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 (NF) describes at least 2 distinct disorders with overlapping features, but they are actually 2 different clinical entities. Neurofibromatosis-1 (NF-1) is by far more common. Neurofibromatosis is a multisystem genetic disorder commonly associated with skin, nervous system, and bone and joint manifestations. NF-1 is the most common of the various conditions referred to as hamartomas.

NF-1 differs from central neurofibromatosis, also known as neurofibromatosis-2 (NF-2). Patients with NF-2 have few dermatological findings, but they have a high incidence of meningiomas and acoustic neuromas. Patients with NF-1 have a better overall long-term prognosis than patients with NF-2. Visual loss secondary to optic nerve glioma is the most important ophthalmologic manifestation of NF-1.

The first description of this disease probably dates back to a 13th century illustration attributed to an Austrian scribe, Heinricus. The first medical descriptions of NF-1 arise in the 1700s, when several medical authors described patients with clinical features of NF-1. It was not until 1882 that Frederich Daniel von Recklinghausen, a German professor of pathology, released a monograph, which reviewed previous literature and characterized the tumors of NF-1 as neurofibromas, consisting of an intense comingling of nerve cells and fibrous tissue.

The popular early 20th century drama The Elephant Man was written by Sir Frederick Treves, a physician, about Joseph Merrick (often referred to erroneously as John Merrick) who lived in the late 1800s and had many skeletal deformities believed to be manifestations of neurofibromatosis. (Since that time, prevailing opinion has shifted, and it is now believed that Mr. Merrick was in fact afflicted with Proteus syndrome.)

Pathophysiology

NF-1 is a progressive genetic disease best known for its heterogeneity and variability. NF-1 can manifest in many different ways in many different tissues within the same person and among family members. Neurofibromatosis is a disorder of the neuroectodermal system that results in benign hamartomatous tumors of any organ or system (most notably the skin, the eyes, and the nervous system) that increase in number and size throughout life. These tumors are of tissues derived from neural crest, particularly sensory nerves, Schwann cells, and melanocytes.

Frequency

United States

An estimated 0.05% of the population worldwide is affected by NF-1. Prevalence is estimated to be about 1 in 3000.

International

Same as in the United States.

Mortality/Morbidity

• Many people with mild neurofibromatosis lead healthy, productive lives with little disability.
• People affected by more severe variants of NF-1 may have a shorter life expectancy if the disease is associated with CNS tumors or other malignancies, mental retardation, or severe seizures.
• In 1944, Sorenson and coworkers conducted a study of 212 affected patients in Denmark and found that patients with NF, particularly the more severe forms requiring hospitalization, have a poorer survival rate. The group with severe NF also had 4 times the increased risk of development of CNS neoplasms during a 40-year follow-up period.¹

Race

No predilection for race exists.

Sex

No predilection for sex exists.

Age

• Initial manifestations most often occur in childhood.
• Clinical signs may be apparent at birth; however, in some affected individuals, signs may not develop until adulthood.
• NF tends to be progressive throughout life, with the number and the size of associated tumors increasing.

CLINICAL

Section 3 of 10  

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

History

In 1987, the National Institute of Health (NIH) Consensus Development Conference on Neurofibromatosis reclassified neurofibromatosis into 2 distinct variants (NF-1 and NF-2) and established diagnostic criteria for the disease. According to the NIH Consensus Statement, diagnosis of NF-1 is established if 2 or more of the following characteristics are present:

1. Six or more café au lait spots, 15 mm or larger, in an adult; 6 or more café au lait spots, 5 mm or larger, in a child (before puberty)
2. Two or more neurofibromas of any type or 1 plexiform neurofibroma
3. Freckling of the axillary or inguinal region, an optic pathway glioma, 2 or more Lisch nodules
4. Characteristic osseous lesions, such as sphenoid dysplasia
5. A first-degree relative with NF-1 (as defined by the above criteria)

Physical

Physical findings are discussed by organ system.

