Therapeutics for Childhood Neurofibromatosis Type 1 and Type 2

Abstract

Neurofibromatosis type 1 (NF1) and type 2 (NF2) are genetically and medically distinct neurocutaneous disorders that are both associated with tumors affecting the central and peripheral nervous systems. NF1 has a frequency of 1 in 3,000, compared with 1 in 30,000 for NF2. Careful surveillance is important for both conditions, to allow early identification and treatment of complications. The most common and important problems in NF1 are cognitive impairment, optic pathway gliomas, plexiform neurofibromas, and orthopaedic issues. Early intervention and tailored educational programs are indicated for learning difficulties. Attention deficit hyperactivity disorder may be amenable to treatment with stimulant medication. A clinical trial is under way to evaluate lovastatin in the treatment of cognitive problems in children with NF1. Chemotherapy with vincristine and carboplatin is the current standard of care for symptomatic optic pathway gliomas, but new agents with improved efficacy are needed. Plexiform neurofibromas may be treated with surgery, but often recur. To date, no medical therapy has proven effective in limiting plexiform neurofibroma growth, but several candidate medications are under consideration in clinical trials. Malignant peripheral nerve sheath tumors may arise in preexisting plexiform neurofibromas, so changes in tumor growth or an increase in pain or focal neurologic deficit should prompt further investigation and early treatment with wide surgical resection, with or without adjuvant chemotherapy or radiotherapy. Specialist surgical intervention may be needed for scoliosis and tibial pseudoarthrosis. In NF2, surgical treatment remains a cornerstone of management for symptomatic progressive vestibular schwannomas, meningiomas, and spinal tumors. Vascular endothelial growth factor inhibitors show promise for the treatment of vestibular schwannomas, with the aim of delaying surgery, and other targeted molecular therapies are becoming available as investigational options. Hearing aids and brainstem and cochlear implants have a role in optimizing functional hearing in some patients. Specialist ophthalmology input should be arranged to monitor for ophthalmologic complications. A coordinated effort is needed to enroll NF1 and NF2 patients in international multicenter clinical trials of promising new pharmacologic agents. Genetic testing is useful for prenatal diagnosis and may be important in understanding individual responses to novel medical therapies in the future. Effective transition to adult services is important, considering the likelihood of further complications in the adult years.

Proposing the use of dental pulp stem cells as a suitable biological model of neurofibromatosis type 1

“…The tumours are named neurofibromas, which develop on the peripheral nerve sheathes consisting of neoplastic Schwann cells, fibroblasts, perineural cells and mast cells [1], and schwannomas, which designate only the neoplastic proliferation of Schwann cells [2]. Neurofibromas are the core findings in NF1 patients, while schwannomas are features displayed in neurofibromatosis type 2 and schwannomatosis [3]. NF1 is an autosomal dominant genetic disorder caused by a mutation in the neurofibromin (NF) gene located on chromosome 17q11.2 [4].…”

Genetic Testing by Cancer Site

“…Mutations are identifiable in 95% of individuals who meet the NF1 clinical diagnostic criteria. 64 In young children with no family history who do not yet meet the diagnostic criteria, genetic testing may aid in differentiating NF1 from other disorders with phenotypic overlap such as Legius syndrome, familial café-au-lait spots, and NF2. Genetic testing may also help identify rare variant forms of the disease that do not satisfy the National Institutes of Health criteria.…”

“…Between the ages of 8 and 18 years, examinations every other year may be sufficient. 58,60,64 Blood pressure monitoring should take place at least annually because of the risk of pheochromocytoma and renal artery stenosis. 58,64 In addition, annual neurological examinations are advisable, with consideration of neuroimaging in the presence of any abnormal findings.…”

“…58,60,64 Blood pressure monitoring should take place at least annually because of the risk of pheochromocytoma and renal artery stenosis. 58,64 In addition, annual neurological examinations are advisable, with consideration of neuroimaging in the presence of any abnormal findings. 58 In addition, ongoing developmental and neuropsychological evaluation is recommended to assess cognitive function and to identify learning disabilities.…”

“…Depending on the location of the lesion, surgical debulking may be possible but is often incomplete, resulting in regrowth. 8,60,64 Optic Pathway Gliomas Once identified, MRI is used to monitor OPGs. Quarterly ophthalmologic evaluation is suggested for the first year, followed by annual examination of patients for at least 3 years or until age 8 years.…”