DiagnosisClinical DiagnosisThe diagnostic criteria for neurofibromatosis 1 (NF1) developed by the National Institutes of Health [NIH 1988] are generally accepted for routine clinical use [Ferner et al 2007, Williams et al 2009]. Clinical diagnosis of NF1 is usually unequivocal in all but the youngest children [DeBella et al 2000b]. The NIH diagnostic criteria for NF1 are met in an individual who has two or more of the following features: Six or more café au lait macules (Figure 1) over 5 mm in greatest diameter in prepubertal individuals and over 15 mm in greatest diameter in postpubertal individuals Two or more neurofibromas (Figure 2) of any type or one plexiform neurofibroma (Figure 3) Freckling in the axillary or inguinal regions Optic glioma Two or more Lisch nodules (iris hamartomas) A distinctive osseous lesion such as sphenoid dysplasia or tibial pseudarthrosis A first-degree relative (parent, sib, or offspring) with NF1 as defined by the above criteria FigureFigure 1. Café au lait macules FigureFigure 2. Neurofibromas FigureFigure 3. Plexiform neurofibroma Adults. The NIH diagnostic criteria are both highly specific and highly sensitive in adults with NF1 [Ferner et al 2007]. Children Only about half of children with NF1 and no known family history of NF meet the NIH criteria for diagnosis by age one year; almost all do by age eight years [DeBella et al 2000a] because many features of NF1 increase in frequency with age [Wolkenstein et al 1996, Friedman & Birch 1997, DeBella et al 2000b]. Children who have inherited NF1 from an affected parent can usually be identified within the first year of life because diagnosis requires just one feature in addition to a positive family history. This feature is usually multiple café au lait spots, which develop in infancy in more than 95% of individuals with NF1 [DeBella et al 2000b, Nunley et al 2009]. Young children with multiple café au lait spots and no other NF1 features whose parents do not show signs of NF1 on careful physical and ophthalmologic examination should be strongly suspected of having NF1 and followed clinically as though they do [Nunley et al 2009]. A definite diagnosis of NF1 can be made in most of these children by age four years using the NIH criteria. Molecular Genetic TestingGene. Heterozygous loss-of-function mutations of NF1 are responsible for the vast majority of cases of NF1. Clinical testing A multi-step mutation detection protocol that identifies more than 95% of pathogenic NF1 mutations in individuals fulfilling the NIH diagnostic criteria is available [Messiaen et al 2000, Wimmer et al 2006, Valero et al 2011]. This protocol, which involves analysis of both mRNA and genomic DNA, includes RT-PCR, direct sequencing, microsatellite marker analysis, MLPA, and interphase FISH. Because of the frequency of splicing mutations and the variety and rarity of individual mutations found in persons with NF1, methods based solely on analysis of genomic DNA have lower detection rates [Wimmer et al 2006, Pros et al 2008]. Sequence analysis detects about 90% of NF1 intragenic mutations. High detection frequency is sometimes achieved by sequence analysis of exons in genomic DNA and of cDNA.Deletion/duplicaition analysis. Testing is sometimes performed to look for whole gene NF1 deletions alone when the "large deletion phenotype" is suspected clinically [Upadhyaya et al 1998, Riva et al 2000, Venturin et al 2004]. Whole-gene deletions occur in 4%-5% of individuals with NF1 [Kluwe et al 2004]. Whole-gene NF1 deletions can be identified by a number of methods (Table 1), including FISH, MLPA, testing for multiple SNPs or other normal allelic genetic markers in the NF1 genomic region [Wimmer et al 2006], and chromosomal microarray analysis [Pasmant et al 2009b].Linkage analysis. Linkage studies are dependent on the availability and willingness of family members to be tested and are based on (1) accurate clinical diagnosis of NF1 in affected family members and (2) accurate understanding of the genetic relationships in the family. Samples from at least two affected individuals are required to perform the analysis. Highly informative and accurate linkage studies should be possible in any family with a sufficient number of unequivocally affected or unaffected members available for testing, as more than 4300 intragenic SNPs are listed for the NF1 locus in dbSNP. Table 1. Summary of Molecular Genetic Testing Used in Neurofibromatosis 1View in own windowGene Symbol Test MethodNF1 Mutations DetectedMutation Detection Frequency by Test Method ^{1Test AvailabilityNF1Sequence analysis Sequence variants 2~90%ClinicalDeletion / duplication anaysis 3Exonic, multiexonic and whole-gene deletions~5%Cytogenetic analysisLarge-scale rearrangements<1%Linkage analysisNot applicableNot applicable1. The ability of the test method used to detect a mutation that is present in the indicated gene2. Examples of mutations detected by sequence analysis may include small intragenic deletions/insertions and missense, nonsense, and splice site mutations.3. Testing that identifies deletions/duplications not readily detectable by sequence analysis of the coding and flanking intronic regions of genomic DNA; included in the variety of methods that may be used are: quantitative PCR, long-range PCR, multiplex ligation-dependent probe amplification (MLPA), and chromosomal microarray (CMA) that includes this gene/chromosome segment.Interpretation of test results. For issues to consider in interpretation of sequence analysis results, click here.Information on specific allelic variants may be available in Molecular Genetics (see Table A. Genes and Mutations and/or Pathologic allelic variants).Testing Strategy To confirm/establish the diagnosis in a probandConfirmatory diagnostic testing is indicated for individuals in whom NF1 is suspected but who do not fulfill the NIH diagnostic criteria. This is rarely necessary after early childhood.Molecular testing for NF1 is infrequently indicated clinically but may be useful in a young child with a serious tumor (e.g., optic glioma) in whom establishing a diagnosis of NF1 would affect management. A multi-step mutation detection protocol that identifies more than 95% of pathogenic NF1 mutations in individuals fulfilling the NIH diagnostic criteria is available [Messiaen et al 2000, Wimmer et al 2006].Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutation in the family.Genetically Related (Allelic) DisordersApparently pathogenic NF1 mutations have been demonstrated in a few individuals or families who do not have NF1 according to the NIH Diagnostic Criteria:A mild variant associated with a 3-bp in-frame deletion of exon 17 (c.2970-2972 delAAT) (NF Consortium nomenclature, exon 22 in NCBI nomenclature), in which neurofibromas are rare and multiple café-au-lait spots may be the only apparent manifestation [Upadhyaya et al 2007, Quintáns et al 2011]Familial spinal neurofibromatosis, in which multiple spinal neurofibromas but few, if any, cutaneous manifestations of NF1 occur [Kaufmann et al 2001, Kluwe et al 2003, Pascual-Castroviejo et al 2007, Upadhyaya et al 2009, Fauth et al 2009, Pizzuti et al 2011]. Despite the name, this condition may also occur in sporadic cases.A similar disorder in a patient with multiple spinal ganglioneuromas (rather than neurofibromas) and multiple subcutaneous tumours [Bacci et al 2010]A man with optic glioma but no other diagnostic features of NF1 [Buske et al 1999]A child with encephalocraniocutaneous lipomatosis [Legius et al 1995] The explanation for the unusual phenotypes in these families is not known.}

Natural HistoryThe clinical manifestations of neurofibromatosis 1 (NF1) are extremely variable [Friedman & Riccardi 1999, Ferner 2007a, Ferner 2007b, Ferner et al 2007, Williams et al 2009]. Multiple café au lait spots occur in nearly all affected individuals, and intertriginous freckling develops in almost 90%. Numerous benign cutaneous neurofibromas are usually present in adults with NF1. About half of persons with NF1 have plexiform neurofibromas, but most are internal and not suspected clinically [Tonsgard et al 1998, Mautner et al 2008]. Most of these tumors grow slowly if at all over periods of years, but very rapid growth can occur in benign lesions, especially in early childhood [Dombi et al 2007, Tucker et al 2009a]. When symptomatic, plexiform neurofibromas can cause disfigurement and may compromise function or even jeopardize life. Ocular manifestations of NF1 include optic gliomas, which may lead to blindness, and Lisch nodules (innocuous iris hamartomas). Symptomatic optic pathway gliomas in individuals with NF1 usually present before age six years with loss of visual acuity or proptosis, but these tumors may not become symptomatic until later in childhood or even in adulthood. Symptomatic optic pathway gliomas in NF1 are frequently stable for many years or only very slowly progressive and some of these tumors even spontaneously regress [Blazo et al 2004, Sylvester et al 2006, Listernick et al 2007, Shamji & Benoit 2007, Nicolin et al 2009, Segal et al 2010, Oh et al 2011]. Scoliosis, vertebral dysplasia, pseudarthrosis, and overgrowth are the most serious bony complications, but osteopenia and osteoporosis are much more frequent among people with NF1. Other medical concerns include vasculopathy, hypertension, intracranial tumors, and malignant peripheral nerve sheath tumors. At least half of individuals with NF1 have a learning disability. Headaches occur frequently, and seizures or hydrocephalus are seen occasionally. Many individuals with NF1 develop only cutaneous manifestations of the disease and Lisch nodules, but the frequency of more serious complications increases with age. Various manifestations of NF1 have different characteristic times of appearance [Friedman & Riccardi 1999, DeBella et al 2000b, Boulanger & Larbrisseau 2005, Williams et al 2009]. For example: Bony manifestations such as anteriolateral tibial bowing are congenital. Café au lait spots are often present at birth and increase in number during the first few years of life. Diffuse plexiform neurofibromas of the face and neck rarely appear after age one year, and diffuse plexiform neurofibromas of other parts of the body rarely develop after adolescence.Deep nodular plexiform neurofibromas are not often seen in early childhood and often remain asymptomatic even in adulthood. Optic gliomas develop in the first six years of life. The rapidly progressive (dysplastic) form of scoliosis almost always develops between ages six and ten years, although milder forms of scoliosis without vertebral anomalies typically occur during adolescence. Malignant peripheral nerve sheath tumors (neurofibrosarcomas) usually occur in adolescence or adulthood. Neurofibromas may affect virtually any organ in the body. Discrete cutaneous and subcutaneous neurofibromas are rare before late childhood. The total number of neurofibromas seen in adults with NF1 varies from a few to hundreds or even thousands. Additional cutaneous and subcutaneous neurofibromas continue to develop throughout life, although the rate of appearance may vary greatly from year to year. Many women experience a rapid increase in the number and size of neurofibromas during pregnancy [Roth et al 2008]. Some individuals with NF1 develop a diffuse