Download Neurofibromatosis Type 1

Neurofibromatosis Type 1
Joanna Spira and Emily Stamell
Neurofibromatosis Type 1 is an autosomal dominantly inherited disease that
affects 1 in 3,000 to 4,000 individuals. The affected genes often show variable
expressivity, as is common with autosomal dominant traits, and is characterized by caféau-lait spots (brownish spots) on the skin, Lisch nodules (benign hamartomatous nodules
on the iris of the eye), and cutaneous and subcutaneous neurofibromas (fleshy benign
tumors that arise along the course of nerves) (Thomas 29). Other more serious symptoms
are possible, albeit less common, and include plexiform neurofibromas, optic and other
central nervous system gliomas, malignant peripheral nerve sheath tumors, osseous
lesions, and vasculopathy (Friedman). Neurofibromatosis Type 1 usually manifests
within the first year of life, but the clinical findings continue to develop over the course
of one’s lifetime.
Genetics, Disease Risks, and Diagnostic Criteria
As stated above, Neurofibromatosis Type I is inherited in an autosomal dominant
fashion; as such, an affected parent has a fifty percent chance of passing the mutant gene
onto his offspring. Of the individuals affected with Neurofibromatosis Type I, fifty
percent are due to a de novo mutation in the NF1 gene. Disease manifestations are
extremely variable even within familial Neurofibromatosis Type 1. The majority of
Neurofibromatosis Type 1 cases are due to a heterozygous mutation in the NF1 gene. In
rare instances, a homozygous mutation in one of the genes associated with hereditary
non-polyposis colon cancer can lead to Neurofibromatosis Type 1. Although DNA-tests
are available for diagnostic purposes, they are rarely needed (Friedman). A clinical
diagnosis can be made by fulfilling two of the following seven criteria: six or more caféau-laity spots, two or more neurofibromas or one plexiform neurofibroma, freckling in
the axillary or inguinal region, optic glioma, two or more lisch nodules, an osseous
lesion, or finally a first degree relative with defined Neurofibromatosis Type 1 disease.
Molecular Biology
The NF1 gene is located on chromosome 17 on the long arm at 11.2. It is a large,
about 360 kilobases with 60 exons, and unusual gene in that one of its introns contains
coding sequences for at least three other genes. Neurofibromatosis Type 1 disease has
been associated with over 500 different mutations in the NF1 gene and no single mutation
is present in more than a few percent of families. The mutations in the NF1 gene cause a
variety of genetic alterations including stop codon mutations, splice site mutations,
deletions, and rearrangements, just to name a few. Most of the germline mutations cause
notable shortening of the gene product, neurofibromin. The normal function of
neurofibromin is not entirely understood, but it has been associated with activation of ras
GTPase, which in turn controls cellular proliferation. Therefore, neurofibromin acts as a
tumor suppressor (Friedman). Neurofibromin is produced in nerve cells and specialized
nerve cells surrounding nerves (Genetics Home Reference). It is believed that a mutation
in the NF1 gene leading to truncation of the gene product is a loss-of-function mutation.
As seen in previous instances with p53 and other tumor suppressor genes, the loss of a
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gene of this nature can cause extensive cellular proliferation and ultimately tumor
growth.
The molecular genetic testing for mutations in the NF1 gene is a multistep
protocol, which is necessary due to the high mutation rate and variability among families.
The first step is an optimized protein truncation test, which can detect as high as eighty
percent of pathogenic mutations. If no mutation is found using this test, Fluorescence In
Situ Hybridization (FISH) analysis is performed to detect possible gene deletions.
Following FISH, direct sequencing of the coding region is performed to identify missense
mutations or deletions or insertions. While southern blots can be done to identify
intrageneic deletions, cytogenetic analysis tests for large-scale rearrangements
(Friedman). Prenatal testing can be performed for high-risk pregnancies via
amniocentesis or chorionic villus sampling if the disease-causing allele within the family
has previously been identified.
