AUTHOR AND EDITOR INFORMATION

Section 1 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

INTRODUCTION

Section 2 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Background

Neurofibromatosis (NF) is a multisystem genetic disorder that commonly is associated with cutaneous, neurological, and orthopedic manifestations. It is the most frequent of the so-called hamartoses.

NF type 1 (NF1) is differentiated from central NF or NF type 2 in which patients demonstrate a relative paucity of cutaneous findings but have a high incidence of meningiomas and acoustic neuromas (which are frequently bilateral). NF1 has a better prognosis with a lower incidence of CNS tumors than NF2. However, morbidity and mortality rates in NF1 are not negligible. Some of the more severe complications are visual loss secondary to optic nerve gliomas, spinal cord tumors, scoliosis, vascular lesions, and long-bone abnormalities, which sometimes necessitate amputation.

Pathophysiology

The manifestations of NF1 result from a mutation in or deletion of the NF1 gene. The gene product neurofibromin serves as a tumor suppressor; decreased production of this protein results in the myriad of clinical features.

Frequency

International

The estimated incidence of NF1 is 1 in 3000, but the actual frequency may be higher because of less than complete ascertainment of mildly affected individuals. Approximately half of affected individuals represent first cases in the family as a result of a new genetic event or mutation.

Mortality/Morbidity

• Lifetime risks for both benign and malignant tumors are increased in NF1-affected individuals.
• Cutaneous or subcutaneous neurofibromas, optic nerve gliomas, dumbbell-shaped spinal cord tumors, and brain tumors represent some of the well-recognized nerve-related neoplasms.
• Malignant peripheral nerve sheath tumors (MPNSTs) and neurosarcomas are not uncommon in adolescents and adults with NF1, with an approximate lifetime risk of 10%. These malignancies frequently arise from large plexiform neurofibromas or extensive peripheral nerve lesions.
• More than 1% of patients with NF1 develop an indolent symmetric sensory axonal neuropathy. However, some cases of polyneuropathy occur in association with diffuse nerve root lesions or MPNSTs.
• Gastrointestinal stromal tumors, often multiple with a predilection for the proximal small bowel, may be seen in patients with NF1.
• Learning disabilities with or without attention deficit hyperactivity disorder (ADHD) are seen in approximately 40% of NF1-affected individuals. A much smaller percentage experience more significant cognitive difficulties such as mild or moderate mental retardation.
• Scoliosis in NF1 is often mild, but a subset of children younger than 10 years develop a more rapidly progressive form of scoliosis that requires aggressive intervention.
• Bony abnormalities may be clinically silent, with radiographic evidence of long bone intramedullary fibrosis, cortical thinning, or vertebral dural ectasias often found incidentally.
  • Sphenoid bone dysplasia and long-bone bowing or pseudarthrosis are common features of NF1.
  • In the past, congenital tibial pseudarthrosis led to below-the-knee amputation; however, recent advances in orthopedic management with limb-sparing procedures have decreased the need for such drastic procedures.
• Hypertension in NF1 can be seen at any age, with many adults with NF1 manifesting the usual essential form of hypertension. However, any person with NF1 and high blood pressure must be evaluated carefully for 2 alternative causes of hypertension (see Prognosis).
  • Pheochromocytomas are not rare in NF1 and can cause severe, fluctuating hypertension.
  • Vascular stenosis (ie, renal artery stenosis secondary to fibromuscular dysplasia) also may result in hypertension that may not respond well to standard pharmacologic management.
• Other vascular lesions, especially in the central nervous system, such as vascular ectasias, stenoses, moyamoya disease, and aneurysms, occur more frequently in patients with NF1.
• Short stature is common in NF1; affected individuals are often shorter than their unaffected siblings.
• Macrocephaly is common in NF1 and should not cause undo alarm if present in affected infants or young children, unless serial head circumference measurements confirm the rapid crossing of percentiles.
• Chiari type 1 malformations are seen with increased frequency in the NF1 population.
• Puberty usually occurs at a normal age, but precocious puberty with growth acceleration may occur in a small number of individuals. When precocious puberty is present, the patient must be evaluated for a chiasmal lesion causing disruption of the hypothalamic-pituitary axis.

