant. No malignant tumours were classified as benign, but two benign tumours were reported as malignant. The SUV was calculated for 20 tumours and was significantly higher in five malignant tumours 5.4 (SD 2.4), than in 15 benign tumours 1.54 (SD 0.7), p=0.002. There was an overlap between benign and malignant tumours in the SUV range 2.7–3.3. CONCLUSIONS 18FDG PET is helpful in determining malignant change in plexiform neurofibromas in NF1. Increased separation between benign and malignant lesions could be obtained by calculating the SUV at about 200 minutes after injection of 18FDG, when the peak activity concentration is obtained in malignant tumours.

Visual outcomes in children with neurofibromatosis type 1-associated optic pathway glioma following chemotherapy: a multicenter retrospective analysis

Optic pathway gliomas (OPGs) occur in 15%-20% of children with neurofibromatosis type 1 (NF1); up to half become symptomatic. There is little information regarding ophthalmologic outcomes after chemotherapy. A retrospective multicenter study was undertaken to evaluate visual outcomes following chemotherapy for NF1-associated OPG, to identify risks for visual loss, and to ascertain indications for treatment. Subjects included children undergoing initial treatment for OPGs with chemotherapy between January 1997 and December 2007. Of 115 subjects, visual acuity (VA) decline and tumor progression were the primary reasons to initiate treatment, although there were significant differences in the pattern of indications cited among the institutions. Eighty-eight subjects and 168 eyes were evaluable for VA outcome. At completion of chemotherapy, VA improved (32% of subjects), remained stable (40%), or declined (28%). Tumor location was the most consistent prognostic factor for poor VA outcome. There was poor correlation between radiographic and VA outcomes. Although visual outcomes for NF1-associated OPG are not optimal, approximately one-third of children regain some vision with treatment. Since radiographic outcomes do not predict visual outcomes, their use as the primary measure of treatment success is in question. The lack of consensus regarding the indications for treatment underlines the need for better standardization of care. Future clinical trials for OPG require standardized visual assessment methods and clear definitions of visual outcomes.

MRI in neurofibromatosis 1. The nature and evolution of increased intensity T2 weighted lesions and their relationship to intellectual impairment.

Thirty eight patients with neurofibromatosis 1 (NF1) had neurological examinations, intellectual assessments and MRI scans. Increased intensity lesions on T2 weighted images were found in 13 patients. These abnormalities were more common in patients aged under 18 years. The lesions occurred predominantly in the basal ganglia, brainstem and cerebellum, and were multiple in 11 patients. They did not produce symptoms or neurological deficit in any patient and did not enhance with gadolinium-meglumine-triamine-pentaacetic acid contrast medium (Gd-DTPA). In 2 patients, however, the abnormalities exerted mass effect distorting the brain and in 3 patients they occurred in conjunction with known gliomas. The lesions remained unchanged over a three year follow up period. The nature of the lesions is uncertain but the fact that they may produce mass effect and occur in association with gliomas suggests that they have malignant potential. There was no correlation between the presence of these abnormalities and intellectual impairment.

Neurofibroma and schwannoma

Purpose of reviewNeurofibromas and schwannomas are benign peripheral nerve sheath tumours that occur as isolated sporadic lesions, but have their major clinical impact on the neurocutaneous diseases neurofibromatosis 1 and neurofibromatosis 2. The gene products neurofibromin and merlin (schwannomin), respectively, are thought to act as tumour suppressors. The aim of this review is to document recent advances in our understanding of the clinical characteristics and pathogenesis of neurofibromas and schwannomas in the neurofibromatoses. Recent findingsAnimal models have shed light on the pathogenesis of neurofibromas confirming that the Schwann cell initiates neurofibroma formation. New data suggest that individuals with neurofibromatosis 1 have a 10% lifetime risk of developing malignant peripheral nerve sheath tumours. Positron emission tomography with the glucose analogue 18-fluorodeoxyglucose might be helpful in the diagnosis of malignant peripheral nerve sheath tumours. Such tumours associated with neurofibromatosis 1 show a loss of neurofibromatosis 1 expression and high levels of Ras, but malignant transformation requires additional genetic events that inactivate key cell cycle regulators. Neurofibromatosis 2-associated vestibular schwannomas have variable growth rates that tend to decline with age. Early microsurgery for small tumours results in optimal preservation of hearing and facial nerve function. Currently, radiosurgery for these lesions produces similar results. Systematic follow-up of both groups will determine the best treatment method. Merlins function as a tumour suppressor has not been elucidated. The control of cell cycle progression and abnormal intracellular and extracellular signalling could all play a part. SummaryMolecular advances will allow a biological approach to targeted therapies for neurofibromas, malignant peripheral nerve sheath tumours and schwannomas. Knowledge of the pathogenesis of these tumours will have implications for our understanding of the neurofibromatoses and of the formation of sporadic tumours.