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Neurofibromatosis

Neurofibromatosis encompasses two very different diseases, Neurofibromatosis 1 (NF1) and Neurofibromatosis 2 (NF2). There are a few overlapping features between them, however, which has resulted in longstanding confusion. The symptoms experienced by people with NF1 and NF2 are generally quite different and the confusion of health care professionals over the similarities and differences can be very frustrating to patients and their families.

Both disorders can be (and usually are) diagnosed based entirely on clinical findings. Genetic testing is available for both types of neurofibromatosis.

Neurofibromatosis 1
Characteristics
- NF1 is characterized by prominent skin features (hyperpigmented macules, termed café-au-lait spots, and nerve tumors that may or may not be close to the skin), optical tumors and other central nervous system tumors, certain bony abnormalities, some learning deficits and increased risk of certain non-nervous system cancers. NF1 is usually noticed during childhood with the development of skin findings.

Symptoms and Treatment - The symptoms of NF1, also called von Recklinghausen disease, vary widely from person to person. Most people with NF1 will have some but not necessarily all of the following:

  • Café-au-lait spots - flat, brown spots that usually appear during first year of life, but can be present at birth. They typically increase in number and size with age, but often fade later in life. About 25 percent of the normal population has one-to-three spots. More than 95 percent of patients with NF1 have them. Half of children with more than six spots and no other features of NF1 will later go on to meet criteria for the disease.
  • Neurofibromas - benign tumors of the coverings of the nerves. There are three main types:

    Cutaneous neurofibromas are soft fleshy tumors arising from the peripheral nerve sheath, usually appearing in late childhood or young adulthood. They can become cosmetically significant and can cause itching or pain. They do not become malignant.

    Subcutaneous neurofibromas are firm, tender nodules along the course of peripheral nerves that usually appear during adolescence or young adulthood.

    Plexiform neurofibromas can involve long portions of one nerve or bundles of nerves. They can be deep inside the body and able to be seen only with scans, or they can be superficial and involve the sin, extremities, head or neck. They are usually not apparent in infancy though the skin overlying it may be darker and/or thickened. They tend to enlarge with age, and can become severely disfiguring.

To date, no effective medical treatment is available for prevention or reduction of neurofibromas. Timing and extent of surgical treatment remains variable and controversial.

For cutaneous and subcutaneous neurofibromas, surgery is usually reserved for patients with significant discomfort or with cosmetically significant lesions. Laser therapy can also be effective, particularly if a large number of neurofibromas are being treated at one time. It is typical that neurofibromas come back, even after treatment.

Plexiform neurofibromas are very challenging to treat. Because they are often large, irregular in shape, prone to bleeding and frequently involve numerous nerves, they are almost impossible to remove completely. Their unpredictable growth patterns also make appropriate treatment choices more difficult. Surgical therapy is generally reserved until the lesion is causing impairment of functioning or discomfort or is cosmetically significant. Spinal plexiform neurofibromas may also be surgically excised, but total removal is often not possible. Regrowth can occur. No medications for treatment of plexiform neurofibromas have been approved, but clinical trials for medical therapy are underway.

Freckling in the armpits and groin – usually not present at birth, but develops during childhood. It most commonly occurs in the armpit or upper thigh areas, but can occur in other areas, particularly in skin folds.

Optic pathway gliomas (brain tumors)

Lisch nodules - raised, usually pigmented, bumps on the iris of the eye. They rarely cause clinically significant symptoms and are benign.

Bone abnormalities such as:

  • Pseudarthrosis – also called false join. This occurs in up to five percent of NF1 patients. This abnormality results from thinning of the long bone cortex, followed by fracture and impaired healing. Half of cases occur before age two.
  • Sphenoid dysplasia - malformation of the eye socket. This can be a disfiguring complication. It can occur with or without an associated plexiform neurofibroma.
  • Vertebral dysplasias - abnormal shape of the bones of the spine
  • Short stature and scoliosis - curvature of the spine. Scoliosis can occur in up to 25 percent of patients. This is most common in girls. Children with NF1 and scoliosis should be referred to an orthopedist with experience treating NF patients.

Macrocephaly – large head size. This occurs in up to half of children with NF1. It is usually due to increased brain size, the cause of which is unclear.

Learning problems and attention deficit disorder - fairly common but tend to be relatively mild.