Race

All races and ethnic backgrounds are affected equally. However, recent evidence indicates that the risk for optic nerve glioma is lower in African Americans than in Caucasians and Hispanics.

Sex

• Males and females are affected equally with this autosomal dominant condition.
• Scoliosis may be especially severe in young girls compared to their male counterparts.

Age

Although the genetic change causing NF1 is present at conception, clinical manifestations may appear slowly over many years.

• Diagnosis often is made earlier in children born to an NF1-affected parent; the clinical criteria for diagnosis are fulfilled more easily, and the clinician may be more attuned to this possible diagnostic concern.
• If an at-risk individual reaches the age of 10 years without meeting the diagnostic criteria for NF1, he or she is unlikely to be affected.

CLINICAL

Section 3 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

History

• Clinical diagnosis requires the presence of at least 2 of 7 criteria to confirm the presence of NF1. Many of these signs do not appear until later childhood or adolescence, and thus confirming the diagnosis often is delayed despite a suspicion of NF1. The 7 clinical criteria used to diagnose NF1 are as follows:
• • Six or more café-au-lait spots or hyperpigmented macules greater than or equal to 5 mm in diameter in children younger than 10 years and to 15 mm in adults
  • Axillary or inguinal freckles
  • Two or more typical neurofibromas or one plexiform neurofibroma
  • Optic nerve glioma
  • Two or more iris hamartomas (Lisch nodules), often identified only through slit-lamp examination by an ophthalmologist
  • Sphenoid dysplasia or typical long-bone abnormalities such as pseudarthrosis
  • First-degree relative (eg, mother, father, sister, brother) with NF1

Physical

• The earliest clinical finding usually seen in children with NF1 is multiple café-au-lait spots.
• • These may be present at birth or may appear over time, frequently increasing in size and number throughout childhood (see Image 1).
  • In adults, café-au-lait spots tend to fade and may be less obvious on clinical examination.
• Axillary or inguinal freckles are rarely present at birth, but appear during childhood through adolescence (see Images 2-3).
• Subcutaneous or cutaneous neurofibromas are seen rarely in young children but appear over time in older children, adolescents, and adults (see Image 4).
• • Deep lesions may be detected only through palpation, whereas cutaneous lesions may appear initially as small papules on the trunk, extremities, scalp, or face.
  • Puberty or pregnancy may be associated with an increased number of neurofibromas as well as more rapid growth of preexisting lesions.
• Plexiform neurofibromas are more diffuse growths that can be locally invasive and quite deep; they may be associated with bony erosion and pain (see Image 5).
• • Plexiform neurofibromas also may be accompanied by overlying hyperpigmentation or hypertrichosis.
  • Rarely, rapid growth of a neurofibroma may occur and can be suggestive of malignant transformation.
• Optic nerve tumors, which may be clinically silent, occur primarily in children younger than 5 years.
• • Asymmetric, noncorrectable visual loss is the most common presenting symptom, but subtle peripheral field defects, color discrimination difficulties, optic nerve pallor, or proptosis may occur without visual acuity problems.
  • Some older children and adolescents may present with worsening vision secondary to a slow-growing optic nerve glioma (ONG) and, therefore, monitoring for visual difficulties should continue throughout childhood and adulthood. Adults may have a visually insignificant optic nerve glioma detected incidentally on a head imaging study.
• Although Lisch nodules occasionally can be seen with a direct or indirect ophthalmoscope, especially in individuals with light-colored irides, they are usually not readily visible without using a slit lamp (see Image 6).
• Choroidal abnormalities with a patchy appearance may also be noted on funduscopic examination using infrared monochromatic light. Retinal corkscrew vascular changes have also been described in some patients with NF1.
• Sphenoid bone dysplasia is usually asymptomatic, but occasionally can be associated with herniation through the bony defect. In the occasional patient with a plexiform neurofibroma of the eyelid, ipsilateral sphenoid dysplasia is frequently present.
• Congenital pseudarthrosis may be evident at birth, with bowing of the tibia being the most typical presentation (see Image 7).
• • Thinning and angulation of long bones can occur throughout early childhood and adolescence, with prominence of the anterior tibia and progressive deformity.
  • Less commonly, bowing of the forearm can occur.
• Scoliosis with or without kyphosis may become evident in childhood or adolescence.
• • When found in a child younger than 10 years, it is associated with a much poorer prognosis and is likely to progress rapidly.
  • Scoliosis detected during adolescence still should be monitored clinically, but is much less likely to require orthopedic intervention.
• Blood pressure should be checked during every clinical visit because of the distinct possibility of alternative causes of hypertension in NF1.
• Head circumference should be monitored throughout the first 3 years of life, as with any child. Relative macrocephaly should not cause alarm, unless serial measurements suggest rapid growth with crossing of 2 or more percentile lines.

