Neurofibromatosis

Neurofibromatosis
Classification and external resources
Back of an elderly woman with Neurofibromatosis.
ICD-10	Q85.0
ICD-9	237.7
ICD-O:	9540/0
eMedicine	derm/287
MeSH	D017253

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.^[1]

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.

Classification

Neurofibromatosis type 1

Neurofibromatosis type 1 - mutation of neurofibromin chromosome 17q11.2. The diagnosis of NF1 is made if any two of the following seven criteria are met:

• Two or more neurofibromas on the skin or under the skin or one plexiform neurofibroma (a large cluster of tumors involving multiple nerves); Neurofibromas are the subcutaneous bumps that are characteristic of the disease and increase in number with age.
• Freckling of the groin or the axilla (arm pit).
• Café au lait spots (pigmented, most often a shade of brown, smooth edges(coast of california)^[2] birthmarks). Six or more measuring 5 mm in greatest diameter in prepubertal individuals and over 15 mm in greatest diameter in postpubertal individuals
• Skeletal abnormalities, such as sphenoid dysplasia or thinning of the cortex of the long bones of the body (i.e. bones of the leg, potentially resulting in bowing of the legs)
• Lisch nodules (hamartomas of iris), freckling in the iris.
• Tumors on the optic nerve, also known as an optic glioma

plexiform neurofibroma

Patient with multiple small cutaneous neurofibromas and a 'café au lait spot' (bottom of photo, to the right of centre). A biopsy has been taken of one of the lesions

Neurofibromatosis type 2

Neurofibromatosis type 2 - mutation of NF2 (Merlin) in chromosome 22q12

• bilateral tumors, acoustic neuromas on the vestibulocochlear nerve (the eighth cranial nerve) leading to hearing loss
  • 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
• Any relative with NF-2.

Schwannomatosis

Schwannomatosis - mutation in both chromosomes 17 and 22

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 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.

Signs and symptoms

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.

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.

Genetics

NF-1 and NF-2 may be inherited in an autosomal dominant fashion, as well as through random mutation.

Neurofibromatosis type 1 is due to mutation on chromosome 17q11.2 , the gene product being Neurofibromin ( a GTPase activating enzyme).^[3]

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.^[4] 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.^[5]

Pathophysiology

Neurofibromatosis affects humans on a genetic level, meaning that it either destroys, or renders defective a specific gene. NF-1

• The gene that NF-1 affects is large, on band 17q11.2. It encodes for a protein called Neurofibromin 1, otherwise known as "the tumor suppressor" protein. This protein is a negative regulator of the Ras kinase pathway^[6]. 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.

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 ^[7]. 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.

Support

There are several national organizations that provide support for those challenged by neurofibromatosis.

• [CTF] - The Children's Tumor Foundation(a non-profit organization working towards a cure for Neurofibromatosis in the United States) http://www.ctf.org

• [NF, Inc.] - (a non-profit organization working towards Neurofibromatosis patient support in the United States) [http://www.nfinc.org

• [Neurofibromatosis Cafe] - (a non-profit organization working providing patient education, awareness and support of Neurofibromatosis in the United States) http://www.reggiebibbs.com

History

Neurofibromatosis was first described in 1882 by the German pathologist Friedrich Daniel von Recklinghausen. He wrote about it in Hämochromatose, Tageblatt der Naturforschenden Versammlung.^[8]

Joseph Merrick, the Elephant Man, was once considered to have been affected with 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.

Society and culture

In popular culture

In the television series Dallas, the inherited neurofibromatosis of the Barnes family is a driving plot device, although the portrayal of the condition does leave something to be desired in terms of scientific fact.

The disease is also a pivotal plot element in the Icelandic film Mýrin (Jar City) and Tainted Blood, the novel on which it was based.

Gillian Anderson, who played Dana Scully on the X-Files, is a spokesperson and helps in the raising of money for neurofibromatosis, because her brother suffers from the disease.

Munya "Mony" Yassir, who was diagnosed with neurofibromatosis at 18 months, appeared in nine episodes of Degrassi: The Next Generation, in season 2.

Neurofibromatosis is mentioned in an episode of House as a possible diagnosis.

In 2010, MTV's True Life showed an episode entitled "I have NF".

Notable Cases

In November 2006, there was an hour-long documentary on the British television network Channel 4 about Facing the World, an organization that helps children with severe facial disfigurements in developing countries. One of the children featured on the documentary was Arianto, an Indonesian boy who suffered from a severe form of neurofibroma resulting in hemifacial giganticism.

Also, in that year, another documentary on BBC2 (edge of life) featured a Neurofibromatosis case. On that documentary was a young teenager, Amit Ghose, who had decided for himself to have corrective surgery at the age of 14. In this case the neurofibroma occurred on the face resulting in the loss of sight in one eye and having to have it removed. This was a case NF Type2 resulting in the disfigurement of the one side of the face leaving the other side completely normal.

In January 2008, 32-year-old Huang Chuncai of China underwent a second operation to remove another 4.5 kg (9.9 lb) of tumor from his face. A previous operation removed 15 kg (33 lb) from what was originally a 23 kg (55.7 lb) tumor.^[9][10]

In March 2007 the treatment of 30-year-old neurofibromatosis patient Pascal Coler of France ended after he had received what his doctors call the world's first successful full face transplant.^[11][12]

See also

• Neurofibroma

References

External links

Neurofibromatosis at the Open Directory Project

• Home Page of the Children's Tumor Foundation (a non-profit organization working towards a cure for Neurofibromatosis in the United States)
• Home page from NF Inc (a non-profit organization working towards Neurofibromatosis patient support in the United States)
• Home Page of the Reggie Bibbs website (a non-profit organization working providing patient education, awareness and support of Neurofibromatosis in the United States)
• Home Page of the Just Ask Foundation website (a non-profit organization working to inspire people with neurofibromatosis to come out of the shadows and into the light of the world by encouraging the people they meet to ask about neurofibromatosis and to raise awareness of the disease throughout the world and United States)
• Home Page (a non-profit organization providing patient information, awareness and support of Neurofibromatosis in the world)
• Chinese man suffering from Neurofibromatosis (videoclip, 2008)