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Neurofibromatosis 1

[NF1, Von Recklinghausen Disease, Von Recklinghausen's Neurofibromatosis]

Summary

Disease characteristics.   Neurofibromatosis 1 (NF1) is characterized by multiple café au lait spots, axillary and inguinal freckling, multiple discrete dermal neurofibromas, and iris Lisch nodules. Learning disabilities are present in at least 50% of individuals with NF1. Scoliosis, vertebral dysplasia, pseudarthrosis, and overgrowth are the most serious bony complications of NF1. Less common but potentially more serious manifestations include plexiform neurofibromas, optic and other central nervous system gliomas, malignant peripheral nerve sheath tumors, osseous lesions, and vasculopathy.

Diagnosis/testing.  The diagnosis of NF1 is based on clinical findings. Heterozygous mutations of the NF1 gene are responsible for the vast majority of cases of neurofibromatosis. Homozygosity for a mutation of one of the genes associated with hereditary non-polyposis colon cancer can produce neurofibromatosis 1 in rare cases. Molecular genetic testing of the NF1 gene is available clinically but is infrequently needed for diagnosis.

Management.  Treatment of manifestations: referral to specialists for treatment of complications involving the eye, central or peripheral nervous 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 problematic as they are frequently stable or only very slowly progressive; dystrophic scoliosis often requires surgical management, whereas non-dystrophic scoliosis can be treated routinely. Surveillance: annual physical examination by a physician familiar with the disease; annual ophthalmologic examination in children, less frequently in adults; regular developmental assessment of children; regular blood pressure monitoring.

Genetic counseling.  NF1 is inherited in an autosomal dominant manner. Half of affected individuals have NF1 as the result of a de novo NF1 gene mutation. The offspring of an affected individual have a 50% risk of inheriting the altered NF1 gene, but the disease manifestations are extremely variable, even within a family. Prenatal testing is available but of limited prognostic value.

Diagnosis

Clinical Diagnosis

The diagnostic criteria for neurofibromatosis 1 (NF1) developed by an NIH Consensus Conference in 1987 are generally accepted for routine clinical use [Gutmann et al 1997]. The clinical diagnosis of NF1 is usually unequivocal in all but the youngest children [DeBella, Szudek et al 2000]. 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

Adults.  The NIH diagnostic criteria are both highly specific and highly sensitive in adults with NF1 [Gutmann et al 1997].

Children

• Only about half of children with NF1 and no known family history of NF meet the NIH criteria for diagnosis by age one year, but almost all do by age eight years [DeBella, Poskitt et al 2000] because many features of NF1 increase in frequency with age [Wolkenstein et al 1996 ; Friedman & Birch 1997 ; DeBella, Szudek et al 2000].
• 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, Szudek et al 2000].
• 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.
• A definite diagnosis of NF1 can be made in most of these children by age four years using the NIH criteria.

Molecular Genetic Testing

GeneReviews designates a molecular genetic test as clinically available only if the test is listed in the GeneTests Laboratory Directory by either a US CLIA-licensed laboratory or a non-US clinical laboratory. GeneTests does not verify laboratory-submitted information or warrant any aspect of a laboratory's licensure or performance. Clinicians must communicate directly with the laboratories to verify information. —ED.

Gene.  Heterozygous mutations of the NF1 gene are responsible for the vast majority of cases of NF1.

Clinical uses

• Confirmatory diagnostic testing for individuals in whom NF1 is suspected but who do not fulfill the NIH diagnostic criteria. Molecular testing for NF1 is infrequently indicated clinically. As a consequence of the large size of the NF1 gene and the fact that many different mutations occur, identification of specific mutations in individuals requires multi-step testing.
• Prenatal diagnosis
• Preimplantation genetic diagnosis

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 on a clinical basis [Messiaen et al 2000 , Messiaen et al 2001]. This protocol begins with an optimized protein truncation test. In some laboratories, this test alone can detect about 80% of pathogenic mutations [Messiaen et al 2000 , Messiaen et al 2001], although lower rates of mutation detection have been reported by others. If a truncated peptide is found, the underlying mutation is identified at both the cDNA and gDNA level by sequencing of the relevant regions. If no mutation is found with the protein truncation test, the protocol continues with the following:

  • FISH analysis for total gene deletions

  • Direct sequencing of the entire coding region for missense mutations or smaller in-frame deletions/insertions escaping detection by PTT

  • Long-range RT-PCR and Southern blot analysis for intragenic deletions

  • Cytogenetic analysis for large-scale rearrangements

• Sequencing of the entire NF1 coding region, including all exons and adjacent intronic sequences and automated comparative sequence analysis, can identify pathogenic mutations in 89% of individuals who meet the NIH Diagnostic Criteria for NF1 [Mattocks et al 2004]. This technique does not detect whole-gene deletions, and the addition of FISH, MLPA (multiplex ligation-dependent probe amplification), or genotyping with multiple microsatellite markers [Kluwe et al 2004] to identify NF1 microdeletions in cases in which sequencing is uninformative would presumably produce a mutation detection frequency similar to that obtained using Messiaen's multi-step protocol.

• Testing for whole-gene deletions.  Testing is sometimes performed to look for whole NF1 gene deletions alone when the "large deletion phenotype" is suspected clinically [Upadhyaya et al 1998 , Riva et al 2000 , Venturin et al 2004]. Whole NF1 gene deletions occur in 4%-5% of individuals with NF1 [Kluwe et al 2004]. Whole NF1 gene deletions can be identified by FISH, MLPA, or testing for multiple SNPs or other polymorphic genetic markers in the NF1 genomic region [Wimmer et al 2006].

• 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 500 intragenic SNPs are listed for the NF1 locus in dbSNP.

Table 1. Molecular Genetic Testing Used in NF1 Test Method NF1 Mutations Detected Mutation Detection Frequency  1,  2 Test Availability Optimized protein truncation testing Nonsense mutations Frameshift mutations Splicing mutations ~80% Clinical Sequence analysis Nonsense mutations Missense mutations Splicing mutations Small deletions or insertions ~90% FISH or MLPA Large (whole gene) deletions ~5% MLPA Small (intragenic) deletions or duplications ~1% Cytogenetic analysis Large-scale rearrangements <1%

1. Proportion of affected individuals with a mutation(s) as classified by test method 2. In individuals with a clinical diagnosis of NF1 established by the NIH Diagnostic Criteria

Interpretation of test results.  For issues to consider in interpretation of sequence analysis results, click here.

Genetically Related (Allelic) Disorders

Apparently pathogenic NF1 mutations have been demonstrated in a few individuals or families who do not have NF1 according to the NIH Diagnostic Criteria:

• Three families with multiple spinal neurofibromas but no café au lait spots [Kaufmann et al 2001 , Kluwe et al 2003]
• A man with optic glioma but no other diagnostic features of NF1 [Buske et al 1999]
• A child with encephalocraniocutaneous lipomatosis [Legius et al 1995]

The relationship of the NF1 mutations to the unusual phenotypes in these families is not understood.

Clinical Description

Natural History

The clinical manifestations of neurofibromatosis 1 (NF1) are extremely variable [Friedman & Birch 1997 , Friedman & Riccardi 1999]. Multiple café au lait spots occur in nearly all affected individuals and intertriginous freckling develops in almost 90%. Numerous benign cutaneous or subcutaneous neurofibromas are usually present in adults with NF1. Plexiform neurofibromas are less common but can cause disfigurement and may compromise function or even jeopardize life. Most are internal, asymptomatic, and not suspected on physical examination [Tonsgard et al 1998]. Ocular manifestations of NF1 include optic gliomas, which may lead to blindness, and Lisch nodules (innocuous iris hamartomas). Scoliosis, vertebral dysplasia, pseudarthrosis, and overgrowth are the most serious bony complications of 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 [North et al 1997 , North 1999]. Among individuals with NF1, headaches occur frequently and seizures or hydrocephalus occasionally [North 1998 , Creange et al 1999 , Vivarelli et al 2003].

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 & Birch 1997 ; Friedman & Riccardi 1999 ; DeBella, Szudek et al 2000 ; Boulanger & Larbrisseau 2005]. 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. In contrast, deep nodular plexiform neurofibromas are not often seen in early childhood and may remain asymptomatic even in adulthood [Tonsgard et al 1998]. Optic gliomas develop in the first six years of life. The rapidly progessive (dysplastic) form of scoliosis almost always develops between six and ten years of age, although milder forms of scoliosis without vertebral anomalies typically occur during adolescence. Malignant peripheral nerve sheath tumors (neurofibrosarcomas) usually occur in adolescents and adults.

