• We are sorry, but NCBI web applications do not support your browser and may not function properly. More information

NCBI Bookshelf. A service of the National Library of Medicine, National Institutes of Health.

Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2014.

Cover of GeneReviews®

GeneReviews® [Internet].

Show details

Neurofibromatosis 1

Synonyms: NF1, Von Recklinghausen Disease, Von Recklinghausen's Neurofibromatosis
, MD, PhD
Department of Medical Genetics
University of British Columbia
Vancouver, Canada

Initial Posting: ; Last Update: May 3, 2012.


Disease characteristics. Neurofibromatosis 1 (NF1) is characterized by multiple café au lait spots, axillary and inguinal freckling, multiple cutaneous neurofibromas, and iris Lisch nodules. Learning disabilities are present in at least 50% of individuals with NF1. Less common but potentially more serious manifestations include plexiform neurofibromas, optic nerve and other central nervous system gliomas, malignant peripheral nerve sheath tumors, scoliosis, tibial dysplasia, and vasculopathy.

Diagnosis/testing. The diagnosis of NF1 is usually based on clinical findings. Heterozygous mutations of NF1 are responsible for the vast majority of cases of neurofibromatosis. Molecular genetic testing of NF1 is rarely needed for diagnosis.

Management. Treatment of manifestations: Referral to specialists for treatment of complications involving the eye, central or peripheral nervous system, cardiovascular system, spine, or long bones; surgical removal of disfiguring or uncomfortable discrete cutaneous or subcutaneous neurofibromas. Surgical treatment of plexiform neurofibromas is often unsatisfactory; complete surgical excision, when possible, of malignant peripheral nerve sheath tumors. Treatment of optic gliomas is generally unnecessary as they are usually asymptomatic and clinically stable. Dystrophic scoliosis often requires surgical management, whereas non-dystrophic scoliosis can usually be treated conservatively.

Surveillance: Annual physical examination by a physician familiar with the disorder; annual ophthalmologic examination in children, less frequently in adults; regular developmental assessment of children; regular blood pressure monitoring; MRI for follow-up of clinically suspected intracranial tumors and other internal tumors.

Genetic counseling. NF1 is inherited in an autosomal dominant manner. Half of affected individuals have NF1 as the result of a de novo NF1 mutation. The offspring of an affected individual are at a 50% risk of inheriting the altered NF1 gene, but the disease manifestations are extremely variable, even within a family. Prenatal testing for pregnancies at increased risk is possible if the disease-causing mutation in a family is known.


Clinical Diagnosis

The 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
Figure 1


Figure 1. Café au lait macules

Figure 2


Figure 2. Neurofibromas

Figure 3


Figure 3. Plexiform neurofibroma

Adults. The NIH diagnostic criteria are both highly specific and highly sensitive in adults with NF1 [Ferner et al 2007].


  • 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 Testing

Gene. 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 1

Gene Symbol Test MethodNF1 Mutations DetectedMutation Detection Frequency by Test Method 1
NF1Sequence analysis Sequence variants 2~90%
Deletion / duplication anaysis 3Exonic, multiexonic and whole-gene deletions~5%
Cytogenetic analysisLarge-scale rearrangements<1%
Linkage analysisNot applicableNot applicable

1. The ability of the test method used to detect a mutation that is present in the indicated gene

2. 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 proband

  • Confirmatory 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.

Clinical Description

Natural History

The 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 Correlations

NF1 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:

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:

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.


Penetrance is virtually complete after childhood.


There is no evidence of anticipation in NF1 except in rare instances in which a child inherits the disease from a parent with mosaicism [Lázaro et al 1995, Consoli et al 2005].


NF1 has been referred to as "peripheral neurofibromatosis" to distinguish it from NF2 ("central neurofibromatosis"), although central nervous system involvement may also occur in NF1.

"Neurofibromatosis" without further specification is sometimes used in the literature to refer to NF1, but this usage is confusing because other authors employ the term "neurofibromatosis" to designate a group of conditions that includes NF2 and other rare variant forms as well as NF1.


NF1 is one of the most common dominantly inherited genetic disorders, occurring with an incidence at birth of approximately one in 3000 individuals [Friedman 1999, Rasmussen & Friedman 2000, Lammert et al 2005a, Evans et al 2010].

Almost half of all affected individuals have a de novo mutation. The mutation rate for NF1 (~1:10,000) is among the highest known for any gene in humans. The cause of the unusually high mutation rate is unknown.

Differential Diagnosis

More 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 NF1

  • Legius 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 Image SimulConsult.jpg, an interactive diagnostic decision support software tool that provides differential diagnoses based on patient findings (registration or institutional access required).


Evaluations Following Initial Diagnosis

To 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 consultation

The 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 Manifestations

Individuals 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.


The 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 symptoms
  • Monitoring 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 Avoid

No 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 Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Pregnancy Management

Although 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 Investigation

Various 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.


Hormonal contraception was not found to stimulate the growth of neurofibromas in women with NF1 [Lammert et al 2006].

Genetic Counseling

Genetic counseling is the process of providing individuals and families with information on the nature, inheritance, and implications of genetic disorders to help them make informed medical and personal decisions. The following section deals with genetic risk assessment and the use of family history and genetic testing to clarify genetic status for family members. This section is not meant to address all personal, cultural, or ethical issues that individuals may face or to substitute for consultation with a genetics professional. —ED.

Mode of Inheritance

Neurofibromatosis 1 (NF1) is inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

  • Approximately 50% of individuals with NF1 have an affected parent and 50% have the altered gene as the result of a de novo gene mutation.
  • Recommendations for the evaluation of parents of a proband with an apparent de novo mutation include medical history and physical examination with particular attention to dermal and other features of NF1. In addition, an ophthalmologic examination (including slit lamp examination) should be performed on both parents to look for Lisch nodules or other ophthalmologic signs of NF1.

Note: The family history may appear to be negative because of failure to recognize NF1 in family members or early death of a parent before the recognition of signs or symptoms.

Sibs of a proband

  • The risk to the sibs of the proband depends on whether one of the proband's parents has NF1.
  • If a parent is affected, the risk to the sibs is 50%.
  • If neither parent of an individual with NF1 meets the clinical diagnostic criteria for NF1 after careful medical history, physical examination, and ophthalmologic examination, the risk to the sibs of the affected individual of having NF1 is low but greater than that of the general population because of the possibility of germline mosaicism. Note: Germline mosaicism for an NF1 mutation has been demonstrated in an apparently unaffected man who had two children with typical NF1 [Lázaro et al 1995] and in a woman with segmental NF who had a child with typical manifestations of NF1 [Consoli et al 2005].

Offspring of a proband

  • Each child of an individual with NF1 has a 50% chance of inheriting the disease-causing mutation.
  • Penetrance is 100%; thus, a child who inherits an NF1 mutation will develop features of NF1, but the disease may be considerably more (or less) severe in an affected child than in his or her affected parent.

Other family members of a proband

  • The risk to other family members depends on the status of the proband's parents.
  • If a parent is affected, his or her own parents and other children are at risk.

Related Genetic Counseling Issues

Possibility of multiple de novo mutations in a single family. Upadhyaya et al [2003] reported the occurrence of three different disease-causing NF1 mutations in one family and advised caution in assuming that the same mutation is present in all members of an affected family. Two independent NF1 mutations have been reported in another family [Klose et al 1999].

Considerations in families with an apparent de novo mutation. When neither parent of a proband with an autosomal dominant condition has clinical evidence of the disorder, it is likely that the proband has a de novo mutation. However, possible non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) or undisclosed adoption could also be explored.

Family planning

  • The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.
  • It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

Molecular genetic testing. Prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis (usually performed at ~15-18 weeks' gestation) or chorionic villus sampling (usually performed at ~10-12 weeks' gestation). The disease-causing allele of an affected family member must be identified [Ars et al 1999, Origone et al 2000] or linkage established in the family [Origone et al 2000] before prenatal testing can be performed.

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Ultrasound examination. Prenatal diagnosis of exceptionally severe NF1 by prenatal ultrasound examination has been reported [McEwing et al 2006], but ultrasound examination is unlikely to be informative in most cases.

Requests for prenatal testing for conditions which (like NF1) can have a wide range of severity and age of onset are not common. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. Although most centers would consider decisions regarding prenatal testing to be the choice of the parents, discussion of these issues is appropriate.

Preimplantation genetic diagnosis (PGD) of NF1 has been reported [Spits et al 2005, Altarescu et al 2006, Vanneste et al 2009, Chen et al 2011] and may be an option for some families in which the disease-causing mutation has been identified.


GeneReviews staff has selected the following disease-specific and/or umbrella support organizations and/or registries for the benefit of individuals with this disorder and their families. GeneReviews is not responsible for the information provided by other organizations. For information on selection criteria, click here.

  • Children's Tumor Foundation: Ending Neurofibromatosis Through Research
    95 Pine Street
    16th Floor
    New York NY 10005
    Phone: 800-323-7938 (toll-free); 212-344-6633
    Fax: 212-747-0004
    Email: info@ctf.org
  • National Library of Medicine Genetics Home Reference
  • Neurofibromatosis, Inc.
    PO Box 66884
    Chicago IL 60666
    Phone: 800-942-6825 (toll-free); 630-627-1115
    Fax: 630-627-1117
    Email: nfinfo@nfinc.org
  • Medline Plus
  • RASopathiesNet
    244 Taos Road
    Atlandena CA 91001
    Phone: 626-676-7694
    Email: lisa@rasopathies.org

Molecular Genetics

Information 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 Databases

Gene SymbolChromosomal LocusProtein NameLocus SpecificHGMD
NF117q11​.2NeurofibrominNF1 homepage - Mendelian genesNF1

Data 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)


Normal 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 GeneReview

DNA Nucleotide Change Protein Amino Acid Change Reference Sequences
c.2970_2972 delAATp.Met992delNM_001042492​.1

Note on variant classification: Variants listed in the table have been provided by the author(s). GeneReviews staff have not independently verified the classification of variants.

Note on nomenclature: GeneReviews follows the standard naming conventions of the Human Genome Variation Society (www​.hgvs.org). See Quick Reference for an explanation of nomenclature.

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.


Medical Genetic Searches: A specialized PubMed search designed for clinicians that is located on the PubMed Clinical Queries page Image PubMed.jpg

