AUTHOR AND EDITOR INFORMATION

Section 1 of 10  

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

INTRODUCTION

Section 2 of 10  

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

Background

Neurofibromatosis is an autosomal dominant disorder that affects the bone, the nervous system, soft tissue, and the skin. At least 8 different clinical phenotypes of neurofibromatosis have been identified and are linked to at least 2 genetic disorders. Clinical manifestations increase over time. Neurologic problems and malignancy development may supervene.

The eMedicine articles Neurofibromatosis, Type 1 and Neurofibromatosis, Type 2 also may be of interest.

Pathophysiology

Neurofibromatosis is a neurocutaneous condition that can involve almost any organ system. Thus, the presenting signs and symptoms may vary widely. Two major subtypes exist: neurofibromatosis 1 (NF-1), which is the most common subtype and is referred to as peripheral NF, and neurofibromatosis 2 (NF-2), which is referred to as central NF. These descriptions are not especially accurate because NF-1 often has central features. A third variant is known as segmental NF; this term is used to describe disease limited to a single body region. Segmental NF may be related to mosaicism or segmental hyperexpression of the condition. Loss of heterozygosity may create the clinical impression of segmental lesions.

Frequency

International

Worldwide, NF-1 occurs in approximately 1 of 2500-3300 live births, regardless of race, sex, or ethnic background. The carrier incidence at birth is 0.0004, and the gene frequency is 0.0002. The incidence of NF-2 is 1 case per 50,000-120,000 population.

Mortality/Morbidity

This disease can involve various body systems over time. Signs can range from benign cutaneous manifestations to profound disfigurement. The mortality rate is higher than that of the healthy population because of the increased potential for malignant transformation of diseased tissues and the development of neurofibrosarcoma. Patients with NF-1 have an estimated 3-15% additional risk of malignant disease in their lifetime.

Race

All racial groups are affected equally.

Sex

Women and men are affected equally by neurofibromatosis.

CLINICAL

Section 3 of 10  

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

History

• Although most individuals who develop neurofibromatosis are not born with café au lait macules, these skin lesions develop during the first 3 years of life, prompting parents to seek medical attention for their child.
• Neurofibromas form in late adolescence.
• Patients may complain of cutaneous discoloration or disfigurement or more serious physical symptoms (eg, pain caused by neurofibromas, pathologic fractures, hypertensive headaches due to pheochromocytoma).

Physical

• Neurofibromatosis is often diagnosed because of unusual pigmentary patterns. Café au lait spots are irregularly shaped, evenly pigmented, brown macules. Most individuals with neurofibromatosis have 6 or more spots that are 1.5 cm or greater in diameter. In young children, 5 or more café au lait macules greater than 0.5 cm in diameter are suggestive of neurofibromatosis and should be pursued. Less than 1% of healthy children have 3 or more such spots, although 1 or 2 café au lait macules are commonly encountered in healthy individuals without disease.
• Lisch nodules are hamartomas of the iris that appear dome shaped and are found superficially around the eyes on slit lamp examination. They are asymptomatic, but they help in confirming the diagnosis of neurofibromatosis.
• Axillary freckling (as well as freckling on the perineum), known as the Crowe sign, is a helpful diagnostic feature in neurofibromatosis. Both axillary freckling and inguinal freckling often develop during puberty. Areas of freckling and regions of hypertrichosis occasionally overlay plexiform neurofibromas.
• Bone involvement can include pseudoarthrosis of the tibia, bowing of the long bones, and orbital defects. Occasionally, pulsating exophthalmos can be encountered due to dysplasia of the sphenoid wings. Mild scoliosis may be encountered, and localized bony hypertrophy, especially on the face, may be identified. Whether these bony changes are caused by diffuse neurofibromas or other kinds of mesodermal defects is not entirely clear.
• Neurofibromas are the most common benign tumor of NF-1. These tumors are composed of Schwann cells, fibroblasts, mast cells, and vascular components. They can develop at any point along a nerve. Three subtypes of neurofibroma exist: cutaneous, subcutaneous, and plexiform. Both cutaneous lesions and subcutaneous lesions are circumscribed; neither is specific for NF-1. These nodules may be brown, pink, or skin colored. They may be soft or firm to the touch, and they may have the pathognomonic buttonhole invagination when pressed with a finger. Plexiform neurofibromas are noncircumscribed, thick, and irregular, and they can cause disfigurement by entwining important supportive structures. The plexiform subtype is specific for NF-1.
• Various neurologic abnormalities may occur. Acoustic nerve involvement and deafness may be seen, and gliomas of the optic nerve also occur. Various tumors, such as astrocytoma, meningioma, intramedullary glioma, and ependymoma, occur with greater frequency in these patients. Tumors may cause increased intracranial pressure, seizure, ataxia, or cranial nerve abnormalities. Schwannomas are uncommon in patients with NF-1, but they can present on spinal nerve sheaths. However, in NF-2, they are the most common tumor, involving cranial and peripheral nerves. The presence of a unilateral vestibular schwannoma (formerly known as an acoustic neuroma) should mandate inclusion of NF-2 in the differential diagnosis.
• Many individuals with neurofibromatosis have below average intelligence. Of patients with NF-1, 25-40% may have learning disabilities, while 5-10% may have mental retardation. Types of learning disabilities may include neuromotor dysfunction and attention deficit hyperactivity disorder, as well as deficits in visuospatial processing.
• Endocrinologic problems associated with neurofibromatosis are common. Short stature and growth hormone deficiency are more common in these patients than in the general population, although the exact incidence is not known. Also, sexual precocity occurs in 3-5% of children who are affected, usually associated with an intracranial tumor. As mentioned, pheochromocytoma can occur.
• Diagnostic criteria for NF-1 (The diagnostic criteria are met if 2 or more of the features listed are present.)^{1, 2}
• • Six or more café au lait macules larger than 5 mm in greatest diameter in prepubertal individuals and those larger than 15 mm in greatest diameter in postpubertal individuals
  • Two or more neurofibromas of any type or 1 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 thinning of the long bone cortex, with or without pseudoarthrosis
  • A first-degree relative with NF-1 according to the above criteria
• Diagnosis criteria for NF-2 (The criteria are met if condition 1 or 2 is present.)
• • Bilateral masses of the eighth cranial nerve seen with appropriate imaging techniques (eg, CT, MRI)
  • A first-degree relative with NF-2 and either (a) a unilateral mass of the eighth cranial nerve or (b) 2 of the following: neurofibroma, meningioma, glioma, schwannoma, or juvenile posterior subcapsular opacity

