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Neurofibromatosis

By

M. Cristina Victorio

, MD, Northeast Ohio Medical University

Last full review/revision Mar 2020| Content last modified Mar 2020
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Neurofibromatosis refers to several related disorders that have overlapping clinical manifestations but that are now understood to have distinct genetic causes. It causes various types of benign or malignant tumors that involve central or peripheral nerves and often causes pigmented skin macules and sometimes other manifestations. Diagnosis is clinical. There is no specific treatment, but benign tumors can be removed surgically, and malignant tumors (which are less common) can be treated with radiation therapy or chemotherapy.

Neurofibromatosis is a neurocutaneous syndrome (a syndrome with neurologic and cutaneous manifestations).

Types

There are several types of neurofibromatosis.

Neurofibromatosis type 1 (NF1, or von Recklinghausen disease) is most prevalent, occurring in 1 of 2500 to 3000 people. It causes neurologic, cutaneous, and sometimes soft-tissue or bone manifestations. The gene for NF1 is located on band 17q11.2 and encodes synthesis of neurofibromin; > 1000 mutations have been identified. Although it is an autosomal dominant disorder, 20 to 50% of cases are caused by a de novo germ cell mutation.

Neurofibromatosis type 2 (NF2) accounts for 10% of cases, occurring in about 1 of 35,000 people. It manifests primarily as congenital bilateral acoustic neuromas (vestibular schwannomas). The gene for NF2 is located on band 22q11 and encodes synthesis of merlin, a tumor suppressor; 200 mutations have been identified. Most people with NF2 inherited it from one of their parents.

Schwannomatosis, a rare disorder, is classified as a 3rd type of neurofibromatosis. In 15% of cases, this type is familial and related to a germline mutation in the SMARCB1 gene, a tumor suppressor gene located at 22q11.23, very close to the NF2 gene. In the remaining cases, the genetic basis is not well-understood, but in tissue from some patients, other mutations in the same gene are involved. Two or more schwannomas develop in spinal and peripheral nerves and are sometimes quite painful; however, acoustic neuromas do not develop. Schwannomatosis used to be considered a form of NF2 because multiple schwannomas are present in both conditions; however, the clinical picture is different, and the genes involved are distinct.

Peripheral and central neurofibromas

Tumors may be peripheral or central.

Peripheral tumors are common in NF1 and can develop anywhere along the course of peripheral nerves. The tumors are neurofibromas, which develop from nerve sheaths and consist of mixtures of Schwann cells, fibroblasts, neural cells, and mast cells. Most appear during adolescence. Occasionally, they transform to malignant peripheral nerve sheath tumors. There are multiple forms:

  • Cutaneous neurofibromas are soft and fleshy.

  • Subcutaneous neurofibromas are firm and nodular.

  • Nodular plexiform neurofibromas may involve spinal nerve roots, typically growing through an intervertebral foramen to cause intraspinal and extraspinal masses (dumbbell tumor). The intraspinal part may compress the spinal cord.

  • Diffuse plexiform neurofibromas (subcutaneous nodules or amorphous overgrowth of underlying bone or Schwann cells) can be disfiguring and may cause deficits distal to the neurofibroma. Plexiform neurofibromas can become malignant and they appear to be the most common precursors to malignant peripheral nerve sheath tumors in people with NF1.

  • Schwannomas are derived from Schwann cells, rarely undergo malignant transformation, and can occur in peripheral nerves anywhere in the body.

Central tumors have several forms:

  • Optic gliomas: These tumors are low-grade pilocytic astrocytomas, which may be asymptomatic or may progress enough to compress the optic nerve and cause blindness. They occur in younger children; these tumors can usually be identified by age 5 and rarely develop after age 10. They occur in NF1.

  • Acoustic neuromas (vestibular schwannomas): These tumors may cause dizziness, ataxia, deafness, and tinnitus due to compression of the 8th cranial nerve; they sometimes cause facial weakness due to compression of the adjacent 7th nerve. They are the distinguishing feature of NF2.

  • Meningiomas: These tumors develop in some people, particularly those with NF2.