Literature Cited

  1. Alkan A, Sigirci A, Kutlu R, Ozcan H, Erdem G, Aslan M, Ates O, Yakinci C, Egri M. Neurofibromatosis type 1: diffusion weighted imaging findings of brain. Eur J Radiol. 2005;56:229–34. [PubMed: 15963674]
  2. Allanson JE, Upadhyaya M, Watson GH, Partington M, MacKenzie A, Lahey D, MacLeod H, Sarfarazi M, Broadhead W, Harper PS, Huson SM. Watson syndrome: is it a subtype of type 1 neurofibromatosis? J Med Genet. 1991;28:752–6. [PMC free article: PMC1017110] [PubMed: 1770531]
  3. Alotaibi H, Ricciardone MD, Ozturk M. Homozygosity at variant MLH1 can lead to secondary mutation in NF1, neurofibromatosis type I and early onset leukemia. Mutat Res. 2008;637:209–14. [PubMed: 17889038]
  4. Altarescu G, Brooks B, Kaplan Y, Eldar-Geva T, Margalioth EJ, Levy-Lahad E, Renbaum P. Single-sperm analysis for haplotype construction of de-novo paternal mutations: application to PGD for neurofibromatosis type 1. Hum Reprod. 2006;21:2047–51. [PubMed: 16740526]
  5. Andersson J, Sihto H, Meis-Kindblom JM, Joensuu H, Nupponen N, Kindblom LG. NF1-associated gastrointestinal stromal tumors have unique clinical, phenotypic, and genotypic characteristics. Am J Surg Pathol. 2005;29:1170–6. [PubMed: 16096406]
  6. Ardern-Holmes SL, North KN. Therapeutics for childhood neurofibromatosis type 1 and type 2. Curr Treat Options Neurol. 2011;13:529–43. [PubMed: 21850405]
  7. Ars E, Kruyer H, Gaona A, Serra E, Lázaro C, Estivill X. Prenatal diagnosis of sporadic neurofibromatosis type 1 (NF1) by RNA and DNA analysis of a splicing mutation. Prenat Diagn. 1999;19:739–42. [PubMed: 10451518]
  8. Ars E, Kruyer H, Morell M, Pros E, Serra E, Ravella A, Estivill X, Lázaro C. Recurrent mutations in the NF1 gene are common among neurofibromatosis type 1 patients. J Med Genet. 2003;40:e82. [PMC free article: PMC1735494] [PubMed: 12807981]
  9. Ars E, Serra E, García J, Kruyer H, Gaona A, Lázaro C, Estivill X. Mutations affecting mRNA splicing are the most common molecular defects in patients with neurofibromatosis type 1. Hum Mol Genet. 2000;9:237–47. [PubMed: 10607834]
  10. Babovic-Vuksanovic D, Ballman K, Michels V, McGrann P, Lindor N, King B, Camp J, Micic V, Babovic N, Carrero X, Spinner R, O'Neill B. Phase II trial of pirfenidone in adults with neurofibromatosis type 1. Neurology. 2006;67:1860–2. [PubMed: 17035676]
  11. Babovic-Vuksanovic D, Messiaen L, Nagel C, Brems H, Scheithauer B, Denayer E, Mao R, Sciot R, Janowski KM, Schuhmann MU, Claes K, Beert E, Garrity JA, Spinner RJ, Stemmer-Rachamimov A, Gavrilova R, Van Calenbergh F, Mautner V, Legius E. Multiple orbital neurofibromas, painful peripheral nerve tumors, distinctive face and marfanoid habitus: a new syndrome. Eur J Hum Genet. 2012;20:618–25. [PMC free article: PMC3355267] [PubMed: 22258529]
  12. Bacci C, Sestini R, Ammannati F, Bianchini E, Palladino T, Carella M, Melchionda S, Zelante L, Papi L. Multiple spinal ganglioneuromas in a patient harboring a pathogenic NF1 mutation. Clin Genet. 2010;77:293–7. [PubMed: 19863548]
  13. Bandipalliam P. Syndrome of early onset colon cancers, hematologic malignancies & features of neurofibromatosis in HNPCC families with homozygous mismatch repair gene mutations. Fam Cancer. 2005;4:323–33. [PubMed: 16341812]
  14. Barton B, North K. Social skills of children with neurofibromatosis type 1. Dev Med Child Neurol. 2004;46:553–63. [PubMed: 15287247]
  15. Barton B, North K. The self-concept of children and adolescents with neurofibromatosis type 1. Child Care Health Dev. 2007;33:401–8. [PubMed: 17584395]
  16. Baujat B, Krastinova-Lolov D, Blumen M, Baglin AC, Coquille F, Chabolle F. Radiofrequency in the treatment of craniofacial plexiform neurofibromatosis: a pilot study. Plast Reconstr Surg. 2006;117:1261–8. [PubMed: 16582798]
  17. Bausch B, Borozdin W, Mautner VF, Hoffmann MM, Boehm D, Robledo M, Cascon A, Harenberg T, Schiavi F, Pawlu C, Peczkowska M, Letizia C, Calvieri S, Arnaldi G, Klingenberg-Noftz RD, Reisch N, Fassina A, Brunaud L, Walter MA, Mannelli M, MacGregor G, Palazzo FF, Barontini M, Walz MK, Kremens B, Brabant G, Pfäffle R, Koschker AC, Lohoefner F, Mohaupt M, Gimm O, Jarzab B, McWhinney SR, Opocher G, Januszewicz A, Kohlhase J, Eng C, Neumann HP. European-American Phaeochromocytoma Registry Study Group; Germline NF1 mutational spectra and loss-of-heterozygosity analyses in patients with pheochromocytoma and neurofibromatosis type 1. J Clin Endocrinol Metab. 2007;92:2784–92. [PubMed: 17426081]
  18. Bensaid B, Giammarile F, Mognetti T, Galoisy-Guibal L, Pinson S, Drouet A, Combemale P. Ann Dermatol Venereol. 2007;134:735–41. [PubMed: 17978710]
  19. Bertola DR, Pereira AC, Passetti F, de Oliveira PS, Messiaen L, Gelb BD, Kim CA, Krieger JE. Neurofibromatosis-Noonan syndrome: molecular evidence of the concurrence of both disorders in a patient. Am J Med Genet A. 2005;136:242–5. [PubMed: 15948193]
  20. Blazo MA, Lewis RA, Chintagumpala MM, Frazier M, McCluggage C, Plon SE. Outcomes of systematic screening for optic pathway tumors in children with Neurofibromatosis Type 1. Am J Med Genet A. 2004;127A:224–9. [PubMed: 15150770]
  21. Bottillo I, Ahlquist T, Brekke H, Danielsen SA, van den Berg E, Mertens F, Lothe RA, Dallapiccola B. Germline and somatic NF1 mutations in sporadic and NF1-associated malignant peripheral nerve sheath tumours. J Pathol. 2009;217:693–701. [PubMed: 19142971]
  22. Boulanger JM, Larbrisseau A. Neurofibromatosis type 1 in a pediatric population: Ste-Justine's experience. Can J Neurol Sci. 2005;32:225–31. [PubMed: 16018159]
  23. Bredella MA, Torriani M, Hornicek F, Ouellette HA, Plamer WE, Williams Z, Fischman AJ, Plotkin SR. Value of PET in the assessment of patients with neurofibromatosis type 1. AJR Am J Roentgenol. 2007;189:928–35. [PubMed: 17885067]
  24. Brems H, Chmara M, Sahbatou M, Denayer E, Taniguchi K, Kato R, Somers R, Messiaen L, De Schepper S, Fryns JP, Cools J, Marynen P, Thomas G, Yoshimura A, Legius E. Germline loss-of-function mutations in SPRED1 cause a neurofibromatosis 1-like phenotype. Nat Genet. 2007;39:1120–6. [PubMed: 17704776]
  25. Brunetti-Pierri N, Doty SB, Hicks J, Phan K, Mendoza-Londono R, Blazo M, Tran A, Carter S, Lewis RA, Plon SE, Phillips WA, O'Brian Smith E, Ellis KJ, Lee B. Generalized metabolic bone disease in Neurofibromatosis type I. Mol Genet Metab. 2008;94:105–11. [PMC free article: PMC2430595] [PubMed: 18289904]
  26. Buske A, Gewies A, Lehmann R, Rüther K, Algermissen B, Nürnberg P, Tinschert S. Recurrent NF1 gene mutation in a patient with oligosymptomatic neurofibromatosis type 1 (NF1). Am J Med Genet. 1999;86:328–30. [PubMed: 10494088]
  27. Cai W, Kassarjian A, Bredella MA, Harris GJ, Yoshida H, Mautner VF, Wenzel R, Plotkin SR. Tumor burden in patients with neurofibromatosis types 1 and 2 and schwannomatosis: determination on whole-body MR images. Radiology. 2009;250:665–73. [PubMed: 19244040]
  28. Cairns AG, North KN. Cerebrovascular dysplasia in neurofibromatosis type 1. J Neurol Neurosurg Psychiatry. 2008;79:1165–70. [PubMed: 18469031]
  29. Carcavilla A, Pinto I, Muñoz-Pacheco R, Barrio R, Martin-Frías M, Ezquieta B. LEOPARD syndrome (PTPN11, T468M) in three boys fulfilling neurofibromatosis type 1 clinical criteria. Eur J Pediatr. 2011;170(8):1069–74. [PubMed: 21365175]
  30. Carey JC. Neurofibromatosis-Noonan syndrome. Am J Med Genet. 1998;75:263–4. [PubMed: 9475594]
  31. Cawthon RM, Weiss R, Xu GF, Viskochil D, Culver M, Stevens J, Robertson M, Dunn D, Gesteland R, O'Connell P, White R. A major segment of the neurofibromatosis type 1 gene: cDNA sequence, genomic structure, and point mutations. Cell. 1990;62:193–201. [PubMed: 2114220]
  32. Chabernaud C, Sirinelli D, Barbier C, Cottier JP, Sembely C, Giraudeau B, Deseille-Turlotte G, Lorette G, Barthez MA, Castelnau P. Thalamo-striatal T2-weighted hyperintensities (unidentified bright objects) correlate with cognitive impairments in neurofibromatosis type 1 during childhood. Dev Neuropsychol. 2009;34:736–48. [PubMed: 20183730]
  33. Chen YL, Hung CC, Lin SY, Fang MY, Tsai YY, Chang LJ, Lee CN, Su YN, Chen SU, Yang YS. Successful application of the strategy of blastocyst biopsy, vitrification, whole genome amplification, and thawed embryo transfer for preimplantation genetic diagnosis of neurofibromatosis type 1. Taiwan J Obstet Gynecol. 2011;50(1):74–8. [PubMed: 21482379]
  34. Chetty SP, Shaffer BL, Norton ME. Management of pregnancy in women with genetic disorders: Part 2: Inborn errors of metabolism, cystic fibrosis, neurofibromatosis type 1, and turner syndrome in pregnancy. Obstet Gynecol Surv. 2011;66:765–76. [PubMed: 22192461]
  35. Clementi M, Milani S, Mammi I, Boni S, Monciotti C, Tenconi R. Neurofibromatosis type 1 growth charts. Am J Med Genet. 1999;87:317–23. [PubMed: 10588837]
  36. Colley A, Donnai D, Evans DG. Neurofibromatosis/Noonan phenotype: a variable feature of type 1 neurofibromatosis. Clin Genet. 1996;49:59–64. [PubMed: 8740913]
  37. Consoli C, Moss C, Green S, Balderson D, Cooper DN, Upadhyaya M. Gonosomal mosaicism for a nonsense mutation (R1947X) in the NF1 gene in segmental neurofibromatosis type 1. J Invest Dermatol. 2005;125:463–6. [PubMed: 16117786]
  38. Coudé FX, Mignot C, Lyonnet S, Munnich A. Academic impairment is the most frequent complication of neurofibromatosis type-1 (NF1) in children. Behav Genet. 2006;36:660–4. [PubMed: 16474913]
  39. Curless RG. Use of "unidentified bright objects" on MRI for diagnosis of neurofibromatosis 1 in children. Neurology. 2000;55:1067–8. [PubMed: 11061281]
  40. De Luca A, Bottillo I, Sarkozy A, Carta C, Neri C, Bellacchio E, Schirinzi A, Conti E, Zampino G, Battaglia A, Majore S, Rinaldi MM, Carella M, Marino B, Pizzuti A, Digilio MC, Tartaglia M, Dallapiccola B. NF1 gene mutations represent the major molecular event underlying neurofibromatosis-Noonan syndrome. Am J Hum Genet. 2005;77:1092–101. [PMC free article: PMC1285166] [PubMed: 16380919]
  41. De Schepper S, Maertens O, Callens T, Naeyaert JM, Lambert J, Messiaen L. Somatic mutation analysis in NF1 café au lait spots reveals two NF1 hits in the melanocytes. J Invest Dermatol. 2008;128:1050–3. [PubMed: 17914445]
  42. DeBella K, Poskitt K, Szudek J, Friedman JM. Use of "unidentified bright objects" on MRI for diagnosis of neurofibromatosis 1 in children. Neurology. 2000a;54:1646–51. [PubMed: 10762507]
  43. DeBella K, Szudek J, Friedman JM. Use of the national institutes of health criteria for diagnosis of neurofibromatosis 1 in children. Pediatrics. 2000b;105:608–14. [PubMed: 10699117]
  44. Dilworth JT, Kraniak JM, Wojtkowiak JW, Gibbs RA, Borch RF, Tainsky MA, Reiners JJ, Mattingly RR. Molecular targets for emerging anti-tumor therapies for neurofibromatosis type 1. Biochem Pharmacol. 2006;72:1485–92. [PubMed: 16797490]
  45. DiPaolo DP, Zimmerman RA, Rorke LB, Zackai EH, Bilaniuk LT, Yachnis AT. Neurofibromatosis type 1: pathologic substrate of high-signal-intensity foci in the brain. Radiology. 1995;195:721–4. [PubMed: 7754001]
  46. Dombi E, Solomon J, Gillespie AJ, Fox E, Balis FM, Patronas N, Korf BR, Babovic-Vuksanovic D, Packer RJ, Belasco J, Goldman S, Jakacki R, Kieran M, Steinberg SM, Widemann BC. NF1 plexiform neurofibroma growth rate by volumetric MRI: relationship to age and body weight. Neurology. 2007;68:643–7. [PubMed: 17215493]