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 [Dugoff & Sujansky 1996].

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 about 50%-75% [North et al 1997 , North 1999 , Kayl & Moore 2000 , Rosser & Packer 2003 , Hyman et al 2005 f, Hyman et al 2006 , Levine et al 2006]. Visual-spatial performance deficits and attention deficits are most often seen [Koth et al 2000 , Mautner et al 2002 , Schrimsher et al 2003 , Hyman et al 2006 , Levine et al 2006], although a variety of learning problems have been described. The learning problems associated with NF1 persist into adulthood [Zoller et al 1997 , 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].

The clinical significance of the so-called "unidentified bright objects" (UBOs) visualized on brain MRI scan in at least 60% of children with NF1 is uncertain [Es et al 1996 ; Menor et al 1998 ; Griffiths et al 1999 ; Rosenbaum et al 1999 ; Curless 2000 ; DeBella, Poskitt et al 2000 ; Boulanger & Larbrisseau 2005 ; Goh et al 2004 ; Gill et al 2006]. 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] 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]. Some studies have suggested that the presence, number, volume, or location of UBOs correlates with learning disabilities in children with NF1, but the findings have not been consistent among investigations [North et al 1997 , North 1999 , Feldmann et al 2003 , Hyman et al 2003 , Goh et al 2004].

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].

Valvar pulmonic stenosis is more common in individuals with NF1 than in the general population [Lin et al 2000]. 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 1999 , Friedman et al 2002 , Tatebe et al 2005 , Kanter et al 2006 , Tang et al 2006]. 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 [Gutmann 1999]. Ectatic vessels and intracranial aneurysms occur more frequently in individuals with NF1 than in the normal population [Rosser et al 2005 , Schievink et al 2005].

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]. 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 frequent in persons with NF1 with optic gliomas who are treated with radiotherapy.

Malignant peripheral nerve sheath tumors are the most frequent malignant neoplasms associated with NF1, occurring in about 10% of affected individuals [Rasmussen et al 2001 , Evans et al 2002 , Walker et al 2006]. 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 [Evans et al 2002 , Hagel et al 2006]. 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].

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].

Generalized osteopenia and frank osteoporosis appear to be more common in people with NF1 than in the general population [Lammert, Kappler et al 2005]. The pathogenesis of these bony changes is not understood, but individuals with NF1 have also been found to have lower-than-expected serum 25-hydroxyvitamin D concentrations [Lammert et al 2006] and decreased muscle cross-sectional area on peripheral quantitative computed tomography [Stevenson et al 2005].

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. 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]. In contrast, persons with NF1 whose mutation is a deletion of the entire NF1 locus show a different pattern, with overgrowth, especially between two and six years of age [Spiegel et al 2005]. The clinical features in some these children resemble those of Weaver syndrome.

Segmental or regional NF is sometimes diagnosed in individuals who have features of NF1 restricted to one part of the body and whose parents are both unaffected [Friedman & Riccardi 1999 , 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 individuals, segmental NF represents mosaicism for a somatic NF1 mutation [Tinschert et al 2000 , Vandenbroucke et al 2004 , Consoli et al 2005]. However, most individuals who have been reported with mosaicism for an NF1 mutation have mild, but not segmental, neurofibromatosis [Wu et al 1997 , Rasmussen et al 1998]. Individuals with segmental NF whose children have typical NF1 have been reported [Oguzkan et al 2004 , Consoli et al 2005].

A Noonan syndrome phenotype occurs in about 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]. Most individuals with NF1-Noonan syndrome have constitutional mutations of the NF1 gene [De Luca et al 2005 ; Huffmeier et al 2006 ; Stevenson, Viskochil et al 2006]. Mutations of the PTPN11 gene, which can be found in about half of all persons with Noonan syndrome, are very rare in persons with the NF1-Noonan syndrome phenotype [De Luca et al 2005].

Although most pregnancies in women with NF1 are normal, serious complications can occur [Dugoff & Sujansky 1996]. 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.