Causes

• Neurofibromatosis is an autosomal dominant neurogenetic disorder. Increased concentrations of nerve growth stimulating activity have been linked with the development of neurofibromatosis. NF-1 is a disorder with variable phenotypic expression. Some patients may primarily have cutaneous expression, while others may have life-threatening or severely disfiguring complications. The variation of this disease is even demonstrated within families. The disease also tends to change and develop with time. Many different mutations in the neurofibromatosis gene have been described. The spontaneous mutation rate is 100 times greater than for many genes, and it is thought to contribute to approximately 30-50% of neurofibromatosis cases.
• NF-I is linked to a large gene on band 17q11.2. It encodes a protein termed neurofibromin, which has a guanosine triphosphatase (GTPase) region that binds to Ras and positively modulates conversion of guanosine triphosphate (GTP) to guanosine diphosphate (GDP). The protein has been shown to be essential for the negative regulation of Ras; this finding suggests that neurofibromin acts as a tumor suppressor. Several studies have confirmed this suggestion. The NF1 gene has at least 59 exons and encodes the 327-d protein known as neurofibromin. Truncations in neurofibromin led to the mutations responsible for NF1 in most cases.
• The gene for NF-2 is on band 22q11.³ Less is known about the action of the protein encoded at this location; however, loss of heterozygosity at this region has been reported in cases of acoustic neuromas, neurofibromas, and meningiomas. Thus, the NF2 gene is speculated to also encode a tumor suppressor.

DIFFERENTIALS

Section 4 of 10  

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

Other Problems to be Considered

Abdominal neurofibromatosis
Neurofibromatosis type 1
Neurofibromatosis type 1 with Noonan syndrome
Neurofibromatosis type 2
Segmental neurofibromatosis

WORKUP

Section 5 of 10  

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

Lab Studies

• Currently, mutation analysis using sophisticated genetic techniques, which are 60-70% accurate in detecting these mutations, is available for NF-1 and NF-2. However, this type of testing is not readily available. Perhaps in coming years, linkage analysis or mutation analysis will be available for the prenatal diagnosis of infants at risk.

Imaging Studies

• Plain radiography may show growth disturbance (ie, hyperplastic bones, "streaky" appearance to the medullary cavity, skull asymmetry, or sphenoid dysplasia), bowing deformities, or pseudoarthrosis of long bones.⁴
• MRI of the brain and the cervical spine may be helpful in patients with NF-1, especially if signs or symptoms suggest lesions.  MRI is used to assess the soft-tissue extent of disease and to determine involvement of the adjacent bone and spinal canal. Neurofibromas demonstrate low or intermediate signal on T1-weighted pulse sequences and homogeneously bright signal on T2-weighted sequences. Heterogeneity on T2-weighted sequences raises suspicion for malignant transformation.⁵
• In patients suspected of having NF-2, MRI of the head is recommended in early adolescence. Dedicated MRI of the internal auditory canals is the most sensitive study for the detection of acoustic neuromas, especially small intracanalicular lesions.
• Optic glioma, a criterion for the diagnosis of NF-1, requires imaging for detection. MRI of the orbits is the study of choice. Using MRI to detect optic gliomas in asymptomatic children with NF-1 is controversial because of the risks associated with the sedation required for an optimal diagnostic MRI.  Large optic nerves likely indicate low-grade gliomas in these patients.  MRI of the brain may demonstrate scattered foci of high T2 signal in the basal ganglia, thalamus, brain stem, and white matter of up to 50% of children with NF.
• 18Fluorodeoxyglucose positron emission tomography (18FDG PET) may be helpful in determining malignant changes in plexiform neurofibromas in persons with NF-1.⁶
• Typical CT findings in persons with NF1 with chest involvement include small well-defined surface neurofibromas, focal thoracic scoliosis, vertebral scalloping, enlarged neural foramina, and characteristic rib notching from adjacent neurofibromas. Dural ectasia, meningoceles, and dumbbell-shaped masses are related to the presence of neurofibromas or abnormal pressure in and around the spinal canal. Dural ectasia is circumferential dilatation of the dural sac with fluid attenuation. The expanding dura can erode the surrounding osseous structures, widening the spinal canal, thinning the lamina, and disrupting the vertebral elements.

