BASICS

DESCRIPTION

• Neurofibromatosis (NF) consists of 2 neurocutaneous genetic disorders that can involve the bones, the nervous system, soft tissue, and the skin. It is the most common hereditary disorder belonging to the group of hamartoses.

– NF1, also known as von Recklinghausen’s NF, is the most common subtype.

– NF2 is also referred to as central NF.

EPIDEMIOLOGY

Incidence

• NF1: 1 case per 3,500 population

• NF2: 1 case per 37,000 population

RISK FACTORS

Genetics

• Neurofibromatosis is an autosomal dominant disorder with complete penetrance and high variability in its expression. Roughly half tend to be familial and the other half sporadic. It is independent of sex or race.

– NF1 – The NF1 gene has been mapped to chromosome 17q11.2. The gene encodes the protein neurofibromin.

– NF2 – The NF2 gene has been mapped to chromosome 22q11. The gene encodes the protein merlin.

GENERAL PREVENTION

Genetic counseling

PATHOPHYSIOLOGY

The gene products of the respective NF genes, neurofibromin for NF1 and merlin for NF2, act as tumor suppressors. A decrease in function of these proteins predisposes one to develop a variety of tumors involving the central and peripheral nervous systems.

ETIOLOGY

Many different mutations in the neurofibromatosis genes have been described respectively for both the NF1 or NF2 genes.

COMMONLY ASSOCIATED CONDITIONS

• Moyamoya disease

– A progressive occlusive disease of the cerebral vasculature with particular involvement of the Circle of Willis

– Linkage studies have linked one of the genes for familial Moyamoya disease to chromosome 17q25, which is in close proximity to the NF1 gene.

– Children often present with signs and symptoms of cerebral ischemic events, whereas, adults may present with signs and symptoms of subarachnoid or intracerebral hemorrhage.

DIAGNOSIS

HISTORY

• Neurofibromatosis Type 1 (NF1)

– Parents may notice their children to have cutaneous discoloration or pathologic fractures.

– Patients may complain of pain caused by neurofibromas or develop hypertensive headaches caused by a pheochromocytoma.

• Neurofibromatosis Type 2 (NF2)

– Patients may present with gradual hearing loss, tinnitus, or vestibular dysfunction secondary to vestibular schwannomas.

– A visual decline secondary to optic nerve sheath meningioma, posterior subcapsular cataract, combined hamartoma of the retina and RPE, or epiretinal membrane may often be a presenting complaint.

PHYSICAL EXAM

• Neurofibromatosis Type 1 (2 of 7 criteria needed)

– 6 or more café-au-lait spots or hyperpigmented macules ≥5 mm in diameter in children younger than 10 years and to 15 mm in adults

– Axillary or inguinal freckles

– 2 or more typical neurofibromas or 1 plexiform neurofibroma involving the upper eyelid

– Optic nerve glioma (seen in 15–20% of patients)

– 2 or more Lisch nodules (iris hamartomas)

– Sphenoid dysplasia or pseudarthrosis of long-bones

– First-degree relative (parent or sibling) with NF1

• Other manifestations of NF1

– Neurological manifestations

– Seizure disorder

– Pilocytic astrocytoma, meningioma, intramedullary glioma, and ependymoma

– Vascular ectasias

– Aneurysms

– Chiari type 1 malformations

– Malignant peripheral nerve sheath tumors

– Dumbbell-shaped tumors of spinal cord

– Ophthalmic manifestations

– Proptosis, strabismus

– Bone manifestations

– Scoliosis, osteoporosis

– Other disorders

Essential hypertension

Pheochromocytomas

Renal artery stenosis

Precocious puberty

Gastrointestinal stromal tumors

Learning disabilities or mild/moderate mental retardation

Vitamin D deficiency

• Neurofibromatosis Type 2 (1 of 2 criteria needed)

– Bilateral cranial nerve eighth masses visualized on MRI

– First-degree relative (parent or sibling) with NF2 and either:

A unilateral eighth nerve mass or,

2 of the following: Neurofibroma, schwannoma, glioma, meningioma, or juvenile posterior subcapsular cataract

• Other manifestations of NF2:

– Neurological manifestations

– Nonvestibular schwannomas usually involving cranial nerves 3 and 5

– Dumbbell-shaped spinal cord schwannoma

– Spinal cord ependymoma, astrocytoma, and meningioma

– Cranial nerve palsies from compression by expanding vestibular schwannoma or nonvestibular cranial nerve schwannoma

– Ophthalmic manifestations

Optic nerve sheath meningioma

Combined hamartoma of the retina and RPE

Epiretinal membrane

Proptosis, strabismus

DIAGNOSTIC TESTS & INTERPRETATION

Lab

Initial lab tests

Gene sequencing, molecular testing, linkage analysis

Follow-up & special considerations

• For a suspected pheochromocytoma:

– Plasma catecholamines and free plasma metanephrine

– 24-hour urine collection to measure urinary free catecholamines (norepinephrine and epinephrine) and their metabolites (normetanephrine, metanephrine, and vanillylmandelic acid)

Imaging

Initial approach

• Radiography

– Plain films of long bones, spine, and ribs

• MRI/CT

– NF1 is associated with optic pathway gliomas and astrocytomas. Focal lesions of high signal intensity on T2-weighted MRI are also noted in cerebellar peduncles, basal ganglia, brainstem and optic radiations.