Causes

• NF1 is an autosomal dominant condition caused by decreased production of the protein neurofibromin, which has a putative tumor suppressor function. Only one NF1 gene need be deleted or mutated to produce the condition.
• The NF1 gene has been localized to the long arm of chromosome 17; more than 250 mutations leading to protein truncation having been identified in affected individuals. A more severe phenotype has been observed in a subset of patients with a complete gene deletion.
• The precise role of neurofibromin is not fully understood, but the multitude of clinical effects suggests that this gene product has diverse functions in various tissues.

DIFFERENTIALS

Section 4 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Other Problems to be Considered

Café-au-lait spots
McCune-Albright syndrome
Acoustic neuroma
Brainstem syndromes
Spinal injury

WORKUP

Section 5 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Lab Studies

• Now that the genetic cause of NF1 has been better defined, a protein truncation assay (PTA), which identifies a proportion of individuals with NF1, has been developed. Complete gene sequencing is also now available.
• • The detection rate using PTA varies from 65-70% in those who clearly have NF1 by clinical criteria, and thus the low sensitivity limits its diagnostic usefulness.
  • For patients with a single clinical finding, such as multiple café-au-lait spots in the absence of a positive family history, PTA (when positive) can be helpful.
  • Sequencing of the neurofibromin gene offers the highest detection rate and may approach 95% in clinically affected individuals.
• NF1 may be diagnosed by either of 2 methods during the prenatal period.
• • In a family with multiple affected members, linkage analysis can track the NF1 gene through the generations to determine which chromosome 17 region the fetus received.
  • For a parent with NF1 who is the only affected family member, PTA or gene sequencing can be used to see if a specific gene mutation can be identified. Identification of the mutation in the affected parent would permit prenatal diagnosis via amniocentesis or chorionic villus sample (CVS).
  • Preimplantation genetic diagnosis could also be offered to couples using in vitro fertilization with selection of unaffected embryos for transfer.