polyneuropathy that may be associated with multiple nerve root tumors and a high risk of malignant peripheral nerve sheath tumors [Drouet et al 2004, Ferner et al 2004].Most individuals with NF1 have normal intelligence, but learning disabilities occur in 50%-75% [Hyman et al 2005, Coudé et al 2006, Hyman et al 2006, Levine et al 2006, Krab et al 2008a, Watt et al 2008, Roy et al 2010, Gilboa et al 2011]. A variety of learning problems have been described; visual-spatial performance deficits and attention deficits are the most common. The learning problems associated with NF1 persist into adulthood [Uttner et al 2003, Pavol et al 2006]. Children with NF1 often have poorer social skills and other personality, behavioral, and quality-of-life differences from children without NF1 [Prinzie et al 2003, Barton & North 2004, Johnson et al 2005, Graf et al 2006, Page et al 2006, Barton & North 2007, Noll et al 2007, Krab et al 2009]. People with NF1 also have larger brains, on average, than people without NF1, but in NF1 gray matter volume is not correlated with IQ [Greenwood et al 2005, Margariti et al 2007].Hypertension is common and may develop at any age [Friedman 1999, Friedman et al 2002, Lama et al 2004]. In most cases, the hypertension is "essential," but a characteristic NF1 vasculopathy can produce renal artery stenosis, coarctation of the aorta, or other vascular lesions associated with hypertension. A renovascular cause is often found in children with NF1 and hypertension [Fossali et al 2000, Han & Criado 2005].NF1 vasculopathy involving major arteries or arteries of the heart or brain can have serious or even fatal consequences [Friedman et al 2002, Tatebe et al 2005, Kanter et al 2006, Tang et al 2006, Cairns & North 2008, Rea et al 2009, Okazaki et al 2010]. Cerebrovascular abnormalities in NF1 typically present as stenoses or occlusions of the internal carotid, middle cerebral, or anterior cerebral artery. Small telangiectatic vessels form around the stenotic area and appear as a "puff of smoke" ("moya-moya") on cerebral angiography [Cairns & North 2008]. Moya-moya develops about three times more often than expected in children with NF1 after cranial irradiation for primary brain tumor [Ullrich et al 2007b]. Ectatic vessels and intracranial aneurysms occur more frequently in individuals with NF1 than in the general population [Rosser et al 2005, Schievink et al 2005]. Valvar pulmonic stenosis is more common in individuals with NF1 than in the general population [Lin et al 2000]. Adults with NF1 may develop pulmonary hypertension, often in association with parenchymal lung disease, another late-onset but potentially quite serious feature of NF1 [Stewart et al 2007a, Zamora et al 2007, Montani et al 2011].In children with NF1, the most common neoplasms (apart from benign neurofibromas) are optic nerve gliomas and brain tumors [Listernick & Gutmann 1999, Korf 2000, Kreusel 2005, Ferner et al 2007, Listernick et al 2007, Ullrich et al 2007a]. Leukemia, especially juvenile chronic myelogenous leukemia and myelodysplastic syndromes, are infrequent in children with NF1 but much more common than in children without NF1. Second central nervous system gliomas subsequently occur in at least 20% of individuals with NF1 who had optic pathway gliomas in childhood [Sharif et al 2006]. Non-optic gliomas and malignant peripheral nerve sheath tumors within the field of treatment are substantially more common in persons with NF1 with optic gliomas who are treated with radiotherapy [Kleinerman 2009].Brain stem and cerebellar astrocytomas in individuals with NF1 may also follow a less aggressive course than in individuals without NF1 [Korf 2000, Vinchon et al 2000, Rosser & Packer 2002, Ullrich et al 2007a]. Occasional regression of these tumors in individuals with NF1 has been reported [Schmandt et al 2000, Rosser & Packer 2002]. Malignant peripheral nerve sheath tumors are the most frequent malignant neoplasms associated with NF1, occurring in approximately 10% of affected individuals [Rasmussen et al 2001, Evans et al 2002, Walker et al 2006, Friedrich et al 2007a, McCaughan et al 2007]. Malignant peripheral nerve sheath tumors tend to occur at a much younger age and to have a poorer prognosis for survival in people with NF1 than in the general population [Evans et al 2002, Hagel et al 2007, Friedrich et al 2007a, McCaughan et al 2007]. Individuals with NF1 who have benign subcutaneous neurofibromas or benign internal plexiform neurofibromas may be at greater risk of developing malignant peripheral nerve sheath tumors than persons with NF1 who lack such benign tumors [Tucker et al 2005, Mautner et al 2008].A variety of other tumors may also be seen in individuals with NF1 [Gutmann & Gurney 1999, Korf 2000, Walker et al 2006], including gastrointestinal stromal tumors [Andersson et al 2005, Takazawa et al 2005, Guillaud et al 2006, Miettinen et al 2006, Kramer et al 2007]. Women with NF1 appear to have a fivefold increased risk of developing breast cancer before age 50 years and 3.5-fold increased risk of developing breast cancer overall [Sharif et al 2007].Generalized osteopenia and frank osteoporosis appear to be more common than expected in persons with NF1 [Kuorilehto et al 2005, Lammert et al 2005b, Dulai et al 2007, Yilmaz et al 2007, Brunetti-Pierri et al 2008, Duman et al 2008, Tucker et al 2009b, Petramala et al 2012]. The pathogenesis of these bony changes is not understood [Schindeler & Little 2008], but individuals with NF1 have often been found to have lower-than-expected serum 25-hydroxyvitamin D concentrations, elevated serum parathyroid hormone levels, and evidence of increased