– Spinal cord tumor, mediastinal mass, deep plexiform neurofibromas, pheochromocytoma

– MRI using 3D volumetrics is the preferred method for following vestibular schwannoma growth for NF2 (1)[B]

Follow-up & special considerations

• Metaiodobenzylguanidine (MIBG) scintigraphy for pheochromocytoma if MRI/CT is not conclusive

• Positron emission tomography (PET) scan for tumor surveillance

• Gallium-67 scintigraphy for malignant large plexiform neurofibromas

• Electroencephalogram (EEG)

Diagnostic Procedures/Other

• Neurofibromatosis Type 1

– Slit-lamp examination for Lisch nodules

• Neurofibromatosis Type 2

– Dilated fundus examinations for inspection of juvenile cataracts or retinal lesions

– Brainstem auditory-evoked response (BAER) for early hearing loss

Pathological Findings

• Neurofibromatosis Type 1

– Neurofibromas are composed of well-differentiated tumors that contain spindle-shaped cells, Schwann cells, fibroblasts, and mast cells.

• Neurofibromatosis Type 2

– Tumors of NF2 may consist of Schwann cells, glial cells, or meningeal cells.

DIFFERENTIAL DIAGNOSIS

• Neurofibromatosis Type 1

– Brainstem gliomas

– Cauda equina and conus medullaris syndromes

– Low-grade astrocytoma

– Meningioma

– NF2

– Spinal cord hemorrhage/infarction

– Spinal epidural abscess

– Legius syndrome (SPRED1 gene mutation)

– McCune-Albright syndrome

• Neurofibromatosis Type 2

– Brainstem gliomas

– Ependymoma

– Meningioma

– NF1

TREATMENT

MEDICATION

• Carboplatin and vincristine for optic nerve gliomas

• Under clinical study are therapeutic uses of erlotinib, bevacizumab, and imatinib mesylate for unresectable, progressive vestibular schwannomas

• Vitamin D supplementation

– May be of benefit in patients with deficiency or osteopenia

ADDITIONAL TREATMENT

General Measures

• Cutaneous examination for documentation of new neurofibromas or progression of preexisting lesions

• Blood pressure monitoring

Issues for Referral

• Neurology – monitor changes in neurological status

• Ophthalmology – annual eye examinations for detection of optic nerve lesions, resection of orbital plexiform neurofibroma, slit-lamp examination, and dilated fundus examination

• Neurosurgery – resection of spinal cord or brain tumor

• Orthopedic – progressive scoliosis, pseudoarthrosis

• Plastic surgery – resection of neurofibromas

• Geneticist – family planning options and prenatal diagnosis

SURGERY/OTHER PROCEDURES

• Neurofibromatosis Type 1

– Radiotherapy may be utilized in children over 5 years of age as an adjunct or as an alternative to surgery for optic nerve gliomas; however, is generally avoided due to an increased risk of secondary malignancy.

– Surgical resection is reserved for large tumors causing mass effect or hydrocephalus and optic pathway gliomas confined to the orbit or optic nerve (2).

• Neurofibromatosis Type 2

– Surgical resection and stereotactic radiotherapy are the mainstay of treatment for vestibular schwannomas.

– Single fraction radiosurgery for spinal cord schwannomas may be used in addition to surgery or as primary therapy.

– TomoTherapy is able to treat a range of neoplasms using a single helical beam with 360 degrees of rotational radiation.

ONGOING CARE

PATIENT EDUCATION

Patients should be made aware of symptoms of worsening vision, tinnitus, hearing loss, or sensory changes that might suggest tumor growth.

PROGNOSIS

• Neurofibromatosis Type 1

– NF1 has a better prognosis due to a lower incidence of CNS tumors than NF2.

– Clinical manifestations often increase over time with a development in a malignancy or neurological deterioration often ensuing.

– Due to the malignant transformation of diseased tissues or development of neurofibrosarcoma, patients have a higher mortality/morbidity than the general population. A reduction of life expectancy by up to 15 years may result.

– 3–15% additional risk of malignant disease during lifetime.

• Neurofibromatosis Type 2

– NF2 is associated with significant morbidity and decreased lifespan.

– As the tumors themselves are relatively indolent, prompt diagnosis and treatment may improve life expectancy to more than 15 years following diagnosis.

COMPLICATIONS

• Neurofibromatosis Type 1

– Visual loss secondary to optic nerve gliomas

– Seizures, spinal cord tumors, scoliosis

• Neurofibromatosis Type 2

– Visual loss from optic nerve meningiomas, cataracts, or combined hamartomas of the retina and RPE

– Hearing loss, tinnitus, seizures

Pregnancy Considerations

• Increase in size of existing neurofibromas and the appearance of new neurofibromas occur commonly in women with NF1 during pregnancy.

• Neurofibromatosis during prenatal period may be diagnosed by:

– Linkage analysis can track the NF genes in a family with multiple affected members to determine which chromosome the fetus received.

– Gene sequencing to identify specific gene mutation in affected parent. This would permit prenatal diagnosis by amniocentesis or chorionic villus sampling.

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