  47. Drouet A, Wolkenstein P, Lefaucheur JP, Pinson S, Combemale P, Gherardi RK, Brugières P, Salama J, Ehre P, Decq P, Créange A. Neurofibromatosis 1-associated neuropathies: a reappraisal. Brain. 2004;127:1993–2009. [PubMed: 15289270]
  48. Dugoff L, Sujansky E. Neurofibromatosis type 1 and pregnancy. Am J Med Genet. 1996;66:7–10. [PubMed: 8957502]
  49. Dulai S, Briody J, Schindeler A, North KN, Cowell CT, Little DG. Decreased bone mineral density in neurofibromatosis type 1: results from a pediatric cohort. J Pediatr Orthop. 2007;27:472–5. [PubMed: 17513973]
  50. Duman O, Ozdem S, Turkkahraman D, Olgac ND, Gungor F, Haspolat S. Bone metabolism markers and bone mineral density in children with neurofibromatosis type-1. Brain Dev. 2008;30:584–8. [PubMed: 18362054]
  51. Easton DF, Ponder MA, Huson SM, Ponder BA. An analysis of variation in expression of neurofibromatosis (NF) type 1 (NF1): evidence for modifying genes. Am J Hum Genet. 1993;53:305–13. [PMC free article: PMC1682337] [PubMed: 8328449]
  52. Evans DG, Baser ME, McGaughran J, Sharif S, Howard E, Moran A. Malignant peripheral nerve sheath tumours in neurofibromatosis 1. J Med Genet. 2002;39:311–4. [PMC free article: PMC1735122] [PubMed: 12011145]
  53. Evans DG, Howard E, Giblin C, Clancy T, Spencer H, Huson SM, Lalloo F. Birth incidence and prevalence of tumor-prone syndromes: estimates from a UK family genetic register service. Am J Med Genet A. 2010;152A:327–32. [PubMed: 20082463]
  54. Evans DG, O'Hara C, Wilding A, Ingham SL, Howard E, Dawson J, Moran A, Scott-Kitching V, Holt F, Huson SM. Mortality in neurofibromatosis 1: in North West England: an assessment of actuarial survival in a region of the UK since 1989. Eur J Hum Genet. 2011;19:1187–91. [PMC free article: PMC3198144] [PubMed: 21694737]
  55. Fadda MT, Giustini SS, Verdino GG, Bartoli DD, Mustazza MC, Iannetti GG, Calvieri SS. Role of maxillofacial surgery in patients with neurofibromatosis type I. J Craniofac Surg. 2007;18:489–96. [PubMed: 17538307]
  56. Fauth C, Kehrer-Sawatzki H, Zatkova A, Machherndl-Spandl S, Messiaen L, Amann G, Hainfellner JA, Wimmer K. Two sporadic spinal neurofibromatosis patients with malignant peripheral nerve sheath tumour. Eur J Med Genet. 2009;52:409–14. [PubMed: 19665063]
  57. Feldmann R, Denecke J, Grenzebach M, Schuierer G, Weglage J. Neurofibromatosis type 1: motor and cognitive function and T2-weighted MRI hyperintensities. Neurology. 2003;61:1725–8. [PubMed: 14694037]
  58. Feldmann R, Schuierer G, Wessel A, Neveling N, Weglage J. Development of MRI T2 hyperintensities and cognitive functioning in patients with neurofibromatosis type 1. Acta Paediatr. 2010;99:1657–60. [PubMed: 21039823]
  59. Ferner RE. Neurofibromatosis 1. Eur J Hum Genet. 2007a;15:131–8. [PubMed: 16957683]
  60. Ferner RE. Neurofibromatosis 1 and neurofibromatosis 2: a twenty first century perspective. Lancet Neurol. 2007b;6:340–51. [PubMed: 17362838]
  61. Ferner RE, Golding JF, Smith M, Calonje E, Jan W, Sanjayanathan V, O'Doherty M. [18F]2-fluoro-2-deoxy-D-glucose positron emission tomography (FDG PET) as a diagnostic tool for neurofibromatosis 1 (NF1) associated malignant peripheral nerve sheath tumours (MPNSTs): a long-term clinical study. Ann Oncol. 2008;19:390–4. [PubMed: 17932395]
  62. Ferner RE, Hughes RA, Hall SM, Upadhyaya M, Johnson MR. Neurofibromatous neuropathy in neurofibromatosis 1 (NF1). J Med Genet. 2004;41:837–41. [PMC free article: PMC1735623] [PubMed: 15520408]
  63. Ferner RE, Huson SM, Thomas N, Moss C, Willshaw H, Evans DG, Upadhyaya M, Towers R, Gleeson M, Steiger C, Kirby A. Guidelines for the diagnosis and management of individuals with Neurofibromatosis 1 (NF1). J Med Genet. 2007;44:81–8. [PMC free article: PMC2598063] [PubMed: 17105749]
  64. Ferner RE, Lucas JD, O'Doherty MJ, Hughes RA, Smith MA, Cronin BF, Bingham J. Evaluation of (18)fluorodeoxyglucose positron emission tomography ((18)FDG PET) in the detection of malignant peripheral nerve sheath tumours arising from within plexiform neurofibromas in neurofibromatosis 1. J Neurol Neurosurg Psychiatry. 2000;68:353–7. [PMC free article: PMC1736834] [PubMed: 10675220]
  65. Ferraz-Filho JR, da Rocha AJ, Muniz MP, Souza AS, Goloni-Bertollo EM, Pavarino-Bertelli EC. Unidentified bright objects in neurofibromatosis type 1: conventional MRI in the follow-up and correlation of microstructural lesions on diffusion tensor images. Eur J Paediatr Neurol. 2012a;16:42–7. [PubMed: 22088602]
  66. Ferraz-Filho JR, da Rocha AJ, Muniz MP, Souza AS, Goloni-Bertollo EM, Pavarino-Bertelli EC. Diffusion tensor MR imaging in neurofibromatosis type 1: expanding the knowledge of microstructural brain abnormalities. Pediatr Radiol. 2012b;42:449–54. [PubMed: 22033857]
  67. Fossali E, Signorini E, Intermite RC, Casalini E, Lovaria A, Maninetti MM, Rossi LN. Renovascular disease and hypertension in children with neurofibromatosis. Pediatr Nephrol. 2000;14:806–10. [PubMed: 10955932]
  68. Frahm S, Mautner VF, Brems H, Legius E, Debiec-Rychter M, Friedrich RE, Knöfel WT, Peiper M, Kluwe L. Genetic and phenotypic characterization of tumor cells derived from malignant peripheral nerve sheath tumors of neurofibromatosis type 1 patients. Neurobiol Dis. 2004;16:85–91. [PubMed: 15207265]
  69. Friedman JM. Vascular and endocrine abnormalities. In: Friedman JM, Gutmann DH, MacCollin M, Riccardi VM, eds. Neurofibromatosis. Phenotype, Natural History, and Pathogenesis. Baltimore, MD: Johns Hopkins University Press; 1999:274-96.
  70. Friedman JM, Arbiser J, Epstein JA, Gutmann DH, Huot SJ, Lin AE, McManus B, Korf BR. Cardiovascular disease in neurofibromatosis 1: report of the NF1 Cardiovascular Task Force. Genet Med. 2002;4:105–11. [PubMed: 12180143]
  71. Friedman JM, Birch PH. Type 1 neurofibromatosis: a descriptive analysis of the disorder in 1,728 patients. Am J Med Genet. 1997;70:138–43. [PubMed: 9128932]
  72. Friedman JM, Riccardi VM. Clinical epidemiological features. In: Friedman JM, Gutmann DH, MacCollin M, Riccardi VM, eds. Neurofibromatosis: Phenotype, Natural History, and Pathogenesis. Baltimore, MD: Johns Hopkins University Press; 1999:29-86.
  73. Friedrich RE, Hartmann M, Mautner VF. Malignant peripheral nerve sheath tumors (MPNST) in NF1-affected children. Anticancer Res. 2007a;27:1957–60. [PubMed: 17649804]
  74. Friedrich RE, Kluwe L, Funsterer C, Mautner VF. Malignant peripheral nerve sheath tumors (MPNST) in neurofibromatosis type 1 (NF1): diagnostic findings on magnetic resonance images and mutation analysis of the NF1 gene. Anticancer Res. 2005a;25:1699–702. [PubMed: 16033085]
  75. Friedrich RE, Mautner VF, Scheuer HA. Loss of heterozygosity in tumor cells of a recurrent mandibular giant cell granuloma in neurofibromatosis type 1. Anticancer Res. 2007b;27:2079–83. [PubMed: 17649825]
  76. Friedrich RE, Schmelzle R, Hartmann M, Fünsterer C, Mautner VF. Resection of small plexiform neurofibromas in neurofibromatosis type 1 children. World J Surg Oncol. 2005b;3:6. [PMC free article: PMC549083] [PubMed: 15683544]
  77. Gallinger S, Aronson M, Shayan K, Ratcliffe EM, Gerstle JT, Parkin PC, Rothenmund H, Croitoru M, Baumann E, Durie PR, Weksberg R, Pollett A, Riddell RH, Ngan BY, Cutz E, Lagarde AE, Chan HS. Gastrointestinal cancers and neurofibromatosis type 1 features in children with a germline homozygous MLH1 mutation. Gastroenterology. 2004;126:576–85. [PubMed: 14762794]
  78. Garcia-Linares C, Fernández-Rodríguez J, Terribas E, Mercadé J, Pros E, Benito L, Benavente Y, Capellà G, Ravella A, Blanco I, Kehrer-Sawatzki H, Lázaro C, Serra E. Dissecting loss of heterozygosity (LOH) in neurofibromatosis type 1-associated neurofibromas: Importance of copy neutral LOH. Hum Mutat. 2011;32:78–90. [PMC free article: PMC3151547] [PubMed: 21031597]
  79. Gilboa Y, Rosenblum S, Fattal-Valevski A, Toledano-Alhadef H, Rizzo AS, Josman N. Using a Virtual Classroom environment to describe the attention deficits profile of children with Neurofibromatosis type 1. Res Dev Disabil. 2011;32:2608–13. [PubMed: 21757320]
  80. Gill DS, Hyman SL, Steinberg A, North KN. Age-related findings on MRI in neurofibromatosis type 1. Pediatr Radiol. 2006;36:1048–56. [PubMed: 16912896]
  81. Goh WH, Khong PL, Leung CS, Wong VC. T2-weighted hyperintensities (unidentified bright objects) in children with neurofibromatosis 1: their impact on cognitive function. J Child Neurol. 2004;19:853–8. [PubMed: 15658789]
  82. Gottfried ON, Viskochil DH, Couldwell WT. Neurofibromatosis Type 1 and tumorigenesis: molecular mechanisms and therapeutic implications. Neurosurg Focus. 2010;28:E8. [PubMed: 20043723]
  83. Gottfried ON, Viskochil DH, Fults DW, Couldwell WT. Molecular, genetic, and cellular pathogenesis of neurofibromas and surgical implications. Neurosurgery. 2006;58:1–16. [PubMed: 16385324]
  84. Graf A, Landolt MA, Mori AC, Boltshauser E. Quality of life and psychological adjustment in children and adolescents with neurofibromatosis type 1. J Pediatr. 2006;149:348–53. [PubMed: 16939745]
  85. Greenwood RS, Tupler LA, Whitt JK, Buu A, Dombeck CB, Harp AG, Payne ME, Eastwood JD, Krishnan KR, MacFall JR. Brain morphometry, T2-weighted hyperintensities, and IQ in children with neurofibromatosis type 1. Arch Neurol. 2005;62:1904–8. [PubMed: 16344348]
  86. Grisart B, Rack K, Vidrequin S, Hilbert P, Deltenre P, Verellen-Dumoulin C, Destrée A. NF1 microduplication first clinical report: association with mild mental retardation, early onset of baldness and dental enamel hypoplasia? Eur J Hum Genet. 2008;16:305–11. [PubMed: 18183042]
  87. Guillaud O, Dumortier J, Bringuier PP, Saurin JC, Poncet G, Boulez J, Henry L, Chayvialle JA, Scoazec JY. Gastroenterol Clin Biol. 2006;30:320–4. [PubMed: 16565672]
  88. Gutmann DH, Collins FS. The neurofibromatosis type 1 gene and its protein product, neurofibromin. Neuron. 1993;10:335–43. [PubMed: 8461130]
  89. Gutmann DH, Donahoe J, Brown T, James CD, Perry A. Loss of neurofibromatosis 1 (NF1) gene expression in NF1-associated pilocytic astrocytomas. Neuropathol Appl Neurobiol. 2000;26:361–7. [PubMed: 10931370]
  90. Gutmann DH, Gurney JG. Other malignancies. In: Friedman JM, Gutmann DH, MacCollin M, Riccardi VM, eds. Neurofibromatosis: Phenotype, Natural History, and Pathogenesis. Baltimore, MD: Johns Hopkins University Press; 1999:231-49.
  91. Gutmann DH, James CD, Poyhonen M, Louis DN, Ferner R, Guha A, Hariharan S, Viskochil D, Perry A. Molecular analysis of astrocytomas presenting after age 10 in individuals with NF1. Neurology. 2003;61:1397–400. [PubMed: 14638962]
  92. Hagel C, Zils U, Peiper M, Kluwe L, Gotthard S, Friedrich RE, Zurakowski D, von Deimling A, Mautner VF. Histopathology and clinical outcome of NF1-associated vs. sporadic malignant peripheral nerve sheath tumors. J Neurooncol. 2007;82:187–92. [PubMed: 17111191]
  93. Han M, Criado E. Renal artery stenosis and aneurysms associated with neurofibromatosis. J Vasc Surg. 2005;41:539–43. [PubMed: 15838492]
  94. Hsieh HY, Fung HC, Wang CJ, Chin SC, Wu T. Epileptic seizures in neurofibromatosis type 1 are related to intracranial tumors but not to neurofibromatosis bright objects. Seizure. 2011;20:606–11. [PubMed: 21621428]
  95. Hüffmeier U, Zenker M, Hoyer J, Fahsold R, Rauch A. A variable combination of features of Noonan syndrome and neurofibromatosis type I are caused by mutations in the NF1 gene. Am J Med Genet A. 2006;140:2749–56. [PubMed: 17103458]