bone resorption [Lammert et al 2006, Brunetti-Pierri et al 2008, Stevenson et al 2008, Tucker et al 2009b, Stevenson et al 2011, Petramala et al 2012]. Bone biopsies from 14 asymptomatic adults with NF1 showed reduced trabecular bone volume, decreased calcium content, increased osteoid, and increased numbers of osteoblasts and osteoclasts [Seitz et al 2010]. Individuals with NF1 tend to be below average in height and above average in head circumference for age [Clementi et al 1999, Szudek et al 2000a, Szudek et al 2000b, Virdis et al 2003]. However, few individuals with NF1 have heights more than three standard deviations below the mean or head circumferences more than four standard deviations above the mean. In contrast, persons with NF1 whose mutation is a deletion of the entire NF1 locus show a different pattern, with overgrowth, especially between ages two and six years [Spiegel et al 2005, Mautner et al 2010, Pasmant et al 2010]. The clinical features in some of these children resemble those of Weaver syndrome. Pubertal development is usually normal, but precocious puberty may occur in children with NF1, especially in those with tumors of the optic chiasm [Virdis et al 2000]. Delayed puberty is also common [Virdis et al 2003]. Segmental or regional NF is diagnosed in individuals who have features of NF1 restricted to one part of the body and whose parents are both unaffected [Ruggieri & Huson 2001, Listernick et al 2003]. In some cases, the unusual distribution of features is probably just a chance occurrence in an individual with NF1. In other instances, segmental NF1 represents mosaicism for a somatic NF1 mutation [Tinschert et al 2000, Vandenbroucke et al 2004, Consoli et al 2005, Maertens et al 2007, Messiaen et al 2011]. However, most individuals who have been reported with mosaicism for an NF1 mutation have mild, but not segmental, neurofibromatosis [Rasmussen et al 1998, Messiaen et al 2011]. Individuals with segmental NF1 whose children have typical NF1 have been reported [Oguzkan et al 2004, Consoli et al 2005]. Two discordant monozygotic twin pairs provide evidence of somatic mosaicism resulting from an NF1 mutation at a very early postzygotic stage [Kaplan et al 2010, Vogt et al 2011]. A Noonan syndrome phenotype occurs in approximately 12% of individuals with NF1 [Colley et al 1996]. The features may include ocular hypertelorism, down-slanting palpebral fissures, low-set ears, webbed neck, and pulmonic stenosis. Relatives of such individuals who are affected with NF1 may or may not have concomitant features of Noonan syndrome. The NF1-Noonan phenotype appears to have a variety of causes, including the occurrence of two different relatively common autosomal dominant mutations in some families and segregation as an NF1 variant in others [Carey 1998, Bertola et al 2005, Thiel et al 2009, Prada et al 2011]. Most individuals with NF1-Noonan syndrome have constitutional mutations of NF1 [De Luca et al 2005, Hüffmeier et al 2006, Stevenson et al 2006a]. Mutations of PTPN11, which can be found in approximately half of all persons with Noonan syndrome, have been reported but are rare in persons with the NF1-Noonan syndrome phenotype [De Luca et al 2005, Sarkozy et al 2007, Carcavilla et al 2011]. LEOPARD syndrome, which resembles Noonan syndrome but is distinguished by the presence of multiple lentigines, sensorineural deafness, and a higher prevalence of hypertrophic cardiomyopathy and electrocardiographic alterations, is also caused by PTPN11 mutations in most cases. However, one individual with LEOPARD syndrome and some features of NF1 has been reported to have an NF1 mutation [Wu et al 1996].Life expectancy. The median life expectancy of individuals with NF1 is approximately eight years lower than in the general population [Evans et al 2011, Wilding et al 2012]. Malignancy (especially malignant peripheral nerve sheath tumors) and vasculopathy are the most important causes of early death in individuals with NF1 [Zöller et al 1995, Rasmussen et al 2001, Evans et al 2011, Masocco et al 2011].Neuroimaging. Enlargement of the corpus callosum is seen in some children with NF1 and has been associated with learning disabilities [Pride et al 2010]. The clinical significance of the so-called "unidentified bright objects" (UBOs) visualized on brain MRI scan in more than 50% of children with NF1 is uncertain [Curless 2000, DeBella et al 2000a, Goh et al 2004, Boulanger & Larbrisseau 2005, Gill et al 2006, Lopes Ferraz Filho et al 2008, Sabol et al 2011, Ferraz-Filho et al 2012a]. These hyperintense lesions seen on T₂-weighted imaging may occur in the optic tracts, basal ganglia, brain stem, cerebellum, or cortex, and usually show no evidence of a mass effect. Typical UBOs are not seen on T₁-weighted MRI imaging or on CT scan. UBOs show signs of abnormal myelin structure on diffusion-weighted MRI [Alkan et al 2005, Tognini et al 2005, Ferraz-Filho et al 2012a, Ferraz-Filho et al 2012b] and correspond pathologically to areas of spongiform myelinopathy [DiPaolo et al 1995]. They may disappear with age and are less common in adults than in children with NF1 [Feldmann et al 2003, Hyman et al 2003, Gill et al 2006]. The presence of UBOs does not appear to be related to the occurrence of seizures in children with NF1 [Hsieh et al 2011]. Some studies have suggested that the presence, number, volume, location, or disappearance of UBOs over time correlates with learning disabilities in children with NF1, but the findings have not been consistent across investigations [North 1999, Feldmann et al 2003, Hyman et al 2003, Goh et al 2004, Hyman et al 2007, Chabernaud et al 2009, Feldmann et al 2010].

