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Source: Creange A, et al. Neurological complications of neurofibromatosis type 1 in adulthood. Brain 1999;122:473-481.
Between 1995 and 1997, prospective evaluation of 158 neurofibromatosis type 1 (NF1) patients (138 persons > 18 years, 20 children) was performed to determine the neurologic morbidity and prognosis of NF1 in adults. Diagnosis was established using NIH criteria and required two or more of the following characteristics, including: 1) six or more cafe-au-lait spots; 2) two or more neurofibromas or one plexiform neurofibroma; 3) axillary or inguinal freckling; 4) optic pathway tumor; 5) two or more Lisch nodules [pigmented iris hamartomas]; 6) distinctive osseous lesions (e.g., sphenoid dysplasia); or 7) a first-degree relative with NF1 (Arch Neurol 1988;45:575-578).
Overall, 55% (n = 87) demonstrated one or more neurological complications, most frequently headache (18%), followed by optic pathway tumor (12.6%). Hydrocephalus (usually due to idiopathic aqueductal stenosis), epilepsy (cryptogenic, or secondary to subdural hematoma, meningioma, or hamartoma in one each), or malignant peripheral nerve sheath tumor (the only neurological cause of death in this series) was seen in approximately 4% each, whereas cerebral tumor (glioma or meningioma) and intraspinal neurofibroma were seen in roughly 3% and 2%, respectively. Two adults had a meningocele and one each had a lacunar infarct (aged 19 years) and progressive spastic paraparesis (onset at age 35 years). Significantly, no adult patient required treatment for optic pathway tumor or brainstem glioma due to their nonprogressive nature, suggesting that repetitive ophthalmological and neurological examinations, rather than neuroimaging studies, may be effective in the follow-up care of these patients. Furthermore, other than four malignant peripheral nerve sheath tumors and one meningioma, life-threatening complications occurred only during childhood, again mitigating the perceived need for frequent radiologic imaging in NF1 adults.
Most correctly identified with Quasimoto, the Hunchback of Notre Dame, and incorrectly with John Merrick, the Elephant Man (who probably had an unrelated disorder termed hemihypertrophy-nevi-hamartoma, or Proteus syndrome, named for the Greek god with protean guises), NF1, peripheral NF, or von Recklinghausen syndrome, should perhaps be more rightfully identified with the teacher (Rudolf Virchow) than the pupil (Tibbles JR, Cohen MM. BMJ 1986;293:683-685; Morse RP. Arch Neurol 1999;56:364-365). Dominantly inherited and traced to a gene at chromosome 17q11.2 coding for neurofibromin, this protein is a modulator of Ras-mediated signal transduction, specifically p21ras, a growth-stimulating protein, suggesting that one of neurofibromin’s functions is to suppress tumor growth. Ras activity, controlled by a regulated GDP/GTP cycle, mediates its proliferative effects by activating a cascade of kinases including Raf, MEK, and ERK1/2, and responds to diverse stimuli, including peptide growth factors, cytokines, and hormones (Vojtek AB, et al. J Biol Chem 1998;273:1925-1928). Mutations that activate Ras are present in an estimated 30% of all tumors, most frequently lung, colon, thyroid, and pancreatic carcinomas, but even this may be an underestimation of its role in human malignancy, as mutation is unnecessary for chronic Ras upregulation (Clark GJ, Der CJ. In: Dickey BF, Birnbaumer L, eds. GTPases in Biology. Berlin: Springer Verlag; 1993:259-288). Up to half of NF1 cases are due to spontaneous new mutations, usually paternal in origin, with a mutation rate 100 times greater than other genes, and with deletions, point mutations, and insertions all described (Jadayel D, et al. Nature 1990;343:558-559; Wallace MR, et al. Nature 1991;353:864-866; Wu BU, et al. Am J Med Genet 1995;59:528-535). NF1 demonstrates variable expressivity both between families and within families but its penetrance is 100% after age 5 years. Presently, recommendations of the American Academy of Pediatrics include annual physical and eye examinations during the school years including blood pressure measurements, a preschool audiologic evaluation, and careful follow-up to monitor for the development of scoliosis, rapid enlargement, or pain due to neurofibromas (Committee on Genetics, AAP. Pediatrics 1995;96:368-372).
NF2 or acoustic NF, diagnosed either by the presence of bilateral vestibular schwannomas or by unilateral schwannoma and a first degree relative with NF2, is due to mutation at chromosome 22q12.2, resulting in inactivation of the gene for neurofibromin 2, termed schwannomin, or "merlin" for the first letters of moesin-, ezrin-, and radixin-like proteins, which share significant homology to the NF2 gene product, and adding-in for protein (Trofatter JA, et al. Cell 1993;72:1-20). Merlin, a novel member of the ERM (ezrin, radixin, moesin) family of actin-associated, cytoskeleton-membrane linker proteins, inhibits cell growth when overexpressed in cell lines and, thus, may also act as a tumor suppressor, possibly by altering cytoskeletal function by interfering with F-actin organization, cell spreading, and cell attachment (Gutmann DH, et al. Hum Mol Genet 1999;8:267-275).
Molecular testing for NF2 is recommended for all persons at risk and, if positive, baseline MRI of the entire neuraxis with follow-up imaging every three years if initially negative (Harsh GR, et al. Arch Otolaryngol Head Neck Surg 1995;121:590-591). Mutation analysis is available for both NF1 and NF2, with a 70% and 60% detection rate, respectively, in known familial cases, but DNA testing is not useful for the isolated NF1 or NF2 patient with no detectable mutation (Karnes PM. Mayo Clin Proc 1998;73:1071-1076). Clinical screening of family members is necessary in these instances. Prenatal diagnosis is possible by linkage analysis only in the presence of several affected family members.
Other variants of neurofibromatosis have been proposed, including NF3 (overlapping NF1 and NF2), NF5 (segmental NF involving the midline and one arm but sparing head and neck structures), NF6 (cafe-au-lait spots only), and NF7 (late onset NF) but these have not been definitively recognized and their molecular biology is not well understood.
a. is localized to chromosome 17q11.2.
b. is a modulator of Ras-mediated signal transduction.
c. mutates 100 times more frequently than most other genes.
d. function appears to be that of tumor growth suppression.
e. All of the above