Imaging Studies

• Radiography
• • Plain films may detect a variety of subtle and not so subtle bony abnormalities associated with NF1 (see Image 7).
  • Radiographs should be obtained when clinical findings suggest possible modeling defects of the long bones or ribs, possible bony erosion secondary to an adjacent plexiform neurofibroma, signs of scoliosis, or bone pain.
• MRI or CT scan
• • In the past, MRI or CT scans have been ordered routinely for patients with NF1. More recently, clinicians have moved away from standard screening and opted for head imaging in patients with specific indications.
  • Some clinicians prefer to perform a baseline CT scan or MRI in children or adults at the time of diagnosis, subsequently recommending another imaging study only if neurological problems arise. Other clinicians feel that baseline studies are of limited value, since detecting an asymptomatic optic nerve glioma would probably not prompt medical intervention.
  • MRI has become the preferred diagnostic head imaging study in NF1.
    • MRI has been shown to frequently detect unidentified bright objects (UBOs) in the brain parenchyma of patients with NF1 (see Image 8).
    • These bright spots seen on T2-weighted images generally do not enhance, cause no mass effect, and often resolve as the individual gets older.
    • They are believed to represent benign hamartomas in NF1 and are seen more often in children with NF1-related learning disabilities.
  • Brain CT scan or MRI should be considered to evaluate ventricular size when increasing head circumferences is noted in an infant or young child. Rarely, hydrocephalus and/or a Chiari type 1 malformation are seen in children and even adults with NF1.
  • MRI is also a valuable tool in evaluating the optic nerves or optic chiasm (see Image 9).
    • It is indicated for patients with optic nerve pallor, visual changes, proptosis, or precocious puberty.
    • Thin cuts through the orbits and optic nerves are an ideal way to identify subtle optic nerve pathology.
  • Head MRI should be considered in patients with headaches that are changing in quality or are increasing in frequency or intensity. Although brain tumors are less common in NF1 than in NF2, they can still occur in this clinical setting.
  • MRI has proven useful in evaluating internal lesions such as mediastinal masses, spinal cord tumors, deep plexiform neurofibromas, neurofibromas of the brachial or sacral plexus, as well as abdominopelvic lesions. Short T1-inversion recovery MR images can be used to accurately estimate the volume of a plexiform neurofibroma, which can be useful for both diagnosis and follow-up.
• Positron emission tomography: F-18 fluorodeoxyglucose (FDG) positron emission tomography (PET) may be used to stage and follow up MPNSTs before, during, and after therapy.

Other Tests

• Electroencephalogram (EEG) is indicated in patients with symptoms suggestive of seizures. Seizures are reported more often in patients with NF1 than in the general population, occurring in between 4 and 7%.
• MRI alone is generally sufficient for medical and/or surgical decision making. Occasionally, myelography is needed to clarify the extent of a spinal cord tumor.

Procedures

• Slit-lamp examination by an experienced ophthalmologist can provide key diagnostic information in older children and adults who have only a single clinical criterion such as multiple café-au-lait spots.
• • The occurrence of Lisch nodules appears to be age dependent; more than 95% of NF1-affected individuals older than 10 years have this iris finding.
  • This examination is invaluable in determining if parents of an affected child carry the NF1 mutation, even when the parent has no other signs of the condition.

Histologic Findings

• Neurofibromas are generally well-differentiated tumors that contain elongated spindle-shaped cells as well as pleomorphic fibroblast-like cells. Rarely, inflammatory cells may be seen in these otherwise benign-appearing lesions.
• Optic gliomas also are indolent, generally very low-grade lesions. In fact, optic nerve lesions associated with NF1 are less aggressive and respond more favorably to current therapies than optic nerve tumors in the general population.
• Occasionally, a neurofibroma (typically large or deep plexiform neurofibroma or peripheral nerve sheath tumor residing within the brachial or pelvic plexus) undergoes malignant transformation to a neurofibrosarcoma. Unlike benign neurofibromas, neurofibrosarcomas are characteristically hypercellular with giant cells, increased numbers of mitoses, and vascular proliferation.
• Because collections of malignant cells may be present between larger masses of benign cells in a plexiform neurofibroma, examining a plexiform tumor carefully (ie, taking samples from multiple regions to confirm that it is indeed benign) is essential.

