Neurofibromatosis

Definition:
Neurofibromatosis (commonly abbreviated NF; neurofibromatosis type 1 is also known as von Recklinghausen disease) is a genetically-inherited disorder in which the nerve tissue grows tumors (i.e., neurofibromas) that may be benign or may cause serious damage by compressing nerves and other tissues. The disorder affects all neural crest cells (Schwann cells, melanocytes and endoneurial fibroblasts). Cellular elements from these cell types proliferate excessively throughout the body, forming tumors; melanocytes also function abnormally in this disease, resulting in disordered skin pigmentation and “cafe-au-lait” spots. The tumors may cause bumps under the skin, colored spots, skeletal problems, pressure on spinal nerve roots, and other neurological problems.
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Neurofibromatosis is an autosomal dominant disorder, which means only one copy of the affected gene is needed for the disorder to develop. 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 can vary, this may be due to variable expressivity. Approximately half of cases are due to de novo mutations and no other affected family members are seen. It affects males and females equally.

Symptoms:
Three distinct types of neurofibromatosis exist, each with different signs and symptoms.
Neurofibromatosis type 1 (also known as “von Recklinghausen disease”) is the most common form of NF, accounting for up to 90% of the cases. NF 1 has a disorder frequency of 1 in 4,000, making it more common than neurofibromatosis type 2, with a frequency of 1 in 45,000 people. It occurs following the mutation of neurofibromin on chromosome 17q11.2. 100,000 Americans have neurofibromatosis. Neurofibromin is a tumor suppressor gene whose function is to inhibit the p21 ras oncoprotein. In absence of this tumor suppressor’s inhibitory control on the ras oncoprotein, cellular proliferation is erratic and uncontrolled, resulting in unbalanced cellular proliferation and tumor development. The diagnosis of NF1 is made if any two of the following seven criteria are met:

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Plexiform neurofibroma on the neck of a patient; plexiform neurofibromas are a cause of morbidity in the affected individuals.

 

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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.

*Two or more neurofibromas on or under the skin, or one plexiform neurofibroma (a large cluster of tumors involving multiple nerves); neurofibromas are the subcutaneous bumps characteristic of the disease, and increase in number with age.

*Freckling of the groin or the axilla (arm pit).

 

*Café au lait spots (pigmented, light brown macules located on nerves, with smooth edged, “coast of California” 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

*Macrocephaly in 30-50% of the pediatric population without any hydrocephalus

*Epilepsy (seizures)

*Juvenile posterior lenticular opacity

NF 1 also increases the risk of tumor development, particularly, meningiomas, gliomas and pheochromocytomas.

Neurofibromatosis type 2 (NF 2):……..CLICK & SEE
Neurofibromatosis type 2 (also called “central neurofibromatosis” is the result of mutation of the merlin (also known as “schwannomin”[1]) in chromosome 22q12. It accounts for only 10% of all cases of NF, and its frequency is lower than NF1. It is also caused by a mutation in a tumor suppressor gene NF2 (whose gene product is schwannomin or merlin). The normal function of merlin is not well understood.  The disorder manifests in the following fashion:

 

*bilateral acoustic neuromas (tumors of the vestibulocochlear nerve or cranial nerve 8 (CN VIII) also known as schwannoma), often 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:
…#headaches
…#balance problems, and peripheral vertigo often due to schwannoma and involvement of the inner ear
…#facial weakness/paralysis due to involvement or compression of the facial nerve (cranial nerve 7 or CN VII)
…#patients with NF2 may also develop other brain tumors, as well as spinal tumors.
…#deafness and tinnitus

NF 2 increases the risk of meningiomas and ependymomas

Schwannomatosis:
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 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 disorder.

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 disorder is one of many factors that makes it difficult to diagnose, and eventually find a prognosis for.

