Von Recklinghausen neurofibromatosis, or neurofibromatosis type 1 (NF1), is a common autosomal dominant disorder that affects 1 in 3000 individuals. It is characterized clinically by the finding of two or more of the following: café-au-lait spots, neurofibromas, freckling in non-sun-exposed areas, optic glioma, Lisch nodules, distinctive bony lesions, and a first-degree relative with NF1. Less common manifestations include short stature and macrocephaly. NF1 patients also can have learning disabilities, seizures, scoliosis, hypertension, plexiform neurofibromas, or pheochromocytomas.
There is a high spontaneous mutation rate in NF1, with 30 to 50 percent of cases representing new mutations. Although the penetrance of NF1 is essentially 100 percent, NF1 tends to show variable expressivity in that there is a wide range of clinical severity and complications in patients within the same family, who all presumably carry the same mutation.
Syndromes related to NF1 include neurofibromatosis type 2 (bilateral vestibular neurofibromatosis), segmental or mosaic NF1, Watson syndrome, and neurofibromatosis 1–Noonan syndrome.
The gene for NF1 was identified by positional cloning and resides on chromosome 17q11.2. This gene has an open reading frame of 8454 nucleotides and spans approximately 300,000 nucleotides of genomic DNA. The messenger RNA is 11,000 to 13,000 nucleotides and is detectable at varying levels in all tissues examined. Germ-line mutations in the NF1 gene have been found in affected patients and range from large (megabase) deletions to missense and nonsense mutations.
The protein product of the NF1 locus (neurofibromin) is 2818 amino acids and is expressed as a 250-kDa protein in brain, spleen, kidney, testis, and thymus. This protein has structural and functional similarity to a family of GTPase-activating proteins (GAPs) that down-regulate a cellular proto-oncogene, p21-ras. ras has been implicated in the control of cell growth and differentiation, and the ability of neurofibromin to down-regulate p21-ras suggests that the loss of neurofibromin may lead to uncontrolled cell growth or tumor formation. Subcellular localization and biochemical purification experiments have demonstrated that neurofibromin is associated with cytoplasmic microtubules.
Somatic mutations in the NF1 gene that result in an absence of neurofibromin expression have been described for a variety of tumor types. Loss of neurofibromin in neuro-fibrosarcomas derived from NF1 patients results in increased p21-ras activation and presumably tumor formation. Neurofibromin expression is also absent in non-NF1 patients' tumors, including metastatic malignant melanomas and neuroblastomas. The loss of neurofibromin in malignancy supports the notion that neurofibromin is a tumor-suppressor gene product.
The diagnosis of neurofibromatosis 1 is based largely on clinical criteria despite progress in defining the molecular genetics of the disorder. Treatment of patients with NF1 is directed at education and genetic counseling, early detection of malignancy, and surveillance for the appearance of complications of NF1.