Neurofibromatosis type I

NF1, Von Recklinghausen Disease, Von Recklinghausen's Neurofibromatosis INTRODUCTION Neurofibromatosis type 1 ( NF1), also known as von Recklinghausen disease, is an autosomal dominant, commonly inherited disease that affects one of every 3000 individuals. The gene responsible for this condition has been isolated by positional cloning to chromosomal region 17q11.2. It spans over 350 kb of genomic DNA and encodes neurofibromin, a protein product of 2818 amino acids that is expressed in various tissues. It is possibly the most common inherited disorder caused by a single gene. SYNDROMS A neurofibroma is a mass lesion of the peripheral nervous system. Its cellular lineage is uncertain, and may derive from Schwann cells, other perineural cell lines, or fibroblasts. Neurofibromas may arise sporadically, or in association with NF-1. A neurofibroma may arise at any point along a peripheral nerve. A cutaneous neurofibroma manifests as single or multiple firm, rubbery bumps of varying sizes on a person's skin. A solitary neurofibroma may also occur in a deeper nerve trunk, and only be seen on cross-sectional imaging (e.g., computed tomography or magnetic resonance) as a fusiform enlargement of a nerve. The hallmark lesion of NF-1 is the plexiform neurofibroma. These lesions are composed of sheets of neurofibromatous tissue that may infiltrate and encase major nerves, blood vessels, and other vital structures. These lesions are difficult and sometimes impossible to routinely resect without causing any significant damage to surrounding nerves and tissue. When a plexiform neurofibroma manifests on a leg or arm, it will cause extra blood circulation, and may thus accelerate the growth of the limb. This may cause considerable difference in length between left and right limbs. To equalize the difference during childhood, there is an orthopedic surgery called epiphysiodesis, where growth at the epiphyseal (growth) plate is halted. It can be performed on one side of the bone to help correct an angular deformity, or on both sides to stop growth of that bone completely. The surgery must also be carefully planned with regard to timing, as it is non-reversible. The goal is that the limbs are at near-equal length at end of growth. Schwannomas are peripheral nerve-sheath tumor seen with increased frequency in NF-1. In practice, the major distinction between a schwannoma and a solitary neurofibroma is that a schwannoma can be resected while sparing the underlying nerve, whereas resection of a neurofibroma requires the sacrifice of the underlying nerve. Malignant peripheral nerve-sheath tumors (MPNST), once called neurofibrosarcomas, can arise from degeneration of a plexiform neurofibroma; this is, however, a rare complication. A plexiform neurofibroma has a lifetime risk of 8-12% of transformation.

DERMATOLOGIC MANIFESTATIONS In addition to the cutaneous neurofibroma, patients with NF-1 develop flat pigmented lesions of the skin called caf au lait spots. NF-1 patients may also get freckles of the axillae (armpits). See Plexiform neurofibroma. CENTRAL NERVOUS SYSTEM MANIFESTATIONS The primary neurologic involvement is of the peripheral nervous system, as described above. Intracranially, NF-1 patients have a predisposition to develop glial tumors of the central nervous system; primarily: optic gliomas and astrocytomas. Another CNS manifestation of NF-1 is the so-called "unidentified bright object" or UBO, which is a lesion which has increased signal on a T2 weighted sequence of a magnetic resonance imaging examination of the brain. These UBOs are typically found in the cerebellar peduncles, pons, midbrain, globus pallidus, thalamus, and optic radiations. Their exact identity remains a bit of a mystery since they disappear over time (usually, by age 16), and they are not typically biopsied or resected. They may represent a focally degenerative bit of myelin. Within the CNS, this manifests as a weakness of the dura, which is the tough covering of the brain and spine. Weakness of the dura leads to focal enlargement (termed dural ectasia) due to chronic exposure to the pressures of CSF pulsation. Radiographically, dural ectasia can lead to scalloping of the posterior vertebral bodies and to the formation of cystic diverticula of the dura of the spine (termedmeningoceles - this meningocele is not related to spina bifida). SKELETAL LESIONS Bones, especially the ribs, can develop chronic erosions (pits) from the constant pressure of adjacent neurofibromas and schwannomas. Similarly, the neural foramen of the spine can be widened due to the presence of a nerve root neurofibroma or schwannoma. In NF-1, these is also a generalized abnormality of the soft tissues, which is referred to as mesodermal dysplasia. This manifests as maldevelopment of skeletal structures, including
Focal scoliosis and/or kyphosis, which is the most common skeletal manifestation of NF-1, occurring in 20% of affected patients. Approximately one quarter of patients will require corrective surgery. Bowing of a long bone with a tendency to fracture and not heal, yielding a pseudarthrosis. The most common bone to be affected is the tibia (causing congenital pseudarthrosis of the tibia or CPT). CPT occurs in 2-4% of individuals with NF-1. Malformation of the facial bones or of the eye sockets (lambdoid suture defects, sphenoid dysplasia) Unilateral overgrowth of a limb