Patients with neurofibromatosis can be affected in many different ways. Morbidity is often a result of plexiform neuromas, optic gliomas, or acoustic neuromas, but mortality can also be associated with malignant transformation of the neuromas, such as neurofibrosarcomas (often there is a malignant transformation in less than 3% of the cases of NF1). There is a high incidence of learning disabilities or cognitive deficit  in patients with NF, particularly NF-1, however severe retardation is not part of the syndrome. Because of the tumor generating nature of the disorder and its involvement of the nervous system and also because of early onset macrocephaly in the pediatric population, there is often an increased chance of development of epilepsy in those affected. Neurofibromatosis also increases the risk of leukemia particularly in children; Children with NF-1 have 200 to 500 times the normal risk of developing leukemia compared to the general population. Since the tumors grow where there are nerves, they can also grow in areas that are visible, causing considerable social suffering for those affected. 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 (such as reduction surgery, or Gamma knife surgery), depending on where the tumors are located. For instance, those affected with NF 2 might benefit from a surgical decompression of the vestibular tumors to prevent deafness

Causes:
What causes neurofibromatosis has yet to be fully explained, but it appears to be mostly due to genetic defects (mutations) that either are passed on by a parent or occur spontaneously at conception. Each form of neurofibromatosis is caused by mutations in different genes.

Neurofibromatosis 1 (NF1)
The NF1 gene is located on chromosome 17. Normally, this gene produces a protein called neurofibromin, which is abundant in nervous system tissue and helps regulate cell growth. A mutation of the NF1 gene causes a loss of neurofibromin, which allows cells to grow uncontrolled. This results in the tumors characteristic of NF1.

Neurofibromatosis 2 (NF2)
A similar problem occurs with NF2. The NF2 gene is located on chromosome 22, which produces a protein called merlin. A mutation of the NF2 gene causes loss of merlin, which also leads to uncontrolled cell growth.

Schwannomatosis
Because schwannomatosis has only recently been identified as a separate type of neurofibromatosis, its exact cause is still under scrutiny. In a small number of familial cases, it’s been associated with a mutation of the SMARCB1/INI1 gene, but in most cases the cause is unknown. The occurrence of schwannomatosis is more spontaneous (sporadic) than inherited.

Risk Factors:
The biggest risk factor for neurofibromatosis is a family history of the disorder. About half of NF1 and NF2 cases are inherited. The remaining cases result from spontaneous mutations that occur at conception.

NF1 and NF2 are both autosomal dominant disorders, which means that any child of a parent with the disorder has a 50 percent chance of inheriting the genetic mutation.

The inheritance pattern for schwannomatosis is less clear. Researchers currently estimate that the risk of inheriting schwannomatosis from an affected parent is around 15 percent.
Complications:
Complications of neurofibromatosis vary, even within the same family. Generally, complications result from tumor growth distorting nerve tissue or pressing on internal organs.

It’s not possible to predict how the disease will progress in any one individual but most people with neurofibromatosis experience a mild or moderate form of the disorder, regardless of type. Usually, serious complications develop prior to adolescence.

Neurofibromatosis 1 (NF1)
Common complications of NF1 include:

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*Neurological problems. Learning difficulties occur in up to 60 percent of NF1 cases and are the most common neurological problem associated with NF1. Uncommon neurological complications associated with NF1 include epilepsy, stroke and buildup of excess fluid in the brain (hydrocephalus).

*Concerns with appearance. Visible signs of neurofibromatosis — such as extensive cafe au lait spots, nerve tumors (neurofibromas) in the facial area or large neurofibromas — can cause anxiety and emotional distress, even if not medically serious.

*Skeletal problems. Some children have abnormally formed bones, which can result in curvature of the spine (scoliosis) and bowed legs. NF1 is also associated with decreased bone mineral density, which increases your risk of weak bones (osteoporosis).

*Visual difficulties. Occasionally in children, a tumor growing on the nerve leading from the eye to the brain (optic nerve) can cause visual problems.

* Increase in neurofibromas. Hormonal changes associated with puberty, pregnancy or menopause may cause an increase in neurofibromas. Most women with NF1 have healthy pregnancies but will likely need to be monitored by an obstetrician familiar with NF1, in addition to her NF1 specialist.

*Cardiovascular problems. People with NF1 have an increased risk of high blood pressure and, rarely, blood vessel abnormalities.