  96. Hummel T, Anyane-Yeboa A, Mo J, Towbin A, Weiss B. Response of NF1-related plexiform neurofibroma to high-dose carboplatin. Pediatr Blood Cancer. 2011;56:488–90. [PubMed: 21225936]
  97. Hyman SL, Arthur Shores E, North KN. Learning disabilities in children with neurofibromatosis type 1: subtypes, cognitive profile, and attention-deficit-hyperactivity disorder. Dev Med Child Neurol. 2006;48:973–7. [PubMed: 17109785]
  98. Hyman SL, Gill DS, Shores EA, Steinberg A, Joy P, Gibikote SV, North KN. Natural history of cognitive deficits and their relationship to MRI T2-hyperintensities in NF1. Neurology. 2003;60:1139–45. [PubMed: 12682321]
  99. Hyman SL, Gill DS, Shores EA, Steinberg A, North KN. T2 hyperintensities in children with neurofibromatosis type 1 and their relationship to cognitive functioning. J Neurol Neurosurg Psychiatry. 2007;78:1088–91. [PMC free article: PMC2117545] [PubMed: 17299016]
  100. Hyman SL, Shores A, North KN. The nature and frequency of cognitive deficits in children with neurofibromatosis type 1. Neurology. 2005;65:1037–44. [PubMed: 16217056]
  101. Ismat FA, Xu J, Lu MM, Epstein JA. The neurofibromin GAP-related domain rescues endothelial but not neural crest development in Nf1 mice. J Clin Invest. 2006;116:2378–84. [PMC free article: PMC1533876] [PubMed: 16906226]
  102. Jentarra GM, Rice SG, Olfers S, Rajan C, Saffen DM, Narayanan V. Skewed allele-specific expression of the NF1 gene in normal subjects: a possible mechanism for phenotypic variability in neurofibromatosis type 1. J Child Neurol. 2012;27:695–702. [PubMed: 22068829]
  103. Johnson H, Wiggs L, Stores G, Huson SM. Psychological disturbance and sleep disorders in children with neurofibromatosis type 1. Dev Med Child Neurol. 2005;47:237–42. [PubMed: 15832546]
  104. Jouhilahti EM, Peltonen S, Callens T, Jokinen E, Heape AM, Messiaen L, Peltonen J. The development of cutaneous neurofibromas. Am J Pathol. 2011;178:500–5. [PMC free article: PMC3070575] [PubMed: 21281783]
  105. Kanter RJ, Graham M, Fairbrother D, Smith SV. Sudden cardiac death in young children with neurofibromatosis type 1. J Pediatr. 2006;149:718–20. [PubMed: 17095352]
  106. Kaplan L, Foster R, Shen Y, Parry DM, McMaster ML, O'Leary MC, Gusella JF. Monozygotic twins discordant for neurofibromatosis 1. Am J Med Genet A. 2010;152A:601–6. [PMC free article: PMC2830382] [PubMed: 20186797]
  107. Kaufmann D, Müller R, Bartelt B, Wolf M, Kunzi-Rapp K, Hanemann CO, Fahsold R, Hein C, Vogel W, Assum G. Spinal neurofibromatosis without cafe-au-lait macules in two families with null mutations of the NF1 gene. Am J Hum Genet. 2001;69:1395–400. [PMC free article: PMC1235551] [PubMed: 11704931]
  108. Kim DH, Murovic JA, Tiel RL, Moes G, Kline DG. A series of 397 peripheral neural sheath tumors: 30-year experience at Louisiana State University Health Sciences Center. J Neurosurg. 2005;102:256–66. [PubMed: 15739553]
  109. King A, Listernick R, Charrow J, Piersall L, Gutmann DH. Optic pathway gliomas in neurofibromatosis type 1: the effect of presenting symptoms on outcome. Am J Med Genet A. 2003;122A:95–9. [PubMed: 12955759]
  110. Kleinerman RA. Radiation-sensitive genetically susceptible pediatric sub-populations. Pediatr Radiol. 2009;39 Suppl 1:S27–31. [PMC free article: PMC2656401] [PubMed: 19083227]
  111. Klose A, Peters H, Hoffmeyer S, Buske A, Lüder A, Hess D, Lehmann R, Nürnberg P, Tinschert S. Two independent mutations in a family with neurofibromatosis type 1 (NF1). Am J Med Genet. 1999;83:6–12. [PubMed: 10076878]
  112. Kluwe L, Siebert R, Gesk S, Friedrich RE, Tinschert S, Kehrer-Sawatzki H, Mautner VF. Screening 500 unselected neurofibromatosis 1 patients for deletions of the NF1 gene. Hum Mutat. 2004;23:111–6. [PubMed: 14722914]
  113. Kluwe L, Tatagiba M, Fünsterer C, Mautner VF. NF1 mutations and clinical spectrum in patients with spinal neurofibromas. J Med Genet. 2003;40:368–71. [PMC free article: PMC1735482] [PubMed: 12746402]
  114. Korf BR. Malignancy in neurofibromatosis type 1. Oncologist. 2000;5:477–85. [PubMed: 11110599]
  115. Krab LC, Aarsen FK, de Goede-Bolder A, Catsman-Berrevoets CE, Arts WF, Moll HA, Elgersma Y. Impact of neurofibromatosis type 1 on school performance. J Child Neurol. 2008a;23:1002–10. [PubMed: 18827266]
  116. Krab LC, de Goede-Bolder A, Aarsen FK, Pluijm SM, Bouman MJ, van der Geest JN, Lequin M, Catsman CE, Arts WF, Kushner SA, Silva AJ, de Zeeuw CI, Moll HA, Elgersma Y. Effect of simvastatin on cognitive functioning in children with neurofibromatosis type 1: a randomized controlled trial. JAMA. 2008b;300:287–94. [PMC free article: PMC2664742] [PubMed: 18632543]
  117. Krab LC, Oostenbrink R, de Goede-Bolder A, Aarsen FK, Elgersma Y, Moll HA (2009) Health-related quality of life in children with neurofibromatosis type 1: contribution of demographic factors, disease-related factors, and behavior. J Pediatr. 154:420-5, 425.e1. [PubMed: 18950800]
  118. Kramer K, Hasel C, Aschoff AJ, Henne-Bruns D, Wuerl P. Multiple gastrointestinal stromal tumors and bilateral pheochromocytoma in neurofibromatosis. World J Gastroenterol. 2007;13:3384–7. [PubMed: 17659681]
  119. Kreusel KM. Ophthalmological manifestations in VHL and NF 1: pathological and diagnostic implications. Fam Cancer. 2005;4:43–7. [PubMed: 15883709]
  120. Kuorilehto T, Pöyhönen M, Bloigu R, Heikkinen J, Väänänen K, Peltonen J. Decreased bone mineral density and content in neurofibromatosis type 1: lowest local values are located in the load-carrying parts of the body. Osteoporos Int. 2005;16:928–36. [PubMed: 15551055]
  121. Lama G, Graziano L, Calabrese E, Grassia C, Rambaldi PF, Cioce F, Tedesco MA, Di Salvo G, Esposito-Salsano M. Blood pressure and cardiovascular involvement in children with neurofibromatosis type1. Pediatr Nephrol. 2004;19:413–8. [PubMed: 14991390]
  122. Lammert M, Friedman JM, Kluwe L, Mautner VF. Prevalence of neurofibromatosis 1 in German children at elementary school enrollment. Arch Dermatol. 2005a;141:71–4. [PubMed: 15655144]
  123. Lammert M, Friedman JM, Roth HJ, Friedrich RE, Kluwe L, Atkins D, Schooler T, Mautner VF. Vitamin D deficiency associated with number of neurofibromas in neurofibromatosis 1. J Med Genet. 2006;43:810–3. [PMC free article: PMC2563168] [PubMed: 16571643]
  124. Lammert M, Kappler M, Mautner VF, Lammert K, Störkel S, Friedman JM, Atkins D. Decreased bone mineral density in patients with neurofibromatosis 1. Osteoporos Int. 2005b;16:1161–6. [PubMed: 15988556]
  125. Lázaro C, Gaona A, Lynch M, Kruyer H, Ravella A, Estivill X. Molecular characterization of the breakpoints of a 12-kb deletion in the NF1 gene in a family showing germ-line mosaicism. Am J Hum Genet. 1995;57:1044–9. [PMC free article: PMC1801366] [PubMed: 7485153]
  126. Legius E, Wu R, Eyssen M, Marynen P, Fryns JP, Cassiman JJ. Encephalocraniocutaneous lipomatosis with a mutation in the NF1 gene. J Med Genet. 1995;32:316–9. [PMC free article: PMC1050386] [PubMed: 7643367]
  127. Levine TM, Materek A, Abel J, O'Donnell M, Cutting LE. Cognitive profile of neurofibromatosis type 1. Semin Pediatr Neurol. 2006;13:8–20. [PubMed: 16818171]
  128. Lim R, Jaramillo D, Poussaint TY, Chang Y, Korf B. Superficial neurofibroma: a lesion with unique MRI characteristics in patients with neurofibromatosis type 1. AJR Am J Roentgenol. 2005;184:962–8. [PubMed: 15728625]
  129. Lin AE, Birch PH, Korf BR, Tenconi R, Niimura M, Poyhonen M, Armfield Uhas K, Sigorini M, Virdis R, Romano C, Bonioli E, Wolkenstein P, Pivnick EK, Lawrence M, Friedman JM. Cardiovascular malformations and other cardiovascular abnormalities in neurofibromatosis 1. Am J Med Genet. 2000;95:108–17. [PubMed: 11078559]
  130. Listernick R, Ferner RE, Liu GT, Gutmann DH. Optic pathway gliomas in neurofibromatosis-1: controversies and recommendations. Ann Neurol. 2007;61:189–98. [PubMed: 17387725]
  131. Listernick R, Gutmann DH. Tumors of the optic pathway. In: Friedman JM, Gutmann DH, MacCollin M, Riccardi VM, eds. Neurofibromatosis: Phenotype, Natural History, and Pathogenesis. Baltimore, MD: Johns Hopkins University Press; 1999:203-30.
  132. Listernick R, Mancini AJ, Charrow J. Segmental neurofibromatosis in childhood. Am J Med Genet A. 2003;121A:132–5. [PubMed: 12910491]
  133. Lopes Ferraz Filho JR, Munis MP, Soares Souza A, Sanches RA, Goloni-Bertollo EM, Pavarino-Bertelli EC. Unidentified bright objects on brain MRI in children as a diagnostic criterion for neurofibromatosis type 1. Pediatr Radiol. 2008;38:305–10. [PubMed: 18231788]
  134. Maertens O, De Schepper S, Vandesompele J, Brems H, Heyns I, Janssens S, Speleman F, Legius E, Messiaen L. Molecular dissection of isolated disease features in mosaic neurofibromatosis type 1. Am J Hum Genet. 2007;81:243–51. [PMC free article: PMC1950809] [PubMed: 17668375]
  135. Maertens O, Prenen H, Debiec-Rychter M, Wozniak A, Sciot R, Pauwels P, De Wever I, Vermeesch JR, de Raedt T, De Paepe A, Speleman F, van Oosterom A, Messiaen L, Legius E. Molecular pathogenesis of multiple gastrointestinal stromal tumors in NF1 patients. Hum Mol Genet. 2006;15:1015–23. [PubMed: 16461335]
  136. Margariti PN, Blekas K, Katzioti FG, Zikou AK, Tzoufi M, Argyropoulou MI. Magnetization transfer ratio and volumetric analysis of the brain in macrocephalic patients with neurofibromatosis type 1. Eur Radiol. 2007;17:433–8. [PubMed: 16733674]
  137. Masocco M, Kodra Y, Vichi M, Conti S, Kanieff M, Pace M, Frova L, Taruscio D. Mortality associated with neurofibromatosis type 1: a study based on Italian death certificates (1995-2006). Orphanet J Rare Dis. 2011;6:11. [PMC free article: PMC3079598] [PubMed: 21439034]
  138. Matsumine A, Kusuzaki K, Nakamura T, Nakazora S, Niimi R, Matsubara T, Uchida K, Murata T, Kudawara I, Ueda T, Naka N, Araki N, Maeda M, Uchida A. Differentiation between neurofibromas and malignant peripheral nerve sheath tumors in neurofibromatosis 1 evaluated by MRI. J Cancer Res Clin Oncol. 2009;135:891–900. [PubMed: 19101731]
  139. Mautner VF, Asuagbor FA, Dombi E, Fünsterer C, Kluwe L, Wenzel R, Widemann BC, Friedman JM. Assessment of benign tumor burden by whole-body MRI in patients with neurofibromatosis 1. Neuro Oncol. 2008;10:593–8. [PMC free article: PMC2666233] [PubMed: 18559970]
  140. Mautner VF, Brenner W, Fünsterer C, Hagel C, Gawad K, Friedrich RE. Clinical relevance of positron emission tomography and magnetic resonance imaging in the progression of internal plexiform neurofibroma in NF1. Anticancer Res. 2007;27:1819–22. [PubMed: 17649778]
  141. Mautner VF, Hartmann M, Kluwe L, Friedrich RE, Fünsterer C. MRI growth patterns of plexiform neurofibromas in patients with neurofibromatosis type 1. Neuroradiology. 2006;48:160–5. [PubMed: 16432718]
  142. Mautner VF, Kluwe L, Friedrich RE, Roehl AC, Bammert S, Högel J, Spöri H, Cooper DN, Kehrer-Sawatzki H. Clinical characterisation of 29 neurofibromatosis type-1 patients with molecularly ascertained 1.4 Mb type-1 NF1 deletions. J Med Genet. 2010;47:623–30. [PubMed: 20543202]
  143. McCaughan JA, Holloway SM, Davidson R, Lam WW. Further evidence of the increased risk for malignant peripheral nerve sheath tumour from a Scottish cohort of patients with neurofibromatosis type 1. J Med Genet. 2007;44:463–6. [PMC free article: PMC2598004] [PubMed: 17327286]
