Neurofibromatosis

Definition

Neurofibromatosis (NF) is a genetic condition in which fleshy tumors called neurofibromas grow throughout the body. Neurofibromatosis was first written up in the medical literature in 1882 by a German physician, Dr. Friedrich Daniel von Recklinghausen.

Description

Neurofibromas are tumors that are composed of the fibrous substance that covers nerve cells. These neurofibromas grow along the nerves in the body (the peripheral nerves), and cause skin and bone abnormalities. Furthermore, while neurofibromas initially start out as benign (non-cancerous) growths, 3–5% of all neurofibromas are converted into malignant (cancerous) tumors. Neurofibromatosis patients are also at risk of developing other types of cancerous tumors of the nervous system.

Neurofibromatosis is divided into two types, NF1 and NF2. NF1, also called Von Recklinghausen disease or peripheral neurofibromatosis, is the most common. Visible skin signs of NF1 tend to be present at birth, or certainly by about age 10. NF1 causes predominantly skin and bone changes, as well as problems due to the growing neurofibromas exerting damaging pressure on peripheral nerves. NF2, also called central neurofibromatosis or bilateral acoustic neurofibromatosis, is less common. Its predominant problem involves neurofibromas growing on the eighth cranial nerve (also known as the acoustic or auditory nerve). These tumors interfere with the functioning of the cranial nerve VIII, causing serious hearing impairment or even profound deafness, as well as a variety of symptoms due to pressure on adjacent nerves that serve the head and neck areas.

Demographics

NF1 occurs in one out of 4,000 births; NF2 occurs in one out of 40,000 births. Males and females are equally affected. In the United States, about 100,000 people are identified as having either NF1 or NF2.

Causes and symptoms

Neurofibromatosis is a genetic disease that is inherited in an autosomal dominant fashion, meaning that only one parent with neurofibromatosis is required to pass on the disease to offspring. Half of all cases of neurofibromatosis is inherited from a parent with the disorder; the other half of cases of neurofibromatosis does not have a history of the disease in a parent. They are considered to have developed the disease due to a spontaneous mutation, which can then be passed on to the patient's own offspring. When one parent has neurofibromatosis, each child has a 50% chance of inheriting the condition.

Neurofibromatosis 1

Patients with NF1 are most often diagnosed in childhood or even infancy. The most common characteristics of NF1 include:

• cafe-au-lait macules (light brown, flat skin patches)
• freckles in the armpit and groin areas (axillary and inguinal freckling)
• neurofibromas on and under the skin, ranging from millimeters to inches (centimeters) in size (an individual may have anywhere from several to thousands of these soft, rubbery, flesh-colored tumors)
• Lisch nodules, tumors within the iris of the eye
• vision problems, probably due to gliomas (tumors made of cells called glial cells that serve a supportive function within the central nervous system ) located within or exerting pressure on the optic nerves
• learning problems or frank mental retardation
• scoliosis (side-to-side curvature of the spine)
• high blood pressure
• short adult height
• early (precocious) puberty
• increased risk of malignant brain and spinal cord tumors, kidney tumors (Wilms' tumor), adrenal tumors (pheochromocytoma), leukemia (cancer of blood cells), and tumors of the tendons, muscles, or connective tissue (rhabdomyosarcoma)

Neurofibromatosis 2

The most common characteristics of NF2 include:

• hearing problems due to neurofibromas in both acoustic nerves

• cataracts, the abnormal clouding of the lens of the eye
• headache , pain or numbness in the face
• problems with balance and coordination when walking, resulting in unsteadiness
• ringing in the ears (tinnitus)
• cafe-au-lait macules (many fewer than in NF1)
• neurofibromas on and under the skin (many fewer than in NF1)

Diagnosis

NF1 is diagnosed when the patient has at least two of the following criteria:

• six or more cafe-au-lait macules that measure more than 0.2 in (5 mm) in children before puberty, or that measure more than 0.6 in (15 mm) in patients after puberty
• demonstration of two or more neurofibromas
• axillary or inguinal freckling
• presence of optic glioma
• presence of two or more Lisch nodules, diagnosed through slit-lamp examination (a slit-lamp is a micro-scope with an extremely strong light that can be focused into a slit in order to examine the eye)
• bone abnormalities such as defects of the skull bone (sphenoid wing) or abnormal thinning of the usually dense outer layer of the long thigh, leg, or arm bones
• a parent, sibling, or child who has been diagnosed with NF1

NF2 is diagnosed when the patient has at least one of the following criteria:

• gadolinium-enhanced magnetic resonance imaging (MRI) scan or other appropriate imaging study that demonstrates tumors of the two cranial nerves VIII
• a parent, sibling, or child who has been diagnosed with NF2, and has either a diagnosed tumor on one cranial nerve VIII or at least two of the following: neurofibroma, meningioma (tumor of the membrane that covers the spinal cord and brain [meninges]), glioma (tumor composed of the supportive cells called glial cells), schwannoma (tumor composed of the schwann cells that normally wrap around nerves throughout the body, creating a sheath that both insulates the nerves and allows nerve conduction to occur more quickly), or a specific type of cataract called a juvenile posterior subcapsular lenticular opacity

Treatment team

Treatment of neurofibromatosis requires a multidisciplinary team approach, with neurologists, ophthalmologists, otolaryngologists (ENTs), neurosurgeons, general surgeons, plastic surgeons, orthopedic surgeons, and dermatologists all collaborating. Depending on the kinds of challenges that the specific patient faces, other team members may include speech and language specialists, learning specialists, occupational therapists, and physical therapists.

Treatment

There is no known cure for either NF1 or NF2. Regular examinations are important in order to catch new developments early, such as the advent of high blood pressure, malignant transformation of a neurofibroma, or development of cataracts.

Treatment is purely supportive and depends on the specific manifestations of the disease in a given patient. For example, a patient with scoliosis may require bracing; patients with cataracts may require surgery; patients with auditory nerve tumors may require traditional scalpel surgery or gamma-knife surgery (also called stereotactic radiosurgery, this is a technique that allows a very focused, very high dose of radiation to be delivered to a carefully designated tissue location). Optic gliomas may be treated with radiation therapy. Any tumors that are impinging on nerves and causing symptoms or tumors that have undergone malignant transformation may require surgical removal, while tumors that are purely problematic from a cosmetic standpoint may be left alone.

Clinical trials

A variety of clinical trials are underway, including studies of several types of drugs such as drug R115777, tipifarnib, pirfenidone, and combination methotrexate/vinblastine therapy, each of which may be useful in shrinking tumors associated with neurofibromatosis. Information about these trials are available through the National Cancer Institute.

Prognosis

Even within the same family, the manifestations and severity of neurofibromatosis can differ widely.

Special concerns

Genetic counseling is crucial for families with a history of neurofibromatosis to help ascertain the risk of future offspring being born with neurofibromatosis.

Resources

BOOKS

Barkovich, A. James, and Ruben I. Kuzniecky. "Neurocutaneous Syndromes." Cecil Textbook of Medicine, edited by Lee Goldman. Philadelphia: W. B. Saunders Company, 2003.

Berg, Bruce O. "Chromosomal Abnormalities and Neurocutaneous Disorders>" Textbook of Clinical Neurology, edited by Christopher G. Goetz. Philadelphia: W. B. Saunders Company, 2003.

Haslam, Robert H. A. "Neurocutaneous Syndromes." Nelson Textbook of Pediatrics, edited by Richard E. Behrman, et al. Philadelphia: W. B. Saunders Company, 2004.

WEBSITES

National Institute of Neurological Disorders and Stroke (NINDS). Neurofibromatosis Fact Sheet. (April 27, 2004). <http://www.ninds.nih.gov>.

ORGANIZATIONS

National Cancer Institute (NCI). 9000 Rockville Pike, Bethesda, MD 20892. [email protected] or [email protected].

The National Neurofibromatosis Foundation, Inc. 95 Pine Street, 16th Floor, New York, NY 10005. (212) 344-NNFF (6633) or (800) 323-7938. [email protected]. <http://www.nf.org>.

Rosalyn Carson-DeWitt, MD