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Neurofibromatosis

by Margaret C. McBride, MD

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.

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 now 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, 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, the same gene is involved. Two or more schwannomas develop in 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 seen in both conditions; however, the clinical picture is different, and the genes involved are now known to be distinct.

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, neurial 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. These neurofibromas can become malignant.

  • 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 can 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

Type 1

Most patients are asymptomatic. Some present with neurologic symptoms or bone deformities. In > 90%, characteristic skin lesions are apparent at birth or develop during infancy. Lesions are medium-brown (café-au-lait), freckle-like macules, distributed most commonly over the trunk, pelvis, and flexor creases of elbows and knees. During late childhood, flesh-colored cutaneous tumors of various sizes and shapes appear, ranging in number from several to thousands. Rarely, plexiform neurofibromas develop, causing an irregularly thickened, distorted structure with grotesque deformities.

Although unaffected children may have 2 or 3 café-au-lait macules, children with NF1 have ≥ 6 such macules and often many more.

Neurologic symptoms vary, depending on location and number of neurofibromas. Bone abnormalities include

  • Fibrous dysplasia

  • Subperiosteal bone cysts

  • Vertebral scalloping

  • Scoliosis

  • 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. Changes in arterial walls may lead to Moyamoya disease 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.

Type 2

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.

Diagnosis

  • Clinical evaluation

  • CT or MRI

Most patients with NF1 are identified during routine examination, examination for cosmetic complaints, or evaluation of a positive family history. Diagnosis of both types is clinical (see Diagnosing Neurofibromatosis). For the few children who have 3 to 5 café-au-lait macules of > 5 mm diameter, the absence of Lisch nodules on ophthalmologic examination suggests NF1 is not present.

MRI is done in patients with neurologic symptoms or signs and in younger children who meet the clinical criteria for NF1 and who may have an optic glioma when detailed visual testing is not possible. T2-weighted MRI may show optic nerve swelling 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.

Diagnosing Neurofibromatosis

Type

Criteria

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, sibling, or child with diagnosed type 1 neurofibromatosis

NF2

1 of the following must be present:

  • Bilateral 8th nerve masses seen with CT or MRI

  • A parent, sibling, or child with type 2 neurofibromatosis 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). Reprinted by permission of The New England Journal of Medicine 318:684–688, 1988; additional data from Plotkin SR, Blakeley JO, Evans DG, et al: Update from the 2011 International Schwannomatosis Workshop: From genetics to diagnostic criteria. American Journal of Medical Genetics (part A) 161(3):405–416, 2013 and Chen SL, Liu C, Liu B, et al: Schwannomatosis: a new member of neurofibromatosis family. Chinese Medical Journal (English) 126(14):2656–60, 2013.

Treatment

  • Possibly surgery or irradiation

No general treatment is available. Neurofibromas that cause severe symptoms may require surgical removal or irradiation, although surgery may obliterate function of the involved nerve. Optic gliomas or CNS lesions that have become malignant may be treated with radiation therapy or chemotherapy.

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 2 main types of neurofibromatosis: NF1 and NF2; they are caused by gene mutations.

  • NF1 causes cutaneous, neurologic, and bone abnormalities.

  • NF2 causes bilateral 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 or treated with radiation therapy.

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