  144. McClatchey AI. Neurofibromatosis. Annu Rev Pathol. 2007;2:191–216. [PubMed: 18039098]
  145. McEwing RL, Joelle R, Mohlo M, Bernard JP, Hillion Y, Ville Y. Prenatal diagnosis of neurofibromatosis type 1: sonographic and MRI findings. Prenat Diagn. 2006;26:1110–4. [PubMed: 16981221]
  146. Mensink KA, Ketterling RP, Flynn HC, Knudson RA, Lindor NM, Heese BA, Spinner RJ, Babovic-Vuksanovic D. Connective tissue dysplasia in five new patients with NF1 microdeletions: further expansion of phenotype and review of the literature. J Med Genet. 2006;43:e8. [PMC free article: PMC2603036] [PubMed: 16467218]
  147. Messiaen L, Vogt J, Bengesser K, Fu C, Mikhail F, Serra E, Garcia-Linares C, Cooper DN, Lazaro C, Kehrer-Sawatzki H. Mosaic type-1 NF1 microdeletions as a cause of both generalized and segmental neurofibromatosis type-1 (NF1). Hum Mutat. 2011;32:213–9. [PubMed: 21280148]
  148. Messiaen L, Yao S, Brems H, Callens T, Sathienkijkanchai A, Denayer E, Spencer E, Arn P, Babovic-Vuksanovic D, Bay C, Bobele G, Cohen BH, Escobar L, Eunpu D, Grebe T, Greenstein R, Hachen R, Irons M, Kronn D, Lemire E, Leppig K, Lim C, McDonald M, Narayanan V, Pearn A, Pedersen R, Powell B, Shapiro LR, Skidmore D, Tegay D, Thiese H, Zackai EH, Vijzelaar R, Taniguchi K, Ayada T, Okamoto F, Yoshimura A, Parret A, Korf B, Legius E. Clinical and mutational spectrum of neurofibromatosis type 1-like syndrome. JAMA. 2009;302:2111–8. [PubMed: 19920235]
  149. Messiaen LM, Callens T, Mortier G, Beysen D, Vandenbroucke I, Van Roy N, Speleman F, Paepe AD. Exhaustive mutation analysis of the NF1 gene allows identification of 95% of mutations and reveals a high frequency of unusual splicing defects. Hum Mutat. 2000;15:541–55. [PubMed: 10862084]
  150. Miettinen M, Fetsch JF, Sobin LH, Lasota J. Gastrointestinal stromal tumors in patients with neurofibromatosis 1: a clinicopathologic and molecular genetic study of 45 cases. Am J Surg Pathol. 2006;30:90–6. [PubMed: 16330947]
  151. Moles KJ, Gowans GC, Gedela S, Beversdorf D, Yu A, Seaver LH, Schultz RA, Rosenfeld JA, Torchia BS, Shaffer LG. NF1 microduplications: identification of seven nonrelated individuals provides further characterization of the phenotype. Genet Med. 2012;14:508–14. [PubMed: 22241097]
  152. Montani D, Coulet F, Girerd B, Eyries M, Bergot E, Mal H, Biondi G, Dromer C, Hugues T, Marquette C, O'Connell C, O'Callaghan DS, Savale L, Jaïs X, Dorfmüller P, Begueret H, Bertoletti L, Sitbon O, Bellanné-Chantelot C, Zalcman G, Simonneau G, Humbert M, Soubrier F. Pulmonary hypertension in patients with neurofibromatosis type I. Medicine (Baltimore). 2011;90:201–11. [PubMed: 21512413]
  153. Muram-Zborovski TM, Stevenson DA, Viskochil DH, Dries DC, Wilson AR. SPRED 1 mutations in a neurofibromatosis clinic. J Child Neurol. 2010;25:1203–9. [PMC free article: PMC3243064] [PubMed: 20179001]
  154. Murovic JA, Kim DH, Kline DG. Neurofibromatosis-associated nerve sheath tumors: case report and review of the literature. Neurosurg Focus. 2006;20:E1. [PubMed: 16459989]
  155. Nicolin G, Parkin P, Mabbott D, Hargrave D, Bartels U, Tabori U, Rutka J, Buncic JR, Bouffet E. Natural history and outcome of optic pathway gliomas in children. Pediatr Blood Cancer. 2009;53:1231–7. [PubMed: 19621457]
  156. NIH; National Institutes of Health Consensus Development Conference Statement: neurofibromatosis. Bethesda, Md, USA, July 13-15, 1987. Neurofibromatosis. 1988;1:172–8. [PubMed: 3152465]
  157. Noll RB, Reiter-Purtill J, Moore BD, Schorry EK, Lovell AM, Vannatta K, Gerhardt CA. Social, emotional, and behavioral functioning of children with NF1. Am J Med Genet A. 2007;143A:2261–73. [PubMed: 17726688]
  158. North K. Cognitive function and academic performance. In: Friedman JM, Gutmann DH, MacCollin M, Riccardi VM, eds. Neurofibromatosis: Phenotype, Natural History, and Pathogenesis. Baltimore, MD: Johns Hopkins University Press; 1999:162-89.
  159. Nunley KS, Gao F, Albers AC, Bayliss SJ, Gutmann DH. Predictive value of café au lait macules at initial consultation in the diagnosis of neurofibromatosis type 1. Arch Dermatol. 2009;145:883–7. [PubMed: 19687418]
  160. Oguzkan S, Cinbis M, Ayter S, Anlar B, Aysun S. Familial segmental neurofibromatosis. J Child Neurol. 2004;19:392–4. [PubMed: 15224714]
  161. Oh KS, Hung J, Robertson PL, Garton HJ, Muraszko KM, Sandler HM, Hamstra DA. Outcomes of multidisciplinary management in pediatric low-grade gliomas. Int J Radiat Oncol Biol Phys. 2011;81:e481–8. [PubMed: 21470783]
  162. Okazaki K, Kakita A, Tanaka H, Kimura K, Minagawa M, Morita T, Takahashi H. Widespread ischemic brain lesions caused by vasculopathy associated with neurofibromatosis type 1. Neuropathology. 2010;30:627–33. [PubMed: 20113403]
  163. Origone P, Bonioli E, Panucci E, Costabel S, Ajmar F, Coviello DA. The Genoa experience of prenatal diagnosis in NF1. Prenat Diagn. 2000;20:719–24. [PubMed: 11015700]
  164. Ostergaard JR, Sunde L, Okkels H. Neurofibromatosis von Recklinghausen type I phenotype and early onset of cancers in siblings compound heterozygous for mutations in MSH6. Am J Med Genet A. 2005;139A:96–105. [PubMed: 16283678]
  165. Page PZ, Page GP, Ecosse E, Korf BR, Leplege A, Wolkenstein P. Impact of neurofibromatosis 1 on Quality of Life: a cross-sectional study of 176 American cases. Am J Med Genet A. 2006;140:1893–8. [PubMed: 16906549]
  166. Parrinello S, Lloyd AC. Neurofibroma development in NF1--insights into tumour initiation. Trends Cell Biol. 2009;19:395–403. [PubMed: 19615906]
  167. Pascual-Castroviejo I, Pascual-Pascual SI, Velazquez-Fragua R, Botella P, Viaño J. Familial spinal neurofibromatosis. Neuropediatrics. 2007;38:105–8. [PubMed: 17712740]
  168. Pasmant E, Sabbagh A, Hanna N, Masliah-Planchon J, Jolly E, Goussard P, Ballerini P, Cartault F, Barbarot S, Landman-Parker J, Soufir N, Parfait B, Vidaud M, Wolkenstein P, Vidaud D, France RN. SPRED1 germline mutations caused a neurofibromatosis type 1 overlapping phenotype. J Med Genet. 2009a;46:425–30. [PubMed: 19366998]
  169. Pasmant E, Sabbagh A, Masliah-Planchon J, Haddad V, Hamel MJ, Laurendeau I, Soulier J, Parfait B, Wolkenstein P, Bièche I, Vidaud M, Vidaud D. Detection and characterization of NF1 microdeletions by custom high resolution array CGH. J Mol Diagn. 2009b;11:524–9. [PMC free article: PMC2765750] [PubMed: 19767589]
  170. Pasmant E, Sabbagh A, Spurlock G, Laurendeau I, Grillo E, Hamel MJ, Martin L, Barbarot S, Leheup B, Rodriguez D, Lacombe D, Dollfus H, Pasquier L, Isidor B, Ferkal S, Soulier J, Sanson M, Dieux-Coeslier A, Bièche I, Parfait B, Vidaud M, Wolkenstein P, Upadhyaya M, Vidaud D. NF1 microdeletions in neurofibromatosis type 1: from genotype to phenotype. Hum Mutat. 2010;31:E1506–18. [PubMed: 20513137]
  171. Pavol M, Hiscock M, Massman P, Moore Iii B, Foorman B, Meyers C. Neuropsychological function in adults with von Recklinghausen's neurofibromatosis. Dev Neuropsychol. 2006;29:509–26. [PubMed: 16671865]
  172. Petramala L, Giustini S, Zinnamosca L, Marinelli C, Colangelo L, Cilenti G, Formicuccia MC, D'Erasmo E, Calvieri S, Letizia C. Bone mineral metabolism in patients with neurofibromatosis type 1 (von Recklingausen disease). Arch Dermatol Res. 2012;304:325–31. [PubMed: 22120694]
  173. Pinson S, Créange A, Barbarot S, Stalder JF, Chaix Y, Rodriguez D, Sanson M, Bernheim A, d'Incan M, Doz F, Stoll C, Combemale P, Kalifa C, Zeller J, Teillac-Hamel D, Lyonnet S, Zerah M, Lacour JP, Guillot B, Wolkenstein P. Arch Pediatr. 2002;9:49–60. [PubMed: 11865551]
  174. Pizzuti A, Bottillo I, Inzana F, Lanari V, Buttarelli F, Torrente I, Giallonardo AT, De Luca A, Dallapiccola B. Familial spinal neurofibromatosis due to a multiexonic NF1 gene deletion. Neurogenetics. 2011;12:233–40. [PubMed: 21365283]
  175. Prada CE, Zarate YA, Hagenbuch S, Lovell A, Schorry EK, Hopkin RJ. Lethal presentation of neurofibromatosis and Noonan syndrome. Am J Med Genet A. 2011;155A:1360–6. [PubMed: 21567923]
  176. Pride N, Payne JM, Webster R, Shores EA, Rae C, North KN. Corpus callosum morphology and its relationship to cognitive function in neurofibromatosis type 1. J Child Neurol. 2010;25:834–41. [PubMed: 20142468]
  177. Prinzie P, Descheemaeker MJ, Vogels A, Cleymans T, Haselager GJ, Curfs LM, Hellinckx W, Onghena P, Legius E, van Lieshout CF, Fryns JP. Personality profiles of children and adolescents with neurofibromatosis type 1. Am J Med Genet A. 2003;118A:1–7. [PubMed: 12605433]
  178. Pros E, Gómez C, Martín T, Fábregas P, Serra E, Lázaro C. Nature and mRNA effect of 282 different NF1 point mutations: focus on splicing alterations. Hum Mutat. 2008;29:E173–93. [PubMed: 18546366]
  179. Quintáns B, Pardo J, Campos B, Barros F, Volpini V, Carracedo A, Sobrido MJ. Neurofibromatosis without neurofibromas: confirmation of a genotype-phenotype correlation and implications for genetic testing. Case Rep Neurol. 2011;3:86–90. [PMC free article: PMC3084038] [PubMed: 21532985]
  180. Raevaara TE, Gerdes AM, Lönnqvist KE, Tybjaerg-Hansen A, Abdel-Rahman WM, Kariola R, Peltomäki P, Nyström-Lahti M. HNPCC mutation MLH1 P648S makes the functional protein unstable, and homozygosity predisposes to mild neurofibromatosis type 1. Genes Chromosomes Cancer. 2004;40:261–5. [PubMed: 15139004]
  181. Rasmussen SA, Colman SD, Ho VT, Abernathy CR, Arn PH, Weiss L, Schwartz C, Saul RA, Wallace MR. Constitutional and mosaic large NF1 gene deletions in neurofibromatosis type 1. J Med Genet. 1998;35:468–71. [PMC free article: PMC1051340] [PubMed: 9643287]
  182. Rasmussen SA, Friedman JM. NF1 gene and neurofibromatosis 1. Am J Epidemiol. 2000;151:33–40. [PubMed: 10625171]
  183. Rasmussen SA, Yang Q, Friedman JM. Mortality in neurofibromatosis 1: an analysis using U.S. death certificates. Am J Hum Genet. 2001;68:1110–8. [PMC free article: PMC1226092] [PubMed: 11283797]
  184. Rea D, Brandsema JF, Armstrong D, Parkin PC, deVeber G, MacGregor D, Logan WJ, Askalan R. Cerebral arteriopathy in children with neurofibromatosis type 1. Pediatrics. 2009;124:e476–83. [PubMed: 19706560]
  185. Riley J, Spiotta A, Boulis N. Experimental therapeutic approaches to peripheral nerve tumors. Neurosurg Focus. 2007;22:E2. [PubMed: 17613211]
  186. Riva P, Corrado L, Natacci F, Castorina P, Wu BL, Schneider GH, Clementi M, Tenconi R, Korf BR, Larizza L. NF1 microdeletion syndrome: refined FISH characterization of sporadic and familial deletions with locus-specific probes. Am J Hum Genet. 2000;66:100–9. [PMC free article: PMC1288315] [PubMed: 10631140]
  187. Rosenfeld A, Listernick R, Charrow J, Goldman S. Neurofibromatosis type 1 and high-grade tumors of the central nervous system. Childs Nerv Syst. 2010;26:663–7. [PubMed: 19937438]
  188. Rosser T, Packer RJ. Intracranial neoplasms in children with neurofibromatosis 1. J Child Neurol. 2002;17:630–7. [PubMed: 12403562]
  189. Rosser TL, Vezina G, Packer RJ. Cerebrovascular abnormalities in a population of children with neurofibromatosis type 1. Neurology. 2005;64:553–5. [PubMed: 15699396]
  190. Roth TM, Petty EM, Barald KF. The role of steroid hormones in the NF1 phenotype: focus on pregnancy. Am J Med Genet A. 2008;146A:1624–33. [PubMed: 18481270]