TREATMENT

Section 6 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Medical Care

• For individuals diagnosed with NF1, routine examinations should focus on the potential complications.
  • Annual examinations permit early detection of problems, decreasing morbidity and improving quality of life.
  • Annual eye examinations are important in early detection of optic nerve lesions.
• Cutaneous examination performed at each visit should look for new neurofibromas or progression of preexisting lesions. Plexiform neurofibromas may be locally invasive, therefore clinical evaluation should be directed at determining the extent of involvement and detecting evidence of bony erosion or nerve entrapment.
• Skeletal involvement, including scoliosis, hemihypertrophy, or long-bone modeling defects, should be documented.
• Blood pressure should be checked at each visit and hypertension treated promptly if detected. Hypertension workup should include evaluation for pheochromocytoma (ie, measurement of urinary catecholamines and metanephrines) and testing for renal artery stenosis. Percutaneous transluminal renal artery angioplasty may, in some cases, effectively treat renal artery stenosis secondary to fibromuscular dysplasia.
• Interval history should focus on subtle sensory or motor symptoms such as paresthesia, radiculopathy, weakness, or muscle atrophy.
• • Patients should be asked about incontinence. At each visit, minor changes in the sensory or motor examination should be documented carefully.
  • Symptoms of spinal cord neurofibromas may be subtle and slowly progressive; prompt identification and early surgical intervention allow for optimal outcome.
• Removal of neurofibromas for medical or cosmetic indications is one of the most common procedures on individuals with NF1.
• • Recent advances in laser technology have permitted nonsurgical removal of small, cutaneous neurofibromas.
  • However, careful surgical resection of small or large neurofibromas may leave an even smaller, less prominent scar.
• Although laser treatment has been used for various cutaneous, hyperpigmented lesions (eg, port-wine stains, tattoos), it has not yet proven successful in permanent removal of café-au-lait spots.

Surgical Care

Surgical resection of neurofibromas can be accomplished by any competent surgeon. Plastic surgery consultation is advisable for areas of great cosmetic concern such as the face.

• Neurofibromas that press on vital structures, obstruct vision, or grow rapidly deserve immediate attention.
• Plexiform neurofibromas may be difficult to approach surgically, often recurring after resection because of residual tumor cell collections deep in soft tissues. Surgeons must realize that removing some of these lesions can result in substantial blood loss and must plan accordingly.
• Symptomatic peripheral nerve sheath tumors located along the nerves of the brachial or pelvic plexus sometimes require surgical intervention with the very real potential for postoperative nerve dysfunction. Added to this is the risk for malignant transformation that carries with it a very poor prognosis; the decision to operate requires much thought and careful consideration. One should always weigh the potential diagnostic benefits taking into account one's index of suspicion for malignancy, against the potential risks for long-term neurologic sequelae.
• For many patients, neurofibromas on the scalp, along the hairline, or around the waist where clothes rub can cause great irritation and discomfort. Therefore, removing these should not be considered cosmetic but a necessary medical procedure.
• Resection of spinal cord tumors is difficult but often necessary to prevent progressive paraplegia or quadriplegia.
• • Acting promptly when neurological symptoms appear is important to maximize operative success.
  • Surgical intervention may not guarantee a complete resection of the tumor, but it may serve a palliative function in some cases.
• Orthopedic intervention is indicated for rapidly progressive scoliosis and for some severe bony defects.
• • Following patients with NF1 when scoliosis is first detected is advisable, so that nonsurgical approaches may be used in an attempt to obviate the need for a future spinal fusion procedure.
  • Limb-sparing procedures in addition to new bracing and casting technologies have decreased the need for amputation in patients with a pseudarthrosis (see Image 10).
  • Patients with long-bone defects are best served by ongoing orthopedic care.
• Some hypertensive patients with renal artery stenosis require surgical resection and repair instead of or following angioplasty.

Consultations

• The neurologist serves as a key consultant and provides valuable information concerning changes in neurological status by performing a complete, focused examination.
• The neurosurgeon serves as an expert consultant when a spinal cord or brain tumor is identified and works closely with the neurologist to determine the optimal timing and best surgical approach on an individual basis.
• The ophthalmologist serves as a valuable member of the NF1 consultation team, evaluating patients on an annual basis for changes in visual acuity, field defects, or appearance of Lisch nodules.
• The geneticist provides information concerning diagnosis, diagnostic testing, inheritance, and risks for recurrence in future children. Family planning options and prenatal diagnosis may be addressed in this clinical setting.
• The orthopedist is a key consultant for the many NF1-related bone abnormalities (eg, scoliosis, pseudarthrosis, hemihypertrophy, bony erosion by plexiform neurofibromas).
• The developmental pediatrician may be an invaluable resource in evaluating a child with NF1 and learning disabilities.
• In addition to these most frequently used consultants, patients may need to see others for specific NF1 concerns. Examples include the following:
  • A nephrologist to help rule out renal vascular lesions
  • A general or plastic surgeon to consider removal of neurofibromas
  • An oncologist to manage and treat symptomatic optic nerve gliomas, brain tumors, neurosarcomas and MPNSTs
  • An otolaryngologist for suspected hearing loss or an acoustic nerve lesion
  • A dermatologist to assess cutaneous lesions
  • An oculoplastic surgeon for an orbital plexiform neurofibroma