Genotype-Phenotype CorrelationsNF1 is characterized by extreme clinical variability, not only between unrelated individuals and among affected individuals within a single family but even within a single person with NF1 at different times in life. Only three clear correlations have been observed between particular mutant NF1 alleles and consistent clinical phenotypes:A deletion of the whole NF1 gene is associated with large numbers and early appearance of cutaneous neurofibromas, more frequent and more severe cognitive abnormalities than average, and sometimes somatic overgrowth, large hands and feet, and dysmorphic facial features [Upadhyaya et al 1998, Riva et al 2000, Venturin et al 2004, Spiegel et al 2005, Mensink et al 2006, Mautner et al 2010, Pasmant et al 2010]. A 3-bp in-frame deletion of exon 17 (c.2970-2972 delAAT) (NF Consortium nomenclature; exon 22 of NCBI nomenclature) is associated with typical pigmentary features of NF1, but no cutaneous or surface plexiform neurofibromas [Upadhyaya et al 2007]. Individuals with duplication of the entire NF1 locus and surrounding genomic region do not have the NF1 phenotype (which is caused by NF1 microdeletion or loss of function mutations) but may have intellectual disability and seizures [Grisart et al 2008, Moles et al 2012]. The NF1 microduplication phenotype is variable, and some individuals with this genomic lesion appear normal. Because several genes in addition to NF1 are involved in the microduplication, it is impossible to know whether the phenotypic abnormalities, when they occur, result from triplication of NF1 or of another gene(s) within the affected region.The consistent familial transmission of NF1 variants such as Watson syndrome (multiple café au lait spots, pulmonic stenosis, and dull intelligence) [Allanson et al 1991, Tassabehji et al 1993] and familial spinal neurofibromatosis [Kaufmann et al 2001, Kluwe et al 2003, Pascual-Castroviejo et al 2007, Upadhyaya et al 2009, Pizzuti et al 2011] also indicates that allelic heterogeneity plays a role in the clinical variability of NF1. Statistical analysis of the NF1 phenotype within and between families suggests that the NF1 mutant allele itself accounts for only a small fraction of phenotypic variation [Sabbagh et al 2009]. Differences in expression of the normal NF1 allele may account for some of the phenotypic variability [Jentarra et al 2012]. Statistical analysis of clinical features in affected families suggests that modifying genes at other loci influence many aspects of the NF1 phenotype [Easton et al 1993, Szudek et al 2000c, Szudek et al 2002, Sabbagh et al 2009]. The extreme clinical variability of NF1 suggests that random events are also important in determining the phenotype of affected individuals. Evidence in support of this interpretation is provided by the occurrence of acquired "second hit" mutations or loss of heterozygosity at the NF1 locus in some instances in the following tumors and other lesions characteristic of NF1:Neurofibromas [Bottillo et al 2009, Steinmann et al 2009, Upadhyaya et al 2009, Thomas et al 2010, Garcia-Linares et al 2011, Jouhilahti et al 2011, Thomas et al 2012] Malignant peripheral nerve sheath tumors [Frahm et al 2004, Upadhyaya et al 2004, Upadhyaya et al 2008, Bottillo et al 2009] Pheochromocytomas [Xu et al 1992, Bausch et al 2007] Astrocytomas [Gutmann et al 2000, Gutmann et al 2003, Tada et al 2003, Upadhyaya et al 2004] Gastrointestinal stromal tumors [Maertens et al 2006, Stewart et al 2007b] Myeloid malignancies from individuals with NF1 [Stephens et al 2006, Steinemann et al 2010]Malignant melanomas [Rübben et al 2006]Mandibular giant cell granulomas [Friedrich et al 2007b]Melanocytes grown from café-au-lait spots [Maertens et al 2007, De Schepper et al 2008] Glomus tumors [Stewart et al 2012]Tissue associated with tibial pseudarthrosis [Stevenson et al 2006b]It seems likely that the clinical variability of NF1 results from a combination of genetic, non-genetic, and stochastic factors. Such complexity and the diversity of constitutional NF1 mutations that occur in this disease will continue to make genotype-phenotype correlation difficult.