• Cutaneous involvement: The cutaneous manifestations of NF-1 are a prominent aspect of this disorder. They include hyperpigmentation, hypopigmentation, and cutaneous neurofibromas.
• • Hyperpigmentation can occur in focal or diffuse forms.
    • Focal hyperpigmentation: Café au lait spots are a distinct area of hyperpigmentation due to an increased number of melanocytes, as well as giant pigment granule (macromelanosome) production by melanocytes. Focal hyperpigmentation also includes axillary and inguinal freckling.
    • Diffuse hyperpigmentation: Diffuse or generalized hyperpigmentation is not well characterized, but often it is noticed by an astute physician or family member.
  • Hypopigmentation can occur in patients with NF-1.
    • Hypomelanotic macules
    • Punctate hypopigmented lesions
    • Local areas of skin hypopigmentation
  • Cutaneous neurofibromas
    • Small, pink-to-skin colored, dome-shaped papules
    • May enlarge, becoming immense soft tissue masses
    • Can occur anywhere on the body
    • Predilection for areolas in females
    • Histologically indistinguishable from the solitary neurofibroma, they appear as well-circumscribed, nonencapsulated spindle cell tumors of the dermis
• CNS involvement: CNS involvement in NF-1 is multifaceted. Abnormalities of CNS development are common. Similarly, functional problems often are noted, and benign and malignant tumors of the CNS occur at a greatly increased incidence in NF-1.
• • Abnormalities of CNS development
    • Simple megalencephaly is common and generally harmless. Its main features are increased brain matter and skull circumference.
    • Hydrocephalus may present at any age and is symptomatic (vomiting, irritability, lethargy, papilledema). If it is not due to a tumor, it usually is treated with a shunt.
    • Vascular occlusions
    • Dural ectasia
    • Absence of the sphenoid wing
    • Lambdoidal suture defect
  • Functional problems include seizures (as many as 5% of patients with NF-1), learning disabilities, and emotional/behavioral disturbances.
  • Benign and malignant tumors of the CNS
    • Nerve root and spinal cord neurofibromas can lead to deficits depending on location.
    • Gliomas are more common in NF-2 but still are associated with NF-1. Incidence of optic nerve and optic chiasm gliomas has been estimated at 1% in NF-1 in a population-based series; however, incidence may be as high as 15% based on more recent data.
    • Meningiomas are more common in patients with NF-2 but can occur in patients with NF-1.
• Skeletal involvement
• • Progressive kyphoscoliosis may lead to paraparesis without intervention.
  • Deformities of long bones include pseudoarthroses, hypertrophy/destruction associated with plexiform neurofibromas, and lytic metaphyseal and diaphyseal defects.
  • Short stature is very common.
• Visceral involvement
• • Neurofibromas of the GI tract
  • Pheochromocytomas occur 10 times more frequently in patients with NF. (Approximately 5-10% of all pheochromocytomas are in patients with NF.)
  • Reports of associations with other soft tissue tumors
• Ophthalmic involvement
• • Lisch nodules are the most common type of ocular involvement in NF-1. Lisch nodules are melanocytic hamartomas, usually clear yellow to brown in color, that appear as well-defined, dome-shaped elevations projecting from the surface of the iris. They may be seen without magnification, but a slit lamp examination may be necessary to differentiate them from nevi on the iris, which present as flat or minimally elevated, densely pigmented lesions with blurred margins. The nodules are not thought to cause any ophthalmologic complication.
  • Lisch nodules are the most common clinical finding in adults older than 20 years with NF-1. Unlike cafe au lait spots, multiple nodules are specific for peripheral neurofibromatosis/NF-1. They are generally absent in central neurofibromatosis/NF-2.
    • Specific for NF-1
    • Smooth, usually bilateral, elevated nodules
    • They usually arise in the first decade; virtually all patients with NF-1 have Lisch nodules by age 20 years.
    • Benign hamartomas, histologically identical to iris nevi
  • Plexiform neurofibromas of the eyelid
    • Thickening of upper lid
    • S-shaped deformity
    • "Bag of worms" sensation
  • Congenital glaucoma ipsilateral to plexiform neurofibromas has been described as a variation of anterior segment developmental disorders.
  • Prominent corneal nerves
  • Hamartomas of the choroid
    • Usually in posterior pole
    • Flat, ill-defined lesions
    • Contain neuronal and melanocytic components
  • Retinal tumors
    • Astrocytic hamartomas (white tumors involving the optic nerve)
    • Combined hamartomas of the retina and retinal pigment epithelium
    • Retinal capillary hemangiomas
    • Absence of the greater wing of the sphenoid bone may lead to pulsatile proptosis.
    • Possible increase in the incidence of choroidal melanomas
    • Optic nerve gliomas have as much as a 15% incidence in NF (may only manifest in 5% of patients with NF). Conversely, if 25% of individuals with gliomas have NF, they can be bilateral. Unilateral decreased acuity with relative afferent pupillary defect (+/-) and strabismus (+/-) may occur. Optic nerve glioma appears on CT scan or MRI as fusiform dilation of optic nerve. They are locally invasive and slow growing with low malignant potential. Chiasmatic gliomas may invade hypothalamus and third ventricle, causing obstructive hydrocephalus.

Causes

• Approximately 50% of cases are transmitted genetically (autosomal dominant). The principal NF-1 genetic defect is located within the long arm of chromosome 17. The NF-1 phenotype has high penetrance but widely variable expression.
• Spontaneous mutations occur in 50% of cases. No specific causes for sporadic mutations have been identified.

