Neurofibromatosis

Neurofibromatosis (commonly abbreviated NF) is a genetically-inherited disorder in which the nerve tissue grows tumors (i.e., neurofibromas) that may be harmless or may cause serious damage by compressing nerves and other tissues. The disorder affects all neural crest cells (Schwann cells, melanocytes, endoneurial fibroblasts). Cellular elements from these cell types proliferate excessively throughout the body forming tumors and the melanocytes function abnormally resulting in disordered skin pigmentation.The tumors may cause bumps under the skin, colored spots, skeletal problems, pressure on spinal nerve roots, and other neurological problems.

Neurofibromatosis is autosomal dominant, which means that it affects males and females equally and is dominant (only one copy of the affected gene is needed to get the disorder). Therefore, if only one parent has neurofibromatosis, his or her children have a 50% chance of developing the condition as well. The severity in affected individuals, however, can vary (this is called variable expressivity). Moreover, in around half of cases there is no other affected family member because a new mutation has occurred.

Diagnostic Criteria

Neurofibromatosis type 2

Neurofibromatosis type 2 is a mutation of NF2 (Merlin) in chromosome 22q12.

• bilateral tumors, acoustic neuromas on the vestibulocochlear nerve (the eighth cranial nerve) leading to hearing loss
• Any relative with NF-2, diagnosed or not

In fact, the hallmark of NF 2 is hearing loss due to acoustic neuromas around the age of twenty
the tumors may cause:

• headache
• balance problems, and Vertigo
• facial weakness/paralysis
• patients with NF2 may also develop other brain tumors, as well as spinal tumors
• Deafness and Tinnitus

Schwannomatosis

The gene involved in Schwannomatosis has yet to be identified.

1. Multiple Schwannomas occur.
2. The Schwannomas develop on cranial, spinal and peripheral nerves.
3. Chronic pain, and sometimes numbness, tingling and weakness.
4. About 1/3 of patients have segmental Schwannomatosis, which means that the Schwannomas are limited to a single part of the body, such as an arm, a leg or the spine.
5. Unlike the other forms of NF, the Schwannomas do not develop on vestibular nerves, and as a result, no loss of hearing is associated with Schwannomatosis.
6. Patients with Schwannomatosis do not have learning disabilities related to the disease.

One must keep in mind, however, that neurofibromatosis can't occur in or affect any of the organ systems, whether that entails simply compressing them (from tumor growth) or in fact altering the organs in some fundamental way. This disparity in the disease is one of many factors that makes it difficult to diagnose, and eventually find a prognosis for.

Genetics and Hereditability

Neurofibromatosis type 1 is due to mutation on chromosome 17q11.2 , the gene product being Neurofibromin ( a GTPase activating enzyme).

Neurofibromatosis type 2 is due to mutation on chromosome 22q , the gene product is Merlin, a cytoskeletal protein. Both NF1 and NF2 are autosomal dominant disorders, meaning that only one copy of the mutated gene need be inherited to pass the disorder. A child of a parent with NF1 or NF2 and an unaffected parent will have a 50%-100% chance of inheriting the disorder, depending on whether the affected parent is heterozygous or homozygous for the trait.

Complicating the question of heritability is the distinction between genotype and phenotype, that is, between the genetics and the actual manifestation of the disorder. In the case of NF1, no clear links between genotype and phenotype have been found, and the severity and specific nature of the symptoms may vary widely among family members with the disorder.[3] In the case of NF2, however, manifestations are similar among family members; a strong genotype-phenotype correlation is believed to exist (ibid).

Both NF1 and NF2 can also appear to be spontaneous mutation, with no family history. These cases account for about one half of neurofibromatosis cases (ibid).

Similar to polydactyly, although NF is a dominant mutation, it is not prevalent in society. Neurofibromatosis-1 is found in approximately 1 in 2,500-3,000 live births (carrier incidence 0.0004, gene frequency 0.0002). NF-2 is less common, having one case in 50,000-120,000 live births.

Mechanism

Neurofibromatosis affects humans on a genetic level, meaning that it either destroys, or renders defective a specific gene.

• The gene that NF-1 affects is large, on band 17q11.2. It encodes for a protein called neurofibromin, otherwise known as "the tumor suppressor" protein. This protein is a negative regulator of the Ras kinase pathway. Neurofibromatosis alters or weakens this protein, allowing rapid, radical growth of cells all over the body, especially around the nervous system. This leads to the normal symptoms for neurofibromatosis – clumpings of these tumors, called neurofibromas and schwannomas.
• Less is known about the NF-2 linked gene. However, it is on band 22q1 and codes for the protein Merlin.

Effects

People with Neurofibromatosis can be affected in many different ways.

• There is a high incidence of learning disabilities in people with NF. It is believed that at least 50% of people with NF have learning disabilities of some type.
• increased chances of development of petit mal epilepsy (a Partial absence seizure disorder)
• The tumors that occur can grow anywhere a nerve is present. This means that:
• They can grow in places that are very visible.
• The tumors can also grow in places that can cause other medical issues that may require them to be removed for the patient's safety.
• Affected individuals may need multiple surgeries, depending on where the tumors are located

Treatment

Because there is no cure for the condition itself, the only therapy for those people with neurofibromatosis is a program of treatment by a team of specialists to manage symptoms or complications. Surgery may be needed when the tumors compress organs or other structures. Less than 10% of people with neurofibromatosis develop cancerous growths; in these cases, chemotherapy may be successful. A new clinical trial at NIH uses a drug called Pegintron. There are some accounts of cures in foreign countries. Though nothing has proved by the American FDA to be effective, alternative resources would say otherwise. Some people may find something in the herbal remedies that can slow down the growth of these tumors.

History

Neurofibromatosis was first described in 1882 by the German pathologist Friedrich Daniel von Recklinghausen. He wrote on it and published it in Hämochromatose, Tageblatt der Naturforschenden Versammlung.

Joseph Merrick, the Elephant Man, was once considered to have been affected with either elephantiasis or neurofibromatosis type I. However, it is now generally believed that Merrick suffered from the very rare Proteus syndrome. This however has given rise to the common misconception that Neurofibromatosis and "Elephant Man Disease" are one and the same.

Related disorders

Neurofibromatosis is considered a member of the neurocutaneous syndromes (phakomatoses). In addition to the types of neurofibromatosis, the phakomatoses also include tuberous sclerosis, Sturge-Weber syndrome and von Hippel-Lindau disease. This grouping is an artifact of an earlier time in medicine, before the distinct genetic basis of each of these diseases was understood.

Neurofibromatosis is also associated with pheochromocytoma.