Differential DiagnosisMore than 100 genetic conditions and multiple congenital anomaly syndromes that include café au lait spots or other individual features of neurofibromatosis type 1 (NF1) have been described, but few of these disorders are ever confused with NF1.Conditions most frequently confused with NF1Legius syndrome, a dominantly inherited condition that includes multiple café-au-lait spots, axillary freckling, macrocephaly and, in some individuals, facial features that resemble Noonan syndrome [Brems et al 2007, Messiaen et al 2009, Pasmant et al 2009a, Spurlock et al 2009, Muram-Zborovski et al 2010] caused by heterozygous mutations in SPRED1. Affected individuals may meet the diagnostic criteria for NF1, but Lisch nodules, neurofibromas, and central nervous system tumors do not usually occur.Homozygosity for one of the genes causing hereditary non-polyposis colon cancer (HNPCC) [Gallinger et al 2004, Raevaara et al 2004, Bandipalliam 2005, Ostergaard et al 2005, Toledano et al 2009]. The cutaneous phenotype is remarkably similar to NF1; however, individuals homozygous for mutations associated with HNPCC usually develop tumors that are typical of HNPCC but with a younger age of onset than seen in HNPCC heterozygotes. This condition is distinguishable from NF1 in that the parents are often consanguineous and one or both parents often have clinical findings and/or a family history of HNPCC. Typically, neither parent has clinical findings of NF1. A pathogenic mutation of NF1 was also demonstrated in white blood cells of one child with homozygous HNPCC, but this child had atypical chronic myeloid leukemia at the time the sample was obtained [Alotaibi et al 2008].Neurofibromatosis type 2 (bilateral vestibular schwannomas, schwannomas of other cranial and peripheral nerves, cutaneous schwannomas, meningiomas, juvenile posterior subcapsular cataract). NF2 is genetically and clinically distinct from NF1. Schwannomatosis (multiple schwannomas of cranial, spinal or peripheral nerves, usually without vestibular, ocular or cutaneous features of NF2) Multiple café au lait spots (an autosomal dominant trait without other features of neurofibromatosis) LEOPARD syndrome (multiple lentigines, ocular hypertelorism, deafness, congenital heart disease) McCune-Albright syndrome (large café au lait spots with irregular margins, polyostotic fibrous dysplasia) Noonan syndrome (short stature, congenital heart defect, broad or webbed neck, and characteristic facies) Multiple endocrine neoplasia type 2B (mucosal neuromas, conjunctival neuromas, pheochromocytoma, medullary carcinoma of the thyroid, ganglioneuromatosis of the gastrointestinal tract, distinctive face with enlarged lips, marfanoid habitus) Multiple lipomatosis (multiple cutaneous lipomas) Bannayan-Riley-Ruvalcaba syndrome (multiple lipomas and hemangiomas, macrocephaly, pigmented macules of the glans penis); included in the PTEN hamartoma tumor syndrome Juvenile hyaline fibromatosis (multiple subcutaneous tumors, gingival fibromatosis) (see Inherited Systemic Hyalinosis) Congenital generalized fibromatosis (multiple tumors of the skin, subcutaneous tissues, skeletal muscle, bones, and viscera) Multiple intradermal nevi (multiple cutaneous tumors) Klippel-Trenaunay-Weber syndrome (cutaneous hemangiomas, varicose veins, arteriovenous fistulas, and hemihypertrophy) Proteus syndrome (hamartomatous overgrowth of multiple tissues, connective tissue nevi, epidermal nevi, hyperostoses) Piebald trait (areas of cutaneous pigmentation and depigmentation with hyperpigmented borders of the unpigmented areas, white forelock) Multiple orbital neurofibromas, painful peripheral nerve tumors, distinctive face and marfanoid habitus [Babovic-Vuksanovic et al 2012]Note to clinicians: For a patient-specific ‘simultaneous consult’ related to this disorder, go to , an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).

