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Neurofibromatosis type 1 (NF1): Pathogenesis, clinical features, and diagnosis

Bruce R Korf, MD, PhD
Section Editors
Marc C Patterson, MD, FRACP
Helen V Firth, DM, FRCP, DCH
Deputy Editor
Elizabeth TePas, MD, MS


There are three major clinically and genetically distinct forms of neurofibromatosis: neurofibromatosis types 1 and 2 (NF1 and NF2) and schwannomatosis. NF1, also known as von Recklinghausen disease, is the most common type. The hallmarks of NF1 are the multiple café-au-lait macules and neurofibromas. The condition is called segmental NF1 when clinical features are limited to one area of the body.

The pathogenesis, clinical features, and diagnosis of NF1 are reviewed here. Management and prognosis are discussed separately (see "Neurofibromatosis type 1 (NF1): Management and prognosis"). The other two forms of neurofibromatosis, NF2 and schwannomatosis, are also discussed in detail separately. (See "Neurofibromatosis type 2" and "Schwannomatosis".)


NF1 is an autosomal dominant genetic disorder with an incidence of approximately 1 in 2600 to 3000 individuals [1,2]. Approximately one-half of the cases are familial (inherited). The remainder are the result of de novo (sporadic) mutations [2]. The de novo mutations occur primarily in paternally derived chromosomes, and the likelihood of de novo NF1 increases with advanced paternal age [3]. The incidence of segmental NF1 is estimated at 1 in 36,000 to 40,000 [4].


NF1 is due to mutations in the NF1 gene, located at chromosome 17q11.2 [5,6]. Neurofibromin, the protein product encoded by the gene, is expressed in many tissues, including brain, kidney, spleen, and thymus [7]. It belongs to a family of guanosine triphosphate hydrolase (GTPase)-activating proteins (GAPs) that stimulate intrinsic GTPase activity in the ras p21 family (21 kD rat sarcoma viral oncogene homologs) [8-10]. Ras activates a number of signaling pathways that includes the stem cell factor (SCF)/c-kit signaling, mechanistic target of rapamycin (mTOR), and mitogen-activated protein kinase (MAPK) pathways.

Mutations in the NF1 gene result in reduced amounts of functional protein, causing the wide spectrum of clinical findings, including NF1-associated tumors [7]. Penetrance, or the likelihood that the individual carrying the mutation will manifest the disease, is complete. NF1 is highly variable in its expression, however (ie, the severity of and specific manifestations of the disorder vary among affected individuals within the same family and from one family to another) [11]. Somatic mutation or loss of heterozygosity at the NF1 locus, in combination with a germline NF1 mutation, leads to complete loss of neurofibromin expression that is seen in NF1 lesions such as pseudoarthrosis [12] and neurofibromas [13]. NF1 therefore functions as a tumor suppressor gene.


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Literature review current through: Sep 2016. | This topic last updated: Jun 19, 2015.
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