Other Tests

• A Wood lamp examination may be useful in patients with very pale skin in an effort to better view café au lait macules.
• Slit-lamp examination is recommended for children older than 6 years to confirm the presence of Lisch nodules.

Histologic Findings

Histologic evaluation of axillary or inguinal freckling reveals increased pigmentation along the basal layer of the epidermis and the presence of macromelanosomes. These macromelanosomes are not usually noted in Albright syndrome. Neurofibromas are characterized by wavy, spindle-shaped nuclei and a loose mucinous stroma.

TREATMENT

Section 6 of 10  

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

Surgical Care

Treatment of neurofibromatosis is predominantly surgical.

• When neurofibromas increase in size or cause pain, malignant transformation should be suspected, and excision or biopsy should be performed.
• Acoustic neuromas and tumors that cause tinnitus and vertigo should be excised with great caution.
• Any signs of epilepsy should be investigated, and responsible tumors should be removed.

Consultations

• Orthopedic physicians should be involved in the management of problems, such as tibial bowing and kyphoscoliosis.
• Plastic surgeons may be included in the correction of deformities, especially those of the face.
• Psychological or psychiatric assessment may be necessary in monitoring language disorders and learning disabilities.
• Considering the autosomal dominant inheritance pattern for neurofibromatosis, genetic counseling should be included in the treatment of all patients affected with this disease.

FOLLOW-UP

Section 7 of 10  

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

Further Outpatient Care

• The American Academy of Pediatrics Committee on Genetics recommends monitoring children with NF-1 by performing annual physical examinations and ophthalmologic evaluations. Audiologic examination should be performed before the child is of school age. A language and speech evaluation should be considered for each child. Children should be examined for the presence of scoliosis. Blood pressure should be checked at least once per year.
• Patients should be continuously monitored for growth, change, or pain in their neurofibromas because this could be a sign of malignant transformation. Biopsy should be performed on any lesion undergoing these changes. A multidisciplinary approach is often beneficial, and follow-up in a multidisciplinary clinic can be helpful when available. The value of regular neuroimaging studies in asymptomatic patients is not clear, but careful surveillance and neurological examination is important for early detection of new or changing tumors.

Complications

• Serious complications other than malignant transformation are relatively infrequent.

Prognosis

• The prognosis of neurofibromatosis is varied, as is the nature of the disease.

Patient Education

• Information about neurofibromatosis support groups should be provided to patients. Support groups may be helpful with psychological issues faced during the course of this lifelong genetic disease.

MISCELLANEOUS

Section 8 of 10  

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

Medical/Legal Pitfalls

• Early diagnosis and genetic counseling are important because of the genetic transmission to future generations. The increase risk of malignant neoplasms warrants regular follow up of patients.

MULTIMEDIA

Section 9 of 10  

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

Media file 1:  Neurofibromas increase in number and size over time. Soft pedunculated neurofibromas are shown here on the arm of a woman with neurofibromatosis type 1.
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Media file 2:  The café au lait macules of neurofibromatosis have an even tan color and a smooth border. The presence of neurofibromas in the upper right corner of the photo as well as the lower left corner make a diagnosis of neurofibromatosis almost certain.
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Media file 3:  Neurofibromas are soft on palpation, and they may exhibit a buttonhole sign, whereby they can be pushed deeper into the dermis.
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Media file 4:  A low-power view of a neurofibroma reveals spindled cells in the dermis (hematoxylin and eosin).
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Media file 5:  Higher-power view of a neurofibroma reveals spindled cells with wavy nuclei embedded in an acidophilic stroma. The mast cells are increased in number.
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Media file 6:  Sheets of spindled cells are depicted in this malignant schwannoma. Malignant degeneration should be expected in a painful or rapidly enlarging tumor in any patient with neurofibromatosis.
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Media file 7:  High-power view of a malignant schwannoma reveals sheets of hyperchromatic spindle cells with pleomorphic nuclei.
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REFERENCES

Section 10 of 10

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

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Article Last Updated: May 6, 2008