DIFFERENTIALS

Section 4 of 10  

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

Other Problems to be Considered

Tuberous sclerosis
Neurofibromatosis-2

WORKUP

Section 5 of 10  

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

Lab Studies

• There are no pertinent lab tests. Tissue biopsy of skin lesions is occasionally necessary to confirm the diagnosis of NF-1.

Imaging Studies

• Plain film imaging of long bones can reveal the metaphyseal and the diaphyseal bone defects when present. Lytic lesions of bones due to adjacent neurofibromas also can be detected radiologically.
• Neuroimaging
• • If optic pathway glioma is suspected, contrast-enhanced CT scan or MRI is indicated. Gliomas have a typical fusiform appearance with kinking.
  • MRI often can show greater soft-tissue definition than CT scan, and it may be particularly useful in detection of intracranial gliomas.

Histologic Findings

Neurofibromas have a typical appearance of markedly enlarged nerves surrounded by thickened perineural structures, which vary depending on location. Lisch nodules of the iris are histopathologically identical to benign iris nevi.

TREATMENT

Section 6 of 10  

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

Medical Care

Medical care of patients with NF-1 depends on accurate diagnosis of specific systemic manifestations.

• Care of cutaneous manifestations
  • No specific treatment of the disorders of pigmentation associated with NF-1 is indicated.
  • Cutaneous neurofibromas can be excised; however, the large number and size of lesions usually precludes effective cosmesis in NF-1.
  • Lesions tend to recur, so excision of a neurofibroma strictly because of its presence generally is not advised, unless the lesion is causing functional impairment and/or pain.
• Care of CNS manifestations
  • Neurosurgical intervention may be necessary in cases of hydrocephalus, by way of placement of a cerebrospinal fluid shunt.
  • Anticonvulsant drugs may be necessary to treat seizures, and anxiolytics and antidepressants often are needed for anxiety disorder and depression.
• Care of skeletal manifestations: Orthopedic intervention is necessary to correct kyphoscoliosis and other bony deformities.
• Care of visceral manifestations: Occasionally, large neurofibromas of the GI tract may cause obstruction, requiring surgical intervention.
• Care of ophthalmic manifestations
• • Congenital glaucoma is a challenge to treat in any setting, and NF-1 is no exception. Medical therapy of glaucoma and surgical intervention (goniotomy, trabeculotomy, trabeculectomy, and aqueous shunting devices) may be necessary.
  • Optic gliomas usually are treated with expectant observation, unless aggressive growth is detected by serial imaging studies. Surgical resection of gliomas is rarely successful, and it is ultimately a virtual guarantee of loss of vision.
  • Radiation treatment of optic gliomas has been studied extensively with varying results. Glaser and coworkers found no benefit of radiation therapy for optic gliomas based on analysis of visual fields.² Other reports have indicated stabilization or improvement of visual functioning in patients with optic gliomas after radiation therapy. Miller, Illif, and Green reported improvement in survival after radiation therapy in patients with postchiasmatic gliomas.³ Observation generally is accepted as the appropriate treatment for optic pathway gliomas.

Surgical Care

See Medical Care.

Consultations

• The ophthalmologist has an important role in diagnosing and treating neurofibromatosis.
• Consult neurosurgeons, orthopedists, and dermatologists as other systemic manifestations arise.

FOLLOW-UP

Section 7 of 10  

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

Complications

• Complications include enlarging benign hamartoma tumors, most notably in the skin, eyes, and nervous system that increase throughout life.

Prognosis

• Prognosis depends greatly on the severity of the disease.
• • Mildly affected patients may have little dysfunction and lead normal lives.
  • More severely affected individuals have poorer survival rates than the general population.
• Visual prognosis is related predominantly to the presence or the absence of an optic pathway glioma or congenital glaucoma.

Patient Education

• Genetic counseling is necessary for patients with NF and their families.
• Approximately one half of all cases of NF occur by spontaneous mutation. This incidence of mutation may be an overestimate in that the parents of the affected patient(s) may have such a mild form of NF-1 that it is not recognized clinically. The presence of a mild form in a family member does not predict the course of the disease in another family member. If it can be ascertained that NF-1 is a spontaneous mutation, then subsequent siblings are at no greater risk than the general population (approximately 1 in 10,000) of spontaneously developing NF-1.

MISCELLANEOUS

Section 8 of 10  

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

Medical/Legal Pitfalls

• Careful ophthalmologic examination is necessary with periodic follow-up care.
• Special attention should be directed to optic nerve function to detect previous undiagnosed gliomas of the optic nerve.

