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Understanding Neurofibromatosis Type 1

Dec 20, 2022 | 0 comments

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Dec 20, 2022 | Essays | 0 comments


Neurofibromatosis is an inherited genetic disorder caused by one or more changed genes. At least two types of neurofibromatosis have been reported: Neurofibromatosis Type 1 (NF1), the most common form affecting nearly 1 individual in every 4000. It was first described in medical research in 1882 when it was referred to as von Recklinghausen disease. Laycock-VA, Thoma, Cooper, et al. (2011, p. 12) indicates that genes act like instructions that control human growth and body functioning. Therefore, any alteration in genetic instructions causes a mutation that can stop the gene from working appropriately. The mutation results from a genetic disorder and any individual suffering from neurofibromatosis type 1 has a mutation in the same gene. Medical literature evidence that neurofibromatosis type 1 results from gene changes that make some cells in the body grow uncontrolled. The growth causes challenges related to neurofibromatosis type 1. The common symptoms of neurofibromatosis type 1 include evidence of six or more light brown spots on the skin, freckling armpit and groin area, two or more neurofibromas, a tumor on the optic nerve, and abnormality in spine development. Currently, there is no cure for neurofibromatosis type 1, yet initial treatment of some problems can reduce and prevent complications. Individuals suffering from the condition should get their spine, blood pressure, and eyes checked annually.

Inheritance of Neurofibromatosis Type 1

Everybody has two copies of the neurofibromatosis type 1 gene; however, an individual only has a single copy changed to develop the disorder (Jett & Friedman 2010, p. 7). The normal copy of the gene cannot compensate for the effects of the copy with the mutation. Therefore, when people with neurofibromatosis type 1 bear children, they can pass their mutated or normal copy of the gene to the offspring. Thus, the chances of inheritance are 1 in 2 or 50 percent of the mutated gene. Likewise, there is a 50 percent chance of their offspring inheriting the normal gene copy. Jett and Friedman (2010, p. 7) find that in some scenarios, an individual with neurofibromatosis type 1 can be the only person affected in the family. In such cases, one of the parents may be so mildly affected that they fail to realize that they have developed the condition. However, if the parents are provided medical screening and found not to be having neurofibromatosis type 1, then the mutation in the gene has probably happened for the first time in the family. Medical literature indicates that such cases occur in 25-50 percent of cases with neurofibromatosis type 1. Meanwhile, the parents can have another child with the disorder when this occurs.

Interesting Research

Dimitrova, Yordanova, and Pavlova et al. (2010, p. 64) conducted research based on a real case study of a 52-year-old patient suffering from neurofibromatosis type 1. According to them, manifestations have been previously observed and described initially by William Smith in 1849. The description followed a classic description by Friedrich Daniel von Recklinghausen in 1882. According to the case study report, neurofibromatosis consists of at least two genetic disorders (NF1 and NF2) described by multiple café-au-lait spots. Moreover, neurofibromas are often soft, lilac pink-colored tumors and sometimes pedunculated or fresh.
Moreover, the National Institutes of Health (2008). established that most people with Neurofibromatosis type 1 never experience problems resulting from the disorder. However, nearly a third of the affected individuals will develop one or numerous conditions during their lifetime. According to the National Institutes of Health, hypertension is a common disease with Neurofibromatosis type 1 and may evolve at any age. The narrowing of the blood vessels occasionally causes high blood pressure in the kidney or through an abnormal growth of a tumor that can be surgically treated.

Furthermore, research shows that nearly a third of children diagnosed with Neurofibromatosis type 1 develop particular learning problems, including challenges to reading and reading or problems in solving mathematical problems. While the difficulties are often not severe, parents and teachers can provide necessary assistance to overcome them in case they are aware of the condition as early as possible. Most common is also conditions of clumsiness or hyperactivity in children with Neurofibromatosis type 1. It is established that a substantially lesser number of people with Neurofibromatosis type 1 develop malignant tumors around the brain and spine cord. The abnormal growths may commence benignly and not spread to other body parts (National Institutes of Health 2008). However, the tumors often arise on the backbone and may occasionally result in pain, numbness, and weakness in the arms or legs. Also, the tumors growing on the optic nerve may result in a squint or blurred vision.


NF1 is considered the most common monogenic disorder affecting humans, especially the nervous system, eyes, blood vessels, and skin. Medical reports indicate that approximately 1 in 3000 people globally has NF1 irrespective of gender, race, or ethnic background (Dimitrova, Yordanova, and Pavlova et al. 2010, p. 62). The disorder is transmitted autosomal, and both men and women have equal chances of being affected. In the UK, the prevalence of the disorder is reported to affect 1 person in every 4000 people.
Genetic Testing
Most individuals with a clinical diagnosis of NF1 will have a mutation in their neurofibromin or the NF1 gene. Genetic testing requires taking a small blood sample from a patient of about 5 milliliters. A genetic doctor will then conduct a laboratory study of the DNA in the blood and observe mutation cases in the NF1 gene. This test may last 1-2 months for the results to be achieved. The procedure involves sequencing the patient’s NF1 gene to observe mutations (Kumar, 2010, p. 6). However, genetic testing is often discouraged because the gene is large, and there might be several possible mutations. Besides, the procedure is often very expensive and greatly discouraged. Since most genetic doctors discourage genetic testing of the NF1 gene, the exception procedure is through physical examination and family history of NF1. If a family member has undergone a test, and a mutation is identified, then it remains relatively easy to examine a similar mutation in another family member.

