Neurofibromatosis (commonly abbreviated NF), a genetically inherited disease that causes tumors to grow on nerve tissue producing skin and bone abnormalities, affects an estimated 100,000 Americans. Neurofibromatosis was first described in 1882 by the German pathologist, Friedrich Daniel von Recklinghausen. Neurofibromatosis is considered a member of the neurocutaneous syndromes (phakomatoses). The other phakomatoses include tuberous sclerosis, Sturge-Weber syndrome and von Hippel-Lindau disease.
Symptoms of Neurofibromatosis
The first noticeable sign of NF is almost always the presence of café au lait spots (pigmented birthmarks). These distinctive spots are non-itchy and painless. They can be found anywhere on the body. Tiny ones, freckles, may be seen under the arms or in the groin area.
The neurofibromas often first appear in childhood, especially during puberty, as brown, pink, or skin-colored nodules. They may be soft or firm to the touch, and disappear into the skin when pressed with a finger. Plexiform neurofibromas are noncircumscribed, thick and irregular and they can cause disfigurement by entwining important supportive structures. The plexiform subtype is specific for NF-1, described below.
There are two types of Neurofibromatoses:
NF-1 – More common, occurring in approximately 1 of 2500-3300 live births. Most people (about 60%) diagnosed with NF-1 have only relatively mild signs, like café-au-lait spots and few neurofibromas, and patients live normal and productive lives. The diagnosis requires any two of the following seven criteria:
1. Two or more skin neurofibromas and one plexiform neurofibroma.
2. Freckling of the groin or the axilla (arm pit) by 10-12 years of age.
3. Six or more café au lait spots measuring 5 mm in diameter prepubertal and over 15 mm postpubertal. Less than 1% of healthy children have 3 or more such spots, although 1 or 2 are commonly encountered in healthy individuals.
4. Skeletal abnormalities, such as sphenoid dysplasia or bowing of the long bones of the body and mild scoliosis, may occur.
5. Lisch nodules (hamartomas of iris), freckling in the iris.
6. Tumors on the optic nerve, also known as an optic glioma.
7. A first-degree relative with a diagnosis of NF-1.
NF-2 – Less common, occurring at a frequency of 1 case per 50,000-120,000. Characteristics include:
1. Bilateral vestibular schwannomas (acoustic neuromas) leading to progressive hearing loss around the age of twenty, even as early as ten years of age.
2. These tumors may also cause:
b. Balance problems and vertigo
c. Facial weakness/paralysis
3. Other brain and spinal tumors such as astrocytoma, meningioma, intramedullary glioma and ependymoma.
4. Any relative with NF-2, diagnosed or not.
Many individuals with neurofibromatosis have below average intelligence. Twenty-five to forty percent of patients with NF-1 may have learning disabilities, while 5-10% may have mental retardation. Types of learning disabilities may include motor dysfunction, attention deficit hyperactivity disorder and deficits in visuospatial processing. Up to 40% of children with NF-1 have seizures. Endocrinologic problems are common, such as short stature and growth hormone deficiency and early or delayed puberty. Sexual precocity occurs in 3-5% of children who are affected, usually associated with an intracranial tumor. Pheochromocytoma may cause high blood pressure.
Causes of Neurofibromatosis
Neurofibromatosis is autosomal dominant, affecting genders and races equally worldwide; therefore, if only one parent has neurofibromatosis, his or her children have a 50% chance of developing the condition as well. Disease severity varies between individuals. Although many affected persons inherit the disorder, between 30% and 50% of new cases arise spontaneously through mutation in an individual’s genes. Neurofibromatosis type 1 has mutation of neurofibromin on chromosome 17q11.2. Neurofibromatosis type 2 has mutation of merlin on chromosome 22q12.
Neurofibromatosis Examination and Tests
Laboratory Studies: Currently, mutation analysis is available for NF-1 and NF-2 (60-70% accurate), however, this type of testing is not readily available. Prenatal diagnosis of familial NF-1 or NF-2 is possible utilizing amniocentesis or chorionic villus sampling procedures.