  191. Roy A, Roulin JL, Charbonnier V, Allain P, Fasotti L, Barbarot S, Stalder JF, Terrien A, Le Gall D. Executive dysfunction in children with neurofibromatosis type 1: a study of action planning. J Int Neuropsychol Soc. 2010;16:1056–63. [PubMed: 20682087]
  192. Rübben A, Bausch B, Nikkels A. Somatic deletion of the NF1 gene in a neurofibromatosis type 1-associated malignant melanoma demonstrated by digital PCR. Mol Cancer. 2006;5:36. [PMC free article: PMC1570477] [PubMed: 16961930]
  193. Ruggieri M, Huson SM. The clinical and diagnostic implications of mosaicism in the neurofibromatoses. Neurology. 2001;56:1433–43. [PubMed: 11409413]
  194. Sabbagh A, Pasmant E, Laurendeau I, Parfait B, Barbarot S, Guillot B, Combemale P, Ferkal S, Vidaud M, Aubourg P, Vidaud D, Wolkenstein P. Unravelling the genetic basis of variable clinical expression in neurofibromatosis 1. Hum Mol Genet. 2009;18:2768–78. [PMC free article: PMC2722187] [PubMed: 19417008]
  195. Sabol Z, Resić B, Gjergja Juraski R, Sabol F, Kovac Sizgorić M, Orsolić K, Ozretić D, Sepić-Grahovac D. Clinical sensitivity and specificity of multiple T2-hyperintensities on brain magnetic resonance imaging in diagnosis of neurofibromatosis type 1 in children: diagnostic accuracy study. Croat Med J. 2011;52:488–96. [PMC free article: PMC3160695] [PubMed: 21853543]
  196. Sarkozy A, Schirinzi A, Lepri F, Bottillo I, De Luca A, Pizzuti A, Tartaglia M, Digilio MC, Dallapiccola B. Clinical lumping and molecular splitting of LEOPARD and NF1/NF1-Noonan syndromes. Am J Med Genet A. 2007;143A:1009–11. [PubMed: 17366582]
  197. Schievink WI, Riedinger M, Maya MM. Frequency of incidental intracranial aneurysms in neurofibromatosis type 1. Am J Med Genet A. 2005;134A:45–8. [PubMed: 15690406]
  198. Schindeler A, Little DG. Recent insights into bone development, homeostasis, and repair in type 1 neurofibromatosis (NF1). Bone. 2008;42:616–22. [PubMed: 18248783]
  199. Schmandt SM, Packer RJ, Vezina LG, Jane J. Spontaneous regression of low-grade astrocytomas in childhood. Pediatr Neurosurg. 2000;32:132–6. [PubMed: 10867559]
  200. Segal L, Darvish-Zargar M, Dilenge ME, Ortenberg J, Polomeno RC. Optic pathway gliomas in patients with neurofibromatosis type 1: follow-up of 44 patients. J AAPOS. 2010;14:155–8. [PubMed: 20451859]
  201. Seitz S, Schnabel C, Busse B, Schmidt HU, Beil FT, Friedrich RE, Schinke T, Mautner VF, Amling M. High bone turnover and accumulation of osteoid in patients with neurofibromatosis 1. Osteoporos Int. 2010;21:119–27. [PubMed: 19415373]
  202. Serletis D, Parkin P, Bouffet E, Shroff M, Drake JM, Rutka JT. Massive plexiform neurofibromas in childhood: natural history and management issues. J Neurosurg. 2007;106(5) Suppl:363–7. [PubMed: 17566202]
  203. Shamji MF, Benoit BG. Syndromic and sporadic pediatric optic pathway gliomas: review of clinical and histopathological differences and treatment implications. Neurosurg Focus. 2007;23:E3. [PubMed: 18004965]
  204. Sharif S, Ferner R, Birch JM, Gillespie JE, Gattamaneni HR, Baser ME, Evans DG. Second primary tumors in neurofibromatosis 1 patients treated for optic glioma: substantial risks after radiotherapy. J Clin Oncol. 2006;24:2570–5. [PubMed: 16735710]
  205. Sharif S, Moran A, Huson SM, Iddenden R, Shenton A, Howard E, Evans DG. Women with neurofibromatosis 1 are at a moderately increased risk of developing breast cancer and should be considered for early screening. J Med Genet. 2007;44:481–4. [PMC free article: PMC2597938] [PubMed: 17369502]
  206. Shen JX, Qiu GX, Wang YP, Zhao Y, Ye QB, Wu ZK. Surgical treatment of scoliosis caused by neurofibromatosis type 1. Chin Med Sci J. 2005;20:88–92. [PubMed: 16075744]
  207. Spiegel M, Oexle K, Horn D, Windt E, Buske A, Albrecht B, Prott EC, Seemanová E, Seidel J, Rosenbaum T, Jenne D, Kehrer-Sawatzki H, Tinschert S. Childhood overgrowth in patients with common NF1 microdeletions. Eur J Hum Genet. 2005;13:883–8. [PubMed: 15856072]
  208. Spits C, De Rycke M, Van Ranst N, Joris H, Verpoest W, Lissens W, Devroey P, Van Steirteghem A, Liebaers I, Sermon K. Preimplantation genetic diagnosis for neurofibromatosis type 1. Mol Hum Reprod. 2005;11:381–7. [PubMed: 15833774]
  209. Spurlock G, Bennett E, Chuzhanova N, Thomas N, Jim HP, Side L, Davies S, Haan E, Kerr B, Huson SM, Upadhyaya M. SPRED1 mutations (Legius syndrome): another clinically useful genotype for dissecting the neurofibromatosis type 1 phenotype. J Med Genet. 2009;46:431–7. [PubMed: 19443465]
  210. Staser K, Yang FC, Clapp DW. Mast cells and the neurofibroma microenvironment. Blood. 2010;116:157–64. [PMC free article: PMC2910605] [PubMed: 20233971]
  211. Steinemann D, Arning L, Praulich I, Stuhrmann M, Hasle H, Stary J, Schlegelberger B, Niemeyer CM, Flotho C. Mitotic recombination and compound-heterozygous mutations are predominant NF1-inactivating mechanisms in children with juvenile myelomonocytic leukemia and neurofibromatosis type 1. Haematologica. 2010;95:320–3. [PMC free article: PMC2817036] [PubMed: 20015894]
  212. Steinmann K, Kluwe L, Friedrich RE, Mautner VF, Cooper DN, Kehrer-Sawatzki H. Mechanisms of loss of heterozygosity in neurofibromatosis type 1-associated plexiform neurofibromas. J Invest Dermatol. 2009;129:615–21. [PubMed: 18800150]
  213. Stephens K, Weaver M, Leppig KA, Maruyama K, Emanuel PD, Le Beau MM, Shannon KM. Interstitial uniparental isodisomy at clustered breakpoint intervals is a frequent mechanism of NF1 inactivation in myeloid malignancies. Blood. 2006;108:1684–9. [PMC free article: PMC1895516] [PubMed: 16690971]
  214. Stevenson DA, Schwarz EL, Viskochil DH, Moyer-Mileur LJ, Murray M, Firth SD, D'Astous JL, Carey JC, Pasquali M. Evidence of increased bone resorption in neurofibromatosis type 1 using urinary pyridinium crosslink analysis. Pediatr Res. 2008;63:697–701. [PMC free article: PMC3235045] [PubMed: 18317233]
  215. Stevenson DA, Viskochil DH, Carey JC, Sheng X, Murray M, Moyer-Mileur L, Shelton J, Roberts WL, Bunker AM, Hanson H, Bauer S, D'Astous JL. Pediatric 25-hydroxyvitamin D concentrations in neurofibromatosis type 1. J Pediatr Endocrinol Metab. 2011;24:169–74. [PMC free article: PMC3246508] [PubMed: 21648285]
  216. Stevenson DA, Viskochil DH, Rope AF, Carey JC. Clinical and molecular aspects of an informative family with neurofibromatosis type 1 and Noonan phenotype. Clin Genet. 2006a;69:246–53. [PMC free article: PMC3243644] [PubMed: 16542390]
  217. Stevenson DA, Zhou H, Ashrafi S, Messiaen LM, Carey JC, D'Astous JL, Santora SD, Viskochil DH. Double inactivation of NF1 in tibial pseudarthrosis. Am J Hum Genet. 2006b;79:143–8. [PMC free article: PMC1474128] [PubMed: 16773574]
  218. Stewart DR, Cogan JD, Kramer MR, Miller WT, Christiansen LE, Pauciulo MW, Messiaen LM, Tu GS, Thompson WH, Pyeritz RE, Ryu JH, Nichols WC, Kodama M, Meyrick BO, Ross DJ. Is pulmonary arterial hypertension in neurofibromatosis type 1 secondary to a plexogenic arteriopathy? Chest. 2007a;132:798–808. [PubMed: 17573495]
  219. Stewart DR, Corless CL, Rubin BP, Heinrich MC, Messiaen LM, Kessler LJ, Zhang PJ, Brooks DG. Mitotic recombination as evidence of alternative pathogenesis of gastrointestinal stromal tumours in neurofibromatosis type 1. J Med Genet. 2007b;44:e61. [PMC free article: PMC2597901] [PubMed: 17209131]
  220. Stewart DR, Pemov A, Van Loo P, Beert E, Brems H, Sciot R, Claes K, Pak E, Dutra A, Lee CC, Legius E. Mitotic recombination of chromosome arm 17q as a cause of loss of heterozygosity of NF1 in neurofibromatosis type 1-associated glomus tumors. Genes Chromosomes Cancer. 2012;51:429–37. [PMC free article: PMC3295917] [PubMed: 22250039]
  221. Sylvester CL, Drohan LA, Sergott RC. Optic-nerve gliomas, chiasmal gliomas and neurofibromatosis type 1. Curr Opin Ophthalmol. 2006;17:7–11. [PubMed: 16436918]
  222. Szudek J, Birch P, Friedman JM. Growth charts for young children with neurofibromatosis 1 (NF1). Am J Med Genet. 2000a;92:224–8. [PubMed: 10817659]
  223. Szudek J, Birch P, Friedman JM. Growth in North American white children with neurofibromatosis 1 (NF1). J Med Genet. 2000b;37:933–8. [PMC free article: PMC1734506] [PubMed: 11106357]
  224. Szudek J, Birch P, Riccardi VM, Evans DG, Friedman JM. Associations of clinical features in neurofibromatosis 1 (NF1). Genet Epidemiol. 2000c;19:429–39. [PubMed: 11108651]
  225. Szudek J, Joe H, Friedman JM. Analysis of intrafamilial phenotypic variation in neurofibromatosis 1 (NF1). Genet Epidemiol. 2002;23:150–64. [PubMed: 12214308]
  226. Tada K, Kochi M, Saya H, Kuratsu J, Shiraishi S, Kamiryo T, Shinojima N, Ushio Y. Preliminary observations on genetic alterations in pilocytic astrocytomas associated with neurofibromatosis 1. Neuro Oncol. 2003;5:228–34. [PMC free article: PMC1920681] [PubMed: 14565158]
  227. Takazawa Y, Sakurai S, Sakuma Y, Ikeda T, Yamaguchi J, Hashizume Y, Yokoyama S, Motegi A, Fukayama M. Gastrointestinal stromal tumors of neurofibromatosis type I (von Recklinghausen's disease). Am J Surg Pathol. 2005;29:755–63. [PubMed: 15897742]
  228. Tang SC, Lee MJ, Jeng JS, Yip PK. Novel mutation of neurofibromatosis type 1 in a patient with cerebral vasculopathy and fatal ischemic stroke. J Neurol Sci. 2006;243:53–5. [PubMed: 16414076]
  229. Tassabehji M, Strachan T, Sharland M, Colley A, Donnai D, Harris R, Thakker N. Tandem duplication within a neurofibromatosis type 1 (NF1) gene exon in a family with features of Watson syndrome and Noonan syndrome. Am J Hum Genet. 1993;53:90–5. [PMC free article: PMC1682238] [PubMed: 8317503]
  230. Tatebe S, Asami F, Shinohara H, Okamoto T, Kuraoka S. Ruptured aneurysm of the subclavian artery in a patient with von Recklinghausen's disease. Circ J. 2005;69:503–6. [PubMed: 15791051]
  231. Thiagalingam S, Flaherty M, Billson F, North K. Neurofibromatosis type 1 and optic pathway gliomas: follow-up of 54 patients. Ophthalmology. 2004;111:568–77. [PubMed: 15019338]
  232. Thiel C, Wilken M, Zenker M, Sticht H, Fahsold R, Gusek-Schneider GC, Rauch A. Independent NF1 and PTPN11 mutations in a family with neurofibromatosis-Noonan syndrome. Am J Med Genet A. 2009;149A:1263–7. [PubMed: 19449407]
  233. Thomas L, Kluwe L, Chuzhanova N, Mautner V, Upadhyaya M. Analysis of NF1 somatic mutations in cutaneous neurofibromas from patients with high tumor burden. Neurogenetics. 2010;11:391–400. [PubMed: 20358387]
  234. Thomas L, Spurlock G, Eudall C, Thomas NS, Mort M, Hamby SE, Chuzhanova N, Brems H, Legius E, Cooper DN, Upadhyaya M. Exploring the somatic NF1 mutational spectrum associated with NF1 cutaneous neurofibromas. Eur J Hum Genet. 2012;20:411–9. [PMC free article: PMC3306856] [PubMed: 22108604]
  235. Tinschert S, Naumann I, Stegmann E, Buske A, Kaufmann D, Thiel G, Jenne DE. Segmental neurofibromatosis is caused by somatic mutation of the neurofibromatosis type 1 (NF1) gene. Eur J Hum Genet. 2000;8:455–9. [PubMed: 10878667]
  236. Tognini G, Ferrozzi F, Garlaschi G, Piazza P, Patti A, Virdis R, Bertolino C, Bertolino G, Manfredini D, Zompatori M, Crisi G. Brain apparent diffusion coefficient evaluation in pediatric patients with neurofibromatosis type 1. J Comput Assist Tomogr. 2005;29:298–304. [PubMed: 15891494]
  237. Toledano H, Goldberg Y, Kedar-Barnes I, Baris H, Porat RM, Shochat C, Bercovich D, Pikarsky E, Lerer I, Yaniv I, Abeliovich D, Peretz T. Homozygosity of MSH2 c.1906G-->C germline mutation is associated with childhood colon cancer, astrocytoma and signs of Neurofibromatosis type I. Fam Cancer. 2009;8:187–94. [PubMed: 19101824]