The average life expectancy of individuals with NF1 is reduced by about 15 years [Zoller et al 1995 , Rasmussen et al 2001]. Malignancy, especially malignant peripheral nerve sheath tumors, and vasculopathy are the most important causes of early death in individuals with NF1.

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 individual with NF1 at different times in life. Only two clear correlations have been observed between particular mutant NF1 alleles and consistent clinical phenotypes:

• A whole NF1 gene deletion is associated with large numbers and early appearance of cutaneous neurofibromas, more frequent and more severe cognitive abnormalities than average, and sometimes somatic overgrowth, large hands and feet, and dysmorphic facial features [Tonsgard et al 1997 , Upadhyaya et al 1998 , Riva et al 2000 , Venturin et al 2004 , Spiegel et al 2005 , Mensink et al 2006].
• A 3-bp in-frame deletion of exon 17 (c.2970-2972 delAAT) is associated with typical pigmentary features of NF1, but no cutaneous or surface plexiform neurofibromas [Upadhyaya et al 2007].

Some investigators interpret this variability as evidence that most complications of NF1 result from the effects of additional random events in individuals [Riccardi 1993]. 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 a variety of tumors characteristic of NF1:

• Neurofibromas [Sawada et al 1996 ; Serra et al 1997 ; Eisenbarth et al 2000 ; John et al 2000 ; Rasmussen et al 2000 ; Rutkowski et al 2000 ; Perry et al 2001 ; Wiest et al 2003 ; Upadhyaya et al 2004 ; De Raedt et al 2006 ; Maertens, Brems et al 2006]
• Malignant peripheral nerve sheath tumors [Rasmussen et al 2000 , Perry et al 2001 , Frahm et al 2004 , Upadhyaya et al 2004]
• Pheochromocytomas [Xu et al 1992]
• Astrocytomas [Gutmann et al 2000 , Gutmann et al 2003 , Tada et al 2003 , Upadhyaya et al 2004]
• Gastrointestinal stromal tumors [Maertens, Prenen et al 2006]
• Juvenile chronic myelogenous leukemia cells from individuals with NF1
• Tissue associated with tibial pseudarthriosis [Stevenson, Zhou et al 2006]

Conversely, consistent familial transmission of NF1 variants such as Watson syndrome (multiple café au lait spots, pulmonic stenosis, and dull intelligence) and familial spinal neurofibromatosis [Ars et al 1998 , Kaufmann et al 2001 , Kluwe et al 2003] indicates that allelic heterogeneity also plays a role in the clinical variability of NF1. In addition, statistical analysis of clinical features in families with NF1 suggests that modifying genes at other loci influence some aspects of the NF1 phenotype [Easton et al 1993 , Szudek et al 2000 ; Szudek et al 2002].

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 very difficult.

Penetrance

Penetrance is virtually complete after childhood.

Anticipation

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

Nomenclature

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.

Prevalence

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, Friedman et al 2005].

Almost half of all affected individuals have a de novo mutation. The mutation rate for the NF1 gene (~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

For current information on availability of genetic testing for disorders included in this section, see GeneTests Laboratory Directory. —ED.

More than 100 genetic conditions and multiple congenital anomaly syndromes that include café au lait spots or other individual features of neurofibromatosis 1 (NF1) have been described, but few of these disorders are ever confused with NF1.

Conditions most frequently confused with NF1 include the following:

• Homozygosity for one of the genes causing hereditary non-polyposis colon cancer (HNPCC) [Puisieux 1999 , Ricciardone et al 1999 , Wang et al 1999 , Trimbath et al 2001 , Vilkki et al 2001 , Whiteside et al 2002 , Gallinger et al 2004 , Raevaara et al 2004 , Ostergaard et al 2005]. 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.
• Neurofibromatosis type 2 (bilateral vestibular schwannomas, schwannomas of other cranial and peripheral nerves, cutaneous schwannomas, meningiomas, juvenile posterial 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)
• 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, ateriovenous 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)

Management

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
• Family 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

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 [Es et al 1996 , Menor et al 1998 , Griffiths et al 1999 , Curless 2000 , Pinson et al 2002 , Blazo et al 2004]. 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 [Gutmann et al 1997 ; DeBella, Szudek et al 2000 ; King et al 2003 ; Thiagalingam et al 2004]. 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 clear benefit.

