& Its Genetic Implications Essay, Research Paper The National Institute of Health defines Neurofibromatoses as group genetic disorders that affects the development and growth of neural cell tissues. These disorders cause tumor growth in nerve tissues, skin changes, and in some cases bone deformities.

& Its Genetic Implications Essay, Research Paper

The National Institute of Health defines Neurofibromatoses as group genetic disorders that affects the development and growth of neural cell tissues. These disorders cause tumor growth in nerve tissues, skin changes, and in some cases bone deformities. Of the eight possible subtypes of Neurofibromatosis (NF) at least 85% are represented by NF Type 1, also known as von Recklinghausen or classic peripheral neurofibromatosis. It has a prevalence of about 1:4000 live births. An additional ten percent have NF Type 2, also known as acoustic or central neurofibromatosis and occurs in about 1:50,000 live births (Baskin 1). This paper will deal only with the more prevalent NF Type 1 and focus on the symptoms of the disease and biochemical aspects of the NF1 and the ethical implication of inherited genetic disorders.

NF1 is an autosomal dominant inherited disease characterized by multiple caf?-au-lait spots, numerous fibromas, and Lisch nodules. Most manifestations appear during childhood and early adult life. Clinical criteria for diagnosing the disease must include two or more of the following symptoms: (1) six or more caf?-au-lait spots larger that 5 mm in pre-pubescent individuals and greater than 15 mm is post-pubescent individuals, (2) two or more neurofibromas of any type or one plexiform neurofibroma, (3) axillary or inguinal freckling, (4) sphenoid bone dysplasia, (5) optic glioma, (6) Lisch nodules, and (7) a family history of NF1. Other manifestations include learning disabilities, epilepsy, mental retardation, scoliosis, gastrointestinal neurofibromas, pheochromacytomas, and renal artery stenosis (Goldman 2074).

Caf?-au-lait spots are pigmented macules of giant melanin granules seen in the basal layer of the epidermis and are distinguished by the presence of more DOPA-positive melanocytes than surrounding skin and a smooth border and light brown color of the macules. Neurofibromas are hamartomatous, a mass of disorganized tissue indigenous to a particular site (Robbins 134), that are composed mostly of Schwann cells, but also contain fibroblasts, mast cells and macrophages. Plexiform neurofibromatoas, large, multilobe pendulous masses, are more deeply situated in large nerves, usually involve the limbs, and are associated with hypertrophy of underlying soft tissues and bones. Lisch nodules, or iris harmartomas, are the most common manifestation of NF1. They are dome shaped, elevated, avascular, melanocytic nodules of the iris with a smooth shape and some translucency (Baskin 1-3).

Neurofibromatosis Type I is an autosomal dominant disorder without predilection for sex, race, or color. It shows with complete penetrance with highly variable expression. The gene is located on chromosome 17q and the gene encompasses around 350 kilobases (Goldman 2074). The gene codes for the protein neurofibromine which resembles certain proteins that inactivate oncogenes (Hulsebos 620); thus lacking neurofibromine can lead to an increased disposition to cancer.

Although the disorder is inherited, the spontaneous mutation rate is between 2.4 and 4.3 x 10-5 ( A predominant paternal derivation suggests that the original mutation occurs in the mitotic divisions that take place during male gametogenesis but not during female gametogenesis. The NF1 gene can show a twelve kilobase deletion involving exons thirty-two through thirty-nine in some cases or a more severe deletion involving a 100 kilobase deletion from exon four near the five prime end of the gene to intron thirty-nine near the three prime end of the gene ( There does not appear to be any correlation between particular genotypes and phenotypes (Goldman 2074).

The sequence of the NF1 gene predicts 2,485 amino acids in the NF1 peptide. The peptide shows some similarity to human GTPase activating protein (GAP). This finding suggests that NF1 codes for a cytoplasmic GAP-like protein that interacts with proteins like the RAS gene product in the control of cell growth in. shows that the tumor suppressing activity of the NF1 protein negatively regulates p21 (RAS) and shows a ?positive? growth role for RAS activity in NF1 tumors. The NF1 gene product neurofibromine contains a GTPase activating protein known as NF1 GRD that downregulates RAS by stimulating intrinsic GTPase. Since RAS and GTP are major regulator molecules in cell growth and differentiation, mutant neurofibromines resulting from somatic mutations in the NF1 gene might interfere with the RAS signaling pathway and thus contribute to the development of tumors (

The probability of transmission of NF1 is 50% with each pregnancy, as with all autosomal dominant disorders, and the affected offspring have a 75% chance of having a mild case of the disorder and of these there is a 25% lifetime risk of developing the moderate to severe form of the disease (Baskin 2). It has been found that patients born of affected mothers inherit a more severe manifestation of the disease than those born of affected fathers ( Of the individuals that inherit neurofibromatosis, the disease appears to worsen with each generation. This fact brings up some ethical situations.

Along with the knowledge and power of genetic information comes responsibility. In the 1970s, guidelines were established that said genetic screening was appropriate if the disorder was serious, the test was accurate and a therapy of intervention was available. The new ability to determine genetic susceptibilities and to identify carriers of recessive diseases presents new challenges to the ethical dilemma.. Do you abort a fetus when you know that he/she manifests a genetic disorder and has only a possibility of having a severe manifestation of the disease, as is the case with neurofibromatosis?

There are many possible outcomes if genetic screening becomes an everyday practice. Will people with genetic flaws, even those that aren?t apparent or disabling, be denied life insurance, health insurance, and access to schools or jobs? Will employers only hire people whose genes indicate resistance to health hazards in the work place? Will social and political pressure be applied to make people make childbearing decisions based on genetic information where mating between those with favorable genes will be encouraged and mating between people with dangerous recessive traits will be prohibited? Will mothers have a choice in deciding if their fetuses will be tested for genetic disorders? (Devore) All of these questions must be answered.

No person should be subjected to unfair discrimination by third parties, insurers, employers, or educational institutions by requiring genetic tests of applicants. Childbearing activities should never be denied to any person for any reason. The desire to bear children is and should remain an intimate decision between two people. Today, some parents still decide to have a child that has been diagnosed with diseases through prenatal testing. In the testing of children it must first be considered if the disease being tested for can be lessened or current or future through medical treatment and if this benefit would be lost by waiting to test for diseases until adulthood. Above all, the people being screen for genetic diseases must be made aware of the consequences that could arise if the test comes back positive. They will have to sign an informed consent form and agree to genetic counseling before and after the screening.

In the case of neurofibromatosis, the outcome of a genetic test can not predict the severity of the disease. In some cases the condition may be mild, or in others very severe and a genetic test can not determine how the disease will manifest itself over the course of a person?s lifetime. The important thing that must be done is to find a treatment for the symptoms of the disease and possibly a cure with gene therapy. But until that time, an effort must be made to curve the serious effects of Neurofibromatosis.

Baskin, Kevin M., MD. Peripheral Neurofibromatosis. Radiology Case of the Week. Virtual Hospital. 7/22/99.

Devore, David. Genetic Screening and Ethics an Overview.


Goldman, et al. Cecil Textbook of Medicine edition 21. 2074. W.B. Saunders Co.: Philidelphia. 2000.

Holtzman, Niel A. MD. & Michael S. Watson Ph.D. Promoting Safe and Effective Genetic Testing in the United States. The National Human Genome Research Institute. 9/97.

The Neurofibromatoses. National Institute of Neurological Disorders and Stroke of the National Institutes of Health. 2/16/00.

Robbins. Basic Pathology 6th Edition. W.B. Sanders Co.:Philidelphia 1997. 134.