  238. Tonsgard JH, Kwak SM, Short MP, Dachman AH. CT imaging in adults with neurofibromatosis-1: frequent asymptomatic plexiform lesions. Neurology. 1998;50:1755–60. [PubMed: 9633723]
  239. Trovó-Marqui AB, Tajara EH. Neurofibromin: a general outlook. Clin Genet. 2006;70:1–13. [PubMed: 16813595]
  240. Tsirikos AI, Saifuddin A, Noordeen MH. Spinal deformity in neurofibromatosis type-1: diagnosis and treatment. Eur Spine J. 2005;14:427–39. [PMC free article: PMC3454658] [PubMed: 15712001]
  241. Tucker T, Friedman JM, Friedrich RE, Wenzel R, Fünsterer C, Mautner VF. Longitudinal study of neurofibromatosis 1 associated plexiform neurofibromas. J Med Genet. 2009a;46:81–5. [PubMed: 18930997]
  242. Tucker T, Schnabel C, Hartmann M, Friedrich RE, Frieling I, Kruse HP, Mautner VF, Friedman JM. Bone health and fracture rate in individuals with neurofibromatosis 1 (NF1). J Med Genet. 2009b;46:259–65. [PubMed: 19066167]
  243. Tucker T, Wolkenstein P, Revuz J, Zeller J, Friedman JM. Association between benign and malignant peripheral nerve sheath tumors in NF1. Neurology. 2005;65:205–11. [PubMed: 16043787]
  244. Ullrich NJ, Raja AI, Irons MB, Kieran MW, Goumnerova L. Brainstem lesions in neurofibromatosis type 1. Neurosurgery. 2007a;61:762–6. [PubMed: 17986937]
  245. Ullrich NJ, Robertson R, Kinnamon DD, Scott RM, Kieran MW, Turner CD, Chi SN, Goumnerova L, Proctor M, Tarbell NJ, Marcus KJ, Pomeroy SL. Moyamoya following cranial irradiation for primary brain tumors in children. Neurology. 2007b;68:932–8. [PubMed: 17372129]
  246. Upadhyaya M, Han S, Consoli C, Majounie E, Horan M, Thomas NS, Potts C, Griffiths S, Ruggieri M, von Deimling A, Cooper DN. Characterization of the somatic mutational spectrum of the neurofibromatosis type 1 (NF1) gene in neurofibromatosis patients with benign and malignant tumors. Hum Mutat. 2004;23:134–46. [PubMed: 14722917]
  247. Upadhyaya M, Huson SM, Davies M, Thomas N, Chuzhanova N, Giovannini S, Evans DG, Howard E, Kerr B, Griffiths S, Consoli C, Side L, Adams D, Pierpont M, Hachen R, Barnicoat A, Li H, Wallace P, Van Biervliet JP, Stevenson D, Viskochil D, Baralle D, Haan E, Riccardi V, Turnpenny P, Lazaro C, Messiaen L. An absence of cutaneous neurofibromas associated with a 3-bp inframe deletion in exon 17 of the NF1 gene (c.2970-2972 delAAT): evidence of a clinically significant NF1 genotype-phenotype correlation. Am J Hum Genet. 2007;80:140–51. [PMC free article: PMC1785321] [PubMed: 17160901]
  248. Upadhyaya M, Kluwe L, Spurlock G, Monem B, Majounie E, Mantripragada K, Ruggieri M, Chuzhanova N, Evans DG, Ferner R, Thomas N, Guha A, Mautner V. Germline and somatic NF1 gene mutation spectrum in NF1-associated malignant peripheral nerve sheath tumors (MPNSTs). Hum Mutat. 2008;29:74–82. [PubMed: 17960768]
  249. Upadhyaya M, Majounie E, Thompson P, Han S, Consoli C, Krawczak M, Cordeiro I, Cooper DN. Three different pathological lesions in the NF1 gene originating de novo in a family with neurofibromatosis type 1. Hum Genet. 2003;112:12–7. [PubMed: 12483293]
  250. Upadhyaya M, Ruggieri M, Maynard J, Osborn M, Hartog C, Mudd S, Penttinen M, Cordeiro I, Ponder M, Ponder BA, Krawczak M, Cooper DN. Gross deletions of the neurofibromatosis type 1 (NF1) gene are predominantly of maternal origin and commonly associated with a learning disability, dysmorphic features and developmental delay. Hum Genet. 1998;102:591–7. [PubMed: 9654211]
  251. Upadhyaya M, Spurlock G, Kluwe L, Chuzhanova N, Bennett E, Thomas N, Guha A, Mautner V. The spectrum of somatic and germline NF1 mutations in NF1 patients with spinal neurofibromas. Neurogenetics. 2009;10:251–63. [PubMed: 19221814]
  252. Uttner I, Wahlländer-Danek U, Danek A. Fortschr Neurol Psychiatr. 2003;71:157–62. [PubMed: 12624853]
  253. Valero MC, Martín Y, Hernández-Imaz E, Marina Hernández A, Meleán G, Valero AM, Javier Rodríguez-Álvarez F, Tellería D, Hernández-Chico C. A highly sensitive genetic protocol to detect NF1 mutations. J Mol Diagn. 2011;13:113–22. [PMC free article: PMC3128626] [PubMed: 21354044]
  254. Valeyrie-Allanore L, Ismaïli N, Bastuji-Garin S, Zeller J, Wechsler J, Revuz J, Wolkenstein P. Symptoms associated with malignancy of peripheral nerve sheath tumours: a retrospective study of 69 patients with neurofibromatosis 1. Br J Dermatol. 2005;153:79–82. [PubMed: 16029330]
  255. Van Meerbeeck SF, Verstraete KL, Janssens S, Mortier G. Whole body MR imaging in neurofibromatosis type 1. Eur J Radiol. 2009;69:236–42. [PubMed: 19091504]
  256. Vandenbroucke I, van Doorn R, Callens T, Cobben JM, Starink TM, Messiaen L. Genetic and clinical mosaicism in a patient with neurofibromatosis type 1. Hum Genet. 2004;114:284–90. [PubMed: 14605872]
  257. Vanneste E, Melotte C, Debrock S, D'Hooghe T, Brems H, Fryns JP, Legius E, Vermeesch JR. Preimplantation genetic diagnosis using fluorescent in situ hybridization for cancer predisposition syndromes caused by microdeletions. Hum Reprod. 2009;24:1522–8. [PubMed: 19278970]
  258. Venturin M, Guarnieri P, Natacci F, Stabile M, Tenconi R, Clementi M, Hernandez C, Thompson P, Upadhyaya M, Larizza L, Riva P. Mental retardation and cardiovascular malformations in NF1 microdeleted patients point to candidate genes in 17q11.2. J Med Genet. 2004;41:35–41. [PMC free article: PMC1757270] [PubMed: 14729829]
  259. Vinchon M, Soto-Ares G, Ruchoux MM, Dhellemmes P. Cerebellar gliomas in children with NF1: pathology and surgery. Childs Nerv Syst. 2000;16:417–20. [PubMed: 10958550]
  260. Virdis R, Sigorini M, Laiolo A, Lorenzetti E, Street ME, Villani AR, Donadio A, Pisani F, Terzi C, Garavelli L. Neurofibromatosis type 1 and precocious puberty. J Pediatr Endocrinol Metab. 2000;13 Suppl 1:841–4. [PubMed: 10969931]
  261. Virdis R, Street ME, Bandello MA, Tripodi C, Donadio A, Villani AR, Cagozzi L, Garavelli L, Bernasconi S. Growth and pubertal disorders in neurofibromatosis type 1. J Pediatr Endocrinol Metab. 2003;16 Suppl 2:289–92. [PubMed: 12729406]
  262. Viskochil DH. The structure and function of the NF1 gene. In: Friedman JM, Gutmann DH, MacCollin M, Riccardi VM, eds. Neurofibromatosis: Phenotype, Natural History, and Pathogenesis. Baltimore, MD: Johns Hopkins University Press; 1999:119-41.
  263. Viskochil D, White R, Cawthon R. The neurofibromatosis type 1 gene. Annu Rev Neurosci. 1993;16:183–205. [PubMed: 8460890]
  264. Vogt J, Kohlhase J, Morlot S, Kluwe L, Mautner VF, Cooper DN, Kehrer-Sawatzki H. Monozygotic twins discordant for neurofibromatosis type 1 due to a postzygotic NF1 gene mutation. Hum Mutat. 2011;32(6):E2134–47. [PubMed: 21618341]
  265. Walker L, Thompson D, Easton D, Ponder B, Ponder M, Frayling I, Baralle D. A prospective study of neurofibromatosis type 1 cancer incidence in the UK. Br J Cancer. 2006;95:233–8. [PMC free article: PMC2360616] [PubMed: 16786042]
  266. Wallace MR, Marchuk DA, Andersen LB, Letcher R, Odeh HM, Saulino AM, Fountain JW, Brereton A, Nicholson J, Mitchell AL, Brownstein BH, Collins FS. Type 1 neurofibromatosis gene: identification of a large transcript disrupted in three NF1 patients. Science. 1990;249:181–6. [PubMed: 2134734]
  267. Warbey VS, Ferner RE, Dunn JT, Calonje E, O'Doherty MJ. [18F]FDG PET/CT in the diagnosis of malignant peripheral nerve sheath tumours in neurofibromatosis type-1. Eur J Nucl Med Mol Imaging. 2009;36:751–7. [PubMed: 19142634]
  268. Watt SE, Shores A, North KN. An examination of lexical and sublexical reading skills in children with neurofibromatosis type 1. Child Neuropsychol. 2008;14:401–18. [PubMed: 17963094]
  269. Widemann BC. Current status of sporadic and neurofibromatosis type 1-associated malignant peripheral nerve sheath tumors. Curr Oncol Rep. 2009;11:322–8. [PubMed: 19508838]
  270. Widemann BC, Salzer WL, Arceci RJ, Blaney SM, Fox E, End D, Gillespie A, Whitcomb P, Palumbo JS, Pitney A, Jayaprakash N, Zannikos P, Balis FM. Phase I trial and pharmacokinetic study of the farnesyltransferase inhibitor tipifarnib in children with refractory solid tumors or neurofibromatosis type I and plexiform neurofibromas. J Clin Oncol. 2006;24:507–16. [PubMed: 16421428]
  271. Wilding A, Ingham SL, Lalloo F, Clancy T, Huson SM, Moran A, Evans DG. Life expectancy in hereditary cancer predisposing diseases: an observational study. J Med Genet. 2012;49:264–9. [PubMed: 22362873]
  272. Williams VC, Lucas J, Babcock MA, Gutmann DH, Korf B, Maria BL. Neurofibromatosis type 1 revisited. Pediatrics. 2009;123:124–33. [PubMed: 19117870]
  273. Wimmer K, Yao S, Claes K, Kehrer-Sawatzki H, Tinschert S, De Raedt T, Legius E, Callens T, Beiglböck H, Maertens O, Messiaen L. Spectrum of single- and multiexon NF1 copy number changes in a cohort of 1,100 unselected NF1 patients. Genes Chromosomes Cancer. 2006;45:265–76. [PubMed: 16283621]
  274. Wise JB, Cryer JE, Belasco JB, Jacobs I, Elden L. Management of head and neck plexiform neurofibromas in pediatric patients with neurofibromatosis type 1. Arch Otolaryngol Head Neck Surg. 2005;131:712–8. [PubMed: 16103304]
  275. Wolkenstein P, Durand-Zaleski I, Moreno JC, Zeller J, Hemery F, Revuz J. Cost evaluation of the medical management of neurofibromatosis 1: a prospective study on 201 patients. Br J Dermatol. 2000;142:1166–70. [PubMed: 10848741]
  276. Wolkenstein P, Frèche B, Zeller J, Revuz J. Usefulness of screening investigations in neurofibromatosis type 1. A study of 152 patients. Arch Dermatol. 1996;132:1333–6. [PubMed: 8915311]
  277. Wu R, Legius E, Robberecht W, Dumoulin M, Cassiman JJ, Fryns JP. Neurofibromatosis type I gene mutation in a patient with features of LEOPARD syndrome. Hum Mutat. 1996;8:51–6. [PubMed: 8807336]
  278. Xu W, Mulligan LM, Ponder MA, Liu L, Smith BA, Mathew CG, Ponder BA. Loss of NF1 alleles in phaeochromocytomas from patients with type I neurofibromatosis. Genes Chromosomes Cancer. 1992;4:337–42. [PubMed: 1377942]
  279. Yang FC, Ingram DA, Chen S, Zhu Y, Yuan J, Li X, Yang X, Knowles S, Horn W, Li Y, Zhang S, Yang Y, Vakili ST, Yu M, Burns D, Robertson K, Hutchins G, Parada LF, Clapp DW. Nf1-dependent tumors require a microenvironment containing Nf1+/-- and c-kit-dependent bone marrow. Cell. 2008;135:437–48. [PMC free article: PMC2788814] [PubMed: 18984156]
  280. Yilmaz K, Ozmen M, Bora Goksan S, Eskiyurt N. Bone mineral density in children with neurofibromatosis 1. Acta Paediatr. 2007;96:1220–2. [PubMed: 17608828]
  281. Yohay KH. The genetic and molecular pathogenesis of NF1 and NF2. Semin Pediatr Neurol. 2006;13:21–6. [PubMed: 16818172]
  282. Yoshida Y, Sato N, Furumura M, Nakayama J. Treatment of pigmented lesions of neurofibromatosis 1 with intense pulsed-radio frequency in combination with topical application of vitamin D3 ointment. J Dermatol. 2007;34:227–30. [PubMed: 17352718]
  283. Zamora AC, Collard HR, Wolters PJ, Webb WR, King TE. Neurofibromatosis-associated lung disease: a case series and literature review. Eur Respir J. 2007;29:210–4. [PubMed: 16870664]
  284. Zöller M, Rembeck B, Akesson HO, Angervall L. Life expectancy, mortality and prognostic factors in neurofibromatosis type 1. A twelve-year follow-up of an epidemiological study in Göteborg, Sweden. Acta Derm Venereol. 1995;75:136–40. [PubMed: 7604643]