Special Concerns

• Psychosocial difficulties are common in NF-1. Adolescents are attuned particularly to body image; therefore, NF-1, with its possible physical disfigurement, can be a source of great angst. Family counseling often is necessary.

MULTIMEDIA

Section 9 of 10  

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

Media file 1:  Typical appearance of multiple Lisch nodules in a patient with neurofibromatosis-1.
	View Full Size Image
Media type:  Photo

Media file 2:  Massive facial deformity in a young girl severely affected by neurofibromatosis-1.
	View Full Size Image
Media type:  Photo

Media file 3:  3-D CT scan of patient in Image 2 showing bony deformities of skull. Note the absence of the greater wing of the sphenoid bone and the enlargement of the infraorbital foramen.
	View Full Size Image
Media type:  CT

Media file 4:  Histopathologic section of a Lisch nodule showing clump of melanocytes (white arrows) within the stroma of the iris (hematoxylin and eosin X 100 magnification).
	View Full Size Image
Media type:  Photo

Media file 5:  Histopathologic section of an eye from a patient with neurofibromatosis-1 with congenital glaucoma. White arrow indicates prominent sclerocorneal nerve. Black arrow indicates angle dysgenesis; no trabecular meshwork or Schlemm canal is identifiable. Yellow arrow indicates ciliochoroidal hyperplasia (hematoxylin and eosin X 40 magnification).
	View Full Size Image
Media type:  Photo

REFERENCES

Section 10 of 10

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

1. Sorensen SA, Mulvihill JJ, Nielsen A. Long-term follow-up of von Recklinghausen neurofibromatosis. Survival and malignant neoplasms. N Engl J Med. Apr 17 1986;314(16):1010-5. [Medline].
2. Glaser JS, Hoyt WF, Corbett J. Visual morbidity with chiasmal glioma. Long-term studies of visual fields in untreated and irradiated cases. Arch Ophthalmol. Jan 1971;85(1):3-12. [Medline].
3. Miller NR, Iliff WJ, Green WR. Evaluation and management of gliomas of the anterior visual pathways. Brain. Dec 1974;97(4):743-54. [Medline].
4. Ariel IM. Tumors of the peripheral nervous system. CA Cancer J Clin. Sep-Oct 1983;33(5):282-99. [Medline].
5. Crowe FW, Schull WJ, Neel JV. A Clinical, Pathological, and Genetic Study of Multiple Neurofibromatosis. 1956.
6. Fountain JW, Wallace MR, Bruce MA, et al. Physical mapping of a translocation breakpoint in neurofibromatosis. Science. Jun 2 1989;244(4908):1085-7. [Medline].
7. Holman RE, Grimson BS, Drayer BP, et al. Magnetic resonance imaging of optic gliomas. Am J Ophthalmol. Oct 15 1985;100(4):596-601. [Medline].
8. Lee V, Ragge NK, Collin JR. Orbitotemporal neurofibromatosis. Clinical features and surgical management. Ophthalmology. Feb 2004;111(2):382-8. [Medline].
9. Lewis RA, Gerson LP, Axelson KA, et al. von Recklinghausen neurofibromatosis. II. Incidence of optic gliomata. Ophthalmology. Aug 1984;91(8):929-35. [Medline].
10. Listernick R, Charrow J, Greenwald MJ, Esterly NB. Optic gliomas in children with neurofibromatosis type 1. J Pediatr. May 1989;114(5):788-92. [Medline].
11. Manger WM, Gifford RW Jr. Pheochromocytoma. 1977.
12. Montgomery AB, Griffin T, Parker RG, Gerdes AJ. Optic nerve glioma: the role of radiation therapy. Cancer. Nov 1977;40(5):2079-80. [Medline].
13. Parker JC Jr, Smith JL, Reyes P, Vuksanovic MM. Chiasmal optic glioma after radiation therapy. Neuro- ophthalmologic/pathologic correlation. J Clin Neuroophthalmol. Mar 1981;1(1):31-43. [Medline].
14. Ricardi VM. Neurofibromatosis: Phenotype, Natural History, and Pathogenesis. 2^nd ed. John Hopkins University Press; 1992.
15. Rubenstein AE, Korf BR. Neurofibromatosis: A Handbook for Patients, Families, and Health Care Professionals. Thieme Medical Publishers; 1990.
16. Ruggieri M, Pavone P, Polizzi A. Ophthalmological manifestations in segmental neurofibromatosis type 1. Br J Ophthalmol. Nov 2004;88(11):1429-33. [Medline].
17. Thiagalingam S, Flaherty M, Billson F. Neurofibromatosis type 1 and optic pathway gliomas: follow-up of 54 patients. Ophthalmology. Mar 2004;111(3):568-77. [Medline].

Article Last Updated: Jun 29, 2006