COGNITIVE PROBLEMS The most common complication in patients with NF-1 is cognitive and learning disability. These cognitive problems have been shown to be present in approximately 80% of children with NF-1 and have significant effects on their schooling and everyday life.[10] The most common cognitive problems are with perception, executive functioning and attention. ADHD has been shown to be

present in approximately 38% of children with NF-1. Speech and language delays have also been identified in approximately 68% of preschool children with NF1.[11] Math and motor deficits are also common. These cognitive problems have been shown to be stable into adulthood and do not get worse unlike some of the other physical symptoms of NF-1.[12] Cause of the syndrome? Normal function of the gene , Mutation in NF-1 gene 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 [Dilworth et al 2006, Gottfried et al 2006, Trov-Marqui & Tajara 2006, McClatchey 2007, Riley et al 2007]. 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, Trov-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. The disorder is caused by a mutation in a gene on chromosome 17. The gene codes for a protein called neurofibromin. This protein regulates the activity of another protein called ras, which promotes cell division. When the NF1 gene is mutated, it usually leads to a shortened version of the neurofibromin protein that cannot bind to ras or regulate its activity. As a result, the ras protein is more active. Cells are told to begin dividing and never told when to stop, causing the formation of tumors. MORE DETAILS ABOUT NF1 GENE What is the official name of the NF1 gene? The official name of this gene is neurofibromin 1. NF1 is the gene's official symbol.

How are changes in the NF1 gene related to health conditions?

neurofibromatosis type 1 - caused by mutations in the NF1 gene

More than 1,000 NF1 mutations that cause neurofibromatosis type 1 have been identified. Most of these mutations are unique to a particular family. Many NF1 mutations result in the production of an extremely short version of neurofibromin. This shortened protein cannot perform its normal job of inhibiting cell division. When mutations occur in both copies of the NF1 gene in Schwann cells, the resulting loss of neurofibromin allows noncancerous tumors called neurofibromas to form. Research indicates that the formation of neurofibromas requires the interaction of Schwann cells with other cells, including mast cells. Mast cells are normally involved in wound healing and tissue repair.
cancers - associated with the NF1 gene

In rare cases, inactivation of one copy of the NF1 gene in each cell increases the risk of developing juvenile myelomonocytic leukemia (JMML). Juvenile myelomonocytic leukemia is cancer of blood-forming tissue that usually occurs in children younger than 2. This condition causes the bone marrow to make an excessive number of immature white blood cells that cannot carry out their normal infection-fighting functions. These abnormal cells can build up in the blood and bone marrow, leaving less room for healthy white blood cells, red blood cells, and platelets. Children affected by this disorder may experience fatigue, fever, and easy bleeding or bruising. Where is the NF1 gene located? Cytogenetic Location: 17q11.2 Molecular Location on chromosome 17: base pairs 29,421,944 to 29,704,694

The NF1 gene is located on the long (q) arm of chromosome 17 at position 11.2. More precisely, the NF1 gene is located from base pair 29,421,944 to base pair 29,704,694 on chromosome 17. How do people get NF1? In about half of all cases, a person inherits the mutated gene from a parent. The disorder is inherited in an autosomal dominant pattern, which means that only one copy of the defective gene has to be inherited for a child to get the disorder. Each child of a parent with NF1 runs a 50 percent risk of getting the disorder. In the other half of NF1 cases, a person will have no family history of the disease. The mutation is new and has likely occurred early in life (during the development of the embryo). The mutation will not be present in every cell of the person's body, just in some of them. But if it does happen to be in the germ cells (egg or sperm), the person can pass it on to their children. New mutations are so frequently the cause of NF1 because the NF1 gene is very large, making it more likely to accrue mutations.

