This article includes discussion of Neurofibromatosis type 1 and intracranial neoplasms of childhood and Elephant man disease. The foregoing terms may include synonyms, similar disorders, variations in usage, and abbreviations.
Neurofibromatosis type 1 is an autosomally dominated inherited genetic condition that predisposes those involved to the development of intracranial neoplasms. Visual pathway gliomas are the most common type of tumor encountered, but other types of low-grade and less frequently high-grade, primary central nervous system tumors may occur. Many patients are diagnosed on the basis of screening studies, and only observation is indicated. However, in others, treatment is needed because of progressive neurologic compromise or visual loss. Due to the potential increased susceptibility of patients with neurofibromatosis type 1 to the deleterious side effects of radiation therapy, such as mutagenesis and vasculopathy, alternative treatments are required for patients with progressive disease. The author reviews the role of chemotherapy for gliomas associated with neurofibromatosis type 1 and its efficacy on disease control and visual outcome. He also discusses the potential role of molecularly targeted therapy in the treatment of neurofibromatosis type 1-associated gliomas.
• Neurofibromatosis type 1 has protean manifestations, of which intracranial gliomas are 1 of the most common.
• Gliomas, especially those of the visual pathway, have a variable, often erratic natural history.
• Gliomas in children with neurofibromatosis type 1, if requiring treatment, may be chemotherapy-sensitive, and radiotherapy should be used as a last resort, given potential long-term sequelae.
Historical note and terminology
Neurofibromatosis type 1 is an autosomally dominant inherited genetic disorder that has variable clinical manifestations. Although numerous types of neurofibromatosis have been postulated, 2 major types are uniformly accepted (Riccardi 1981; Riccardi and Mulvihill 1981; Berg 1994). Neurofibromatosis type 1, also known as von Recklinghausen disease, is the most common and is characterized by multiple peripheral neurofibromas and the classical hyperpigmented macules, historically described as café-au-lait spots. Neurofibromatosis type 2, also called central neurofibromatosis, is another disease entity with features that overlap with neurofibromatosis type 1. Neurofibromatosis type 1 is associated with a higher incidence of primary central nervous system tumors.
At a consensus developmental conference on neurofibromatosis, held at the National Institutes of Health in 1987, diagnostic criteria were agreed on for the clinical diagnosis of neurofibromatosis type 1 (Berg 1994). The diagnostic criteria for neurofibromatosis type 1 is met in an individual if 2 or more of the following are found: (1) 2 or more neurofibromas of any type, or 1 plexiform neuroma; (2) freckling in the axillary or inguinal region; (3) optic glioma; (4) 2 or more Lisch nodules (iris hamartomas); (5) a distinctive osseous lesion, such as sphenoid dysplasia or thinning of the long bones of the cortex with or without pseudoarthrosis; (6) a first degree relative meeting the above criteria. For the vast majority of patients, diagnosis can be made on clinical grounds, although improved blood testing for the gene defect is now available with high sensitivity and specificity.
In distinction, an individual is diagnosed to have neurofibromatosis type 2 if the person has bilateral eighth nerve masses seen with appropriate imaging techniques or a first degree relative with neurofibromatosis type 2 and either: (1) a unilateral eighth nerve mass, (2) 2 or more of the following: neurofibroma, meningioma, glioma, schwannoma, or juvenile posterior subcapsular lenticular opacity.
The most famous representation of a patient with neurofibromatosis is Sir Frederick Treves' depiction of Joseph Merrick under the misleading nomenclature of the "Elephant Man disease" (Treves 1923). Although neurofibromatosis was brought into the public consciousness by Treves' depiction of Merrick in a widely performed play, and later a movie on the Englishman's life, it is now generally accepted that Merrick probably had Proteus Syndrome rather than neurofibromatosis type 1.
The association between neurofibromatosis type 1 and both central and peripheral nervous system tumors is well documented (Cohen and Rothner 1989; Uusitalo et al 2016). However, the exact incidence of such tumors in patients with neurofibromatosis type 1 remains unknown. Abnormalities within the brain are frequently noted in patients with neurofibromatosis type 1 (Menor et al 1991; Prada et al 2015). Some of these abnormalities seem to be transient, or at least more common in the early years of life, and the distinction between hamartomas or dysmature regions of brain and infiltrating low-grade gliomas is often impossible to make early in the course of the illness. These MR abnormalities, which may represent tumors, but more likely are non-neoplastic processes, are most commonly focal areas of increased signal intensity on T2-weighted MR images. These bright areas have also been termed as focal areas of signal intensity.
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