Activity

No activity restrictions are necessary, except for an individual with specific orthopedic concerns (as recommended by the consulting surgeon).

• Patients with spinal fusion procedures as well as individuals with significant long-bone weakness or pseudarthrosis may need to limit certain athletic activities.
• Patients with neurological sequelae from spinal cord lesions may be restricted in their activities secondary to physical disabilities.

MEDICATION

Section 7 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

No known medical therapies are beneficial to patients with NF1. Several drug trials have been initiated, looking for medications that slow or halt the growth of neurofibromas. Thus far, none of these medications have demonstrated significant benefit, although various research trials involving chemotherapeutic and other agents are underway in an attempt to slow the growth of plexiform neurofibromas.

For a small subset of patients with pruritus due to cutaneous neurofibromas, diphenhydramine may provide some temporary relief. Such patients also are encouraged to avoid hot showers and baths, since hot temperatures may exacerbate itching.

Treatment with carboplatin shows efficacy in controlling the growth of visually significant optic gliomas.

Drug Category: Antihistamines

These agents may control itching by blocking effects of endogenously released histamine.

Drug Category: Antineoplastics

The agent carboplatin has been used in the treatment of visually significant optic nerve gliomas.

FOLLOW-UP

Section 8 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Further Inpatient Care

• Hospitalization may be necessary for major surgical procedures and workup of uncontrolled hypertension.
• Many minor surgical procedures (eg, removal of cutaneous neurofibromas) may be done in an outpatient surgical setting.

Further Outpatient Care

• Although patients with NF1 can be cared for in the primary care setting, additional medical concerns need to be addressed on a routine basis.
• Some practitioners believe patients should be seen on an annual basis in a comprehensive NF center; others consider themselves capable of providing the annual care and refer to consultants only for medical complications.
• An outline of reasonable guidelines in caring for patients with NF1 is as follows:
• • Annual examinations should focus on potential complications of NF.
    • Each examination should include blood pressure measurement, assessment of the skin for typical lesions (including early or growing neurofibromas), visual acuity check, evaluation of the eyes for evidence of proptosis or strabismus, and examination of the spine and extremities for any abnormalities.
    • Neurologic evaluation should include a careful history for headaches or motor or sensory symptoms as well as a comprehensive motor and sensory examination.
  • Annual ophthalmologic examinations should check for optic nerve pallor, visual acuity changes, visual field defects, and Lisch nodules. Patients should be referred to an ophthalmologist promptly if the treating physician has any concerns about visual acuity, evidence of proptosis, or a palpebral plexiform neurofibroma obstructing vision.

Complications

• Locally invasive plexiform neurofibromas
• Optic nerve gliomas, especially in children younger than 5 years
• Dumbbell-shaped spinal cord neurofibromas or neurofibromas of the brachial or sacral plexus
• Peripheral neuropathy
• Scoliosis
• Hypertension due to pheochromocytoma or renal vascular stenosis secondary to fibromuscular dysplasia
• Bony modeling defects that may lead to pseudarthrosis, thoracic cage asymmetry, or pathologic fractures
• Increased risk for brain tumors, leukemia, and other malignancies of neural crest origin (including neurofibrosarcomas and MPNSTs)
• Learning disabilities, attention deficit disorder (ADD), attention deficit hyperactivity disorder (ADHD), or rarely, mental retardation

Prognosis

• Although most individuals with NF1 lead relatively long and healthy lives, the overall life expectancy may be reduced by as much as 15 years. The major causes for this increased morbidity and subsequent mortality are hypertension, sequelae of spinal cord lesions, and malignancy.
• Prompt attention to complications of NF1 and early detection of medical problems may significantly reduce the overall morbidity and mortality rates.

