Neurofibromatosis (NF) is a term applied to important human disorders that are inherited in an autosomal dominant fashion (i.e., on average half of the children of a person with the disease gene will inherit the disorder) and involve the formation of benign tumors in the nervous system.

Neurofibromatosis Type 1 (NF1)

Neurofibromatosis 1, also known as von Recklinghausen neurofibromatosis, is one of the most frequent dominant disorders in man, affecting ~1 in 3,000 births. A hallmark of NF1 is the wide variation in expression of its symptoms, which include abnormally pigmented patches of skin (café-au-lait spots), hamartomas in the iris of the eye (Lisch nodules), and benign neurofibromas (peripheral nerve tumors consisting mainly of Schwann cells with fibroblasts, mast cells, and other cellular elements) that may be profoundly disfiguring. About 5% of NF1 patients develop malignant peripheral nerve sheath tumors (malignant neurofibrosarcomas) that are often fatal. NF1 patients show increased risk for several other tumors, such as optic gliomas, astrocytomas and juvenile malignant myeloid disorders, making it a familial cancer syndrome. Other frequent features of NF1 are learning disabilities and skeletal abnormalities. NF1 is caused by inactivating mutations in a tumor suppressor gene on chromosome 17q which encodes neurofibromin, a large protein with a RasGTPase activating domain that implicates it as a regulator of signalling pathways within cells.

Neurofibromatosis Type 2 (NF2)

Neurofibromatosis 2 is a less common but extremely serious disorder, occurring with an incidence of ~1 in 40,000 persons. The characteristic growth of NF2 is the vestibular schwannoma, a benign, slow growing tumor on the vestibular branch of the acoustic nerve (8th cranial nerve) that can cause loss of hearing and balance, and usually occurs bilaterally. However, other nervous system tumors, particularly meningiomas, spinal schwannomas, and ependymomas, are also frequent. In addition, many patients develop cataracts. The same tumor types that occur as multiple growths in NF2 also occur as sporadic, solitary tumors in the general population. The tumors of NF2 are histologically benign, but their anatomical locations make management difficult. While they cause functional loss by compressing adjacent nerves, surgical removal often risks permanent nerve damage. The growth of Schwann cells to produce schwannomas or arachnoidal cells of the meninges to produce meningiomas in NF2 (and in most sporadic equivalents) is due to inactivating mutations in a tumor suppressor gene on chromosome 22q, which encodes merlin. Merlin is a 66 kDa protein related to the ERM family proteins (ezrin, radixin moesin), which act to link proteins in the cell membrane to the actin cytoskeleton. Like the ERMs, merlin has an amino-terminal FERM domain (protein 4.1 family domain) and a long carboxyl-terminal alpha helical region, and has been localized to areas of membrane remodeling, suggesting a role in cell communication, adhesion and motility.

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Schwannomatosis

Schwannomatosis is a third form of NF that has only recently been recognized. The incidence is estimated to be ~1 in 40,000 with familial occurence uncommon as up to 90% of affected people have apparently sporadic disease. Persons with schwannomatosis develop multiple schwannomas on cranial, spinal and peripheral nerves, but they do not develop bilateral vestibular tumors and do not go deaf. Unlike other forms of NF, affected individuals usually do not develop other types of tumors and do not have learning disabilities. Like NF2, the tumors are benign. Persons with schwannomatosis usually have much greater problem with pain than with neurological disability although, as with all forms of NF, schwannomatosis may vary greatly among patients. Many familial cases of schwannomatosis are caused by genetic defects in the SMARCB1 gene, a tumor suppressor that regulates cell cycle, growth and differentiation.

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