*Cancer. Less than 10 percent of people with NF1 develop cancerous (malignant) tumors. These usually arise from neurofibromas under the skin or plexiform neurofibromas involving multiple nerves. Monitor neurofibromas vigilantly for any change in appearance, size or number. Changes may indicate cancerous growth. The earlier a malignancy is detected, the better the chances for effective treatment. People with NF1 also have a higher risk of other forms of cancer, such as breast cancer, leukemia, brain tumors and some types of soft tissue cancer.

Neurofibromatosis 2 (NF2)
Expanding tumors in people with NF2 may cause:

*Partial or total deafness

*Facial nerve damage

*Visual difficulties

*Weakness or numbness in the extremities

*Multiple benign brain tumors (meningiomas) requiring frequent surgeries

Schwannomatosis complications
The pain caused by schwannomatosis can be debilitating and may require surgical treatment or management by a pain specialist.
Diagnosis:
Prenatal testing

Embryo:
For embryos produced via in vitro fertilisation, it is possible via preimplantation genetic diagnosis (PGD) to screen for NF-1.

“PGD has about 95-98% accuracy but requires that the partner with NF2 have a recognizeable genetic mutation, which is only the case for about 60% of people with a clinical diagnosis of NF2. Having the initial genetic testing to determine if the mutation is recognizeable takes approximately 6 months, and then preparing the probes for the PDG testing takes approximately another 6 months.”

PGD can not be used to detect Schwannomatosis?, because the gene for it has not yet been identified.

Foetus:
Chorionic villus sampling or amniocentesis can be used:

*To detect Neurofibromatosis type I?.

*To detect Neurofibromatosis type II? with 95% accuracy.

*Can not be used to detect Schwannomatosis?, because the gene for it has not yet been identified.

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.

Genetics:
Neurofibromatosis type 1 is caused by mutation on chromosome 17q11.2 , the gene product being neurofibromin (a regulator of the GTPase activating enzyme (GAP)). Neurofibromatosis type 2 is due to mutation on chromosome 22q, the gene product is merlin, a cytoskeletal protein.

Both NF-1 and NF-2 are autosomal dominant disorders, meaning only one copy of the mutated gene need be inherited to pass the disorder. A child of a parent with NF-1 or NF-2 and an unaffected parent will have a 50%-100% chance of inheriting the disorder, depending on whether the affected parent is heterozygous (Aa) or homozygous (AA) for the trait (“A” depicts the affected dominant allele, while “a” depics the recessive allele).

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

 

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 the specific nature of the symptoms may vary widely among family members with the disorder. This is a good example of the phenomenon of variable expressivity: the differing severities of disease in different individuals with the same genotype.  In the case of NF-2, however, manifestations are similar among family members; a strong genotype-phenotype correlation is believed to exist. Both NF-1 and NF-2 can also appear to be spontaneous de novo mutations, with no family history. These cases account for about one half of neurofibromatosis cases.

Similar to polydactyly, NF is also a autosomally dominant mutation, that is not prevalent in the society. Neurofibromatosis-1 is found in approximately 1 in 2,500-3,000 live births (carrier incidence 0.0004, gene frequency 0.0002) and is more common than NF-2.

 

Treatment:
There is at present  no cure for NF but the Neurofibromatosis Association is optimistic that there will be an effective treatment within the next five to ten years. For families with NF, genetic screening and counselling is available.

Most people don’t need any treatment but surgery may be necessary to remove some tumours (such as acoustic neuromas or brain tumours) and this can cause complications such as facial paralysis.

Treatment for complications such as epilepsy is given as appropriate. Vision and hearing are regularly tested. Special education is provided for those children with learning difficulties.

Disclaimer: This information is not meant to be a substitute for professional medical advise or help. It is always best to consult with a Physician about serious health concerns. This information is in no way intended to diagnose or prescribe remedies.This is purely for educational purpose
Resources:
http://en.wikipedia.org/wiki/Neurofibromatosis
http://www.mayoclinic.com/health/neurofibromatosis/DS01185
http://www.bbc.co.uk/health/physical_health/conditions/neurofibroma1.shtml

http://www.jyi.org/news/nb.php?id=895

https://runkle-science.wikispaces.com/NEUROFIBROMATOSIS

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