Imaging Studies: Plain radiography may show growth disturbance (i.e., hyperplastic bones, “streaky” appearance to the medullary cavity, skull asymmetry or sphenoid dysplasia), bowing deformities or pseudoarthrosis of long bones. MRI of the brain and the cervical spine may be helpful in patients with NF-1 to assess the extent of disease and determine involvement of the adjacent bone and spinal canal.
For patients suspected of having NF-2, dedicated gadolinium MRI of the brain and internal auditory canals is needed to detect small intracanalicular vestibular schwannomas. Gadolinium MRI of the orbits is the study of choice for optic gliomas. Large optic nerves likely indicate low-grade gliomas in these patients. MRI of the brain may demonstrate scattered foci of high T2 signal in the basal ganglia, thalamus, brain stem and white matter of up to 50% of children.
Malignant changes in plexiform neurofibromas may be detected by 18 Fluorodeoxyglucose positron emission tomography (18FDG PET). Typical CT findings in persons with NF-1 with chest involvement include small well-defined surface neurofibromas, focal thoracic scoliosis, vertebral scalloping, enlarged neural foramina and characteristic rib notching from adjacent neurofibromas. Dural ectasia, meningoceles and dumbbell-shaped masses are related to abnormal pressure in and around the spinal canal. Dural ectasia is circumferential dilatation of the dural sac with fluid attenuation. The expanding dura can erode the surrounding osseous structures, widening the spinal canal, thinning the lamina and disrupting the vertebral elements.
Other Tests: A Wood lamp examination may be useful in patients with very pale skin in an effort to better view café au lait macules. Slit-lamp examination is recommended for children older than 6 years to confirm the presence of Lisch nodules.
Because there is no cure for the disease itself, the only therapy for those with neurofibromatosis is a program of treatment by a team of specialists to manage symptoms and complications. Surgery may be needed when tumors compress organs or other structures. Three to five percent of all people with neurofibromatosis develop cancerous growths; in these cases, chemotherapy may be successful.
Treatment of neurofibromatosis is predominantly surgical. When neurofibromas increase in size or cause pain, malignant transformation should be suspected and excision or biopsy should be performed. Vestibular schwannomas and tumors that cause tinnitus and vertigo should be excised with great caution. Gamma-knife radiosurgery is another treatment modality. Any signs of epilepsy should be investigated and responsible tumors should be removed.
Orthopedic surgeons should be involved for tibial bowing and kyphoscoliosis. Plastic surgeons are often recommended for correction of deformities, especially of the face. Psychological assessment may be necessary in monitoring language and learning disabilities. Genetic counseling for all patients affected with NF is recommended. In 2000, the U.S. Food and Drug Administration (FDA) approved an auditory brainstem implant for people with NF-2 who have lost their hearing. This device transmits sound signals directly to the brain, enabling the person to hear certain sounds, including speech.
Further Outpatient Care
The American Academy of Pediatrics Committee on Genetics recommends monitoring children with NF-1 by performing annual physical examinations and ophthalmologic evaluations. An audiologic examination should be performed before the child is of school age. A language and speech evaluation should be considered for each child. Children should be examined for the presence of scoliosis. Blood pressure should be checked at least once per year. Patients should be continuously monitored for growth, change or pain in their neurofibromas, because this could be a sign of malignant transformation. Biopsy should be performed on any lesion undergoing these changes.
For further information about Neurofibromatosis, please refer to the following organizations or click on the following links:
National Cancer Institute (NCI)
National Institutes of Health, DHHS
6116 Executive Boulevard, Ste. 3036A, MSC 8322
Bethesda, MD 20892-8322
Tel: 800-4-CANCER (422-6237) 800-332-8615 (TTY)
International RadioSurgery Association
3002 N. Second Street
Harrisburg, PA 17110