Neurofibtomatosis NF1 and NF2 - Essay Example

?Neurofibromatosis (NF1 and NF2) The neurofibromatosis are a group of autosomal dominant hereditary diseases that are characterized by development oftumors of the embryonic outer and middle layers (ectodermal and mesodermal tissues). On the basis of clinical presentation and genetics, they have been classified under two major forms – neurofibromatosis type 1 (NF1) and neurofibromatosis type 2 (NF2). (Korf, 1997) Neurofibromatosis type 1 There have been reports describing patients with features suggestive of neurofibromatosis as early as the 17th century. (Hirsch, Murphy and Radcliffe, 2001). In 1882, Friedrich von Recklinghausen was the first person to conclude that the tumors characteristic of the disease arise from nerve tissue. Thereafter, this affliction is also known as von Recklinghausen’s disease. (Von Recklinghausen, 1882). Crowe, Schull and Neel estimated that the prevalence of NF1 in the general population was 1 in 5000. Moreover, though all persons having the NF1 genes will show features of the disease, there is a large amount of variation shown in the presentation of this disease even in the same family. (Crowe, Schull and Neel, 1956). Moreover, sporadic cases are known to occur (without any family history of the disease), believed to result from germ cell mutations. (Mulvihill etal, 1990). Neurofibromatosis 2 Kantner, Eldridge, Fabricant, Allen, and Koerber found that amongst patients thought to suffer from neurofibromatosis, a certain subset of patients had propensity to develop central nervous system tumors, especially, tumors of the auditory nerves (acoustic neuromas). These patients were genetically and clinically distinct from the other neurofibromatosis patients and were subsequently identified as NF2. (Kantner, Eldridge, Fabricant, Allen, and Koerber, 1980) The prevalence of NF2 is less, estimated to be in the range of 1 in 210 000 population. (Husom, 1989.) Body Systems Affected NF1 mainly affects the skin, peripheral nerves, optic nerve, iris and long bones (e.g. those of the extremities) of the body. NF2, on the other hand, affects the central nervous system and causes the premature formation of cataract in the eyes. Characteristics of the Disease Gutman etal have summarized the features of the diseases. (Gutman, 1997). Neurofibromatosis 1 is characterized by the presence of cafe-au-lait spots, brownish colored patches on the skin. They may also display freckling in the axilla or groin. They develop tumors of the peripheral nerves called neurofibromas, which can arise in the nerve endings in the skin (cutaneous neurofibromas), peripheral nerves (nodular neurofibromas) or optic nerves (optic gliomas). Extensive tumor formation in the peripheral nerves is the most easily identifiable feature of NF1, leading to grotesque disfiguration of the face and limbs, a condition known as plexiform neurofibromatosis. The so-called Elephant Man, Mr. John Merrick is believed to be a victim of this condition. In addition, patients with NF1 may suffer from thinning of the long bones of the body. Some patients develop typical tumors in the iris of the eye called Lisch nodules. Patients with NF1 also have an increased tendency to develop other tumors like those of the adrenal gland (phaeochromcytoma), thyroid and parathyroid glands (as part of a syndrome called Multiple Endocrinal Neoplasia), small intestinal tumors and chronic myeloid leukemia. These patients often have a larger than average sized skull (macrocephaly) and are shorter in stature. Abnormalities in the functioning of the pituitary gland may lead to precocious puberty and growth hormone deficiency. They may also have learning disabilities. Other problems associated more frequently with this condition are epilepsy, headaches and deafness. The characteristic feature of NF2 is bilateral vestibular schwannomas or acoustic neuromas (tumors of the 8th cranial nerve – the auditory nerve). As a result, these patients present with gradual, progressive hearing loss. Other central nervous system tumors like gliomas and shwannomas are also seen as is the premature development of cataracts in the eyes. The National Institute of Health established criteria which have to be fulfilled in order to diagnose a person as suffering from NF1 or NF2: (NIH, 1988) Neuroflbromuatosis type 1: The diagnostic criteria are met in an individual if two or more of the following are found: (a) 6 or more cafe-au-lait patches >5 mm in greatest diameter in prepubertal individuals and >15 mm in greatest diameter in postpubertal individuals. (b) 2 or more neurofibromas of any type or one plexiform neurofibroma . (c) Freckling in the axillary or inguinal regions. (d) Optic glioma. (e) 2 or more Lisch nodules (iris hamartomas). (f) A distinctive osseous lesion such as sphenoid dysplasia or thinning of long bone cortex with or without pseudoarthrosis. (g) A first degree relative (parent, sibling, or offspring) with type 1 by the above criteria. Neurofibromatosis type 2: The criteria are met by an