Symptoms and Signs

Neurofibromatosis type 1 (NF1)

Most patients with NF1 are asymptomatic. Some present with neurologic symptoms or bone deformities. In > 90%, characteristic skin lesions are apparent at birth or develop during infancy.

Café-au-lait lesions are medium-brown (café-au-lait), freckle-like macules, distributed most commonly over the trunk, pelvis, and flexor creases of elbows and knees. Although children who do not have neurofibromatosis may have 2 or 3 café-au-lait lesions, children who have NF1 have ≥ 6 such macules and often many more. These macules are > 5 mm in affected prepubertal children and > 15 mm in postpubertal patients (see table Diagnosing Neurofibromatosis).

Cutaneous neurofibromas, which arise along small peripheral nerves, are common. During late childhood, these flesh-colored cutaneous tumors of various sizes and shapes appear, ranging in number from several to thousands. They are usually asymptomatic.

Plexiform neurofibromas can develop and have a tendency to grow to large sizes, causing irregularly thickened, distorted structures, sometimes with grotesque deformities that can impinge on nerves and other structures. Plexiform neurofibromas can also involve cranial nerves, typically the 5th, 9th, and 10th.

Neurologic symptoms vary, depending on location and number of neurofibromas. Larger neurofibromas may press on their nerve of origin and cause distal paresthesia, pain, and sensory loss or weakness, depending on the function of the nerve that is involved. Neurofibromas that form along spinal nerve roots, especially where the nerve roots are contained by bone, can compress the nerve roots and cause radicular pain, weakness, or widespread sensory loss in that nerve distribution. Plexiform neurofibromas that compress cranial nerves cause deficits typical of those nerves.

Skin Manifestations of Neurofibromatosis Type 1

Bone abnormalities include

  • Subperiosteal bone cysts

  • Vertebral scalloping

  • Thinning of the long-bone cortex

  • Pseudarthrosis

  • Absence of the greater wing of the sphenoid bone (posterior orbital wall), with consequent pulsating exophthalmos

An optic glioma and Lisch nodules (iris hamartomas) occur in some patients. Optic gliomas are typically asymptomatic and do not require treatment unless they progressively increase in size.

Patients with NF1 can also have changes in their arterial walls that may lead to Moyamoya syndrome (stenosis or occlusion of arteries in and around the circle of Willis with formation of small collateral arteries), or intracranial artery aneurysms. Some children have learning problems and slightly larger heads.

Children and adolescents with NF1 may have childhood chronic myelomonocytic leukemia (juvenile myelomonocytic leukemia) and rhabdomyosarcoma. Pheochromocytomas may occur at any age.

Malignant tumors are much less common but still more common than in the general population; they include supratentorial or brain stem gliomas and transformation of plexiform neurofibromas to malignant peripheral nerve sheath tumors. These tumors may develop at any age.

Neurofibromatosis type 2 (NF2)

In NF2, bilateral acoustic neuromas develop and become symptomatic during childhood or early adulthood. They cause hearing loss, unsteadiness, and sometimes headache or facial weakness. Bilateral 8th cranial (vestibulocochlear) nerve masses may be present. Family members may have gliomas, meningiomas, or schwannomas.

Schwannomatosis

In schwannomatosis, multiple schwannomas develop on cranial, spinal, and peripheral nerves. Acoustic neuromas do not develop, and patients do not become deaf. Also, the other types of tumors that sometimes occur in neurocutaneous disorders do not develop.

The first symptom of schwannomatosis is usually pain, which may become chronic and severe. Other symptoms may develop, depending on the location of the schwannomas.

Diagnosis

  • Clinical evaluation

  • Brain MRI or head CT

Most patients with NF1 are identified during routine examination, examination for cosmetic complaints, or evaluation of a positive family history. (See also guidelines for the diagnosis and management of individuals with NF1 from the United Kingdom Neurofibromatosis Association Clinical Advisory Board, guidelines for the health supervision of children with NF1 from a collaboration of experts, clinical practice guidelines for the care of adults with NF1 from the American College of Medical Genetics and Genomics.)

Diagnosis of all 3 types is clinical (see Table: Diagnosing Neurofibromatosis) by detailed physical examination focused on the cutaneous, skeletal, and neurologic systems. NF1 should be suspected and monitored for in children who have multiple café-au-lait spots even if they do not have other features or family history of NF1.

