Neurofibromatosis is a neurocutaneous syndrome (a syndrome with neurologic and cutaneous manifestations).
Types of Neurofibromatosis
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 Autosomal Dominant Genetic disorders determined by a single gene (Mendelian disorders) are easiest to analyze and the most well understood. If expression of a trait requires only one copy of a gene (one allele)... read more , 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 Schwannoma A vestibular schwannoma, also called an acoustic neuroma, is a Schwann cell–derived tumor of the 8th cranial nerve. Symptoms include unilateral hearing loss. Diagnosis is based on audiology... read more (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 Schwannoma A vestibular schwannoma, also called an acoustic neuroma, is a Schwann cell–derived tumor of the 8th cranial nerve. Symptoms include unilateral hearing loss. Diagnosis is based on audiology... read more (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 Meningiomas Meningiomas are benign tumors of the meninges that can compress adjacent brain tissue. Symptoms depend on the tumor’s location. Diagnosis is by MRI with contrast agent. Treatment may include... read more
: These tumors develop in some people, particularly those with NF2.
Symptoms and Signs of Neurofibromatosis
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 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.
This photo shows multiple neurofibromas (raised brownish nodules) and café au lait spots (flat brownish spots) on the back of a patient with neurofibromatosis.
DR HAROUT TANIELIAN/SCIENCE PHOTO LIBRARY
This photo shows neurofibromas (raised brownish nodules) and café-au-lait spots (flat brownish spots) on a patient with neurofibromatosis.
Image courtesy of Karen McKoy, MD.
This patient with neurofibromatosis type 1 has multiple café-au-lait spots (rounded hyperpigmented macules) and neurofibromas (raised nodules).
© Springer Science+Business Media
This photo shows axillary freckle-like macules in NF1.
© Springer Science+Business Media
Café-au-lait spots are sharply demarcated medium-brown macules that are present in most patients with neurofibromatosis type 1 (NF1).
By permission of the publisher. From Oster A, Rosa R: Atlas of Ophthalmology. Edited by R Parrish II and HW Flynn Jr. Philadelphia, Current Medicine, 2000.
The back and arms of this 69-year-old man are covered with small neurofibromas, and there is a café-au-lait spot just medial to his right scapula.
By permission of the publisher. From Bird T, Sumi S: Atlas of Clinical Neurology. Edited by RN Rosenberg. Philadelphia, Current Medicine, 2002.
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 Proptosis This photo shows a woman's slightly bulging left eye (proptosis), caused by a meningioma. Proptosis is protrusion of the eyeball. Exophthalmos means the same thing, and this term is usually... read more
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 Chronic Myeloid Leukemia (CML) Chronic myeloid leukemia (CML) occurs when a pluripotent stem cell undergoes malignant transformation and clonal myeloproliferation, leading to a striking overproduction of mature and immature... read more (juvenile myelomonocytic leukemia) and rhabdomyosarcoma Rhabdomyosarcoma Rhabdomyosarcoma is a cancer arising from embryonal mesenchymal cells that have potential to differentiate into skeletal muscle cells. It can arise from almost any type of muscle tissue in any... read more . Pheochromocytomas Pheochromocytoma A pheochromocytoma is a catecholamine-secreting tumor of chromaffin cells typically located in the adrenals. It causes persistent or paroxysmal hypertension. Diagnosis is by measuring catecholamine... read more 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 Gliomas Gliomas are primary tumors that originate in brain parenchyma. Symptoms are diverse and vary by location, manifesting as focal neurologic deficits, encephalopathy, or seizures. Diagnosis is... read more 
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 Vestibular Schwannoma A vestibular schwannoma, also called an acoustic neuroma, is a Schwann cell–derived tumor of the 8th cranial nerve. Symptoms include unilateral hearing loss. Diagnosis is based on audiology... read more 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 Meningiomas Meningiomas are benign tumors of the meninges that can compress adjacent brain tissue. Symptoms depend on the tumor’s location. Diagnosis is by MRI with contrast agent. Treatment may include... read more , 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 of Neurofibromatosis
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 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.
Treatment of Neurofibromatosis
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.
More Information
The following are some English-language resources that may be useful. Please note that THE MANUAL is not responsible for the content of these resources.
United Kingdom Neurofibromatosis Association Clinical Advisory Board: Guidelines for the diagnosis and management of individuals with NF1
Guidelines for the health supervision of children with NF1 from a collaboration of experts
American College of Medical Genetics and Genomics: Clinical practice guidelines for the care of adults with NF1
Drugs Mentioned In This Article
| Drug Name | Select Trade |
|---|---|
sirolimus |
HYFTOR, Rapamune |