ManagementEvaluations Following Initial DiagnosisTo establish the extent of disease in an individual diagnosed with neurofibromatosis 1 (NF1), the following evaluations are recommended:Personal medical history with particular attention to features of NF1 Physical examination with particular attention to the skin, skeleton, cardiovascular system, and neurologic systems Ophthalmologic evaluation including slit lamp examination of the irides Developmental assessment in children Other studies only as indicated on the basis of clinically apparent signs or symptoms Genetics consultationThe value of performing routine head MRI scanning in individuals with NF1 at the time of diagnosis is controversial. Proponents state that such studies are useful in helping to establish the diagnosis in some individuals, in identifying complications before they become clinically apparent in others, and in evaluating the context in which extracranial complications occur in still others [Pinson et al 2002, Blazo et al 2004, Lopes Ferraz Filho et al 2008, Sabol et al 2011]. Those who oppose routine MRI scanning point to its nonspecificity and difficulty in reliably diagnosing UBOs, the cost of such testing, and the fact that clinical management should not be affected by finding intracranial lesions such as UBOs or optic nerve thickening in asymptomatic individuals [DeBella et al 2000b, King et al 2003, Thiagalingam et al 2004, Ferner et al 2007, Listernick et al 2007, Williams et al 2009]. In fact, finding such lesions may result in regularly repeating the MRI scan despite the continued absence of related symptoms, adding further to the cost as well as to the anxiety of the individual and family, without any benefit. In addition, family history with particular attention to features of NF1, physical examination, and ophthalmic examination (including slit lamp exam) should be performed on both parents to determine if the condition was inherited or occurred de novo. This determination is necessary for genetic counseling.Treatment of ManifestationsIndividuals with NF1 who have abnormalities involving the eye, central or peripheral nervous system, spine or long bones, or cardiovascular system should be referred to an appropriate specialist for treatment.Discrete cutaneous or subcutaneous neurofibromas that are disfiguring or in inconvenient locations (e.g., at belt or collar lines) can be removed surgically, or, if small, by laser or electrocautery. This aspect of treatment is important: the disfigurement caused by NF1 is the most distressing disease manifestation for many individuals [Wolkenstein et al 2000]. Plexiform neurofibromas may grow to enormous size and can cause serious disfigurement, overgrowth, or impingement on normal structures. The extent of plexiform neurofibromas seen on the surface of the body often cannot be determined by clinical examination alone, and many internal neurofibromas, even large ones, may be unsuspected on clinical examination. MRI is the method of choice for demonstrating the size and extent of plexiform neurofibromas [Lim et al 2005, Mautner et al 2006, Matsumine et al 2009, Mautner et al 2008, Cai et al 2009] and for monitoring their growth over time [Dombi et al 2007, Tucker et al 2009a, Van Meerbeeck et al 2009]. Surgical treatment of plexiform neurofibromas is often unsatisfactory because of their intimate involvement with nerves and their tendency to grow back at the site of removal [Kim et al 2005, Wise et al 2005, Gottfried et al 2006, Murovic et al 2006, Fadda et al 2007, Serletis et al 2007].In one small series in which surgical removal of superficial plexiform neurofibromas was undertaken in children while the tumors were still relatively small, it was possible to resect the neurofibromas without producing any neurologic deficit [Friedrich et al 2005b].Radiotherapy is contraindicated because of the risk of inducing malignant peripheral nerve sheath tumors in these genetically predisposed individuals [Evans et al 2002]. A 54% reduction in the volume of a plexiform neurofibroma has been reported in an individual with NF1 who received two cycles of carboplatin chemotherapy for a coincident seminoma [Hummel et al 2011].An anecdotal case has been reported in which dramatic shrinkage of a large plexiform neurofibroma occurred after treatment with imatinib, a tyrosine kinase inhibitor [Yang et al 2008, Staser et al 2010]. A clinical trial of this therapy is in progress.Pain, development of a neurologic deficit, or enlargement of a preexisting plexiform neurofibroma may signal a malignant peripheral nerve sheath tumor and require immediate evaluation [Valeyrie-Allanore et al 2005]. Examination by MRI and PET [Ferner et al 2000, Friedrich et al 2005a, Bensaid et al 2007, Bredella et al 2007, Mautner et al 2007, Ferner et al 2008, Matsumine et al 2009, Warbey et al 2009] is useful in distinguishing benign and malignant peripheral nerve sheath tumors, but definitive differentiation can only be made by histologic examination of the tumor. Complete surgical excision, when possible, is the only treatment that offers the possibility of cure of malignant peripheral nerve sheath tumors. Adjuvant chemotherapy or radiotherapy is sometimes used as well, although benefit has not been clearly established [Gottfried et al 2006, Murovic et al 2006, Friedrich et al 2007a].Most optic pathway gliomas found on MRI in people with NF1 are asymptomatic [Sylvester et al 2006, Listernick et al 2007, Nicolin et al 2009, Segal et al 2010, Oh et al 2011]. Thus, most people with NF1 who develop optic nerve gliomas do not require treatment. Chemotherapy is the treatment of choice for most progressive optic pathway gliomas in children with NF1 [Nicolin et al 2009, Rosenfeld et al 2010, Ardern-Holmes & North 2011]. Surgical treatment of optic nerve glioma is usually reserved for cosmetic palliation in a blind eye, and radiotherapy is usually avoided because of the risk of inducing malignancy or moya-moya in the exposed field [Evans et al 2002, Ullrich et al 2007a]. The natural history of brain stem and cerebellar astrocytomas in individuals with NF1 should be taken into consideration in deciding on management of such tumors. Dystrophic scoliosis in children with NF1 often requires surgical management, which may be complex and difficult [Shen et al 2005, Tsirikos et al 2005]. Non-dystrophic scoliosis in persons with NF1 can be treated in a manner similar