How do doctors diagnose NF1? Most of the time, the NF1 is diagnosed by its physical symptoms (tumors or cafe au lait spots), or by a family history of the disorder. The cafe au lait spots usually appear within the first two years of a child's life. NF1 can be diagnosed by sequencing a person's NF1 gene to identify mutations. But because of the gene's large size and the high number of possible mutations that can occur, genetic testing is usually not practical - and very expensive. Physicians usually won't recommend genetic testing for two simple reasons: a diagnosis of NF1 is fairly easy to confirm on the basis of its physical signs, and genetic testing offers no extra benefits for treatment at this time. One exception to this is for people who have a family history of NF1. If another family member has been tested, and the mutation has been identified, then it becomes relatively easy to look for

that same mutation in other family members. Finding the mutation would then confirm the diagnosis of NF1. 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]. The 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 caf au lait macules over 5 mm in greatest diameter in prepubertal individuals and over 15 mm in greatest diameter in postpubertal individuals Two or more neurofibromas of any type or one plexiform neurofibroma 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

Complications : Chronic pain, numbness, and/or paralysis due to the peripheral nerve sheath tumors Blindness due to optic nerve gliomas Chronic hypertension from renal artery anomalies or pheochromocytoma, which patients with NF-1 are at increased risk of developing. Brain tumors Neurologic impairment due to severe spinal scoliosis and/or kyphosis, including but not limited to hydrocephalus Amputation due to a tibial pseudarthrosis Malignant degeneration of a plexiform neurofibroma into malignant peripheral nerve sheath tumor (MPNST), occurring in 8-12% Depression due to the shame of the disfigurement NF can cause to the body and face Social anxiety is also common among NF sufferers because of the reaction of others to the condition

Interesting facts about NF1 People who have NF1 may have very few neurofibromas or they may have thousands of them throughout their body. Neurofibromatosis was first described in medical literature by Dr. Friedrich von Recklinghausen. NF was called Von Recklinghausen's disease for many years.

Diagnosis/testing The diagnosis of NF1 is usually based on clinical findings. Heterozygous mutations of the NF1 gene are responsible for the vast majority of cases of neurofibromatosis. 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, 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 problematic as they are usually asymptomatic and clinically stable or only very slowly progressive. Dystrophic scoliosis often requires surgical management, whereas nondystrophic 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 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 for pregnancies at increased risk is possible if the disease-causing mutation in a family is known. MOLECULAR GENETIC TESTING Gene. Heterozygous mutations of the NF1 gene 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]. 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 much lower detection rates [Wimmer et al 2006, Pros et al 2008]. 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 1700 intragenic SNPs are listed for the NF1 locus in dbSNP. Table 1. Summary of Molecular Genetic Testing Used in Neurofibromatosis 1
Gene Symbo Test Method l NF1 Mutations Detected Nonsense mutations Sequence analysis of mRNA and genomic DNA Missense mutations Splicing mutations Small deletions or insertions Large (whole-gene) deletions Small (intragenic) deletions or duplications Large-scale rearrangements ~90% Mutation Detection Frequency by Test Method 1 Test Availabili ty

NF1

Deletion/duplication anaysis (e.g., FISH, MLPA) 2 Deletion/duplication anaysis (e.g., MLPA) Cytogenetic analysis

Clinical ~5%

~1%

<1%

Test Availability refers to availability in the GeneTests Laboratory Directory. 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. 1. In individuals with a clinical diagnosis of NF1 established by the NIH Diagnostic Criteria 2. Testing that identifies deletions/duplications not detectable by sequence analysis of genomic DNA; a variety of methods including PCR, real-time PCR, long-range PCR, multiplex ligation dependent probe amplification (MLPA), and array GH may be used. Testing Strategy Confirming 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. 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.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutation in the family. Genetically Related (Allelic) 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: A mild variant associated with a 3-bp inframe deletion of exon 17 (c.2970-2972 delAAT), in which neurofibromas are rare and multiple caf-au-lait spots may be the only apparent manifestation [Upadhyaya et al 2007] Familial spinal neurofibromatosis, in which multiple spinal neurofibromas but few, if any, cutaneous manifestations of NF1 occur [Kaufmann et al 2001, Kluwe et al 2003, Upadhyaya et al 2009] 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. 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 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 [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].

The consistent familial transmission of NF1 variants such as Watson syndrome (multiple caf 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, Upadhyaya et al 2009] also indicates that allelic heterogeneity 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 2000c, Szudek et al 2002]. On the other hand, the extreme clinical variability of NF1 suggests the importance of random events in determining the phenotype in 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 the following tumors and other lesions characteristic of NF1:

Neurofibromas [Upadhyaya et al 2004, De Raedt et al 2006, Maertens et al 2006a, Spurlock et al 2007, Upadhyaya et al 2008b, Steinmann et al 2009, Upadhyaya et al 2009] Malignant peripheral nerve sheath tumors [Frahm et al 2004, Upadhyaya et al 2004, Bottillo et al 2009, Upadhyaya et al 2008a] 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 et al 2006b, Stewart et al 2007] Juvenile chronic myelogenous leukemia cells from individuals with NF1 [Stephens et al 2006] Malignant melanoma [Rbben et al 2006] Melanocytes grown from caf-au-lait spots [Maertens et al 2007, De Schepper et al 2008] Tissue associated with tibial pseudarthrosis [Stevenson et al 2006b]

It seems likely that the clinical variability of NF1 results from a combination of genetic, nongenetic, 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 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 [Lzaro 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 et al 2005a]. 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.