individual who has: (1) Bilateral eighth nerve masses seen with appropriate imaging techniques (for example, computed tomography or magnetic resonance imaging) or (2) A first degree relative with type 2 and either: (a) unilateral eighth nerve mass or (b) two of the following: neurofibroma (nerve tumor), meningioma, glioma, schwannoma (different type of brain tumors), juvenile posterior subcapsular lenticular opacity (cataract in children or adolescents). Risk Factors: NF1 is known to be caused by mutation of a gene located on the 17th chromosome, the so-called NF1 gene. It is an autosomal dominant condition with almost 100% penetrance. This means that the person bearing this mutated gene will display the features of the disease. Thus, if one parent has NF1, the offsprings have 50% risk of getting the gene and hence, the disease. However, if both parents have the gene, the offsprings will definitely get the disease. About 50% of NF1 cases result from new mutations. NF2 occurs as a result genetic mutation in the 22nd chromosome. It, too, has an autosomal dominant transmission and hence, the risk of an offspring with one parent with the NF2 gene acquiring the disease is 50%. Interestingly, the risk of transmission in an apparently sporadic case is less than 50% due to a genetic phenomenon known as mosaicism. (Evans etal, 1998). Management Once the diagnosis of NF1 or NF2 is made on the basis of the criteria described above, the family members should be screened for the disease. Though genetic testing for the mutations has been developed, the tests are too lengthy and costly and not specific enough to be of practical use. Their implementation is restricted to certain special circumstances like pre-natal diagnosis (trying to establish a diagnosis while the baby is in its mother’s womb) or pre-implant testing for in-vitro fertilization program (test-tube baby). Imaging tests like CAT scan or MRI may be needed to evaluate the central nervous system for tumors like acoustic neuromma, optic nerve glioma, schwannoma or spinal tumors. Opthalmic examination using the slit lamp may be useful to diagnose conditions like Lisch nodules or premature cataracts. After this, the management consists of trying to deal with the complications as they arise. In childhood, NF1 patients may have thinning of bones of the leg, leading to bow legs and a predisposition to fracture. A prompt referral to an orthopaedic can prevent such an eventuality. In pre-school years, screening by ophthalmic examination should begin to detect the presence of optic nerve tumors (gliomas). Usually, such tumors are self-limiting and do not lead to visual impairment. However, if they are progressive, they can be treated with either chemotherapy or radiation. Highly precise radiotherapy is a recent development and this ‘gamma knife’ technology may prove to be a boon for this condition. Learning disabilities are common and may be associated with poor motor skills. Such children should have access to specialized teaching institutes. Children with NF1 may develop hypertension due to associated phaeochromcytoma (a tumor of the adrenal gland) or other reasons (like narrowing of the artery supplying blood to the kidney – renal artery stenosis) and this has to be looked for and treated. Plexiform neurofibromatosis is the most disfiguring complication of NF1 and is difficult to treat as the tumor is diffuse and not easily removable by surgery. Even if successfully removed, it is prone to recurrence. Children with NF2 may develop hearing impairment due to acoustic neuromas and require surgery. If they develop deafness, state-of-the-art technologies like cochlear implants or auditory cortex implants may help them. Similarly they may develop brain tumors like gliomas which may lead to epilepsy that has to be treated. Central nervous system tumors may require repeated imaging using CT scan or MRI, which may pave the way for future surgery. Genetic counseling should be provided in adolescence so that these young people are able to make informed decisions about their lives. Research in Neurofibromatosis Evans etal summarized the status of research in neurofibromatosis. (Evans, 2009). While the genes responsible for development of NF1 and NF2, have been identified, we still do not have rapid, cost-effective and simple ways to detect these mutations and hence, the diagnosis of these conditions more or less relies on clinical features. Research is being done in this area. Further scope of research lies in genetic engineering to perhaps correct the defect so that it is not transmitted to the offspings. However, this lies far in the future. Drug trials are underway for treating plexiform neurofibrosmatosis and learning disabilities associcated with NF1. The problem with NF2 research is that it is a relatively rare condition and hence it is difficult to accrue sufficient subjects to carry out investigation into this disease. Hence, research is going on to develop animal models and cell lines through tissue culture to provide subject matters. Various molecules, chief among them a group known as monoclonal antibodies, are being investigated for their potential benefit in central nervous tumors like acoustic neuroma and cerebral meningioma, associated with NF2. Thus, a lot of research is being carried out in various aspects of this disease and hopefully, this may lead to discoveries that can ameliorate the lot of these patients. Information and Support There are several associations and organizations actively involved in providing information and support to the patients and their families. A brief list is given below: 1. National Neurofibromatosis Foundation. 