Bipolar Model of NF1

The structure and function of the NF1 gene are quite an interesting study. The NF1 gene spans 283 kilobases of genomic DNA and consists of 61 exons. Neurofibromin is a 327 kDa encoded protein by the NF1 gene that gets translated from 12 kb messenger mRNA transcript through various alternative isoforms (Stenson, Ball, Howells, Phillips, et al. 2008, p. 125). Neurofibromin contains 2 818 amino acids that get expressed at a low level in every cell, with greater changes in the nervous system. This is a negative active Ras regulator and the related Ras/MAPK signaling pathway. Likewise, neurofibromin consists of a Ras-specific GTPase that activates protein (GAP)-related domain, directly interacting with Ras, leading to an aggressive change that highly stimulates the Ras protein intrinsic GTPase activity. This substantially accelerates the conversion of the active GDP-bound form and affects the net fall in overall cell signaling. As the Ras/MAPK cascade is essential for controlling cell growth and differentiation, a lack of functional neurofibromin leads to the constitutive activation of the signaling pathway and the unregulated growth of malignant cells.

Homozygous Versus Heterozygous

Neurofibromatosis type 1 (NF1) is a common monogenic condition resulting from deregulated tissue growth caused by mutations in the tumor suppressor gene NF1. Individuals with homozygous mutations in MSH6 have higher chances of developing an NF1-like phenotype, such as multiple CALMs. The condition can be caused by homozygosity in one of the genes related to hereditary NF1 (Jacks, Shih, Schmitt, et al. 1994, p. 64). Persons homozygous for mutations related to NF1 can develop tumors typical of the disorder with a younger onset age most probable. Parents of children who are homozygous for genetic changes associated with NF1 are often consanguineous and may have a family history of NF1. Therefore, persons previously described with pathogenic NF1 mutations may also not have NF1. According to Jacks, Shih, Schmitt, et al. (1994, p. 64), individuals with heterozygous mutations in their NF1 and TP53 genes have higher chances of developing a malignancy. Perhaps, this evidences that TP53 gene loss is critical to the transformation. Meanwhile, the homozygous loss of the cyclin-dependent kinase inhibitor 2A gene with specific encoding p16INK4A and p14ARF has also been associated with NF1 malignancy.

Future Treatment

The complicated picture underlying the molecular nature of neurofibromatosis type 1 tumorigenesis has become more defined, and future treatment regimes are expected to improve. While the future treatment is inspiring, optimal survival chances of neurofibromatosis type 1 depend on surgical resection, despite the high chance of malignancy. Theos and Korf (2006, p. 4) suggested the recruitment of supporting cells surrounding the neurofibroma and aberrant Remak bundles, which could explain how the neurofibroma integrates into the surrounding tissue. It is established that this may result in surgical difficulties, further leading to tumor recurrence. Additionally, medical researchers have hinted that surgical interference may even elevate the recruitment of surrounding cell types, thereby increasing the growth of lesions and leading to the formation of new neurofibroma. Previous clinical and preclinical trials directed towards various components of the Ras/MAPK signaling pathway and associated growth factor receptors appear more motivating. However, treatment using multiple drugs may likely offer more effective for NF1 tumors.


Clinically, NF1 is characterized by multiple café-au-lait spots, multiple cutaneous neurofibromas, and inguinal freckling. It is established that biallelic inactivation of the NF1 gene leads to the complete loss of functional neurofibromin. This initiates the pathogenic process that eventually leads to the formation of nerve sheath tumors. Inactivation of the NF1 gene may occur via relatively subtle lesions affecting limited DNA bases. Likewise, it may involve large genomic changes that affect large chromosomal regions or the entire chromosome. NF1 disorder is a highly personal condition that exhibits severe somatic mutational heterogeneity between and within patients. Ultimately, these mutations are responsible for molecular alterations, leading to tumors forming. Therefore, a proper comprehension of how these mutations result in tumorigenesis would be better for the provision of genetic counseling as well as exploring innovative avenues for developing new therapies based on drugs.


Dimitrova, Yordanova, and Pavlova et al. (2010). A case of neurofibromatosis type 1. Journal of IMAB, vol 14, No. 1. Pp 61-67.

Jacks, T., Shih, T., Schmitt, E., Bronson, R., Bernards, A., & Weinberg, R. (1994). Tumor predisposition in mice heterozygous for a targeted mutation in NF1. Nat Genet;7: 353-61.

Jett, K., & Friedman, M. (2010). Clinical and genetic aspects of neurofibromatosis 1. Genetics in Medicine: 12, 1–11

Kumar, S. (2010). Neurofibromatosis Type 1: Involvement of NF1 Mutations in Nervous System Tumours and Learning and Cognitive Dysfunction in this Disorder Journal On Developmental Disabilities, Volume 11 Number 2

Laycock-VA, S., Thoma, N., Cooper, N., & Upadhyaya, M. (2011). Neurofibromatosis type 1-associated tumors: Their somatic mutational spectrum and pathogenesis. Journal of Medical Genetics

National Institutes of Health Consensus Development Conference. (2008). Neurofibromatosis. Arch Neurol Chicago, 45: 575.

Stenson, P.D., Ball, E., Howells, K., Phillips, A. et al. (2008). Human Gene Mutation Database: Towards a comprehensive central mutation database. Journal of. Medical. Genetics. Vol. 45, pp. 124–126.

Theos, A., & Korf, B. (2006). Pathophysiology of Neurofibromatosis Type 1. Review: Physiology In Medicine: A Series Of Articles Linking Medicine With Science. American College of Physicians Internal Medicine.

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