General Considerations - Because of the complexity of the disorder, patients with NF1 are often best served by being followed at a neurofibromatosis center with a multidisciplinary team including genetics, neurology, neurosurgery, ophthalmology, orthopedics, dermatology, plastic surgery, neuropsychology and oncology. Patients with NF1 should undergo physical examinations twice a year, at least until age five, and yearly thereafter. Because of certain risks associated with these patients, blood pressure should be checked at least twice yearly. Special attention should be paid to early detection of scoliosis, evidence of limb bowing or pseudarthrosis, presence of or change in the cutaneous manifestations, and signs of precocious or delayed puberty. Head circumference should be checked regularly for signs of rapid growth, particularly in the first three years of life. Behavior and development should be followed carefully for signs of learning disability and ADHD. Patients with NF1 should also undergo yearly neurologic and ophthalmologic evaluation.

Neurofibromatosis 2
Characteristics
- The features of NF2 are restricted almost entirely to tumors of the nervous system (particularly schwannomas) with few skin or non-nervous system related abnormalities. NF2 is generally noticed during young adulthood, most commonly with hearing loss with the development of vestibular schwannomas or with other symptoms secondary to meningiomas or spinal schwannomas. The average age of symptom onset in patients with NF2 is about 20 years, while the average age of diagnosis is at about age 28.

Symptoms and Treatment: - NF2, also known as “central NF” is much less common than NF1. The severity of symptoms varies widely from patient to patient.

Other features which may be seen in patients include:

  • Meningiomas - tumors arising from the covering of the brain or spinal cord. They occur in about half of patients with NF2. Treatment is surgical unless the tumor is inaccessible, in which case, radiation therapy may be considered.
  • Schwannomas - benign tumors arising from the nerves. This is the most prevalent tumor type in NF2. About 98 percent of patients with NF2 develop tumors on the auditory nerve, called vestibular schwannomas. NF2 is usually not diagnosed until late adolescence or early adulthood when symptoms, often hearing loss, associated with these tumors typically occur. In addition to vestibular schwannomas, tumors can occur along other cranial nerves (particularly the trigeminal nerve), spinal roots and peripheral nerves. Auditory symptoms, like hearing loss or ringing in the ears, are usually the first symptom caused by their growth. They are usually slow growing and cause slow deterioration in hearing. Eventually, balance and other cranial nerve functions may become impaired. Brainstem compression and obstructive hydrocephalus (water on the brain) can occur. The decision to treat is highly individualized and depends on the degree of hearing loss, the size of the tumor, the presence and degree of contralateral symptoms and the presence of signs or symptoms of other cranial nerve or brainstem dysfunction. Treatment is usually surgical, though radiation therapy and radiosurgery are also used. Depending on the type and extent of surgery, hearing loss may be worse post-operatively and may be accompanied by facial or other cranial nerve palsies and headache. Small tumors can often be removed with preservation of hearing. Surgery for larger tumors carries a higher risk of deafness and other cranial nerve dysfunction. For patients who are surgically deafened, one option may include the placement of an auditory brain-stem implant (ABI), which is essentially a cochlear implant with a modified proximal electrode. Schwannomas arising from other cranial nerves are generally surgically removed if necessary. Spinal schwannomas occur in up to 80 percent of patients with NF2, though most are small and asymptomatic. They are slow-growing. Surgical resection is performed in patients with severe or progressive symptoms. Peripheral schwannomas can arise on any peripheral nerve and can cause pain or weakness.
  • Cataracts
  • Tumors of the spinal cord - glial tumors, including ependymomas and astrocytomas, are also more prevalent in patients with NF2. Again, treatment is generally primarily surgical, performed when they become clinically significant.

An initial evaluation of persons with NF2 should include neurologic and ophthalmologic examinations, formal audiologic testing, and a gadolinium enhanced MRI of the brain with thin cuts through internal auditory canals for most patients. A spinal MRI should be considered if there are signs or symptoms suggestive of spinal cord injury. Genetic counseling, including consideration of genetic and/or radiologic screening of at risk relatives should also be provided.

Any new neurologic signs or symptoms need to be evaluated promptly in patients with NF2. For most patients, yearly evaluations should include a thorough clinical/neurologic exam, audiologic testing and brain MRI. Serial spine MRIs need only be performed in patients with known large or symptomatic spinal tumors.

Johns Hopkins Care
Neurofibromatosis Types 1 and 2 are complex disorders with many symptoms involving many organ systems. As a result, it is important for patients with NF to be followed at a center that is very familiar with the symptoms of these disorders and knowledge of the natural history of NF. Furthermore, it is essential to have access to many different types of subspecialists. At Johns Hopkins, we provide multidisciplinary, coordinated care for adults and children.

 

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