Brain MRI is done in patients with neurologic symptoms or signs and, when detailed visual testing is not possible, in younger children who meet the clinical criteria for NF1 and who may have an optic glioma. T2-weighted MRI may show thickening or tortuosity of the optic nerves and parenchymal hyperintense lesions that change over time and correlate with small cystic structures in NF1; MRI may help identify acoustic neuromas or meningiomas in NF2. If acoustic neuroma is suspected, CT of the petrous ridge can be done; it typically shows widening of the auditory canal.

Genetic testing is not typically done in these disorders because not all mutations are known and the clinical criteria are clear.

Table
icon

Diagnosing Neurofibromatosis

Type

Criteria

Neurofibromatosis type 1 (NF1)

2 of the following must be present:

  • 6 café-au-lait macules with a diameter at the widest point of > 5 mm in prepubertal patients and > 15 mm in postpubertal patients

  • 2 neurofibromas of any type or 1 plexiform neurofibroma

  • Freckling in the axillary or inguinal region

  • Optic glioma

  • 2 Lisch nodules (iris hamartomas)

  • A distinctive osseous lesion (eg, sphenoid dysplasia, thinning of long-bone cortex), with or without pseudarthrosis

  • A parent or sibling with diagnosed NF1

Neurofibromatosis type 2 (NF2)

1 of the following must be present:

  • Bilateral 8th nerve masses seen with CT or MRI

  • A parent or sibling with NF2 and either a unilateral 8th nerve mass or any 2 of the following: Neurofibroma, meningioma, glioma, schwannoma, or juvenile posterior subcapsular lenticular opacity

Schwannomatosis

  • ≥ 2 nonintradermal schwannomas (at least one pathologically determined)

  • No evidence of vestibular neuroma on high-resolution MRI

  • No known NF1 gene mutation

  • A pathologically confirmed nonvestibular schwannoma and a 1st-degree relative who meets the criteria above

Adapted from Martuza RL, Eldredge R: Neurofibromatosis 2 (bilateral acoustic neurofibromatosis). N Engl J Med 318(11):684–688, 1988; additional data from Plotkin SR, Blakeley JO, Evans DG, et al: Update from the 2011 International Schwannomatosis Workshop: From genetics to diagnostic criteria. Am J Med Genet A 161(3):405–416, 2013, and Chen SL, Liu C, Liu B, et al: Schwannomatosis: A new member of neurofibromatosis family. Chin Med J (Engl) 126(14):2656–2660, 2013.

Treatment

  • For symptomatic neurofibromas, possibly surgery or removal by laser or electrocautery

  • For malignant tumors, chemotherapy

No general treatment for neurofibromatosis is available.

Neurofibromas that cause severe symptoms may require surgical removal or, if small, removal by laser or electrocautery. Surgical removal of plexiform neurofibromas may obliterate function of the involved nerve, and the neurofibromas have a tendency to recur at the site of removal. There are ongoing clinical trials on several medical treatments of plexiform and spinal neurofibromas, including the use of sirolimus.

Most optic gliomas are asymptomatic and just need to be monitored for progression. For both progressive optic gliomas and central nervous system lesions that have become malignant, chemotherapy is the treatment of choice.

Genetic counseling is advisable. If either parent has neurofibromatosis, risk to subsequent offspring is 50%; if neither has it, risk for subsequent children is unclear because new mutations are common, particularly in NF1.

Key Points

  • There are 3 types of neurofibromatosis (NF): NF1, NF2, and schwannomatosis, caused by gene mutations.

  • NF1 typically causes cutaneous, neurologic, and bone abnormalities but can affect almost any part of the body.

  • NF2 causes bilateral acoustic neuromas.

  • Schwannomatosis causes multiple nonintradermal schwannomas; it does not cause acoustic neuromas.

  • Diagnosis is made using clinical criteria; neuroimaging is done if patients have neurologic abnormalities.

  • There is no specific treatment, but neurofibromas that cause severe symptoms may be removed surgically.

  • Malignant tumors may require chemotherapy.

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