to idiopathic scoliosis.SurveillanceThe following are recommended:Annual physical examination by a physician who is familiar with the individual and with the disease Annual ophthalmologic examination in early childhood, less frequent examination in older children and adults Regular developmental assessment by screening questionnaire (in childhood) Regular blood pressure monitoring Other studies only as indicated on the basis of clinically apparent signs or symptomsMonitoring of those who have abnormalities of the central nervous system, skeletal system, or cardiovascular system by an appropriate specialist Similar recommendations have recently been made by others for the health supervision of individuals with NF1 [Ferner et al 2007, Williams et al 2009]. Agents/Circumstances to AvoidNo limitations are necessary for most individuals with NF1. Limitations may be required if certain particular features such as tibial dysplasia or dysplastic scoliosis are present; in these instances the limitation is determined by the feature, not by the presence of NF1 itself. Radiotherapy of individuals with NF1 appears to be associated with a high risk of developing malignant peripheral nerve sheath tumors within the field of treatment [Evans et al 2002, Sharif et al 2006].Evaluation of Relatives at RiskSee Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes. Pregnancy ManagementAlthough most pregnancies in women with NF1 are normal, serious complications can occur [Dugoff & Sujansky 1996, Chetty et al 2011]. Many women with NF1 experience a rapid increase in the number and size of neurofibromas during pregnancy. Hypertension may first become symptomatic or, if preexisting, may be greatly exacerbated during pregnancy. Large pelvic or genital neurofibromas can complicate delivery, and cesarean section appears to be necessary more often in pregnant women with NF1 than in other women. Therapies Under InvestigationVarious medical treatments for plexiform and spinal neurofibromas are being evaluated in clinical trials [Babovic-Vuksanovic et al 2006, Dilworth et al 2006, Gottfried et al 2006, Widemann et al 2006, Riley et al 2007, Williams et al 2009, Gottfried et al 2010, Ardern-Holmes & North 2011].* Radiofrequency therapy has shown some promise for treatment of facial diffuse plexiform neurofibromas and café-au-lait spots in small clinical series [Baujat et al 2006, Yoshida et al 2007].Controlled trials of several therapeutic approaches to malignant peripheral nerve sheath tumors are available to individuals with NF1 [Dilworth et al 2006, 2006, Widemann 2009, Gottfried et al 2010].* Several controlled trials for treatment of optic pathway gliomas are available to individuals with NF1 [Ardern-Holmes & North 2011].* A clinical trial of simvastatin therapy for learning disabilities in children with NF1 found no benefit [Krab et al 2008b]. Another trial of lovastatin therapy for learning disabilities in NF1 is in progress [Ardern-Holmes & North 2011].* * Note: NIH ClinicalTrials.gov has a more complete list of current clinical trials for NF1 than the Children’s Tumor Foundation.OtherHormonal contraception was not found to stimulate the growth of neurofibromas in women with NF1 [Lammert et al 2006].

Molecular GeneticsInformation in the Molecular Genetics and OMIM tables may differ from that elsewhere in the GeneReview: tables may contain more recent information. —ED.Table A. Neurofibromatosis 1: Genes and DatabasesView in own windowGene SymbolChromosomal LocusProtein NameLocus SpecificHGMDNF117q11​.2NeurofibrominNF1 homepage - Mendelian genesNF1Data are compiled from the following standard references: gene symbol from HGNC; chromosomal locus, locus name, critical region, complementation group from OMIM; protein name from UniProt. For a description of databases (Locus Specific, HGMD) to which links are provided, click here.Table B. OMIM Entries for Neurofibromatosis 1 (View All in OMIM) View in own window 162200NEUROFIBROMATOSIS, TYPE I; NF1 613113NEUROFIBROMIN 1; NF1Normal allelic variants. NF1 was identified and the protein product characterized by Cawthon et al [1990] and Wallace et al [1990]; the entire cDNA sequence was described by Gutmann & Collins [1993] and Viskochil et al [1993]. The gene is large (~350 kilobases and 60 exons) and codes for at least three alternatively spliced transcripts [Viskochil 1999]. NF1 is unusual in that one of its introns contains coding sequences for at least three other genes. Pathologic allelic variants. More than 500 different mutations of NF1 have been identified. Most mutations are unique to a particular family. Many mutations have been observed repeatedly, but none has been found in more than a few percent of families studied [Ars et al 2003]. Many different kinds of mutations have been observed, including stop mutations, amino acid substitutions, deletions (which may involve only one or a few base pairs, multiple exons, or the entire gene), insertions, intronic changes affecting splicing, alterations of the 3' untranslated region of the gene, and gross chromosomal rearrangements. More than 80% of the germline mutations described in individuals with NF1 appear to cause severe truncation of the gene product, often by altering mRNA splicing [Ars et al 2000, Messiaen et al 2000, Ars et al 2003]. Table 2. NF1 Pathologic Allelic Variant Discussed in This GeneReviewView in own windowDNA Nucleotide Change Protein Amino Acid Change Reference Sequencesc.2970_2972 delAATp.Met992delNM_001042492​.1
NP_001035957​.1 See Quick Reference for an explanation of nomenclature. GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org).Normal gene product. The protein product, neurofibromin, has a calculated molecular mass of approximately 327 kd. The function of neurofibromin is not fully understood. It activates ras GTPase, thereby controlling cellular proliferation and acting as a tumor suppressor [Parrinello & Lloyd 2009, Gottfried et al 2010]. Neurofibromin probably has other functions as well, including regulation of adenylyl-cyclase activity and intracellular cyclic-AMP generation [Gottfried et al 2006, Ismat et al 2006, Trovó-Marqui & Tajara 2006, Yohay 2006, McClatchey 2007]. Abnormal gene product. NF1 is presumed to result from a loss-of-function mutation because most germline mutations cause truncation of the gene product [Messiaen et al 2000] and deletion of the entire gene causes typical, although often severe, NF1.