Suggested Reading

  1. Ferner RE, Huson SM, Evans DGR. Neurofibromatoses in Clinical Practice. London, UK: Springer; 2011.
  2. Gutmann DH, Collins FS. Neurofibromatosis 1. In: Valle D, Beaudet AL, Vogelstein B, Kinzler KW, Antonarakis SE, Ballabio A, eds. The Online Metabolic and Molecular Bases of Inherited Disease (Scriver’s OMMBID). New York, NY: McGraw-Hill. Chap 39. Available at www​.ommbid.com. Accessed 7-16-12.
  3. Kaufmann D, ed. Neurofibromatoses. Monographs in Human Genetics. Vol 16. Basel, Switzerland: Karger; 2008.
  4. Korf BR, Rubenstein AE. Neurofibromatosis: A Handbook for Patients, Families, and Health Care Professionals. 2 ed. New York, NY: Thieme Medical Publishers; 2005.

Chapter Notes

Revision History

  • 3 May 2012 (me) Comprehensive update posted live
  • 2 June 2009 (me) Comprehensive update posted live
  • 31 January 2007 (me) Comprehensive update posted to live Web site
  • 5 October 2004 (me) Comprehensive update posted to live Web site
  • 30 September 2002 (me) Comprehensive update posted to live Web site
  • 2 October 1998 (pb) Review posted to live Web site
  • Spring 1996 (jmf) Original submission
Copyright © 1993-2014, University of Washington, Seattle. All rights reserved.

For more information, see the GeneReviews Copyright Notice and Usage Disclaimer.

For questions regarding permissions: ude.wu@tssamda.

Bookshelf ID: NBK1109PMID: 20301288
PubReader format: click here to try


Tests in GTR by Gene

Tests in GTR by Condition

Related information

  • MedGen
    Related information in MedGen
  • OMIM
    Related OMIM records
  • PMC
    PubMed Central citations
  • PubMed
    Links to pubmed
  • Gene
    Gene records cited in chapters on the NCBI bookshelf. Links are provided by the authors or the NCBI Bookshelf staff.

Related citations in PubMed

See reviews...See all...

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...