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Neurobromatosis
By Margaret C. McBride, MD, Northeastern Ohio Universities
Colleges of Medicine and Pharmacology, Rootstown;Akron
Childrens Hospital
Click here for
Patient Education
Neurobromatosis 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 specic treatment,
but benign tumors can be removed surgically, and malignant tumors (which are less common) can
be treated with radiation therapy or chemotherapy.
Neurobromatosis is a neurocutaneous syndrome (a syndrome with neurologic and cutaneous
manifestations).

Types
There are several types of neurobromatosis.
Neurobromatosis 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
neurobromin; > 1000 mutations have been identied. Although it is an autosomal dominant
disorder, 20 to 50% of cases are caused by a de novo germ cell mutation.
Neurobromatosis 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 identied. Most people with NF2 inherited it from one of their parents.
Schwannomatosis, a rare disorder, is classied as a 3rd type of neurobromatosis. 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 peripheral nerves and are sometimes
quite painful; however, acoustic neuromas do not develop. Schwannomatosis used to be
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considered a form of NF2 because multiple schwannomas are seen in both conditions; however,
the clinical picture is different, and the genes involved are distinct.

Peripheral and central neurobromas

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 neurobromas, which develop from nerve sheaths and consist of mixtures
of Schwann cells, broblasts, neural cells, and mast cells. Most appear during adolescence.
Occasionally, they transform to malignant peripheral nerve sheath tumors. There are multiple
forms:
Cutaneous neurobromas are soft and eshy.
Subcutaneous neurobromas are rm and nodular.
Nodular plexiform neurobromas 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 neurobromas (subcutaneous nodules or amorphous overgrowth of
underlying bone or Schwann cells) can be disguring and may cause decits distal to the
neurobroma. These neurobromas 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 be identied 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 with type 1 neurobromatosis 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 (caf-au-lait), freckle-like macules, distributed most commonly over the
trunk, pelvis, and exor creases of elbows and knees. During late childhood, esh-colored
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cutaneous tumors of various sizes and shapes appear, ranging in number from several to
thousands. Rarely, plexiform neurobromas develop, causing an irregularly thickened, distorted
structure with grotesque deformities.

Neurobromatosis (Caf-au-Lait Spots and Neurobromas)

Springer Science+Business Media

Skin Manifestations in NF1

Springer Science+Business Media
Although unaffected children may have 2 or 3 caf-au-lait macules, children with NF1 have 6 such
macules and often many more.
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Neurologic symptoms vary, depending on location and number of neurobromas.

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 neurobromas
to malignant peripheral nerve sheath tumors. These tumors may develop at any age.

Neurobromatosis (Caf-au-Lait Spots)

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.
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Neurobromatosis (Neurobromas)
By permission of the publisher. From Bird T, Sumi S: Atlas of Clinical Neurology . Edited by RN
Rosenberg. Philadelphia, Current Medicine, 2002.

Neurobromatosis (Skeletal Anomalies)

By permission of the publisher. From Kotagal S, Bicknese A, Eswara M: Atlas of Clinical Neurology .
Edited by RN Rosenberg. Philadelphia, Current Medicine, 2002.

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Neurobromatosis (Lisch Nodules)

By permission of the publisher. From Kotagal S, Bicknese A, Eswara M: Atlas of Clinical Neurology .
Edited by RN Rosenberg. Philadelphia, Current Medicine, 2002.

Type 2
In type 2 neurobromatosis, 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 rst 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
CT or MRI
Most patients with NF1 are identied during routine examination, examination for cosmetic
complaints, or evaluation of a positive family history.
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Diagnosis of all 3 types is clinical (see Table: Diagnosing Neurobromatosis). For the few children
who have 3 to 5 caf-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, 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 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 Neurobromatosis
Type

Criteria
2 of the following must be present:
6 caf-au-lait macules with a diameter at the widest point of > 5 mm in prepubertal patients
and > 15 mm in postpubertal patients
2 neurobromas of any type or 1 plexiform neurobroma

NF1

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 type 1 neurobromatosis
1 of the following must be present:

NF2

Bilateral 8th nerve masses seen with CT or MRI

A parent or sibling with type 2 neurobromatosis and either a unilateral 8th nerve mass or any 2
of the following: Neurobroma, meningioma, glioma, schwannoma, or juvenile posterior
subcapsular lenticular opacity
2 nonintradermal schwannomas (at least one pathologically determined)
No evidence of vestibular neuroma on high-resolution MRI

Schwannomatosis

No known NF1 gene mutation

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

Adapted from Martuza RL, Eldredge R: Neurobromatosis 2 (bilateral acoustic neurobromatosis). Reprinted by permission
of The New England Journal of Medicine 318:684688, 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):405416, 2013 and Chen SL, Liu C, Liu B, et al: Schwannomatosis: a new member of
neurobromatosis family. Chinese Medical Journal (English) 126(14):265660, 2013.

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Treatment
Possibly surgery or irradiation
No general treatment for neurobromatosis is available. Neurobromas 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 neurobromatosis, 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 neurobromatosis: NF1, NF2, and schwannomatosis, caused by gene
mutations.
NF1 causes cutaneous, neurologic, and bone abnormalities.
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 specic treatment, but neurobromas that cause severe symptoms may be
removed surgically or treated with radiation therapy.
Last full review/revision April 2016 by Margaret C. McBride, MD
2016 Merck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc., Kenilworth, NJ, USA

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