This article includes discussion of neurofibromatosis 1, neurofibromatosis type 1, NF1, peripheral neurofibromatosis, Von Recklinghausen neurofibromatosis, tumor predisposition syndrome, RASopathy, café-au-lait spot (CaLS, CALS, café-au-lait macules, CaLM, CALM), neurofibroma, plexiform neurofibroma, freckling (lentigine, Cowe sign), optic pathway glioma (OPG, optic glioma), Lisch nodule (iris hamartoma), and osseous lesion (orthopedic lesion, sphenoid wing dysplasia, long bone dysplasia, pseudoarthrosis). The foregoing terms may include synonyms, similar disorders, variations in usage, and abbreviations.
Neurofibromatosis 1 is a common autosomal dominant neurocutaneous disorder displaying a typical pattern of dermatologic and systemic findings. In this article, the authors discuss diagnosis, clinical manifestations, treatment, and advancements in neurofibromatosis 1.
• Neurofibromatosis 1 (NF1) is a common autosomal dominant neurocutaneous disorder caused by germline mutations in the NF1 gene at chromosome 17 that encodes the protein neurofibromin; penetrance is complete, but expression is highly variable and age-dependent.
• Mosaic forms of neurofibromatosis 1 (MNF1 or segmental NF1) are caused by somatic mosaicism due to a postzygotic mutation in the NF1 gene, and are characterized by neurofibromatosis 1 manifestations limited to 1 or multiple body segments (localized or generalized mosaic forms of neurofibromatosis 1); 30% have neurofibromatosis 1 complications and 6% have offspring with complete neurofibromatosis 1.
• Neurofibromatosis 1 is characterized by 2 of the following 7 criteria: 6 café-au-lait spots, skinfold freckles, 2 neurofibromas or 1 plexiform neurofibroma, 2 Lisch nodules, distinctive osseous lesion, optic pathway glioma, and/or a first-degree relative with neurofibromatosis 1.
• Ninety-five percent of neurofibromatosis 1 patients meet diagnostic criteria by the age of 8 years, and approximately 100% by the age of 20 years.
• Legius syndrome is a neurofibromatosis 1-like syndrome caused by a germline mutation in the SPRED1 gene, and characterized by café-au-lait spots, axillary freckling, and macrocephaly, but lacking peripheral and nervous system tumors, typical osseous lesions, and Lisch nodules; about 50% of Legius syndrome patients fulfill the neurofibromatosis 1 diagnostic criteria based on their cutaneous findings.
• NF1 is a tumor-suppressor gene; neurofibromatosis 1 is thus a tumor-predisposition syndrome and neurofibromatosis 1 patients have a propensity to develop both benign and malignant tumors through acquired inactivation of the functioning NF1 allele, with a cumulative risk of malignancy at 20% by age 50.
• Health supervision and management guidelines and recommendation for tumor surveillance for neurofibromatosis 1 patients are available.
Neurofibromatosis 1, previously known as von Recklinghausen disease, was first described in 1882 by the pathologist Frederick von Recklinghausen, who also identified the neural origin of neurofibromas. The other hallmark features of the disease were later described, including the café-au-lait spots by Marie Bernard in 1896, the Lisch nodules by the ophthalmologist Karl Lisch in 1937, and the skinfold freckling (or Crowe sign) by Dr. Frank Crowe in 1964 (Anderson and Gutmann 2015).
The mode of inheritance, high penetrance rate, and high frequency of new mutations, along with the broad spectrum of complications, were recognized by the 1950s. Increased clinical and laboratory research in the 1970s eventually lead to the localization of the NF1 gene locus on chromosome 17 in 1987. In 1988, the U.S. National Institutes of Health convened a consensus conference to establish diagnostic criteria for neurofibromatosis 1, and these are still in use today (Table 1) (National Institutes of Health 1988). The NF1 gene was discovered in 1990 (Anderson and Gutmann 2015).
Although both the central and peripheral forms of neurofibromatosis were recognized in the 19th century, for many years neurofibromatosis was discussed as a single entity. Not until 1980 was neurofibromatosis type 2, previously thought to be a central form of neurofibromatosis, recognized to be a distinct genetic disease (Tonsgard 2006). Today there are 3 major clinically and genetically distinct forms of neurofibromatosis: neurofibromatosis 1 and 2 and schwannomatosis. Of these, neurofibromatosis 1 constitutes 90% of neurofibromatosis cases and is 1 of the most common autosomal dominant disorders in humans.
*According to National Institutes of Health in force since 1988 (National Institutes of Health 1988). The National Institutes of Health diagnostic criteria are highly specific and sensitive by the age of 8 years where 97% of patients meet diagnostic criteria, and 100% by age 21.