Similar recommendations have been made by others for the health supervision of individuals with NF1 [Gutmann et al 1997 , Pinson et al 2002 , Ferner et al 2006].

A much more extensive routine evaluation including the following is advocated by some authorities [Riccardi 1999]:

• Psychological testing
• MRI scan of the orbits and brain
• Plain radiographs of the skull, chest, and spine
• Electroencephalogram
• Audiogram, brain stem auditory evoked response, or both

Treatment of Manifestations

Individuals with NF1 who have complications involving the eye, central or peripheral nervous system, spine, or long bones 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. 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 usually the method of choice for demonstrating the size and extent of plexiform neurofibromas [Lim et al 2005 , Mautner et al 2006], but other imaging methods may also be very valuable in some circumstances [Hillier & Moskovic 2005 , Restrepo et al 2005]. 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 [Neville et al 2001 , Packer et al 2002 , Packer & Rosser 2002 , Kim et al 2005 , Wise et al 2005 , Gottfried et al 2006 , Murovic et al 2006].

Pain, development of a neurologic deficit, and 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 PET and MRI [Ferner et al 2000 , Friedrich et al 2005] may be 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. Adjuvent chemotherapy or radiotherapy is sometimes used as well, although benefit has not been clearly established [Gottfried et al 2006 , Murovic et al 2006].

Treatment of optic gliomas in individuals with NF1 is problematic [Sylvester et al 2006]. Most individuals with optic nerve thickening on MRI scan are asymptomatic and remain so. The natural history of symptomatic optic nerve gliomas in NF1 differs from that in individuals who do not have NF1 because these tumors are frequently stable for many years or only very slowly progressive in NF1 [Chan et al 1998 , Listernick et al 1999 , Listernick & Gutmann 1999 , Allen 2000 , Grill et al 2000 , Rosser & Packer 2002 , Singhal et al 2002 , Astrup 2003 , Czyzyk et al 2003 , Blazo et al 2004]. Optic gliomas may even spontaneously regress in NF1 [Perilongo et al 1999 , Parsa et al 2001 , Zizka et al 2001 , Rosser & Packer 2002 , Astrup 2003]. Thus, many individuals with NF1 who develop optic nerve gliomas do not require treatment. The best method of treatment of individuals with NF1 who have progressive visual deterioration associated with optic nerve glioma has not yet been determined.

Brain stem and cerebellar astrocytomas in individuals with NF1 may also follow a less aggressive course than in individuals without NF1 [Pollack et al 1996 , Korf 2000 , Vinchon et al 2000 , Rosser & Packer 2002]. Occasional regression of these tumors in individuals with NF1 has also been reported [Leisti et al 1996 , Schmandt et al 2000 , Rosser & Packer 2002]. This 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.

Surveillance

• Annual physical examination by a physician who is familiar with the individual and with the disease
• Annual ophthalmologic examination in childhood, less frequent examination in 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

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, but 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].

Testing of Relatives at Risk

Both parents and all children of an individual with NF1 should undergo careful physical examination and ophthalmologic assessment (including a slit-lamp examination).

Therapies Under Investigation

Clinical trials of various medical treatments for plexiform and spinal neurofibromas are underway [Liebermann & Korf 1999 , Packer et al 2002 , Packer & Rosser 2002 , Babovic-Vuksanovic et al 2006 , Gottfried et al 2006 , Widemann et al 2006]. ^*

Radiofrequency therapy has shown some promise for treatment of facial diffuse plexiform neurofibromas in a small clinical series [Baujat et al 2006].

Controlled trials of several therapeutic approaches to malignant peripheral nerve sheath tumors are available to individuals with NF1 [Gottfried et al 2006]. ^*

Several controlled trials for treatment of optic pathway gliomas are available to individuals with NF1. ^*

Several controlled trials of statins for treatment of learning disabilities in children with NF1 are in progress. ^*

* See www.ctf.org/research/nf1 .

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.

Other

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. To find a genetics or prenatal diagnosis clinic, see the GeneTests Clinic Directory. —ED.