Patient Education

• Patients and their families may be referred to NF-specific national and regional support groups for continuous updates on treatment advances and for emotional support. The previous National NF Foundation, Inc, now renamed The Children's Tumor Foundation, has a toll-free telephone number (1-800-323-7938). Parents and families can sign up to receive a newsletter. Neurofibromatosis, Inc is another support and resource group with a toll-free telephone number (1-800-942-6825).
• Inform patients of symptoms that would require immediate medical attention, including headaches increasing in intensity or frequency or focal neurological deficits.

MISCELLANEOUS

Section 9 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Medical/Legal Pitfalls

• Failure to identify scoliosis in a child or an adolescent, so that nonsurgical approaches may be instituted as early as possible
• Failure to identify spinal cord lesions early, so that interventions can be initiated prior to permanent neurological damage
• Failure to identify and appropriately treat alternative causes of hypertension
• Failure to identify optic nerve gliomas and other CNS tumors early so that interventions can be initiated
• Failure to provide appropriate genetic counseling

MULTIMEDIA

Section 10 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Media file 1:  Café-au-lait spots in a 4-year-old boy.
	View Full Size Image
Media type:  Photo

Media file 2:  Axillary freckles.
	View Full Size Image
Media type:  Photo

Media file 3:  Inguinal freckles.
	View Full Size Image
Media type:  Photo

Media file 4:  Multiple neurofibromas in a 28-year-old man.
	View Full Size Image
Media type:  Photo

Media file 5:  Plexiform neurofibroma of the right thigh.
	View Full Size Image
Media type:  Photo

Media file 6:  Lisch nodules.
	View Full Size Image
Media type:  Photo

Media file 7:  Radial and ulnar bowing and obliteration of the intramedullary spaces.
	View Full Size Image
Media type:  X-RAY

Media file 8:  Unidentified bright object (UBO) within the brain parenchyma.
	View Full Size Image
Media type:  MRI

Media file 9:  Left optic nerve glioma with thickening of the nerve and proptosis.
	View Full Size Image
Media type:  MRI

Media file 10:  Below-the-knee amputation for tibial pseudarthrosis.
	View Full Size Image
Media type:  Photo

Media file 11:  The young woman pictured here has a plexiform neurofibroma of the eyelid.
	View Full Size Image
Media type:  Photo