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, Mautner et al 2008, Cai et al 2009, Matsumine et al 2008] 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].

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 2007]. Most optic pathway gliomas found on MRI in people with NF1 are asymptomatic [Sylvester et al 2006, Listernick et al 2007]. 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 [Sylvester et al 2006, Dalla Via et al 2007, Lee 2007, Listernick et al 2007, Shamji & Benoit 2007]. 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.
SURVEILLANCE

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, 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

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.
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].* Radiofrequency therapy has shown some promise for treatment of facial diffuse plexiform neurofibromas and caf-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, Gottfried et al 2006].* Several controlled trials for treatment of optic pathway gliomas are available to individuals with NF1 [Dalla Via et al 2007, Listernick et al 2007].*

The use of statins for treatment of learning disabilities in children with NF1 is being evaluated in clinical trials [Krab et al 2008b].* * Note: NIH ClinicalTrials.gov has a more complete list of current clinical trials for NF1 than the Childrens Tumor Foundation. other affected individuals.

GENETIC COUNSELING
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 [Lzaro 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 on 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 maternity (e.g., with assisted reproduction) 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. 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. 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 when the sensitivity of currently available testing is less than 100%. See DNA banking. 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 approximately 15 to 18 weeks' gestation or chorionic villus sampling (CVS) at approximately 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 [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 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, discussion of these issues is appropriate. for a list of laboratories offering

Preimplantation genetic diagnosis (PGD) of NF1 has been reported [Spits et al 2005, Altarescu et al 2006, Vanneste et al 2009] and may be available for families in which the disease-causing mutation has been identified. For laboratories offering PGD, see MOLECULAR GENETICS Table A. Neurofibromatosis 1: Genes and Databases
Gene Chromosomal Symbol Locus NF1 17q11.2 Protein Name Neurofibro min Locus Specific NF1 germline at Center for Medical Genetics, Ghent, Belgium NF1 somatic at Center for Medical Genetics, Ghent, Belgium HGM D NF1

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) linked to, click here. Table B. OMIM Entries for Neurofibromatosis 1 (View All in OMIM)
16220 NEUROFIBROMATOSIS, TYPE 0 I; NF1 61311 NEUROFIBROMIN 1; NF1 3

Normal allelic variants. The NF1 gene 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 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, Ars et al 2003]. Databases of pathologic NF1 mutations are available: see www.nfmutation.org and www.hgmd.org. Table 2. Selected NF1 Pathologic Allelic Variants
DNA Protein Reference

Nucleotide Change

Amino Acid Change

Sequences

c.2970_2972 delAAT

NM_00104249 p.Met992de 2.1 l NP_00103595 7.1

POPULATION GENETICS Littler and Morton (1990) reviewed data from 4 studies on NF1, with the following results: the carrier incidence at birth was 0.0004; the gene frequency was 0.0002; and the proportion of cases due to fresh mutation was 0.56. Lazaro et al. (1994) gave the incidence of NF1 as approximately 1 in 3,500 and stated that about half of cases are the result of new mutations. Garty et al. (1994) found an unusually high frequency of NF1 in young Israeli adults. They surveyed 374,440 17-year-old Jewish recruits for military service and concluded that 390 of them had NF1. The prevalence was 1.04/1,000 (0.94/1,000 for males and 1.19/1,000 for females), which was 2 to 5 times greater than the previously reported prevalence. NF1 was more common in young adults whose parents were of North African and Asian origin (1.81/1,000 and 0.95/1,000, respectively) and less common in those of European and North American origin (0.64/1,000). All these differences were statistically significant; Garty et al. (1994) suggested that they may be partially explained by the more advanced parental age of the NF group (as suggested by the larger number of children in the North African and Asian families) or by founder effect or both. Poyhonen et al. (2000) studied the epidemiology of NF1 in northern Finland. The observed overall prevalence of NF1 was 1 in 4,436 and the incidence 1 in 3,647. There was no evidence of geographic clustering of NF1, nor was there any sign of linkage disequilibrium in DNA studies.