Mode of Inheritance

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

Risk to Family Members

Parents of a proband

• About 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 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 upon 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.
• Germline mosaicism for an NF1 mutation has been demonstrated in an apparently unaffected man who had two children with typical NF1 [Lazaro 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 mutant gene. 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 upon the status of the proband's parents. If a parent is found to be 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 undisclosed adoption should also be explored.

Family planning.  The optimal time for determination of genetic risk and genetic counseling regarding prenatal testing is before pregnancy.

DNA banking.  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. DNA banking is particularly relevant in situations in which the sensitivity of currently available testing is less than 100%. See DNA Banking for a list of laboratories offering this service.

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 about 15-18 weeks' gestation or chorionic villus sampling (CVS) at about ten to 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 [Clementi et al 1996 , 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 [Drouin et al 1997 , McEwing et al 2006], but ultrasound examination is unlikely to be informative in most cases.

Requests for prenatal testing for conditions such as NF1 which 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 about prenatal testing to be the choice of the parents, careful discussion of these issues is appropriate.

Preimplantation genetic diagnosis (PGD) of NF1 has been reported [Spits et al 2005] and may be available for families in which the disease-causing mutation has been identified in an affected family member. For laboratories offering PGD, see .

Molecular Genetics

Information in the Molecular Genetics tables is current as of initial posting or most recent update. —ED.

Normal allelic variants: The NF1 gene was identified and the protein product characterized in 1990 [Cawthon et al 1990 , Wallace et al 1990]; the entire cDNA sequence was described in 1993 [Gutmann & Collins 1993 , Viskochil et al 1993]. The gene is large (~350 kilobases and 60 exons) and codes for at least three alternatively spliced transcripts [Shen et al 1996 , 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 the NF1 gene 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 , Messiaen et al 2001 , Ars et al 2003]. Databases of pathologic NF1 mutations are available: see www.nfmutation.org and www.hgmd.org .

Normal gene product: The protein product, neurofibromin, has a calculated molecular mass of approximately 327 kd. The function of neurofibromin is not fully understood. It appears to activate ras GTPase, thereby controlling cellular proliferation and acting as a tumor suppressor [Viskochil 1999 , Cichowski & Jacks 2001 , Zhu & Parada 2001 , Gottfried et al 2006 , Trovo-Marqui & Tajara 2006]. Neurofibromin probably has other functions as well, including regulation of adenylyl-cyclase activity and intracellular cyclic-AMP generation [Dasgupta et al 2003 , Rubin & Gutmann 2005 , Ward & Gutmann 2005 , Gottfried et al 2006 , Ismat et al 2006 , Trovo-Marqui & Tajara 2006 , Yohay 2006].

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 , Messiaen et al 2001] and deletion of the entire gene causes typical, although often severe, NF1.

Resources

GeneReviews provides information about selected national organizations and resources for the benefit of the reader. GeneReviews is not responsible for information provided by other organizations. -ED.

References

Published Statements and Policies Regarding Genetic Testing

No specific guidelines regarding genetic testing for this disorder have been developed.

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Suggested Readings

• Ferner RE (2007) Neurofibromatosis 1. Eur J Hum Genet [Epub ahead of print]
  
  
• Gutmann DH and Collins FS (revised 2002) Neurofibromatosis 1. In: Scriver CR, Beaudet AL, Sly WS, Valle D, Vogelstein B (eds) The Metabolic and Molecular Bases of Inherited Disease (OMMBID), McGraw-Hill, New York, Chap 39. www.ommbid.com
  
  
• Huret JL and Wimmer K (updated 2006) Neurofibromatosis type 1 (NF1). Atlas of Genetics and Cytogenetics Oncology and Haematology. atlasgeneticsoncology.org
  
  
• Korf BR, Rubenstein AE (2005) Neurofibromatosis: A Handbook for Patients, Families, and Health Care Professionals, 2nd ed. Thieme Medical Publishers, New York
  
  
• Theos A and Korf BR (2006) Pathophysiology of neurofibromatosis type 1. Ann Intern Med 144:842-9 [Medline]
  
  
• Tonsgard JH (2006) Clinical manifestations and management of neurofibromatosis type 1. Semin Pediatr Neurol 13:2-7 [Medline]
  
  

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