95 Pine Street - 16th Floor New York, N.Y. 10005 fax (212) 747-0004 voice (212) 344-NNFF/6633. voice (800) 323-7938 (National Office hours are Monday through Friday, 9 AM to 5 PM EST) Voice mail messages for the NNFF may be left by calling either phone after hours.) e-mail NNFF@aol.com 2. Neurofibromatosis, Inc 8855 Annapolis Road Suite 110 Lanham, MD 20706-2924 (301) 577-8984 (Voice) (800) 942-6825 (Toll-free) (301) 577-0016 (Fax). 3. Acoustic Neuroma Association P.O. Box 12402 Atlanta, GA 30355 (404) 237-8023 FAX (404) 237-2704 4. Acoustic Neuroma Association of Canada PO Box 369 Edmonton, AB T5J 2J6 Canada (403) 428-3384. 5. Children's Tumor Foundation 95 Pine Street, 16th Floor New York, NY 10005-4002. Phone: 212-344-6633  Toll Free: 1-800-323-7938 Fax: 212-747-0004. Office hours: Monday - Friday, 9:00 AM - 5:00 PM EST Voice mail messages may be left at either phone after hours. info@ctf.org 6. Neurofibromatosis Clinics Assocation. P.O. Box 14185 Pittsburgh, PA 15239 (412) 795-3029 (phone) info@nfpittsburgh.org NFCA Social Worker: NFSocialWorker@nfpittsburgh.org Effective way to spread information on the disease With the advent of the world wide web, information dissemination has become far easier than before. The best way to create awareness about neurofibromatosis would be through an internet campaign. Creating a database of families in the state and country having members suffering from neurofibromatosis would be the next step. The members could then be counseled regularly via personal meetings, home visits, telephone or email. Support groups could be organized. The district school associations could be actively involved in the process as the symptoms and signs of the disease appear in the early schooling years, especially learning disabilities and impaired motor skills. Suggestion for a Spokesperson for Neurofibromatosis The most famous person supposedly affected by plexiform neurofibromatosis was John Merkel. A Hollywoood production titled “The Elephant Man” had immortalized his courage and conviction in the face of his affliction, staring John Hunt as Mr. Merkel and Anthony Hopkins in a major role. I would suggest Anthony Hopkins as a spokesperson for the campaign. The other character ideally suited would be Davy Jones from the motion picture ‘Pirates of the Caribbean: Dead Man’s Chest’. His appearance is not unlike that of a person severely afflicted with plexiform neurofibromatosis. References Crowe, F.W., Schull WJ, and Neel, J.V. (1956). A Clincal, Pathological, and Genetic study of Multiple Neurofibromatosis. Springfield, IL. Charles C. Thomas. Evans, D.G., etal. (2009). Consensus recommendations to accelerate clinical trials for neurofibromatosis type 2. Clinical Cancer Research, 15, 5032-5039. Evans, D.G.R., etal. (1998). Mosaicism in classical neurofibromatosis type 2: a common mechanism for sporadic disease in tumor pronesyndromes? American Journal of Human Genetics, 63, 727-736. Gutman, D.H., etal. (1997). The diagnostic evaluation of multidisciplinary management of neurofibromatosis 1 and neurofibromatosis 2. Journal of the American Medical Association, 278, 51-57. Hirsch, N.P., Murphy, A., Radcliffe, J.J. (2001). Neurofibromatosis: clinical presentations and anesthetic implications. British Journal of Anaesthesia, 86, 555-564. Husom, S.M. (1989). Recent developments in the diagnosis and management of neurofibromatosis. Archives of Diseases of Children, 64,745-749. Kantner, W.R., Eldridge, R., Fabricant, R., Allen, J.C., and Koerber, T. (1980). Central neurofibromatosis with bilateral acoustic neuroma: Genetic, clinical and biochemical distinctions from peripheral neurofibromatosis. Neurology, 30, 851-859. Korf, B.R. (1997). Neurocutaneous syndromes: Neurofibromatosis 1, neurofibromatosis 2, and tuberous sclerosis. Current Opinions in Neurology, 10, 131-136. Mulvihill, J.J., Parry, D.M., Sherman J.L., Pikus A., Kaiser-Kupfer M.I., Eldridge R. (1990). NIH Conference: Neurofibromatosis 1 (Recklinghausen disease) and Neurofibromatosis 2 (bilateral acoustic neurofibromatosis). An update. Annals of Internal Medicine, 113, 39-52. National Institutes of Health (1988). National Institutes of Health Consensus Development Conference. Neurofibromatosis Conference Statement. Archives of Neurology, 45, 575-578. Von Recklinghausen, F.D. (1882). Ueber die multiplen Fibrome der Hout und ihre Beziehung zu den multiplen Neuromen. Hirschwald, Berlin. Read More