REFERENCES

Section 11 of 11

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

• AAP Committee on Genetics. Health supervision for children with neurofibromatosis. Pediatrics. Aug 1995;96(2 Pt 1):368-72. [Medline].
• Chander S, Westphal SM, Zak IT, et al. Retroperitoneal malignant peripheral nerve sheath tumor: evaluation with serial FDG-PET. Clin Nucl Med. Jul 2004;29(7):415-8. [Medline].
• DeClue JE, Cohen BD, Lowy DR. Identification and characterization of the neurofibromatosis type 1 protein product. Proc Natl Acad Sci U S A. Nov 15 1991;88(22):9914-8. [Medline].
• Deliganis AV, Geyer JR, Berger MS. Prognostic significance of type 1 neurofibromatosis (von Recklinghausen Disease) in childhood optic glioma. Neurosurgery. Jun 1996;38(6):1114-8; discussion 1118-9. [Medline].
• Denckla MB, Hofman K, Mazzocco MM. Relationship between T2-weighted hyperintensities (unidentified bright objects) and lower IQs in children with neurofibromatosis-1. Am J Med Genet. Feb 16 1996;67(1):98-102. [Medline].
• Drouet A, Wolkenstein P, Lefaucheur JP, et al. Neurofibromatosis 1-associated neuropathies: a reappraisal. Brain. Sep 2004;127(Pt 9):1993-2009. [Medline].
• Dugoff L, Sujansky E. Neurofibromatosis type 1 and pregnancy. Am J Med Genet. Dec 2 1996;66(1):7-10. [Medline].
• Evans DG, Baser ME, McGaughran J, et al. Malignant peripheral nerve sheath tumours in neurofibromatosis 1. J Med Genet. May 2002;39(5):311-4. [Medline].
• Ferner RE, Hughes RA, Hall SM, et al. Neurofibromatous neuropathy in neurofibromatosis 1 (NF1). J Med Genet. Nov 2004;41(11):837-41. [Medline].
• Gutmann DH, Collins FS. The neurofibromatosis type 1 gene and its protein product, neurofibromin. Neuron. Mar 1993;10(3):335-43. [Medline].
• Habiby R, Silverman B, Listernick R. Precocious puberty in children with neurofibromatosis type 1. J Pediatr. Mar 1995;126(3):364-7. [Medline].
• Hughes RJ, Scoble JE, Reidy JF. Renal angioplasty in non-atheromatous renal artery stenosis: technical results and clinical outcome in 43 patients. Cardiovasc Intervent Radiol. Sep-Oct 2004;27(5):435-40. [Medline].
• Karadimas P, Hatzispasou E, Bouzas EA. Retinal vascular abnormalities in neurofibromatosis type 1. J Neuroophthalmol. Dec 2003;23(4):274-5. [Medline].
• Korf BR. Malignancy in neurofibromatosis type 1. Oncologist. 2000;5(6):477-85. [Medline].
• Levy AD, Patel N, Abbott RM, et al. Gastrointestinal stromal tumors in patients with neurofibromatosis: imaging features with clinicopathologic correlation. AJR Am J Roentgenol. Dec 2004;183(6):1629-36. [Medline].
• Listernick R, Ferner RE, Piersall L, et al. Late-onset optic pathway tumors in children with neurofibromatosis 1. Neurology. Nov 23 2004;63(10):1944-6. [Medline].
• NIH Consensus Development Conference. Neurofibromatosis. Conference statement. Arch Neurol. May 1988;45(5):575-8. [Medline].
• Nakakura S, Shiraki K, Yasunari T, et al. Quantification and anatomic distribution of choroidal abnormalities in patients with type I neurofibromatosis. Graefes Arch Clin Exp Ophthalmol. Oct 2005;243(10):980-4. [Medline].
• North KN, Riccardi V, Samango-Sprouse C. Cognitive function and academic performance in neurofibromatosis. 1: consensus statement from the NF1 Cognitive Disorders Task Force. Neurology. Apr 1997;48(4):1121-7. [Medline].
• Riccardi VM. Neurofibromatosis: Phenotype, Natural History and Pathogenesis. 2nd ed. Johns Hopkins University Press. 1992;[Medline].
• Scott RM, Smith JL, Robertson RL, et al. Long-term outcome in children with moyamoya syndrome after cranial revascularization by pial synangiosis. J Neurosurg. Feb 2004;100(2 Suppl Pediatrics):142-9. [Medline].
• Solomon J, Warren K, Dombi E, et al. Automated detection and volume measurement of plexiform neurofibromas in neurofibromatosis 1 using magnetic resonance imaging. Comput Med Imaging Graph. Jul 2004;28(5):257-65. [Medline].
• Zacharia TT, Jaramillo D, Poussaint TY, Korf B. MR imaging of abdominopelvic involvement in neurofibromatosis type 1: a review of 43 patients. Pediatr Radiol. Mar 2005;35(3):317-22. [Medline].
• Zoller M, Rembeck B, Akesson HO. Life expectancy, mortality and prognostic factors in neurofibromatosis type 1. A twelve-year follow-up of an epidemiological study in Goteborg, Sweden. Acta Derm Venereol. Mar 1995;75(2):136-40. [Medline].

Article Last Updated: Mar 13, 2006