What is the condition and its etiology?
See p. 18.
Neurofibromatosis, first described in 1882, is neurocutaneous genetic disorder of the neural crest cells (Schwann cells, melanocytes, and endoneurial fibroblasts), and is characterized by a diverse spectrum of clinical manifestations. This condition is rarely addressed in the emergency department, but knowledge of the disease and its potential complications is valuable. Neurofibromatosis (NF) consists of two distinct conditions, NF type 1 (von Recklinghausen disease), NF2 and schwannomatosis. NF1, the most common form, accounts for nearly 90 percent of cases.
NF1 is an autosomal dominant disorder, but 30-50 percent of cases are the result of a sporadic (noninherited) mutation. Sporadic genetic mutations are more common in the chromosome derived from the father, for unknown reasons. (Hum Genet 1992;88:279.) The severity of the condition is affected by genetic expression variables. (See FastLinks for NF information page from NINDS.) The NF1 gene has been mapped to chromosome 17q11.2 (Am J Hum Genet 1989;44:20), and was found to be part of a family of tumor suppressor genes. The NF1 gene, cloned in 1990, produces the protein neurofibromin, which negatively regulates the cellular Ras signal transduction pathway. (Can J Neurol Sci 1998;25:181; J Neurosci 2012;32:14087.) Neurofibromin has been found in many body tissues, including the spleen, brain, and kidney.
Given the variable genetic expression, patients with NF1 present with a variety of features and disease severity. (J Med Genet 2012;49(8):483.) Diagnostic criteria exist (Pediatrics 2000;105[3 Pt 1]:608), but the pathognomonic findings of NF1 are cutaneous neurofibromas (benign tumors comprised of Schwann cells, fibroblasts, and mast cells) and multiple (six or more) café au lait spots (flat hyperpigmented lesions). Neurofibromas can be cutaneous (most common, benign fleshy peripheral nerve sheath tumors), subcutaneous, nodular plexiform (deep tumors along peripheral nerve roots), or diffuse plexiform (highly vascular tumors that involve multiple nerve bundles). Depending on the location, size, and density, neurofibromas can cause minimal to significant morbidity including pain and compressive or obstructive pathology of adjacent structures.
Other clinical features of NF1 include freckling in the axillary or inguinal regions, optic glioma (most are slow growing and premalignant), Lisch nodules (pigmented iris hamartomas, often raised but do not affect vision), and bony lesions such as dysplasia or thinning of the long bone cortex with or without pseudarthrosis (nonunion). Other features include scoliosis, osteoporosis, macrocephaly, seizures, peripheral neuropathy, early onset hypertension (can develop in childhood), and cognitive deficits. Severe cases are rare (<5%), and can include intellectual disability, early development of cutaneous lesions, and dysmorphic facial features. (Am J Med Genet 1997;73:80.) The diagnosis of NF1 can be made clinically or definitively by genetic testing. One study found that nearly 50 percent of patients were diagnosed with NF1 by age 1, greater than 45 percent by age 8, and all by age 20. (Pediatrics 2000;105[3 Pt 1]:608.)
Patients with NF1 appear to be at higher risk for developing malignancies (two to five times more than the general population), and it is the most common tumor-predisposing disease in humans. (Can J Neurol Sci 1998;25:181, N Engl J Med 1986;314:1010.) Malignant transformation is most common from optic glioma or plexiform neurofibroma lesions (they transform into malignant peripheral nerve sheath tumors, formerly neurofibrosarcomas). There is no cure for NF1. Surgical excision, radiation, and chemotherapy may be used to reduce tumor burden, particularly when vision is threatened by optic nerve involvement or when malignant transformation occurs. Bony malformations may also be amenable to surgical reconstruction.
NF2 (also called central neurofibromatosis), far less common than NF1, predisposes individuals to the development of multiple tumors in the nervous system. NF2 is the result of mutations to the NF2 tumor suppressor gene, located on chromosome 22, which produces merlin. (Nature 1986;322:644.) Mutations can be inherited (autosomal dominant) or sporadic, with variable genetic expression.
The most common lesions (more than 90%) are bilateral vestibular schwannomas (they typically develop by age 30). These are slow-growing tumors on the vestibulocochlear (auditory vestibular) cranial nerve 8. These lesions can cause hearing loss, tinnitus, vertigo, and coordination dysfunction. Patients with NF2 can also have schwannomas of other cranial nerves and intracranial and spinal meningiomas. Depending on the location, patients can have severe pain, weakness, or paresthesias. Other characteristic lesions of NF2 include eye lesions (cataracts [as many as 80%] and retinal changes) and skin lesions (subcutaneous tumors and skin plaques). Guidelines exist for the clinical diagnosis (Genet Med 2011;13:576), but can be validated by genetic testing.
Treatment of NF2 is watchful waiting to determine morbidity. Treatment may include radiation or surgical excision if symptoms warrant treatment to maintain quality of life, but is complicated by the location and fact that most tumors extend along the facial nerve fibers and are often multifocal. (Orphanet J Rare Dis 2009;4:16.)
This patient was diagnosed with a viral syndrome, and discharged to routine primary care follow-up.
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* Read more about neurofibromatosis from the National Institute of Neurological Disorders and Stroke at http://1.usa.gov/W0bMcq.
* Read all of Dr. Wiler's past columns at http://bit.ly/WilerConsult.
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