Prognosis
The disease generally presents in early childhood with multiple café-au-lait spots
which grow in size as the individual ages. Later in childhood, freckles in the axillary or
inguinal regions can develop in addition to lisch nodules and optic gliomas.
Neurofibromas, which are benign tumors, are more common in adults with
Neurofibromatosis 1. Cancerous tumors along nerves can develop in adolescence or
adulthood. Individuals diagnosed with Neurofibromatosis 1 are at an increased risk of
developing other forms of cancers. In addition, high blood pressure and scoliosis are
sometimes associated with this disease. Mental retardation is present in less than ten
percent of individuals with Neurofibromatosis 1, although about half of the children
present with learning disabilities.
Possible Treatment
Since Neurofibromatosis Type 1 has many clinical manifestations that vary
depending on the individual, treatment plans are based solely on the individual’s disease
presentation. The disease is not treated as a whole, but rather individual symptoms are
dealt with. The primary complaint of individuals with Neurofibromatosis Type 1,
regardless of other serious complications, is the disfigurement caused by the cutaneous
and subcutaneous neurofibromas (Wolkenstein et al.). Complications with the eye,
central nervous system, peripheral nervous system, spine, or long bones are referred to
specialists for further treatment. Plexiform neurofibromas can lead to progressive lesions
that cause significant morbidity. Current treatment for plexiform neufibromas is surgery,
although other treatment options are being investigated (Packer et al.). Optic gliomas can
range from asymptotic to rapidly growing tumors. Additionally, little is known about the
natural course of this tumor growth and therefore there is no clear treatment plan (Czycyk
et al.). Brain stem and cerebellar astrocytomas have a less aggressive course in
individuals with Neurofibromatosis 1 than individuals without the disease since
spontaneous regressions of the growth have been reported (Leisti et al). Individuals
afflicted with Neurofibromatosis 1 have no physical limitations unless any of the other
clinical manifestations that accompany Neurofibromatosis 1 requires it.
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Conclusion
Neurofibromatosis Type 1 is a defined autosomal dominant disorder that
manifests itself in numerous ways. As a result, it is necessary to be familiar with the
diagnostic criteria as well as the variety of clinical manifestations in order to make a
proper diagnosis. In addition, there is no way to predict the severity of the disease
manifestations regardless of the status of first-degree relatives. Neurofibromatosis Type 1
represents a genetic disease that is primarily diagnosed based on clinical findings. Due to
the variability in the genetic mutations that cause Neurofibromatosis Type 1, it is more
efficient and easier to diagnose the disease based on such clinical manifestations.
References
Czycyk, E., S. Jozwiak, M. Roszkowski, et al. “Optic Pathway Gliomas in Children with
and without Neurofibromatosis 1.” Journal of Child Neurology. 18.7 (2003) 471.
Friedman, J. M. MD, PhD. “Neurofibromatosis Type 1.” GeneReviews. 5 October 2004
<http://www.genetests.org/query?dz=nf1>.
Gelehrter, Thomas D., Francis S. Collins, and David Ginsburg. Principles of Medical
Genetics. Baltimore: Williams and Wilkins, 1998.
Leisti, E. L., J. Pyhtinen, and M. Poyhonen. “Spontaneous Decrease of Pilocytic
Astrocytoma in Neurofibromatosis Type 1.” American Journal of Neuroradiology. 17.9
(1996) 1691.
“Neurofibromatosis Type 1,” Genetics Home Reference. US National Library of
Medicine. 17 November 2006
sh<http://ghr.nlm.nih.gov/condition=neurofibromatosistype1>.
“NF1 Gene,” Genetics Home Reference. US National Library of Medicine. 17 November
2006 <http://ghr.nlm.nih.gov/gene=nf1>.
Packer, R. J., and T. Rosser. “Therapy for Plexiform Neurofibromas in Children with
Neurofibromatosis 1: An Overview.” Journal of Child Neurology. 17.8 (2002) 638.
Wolkenstein P., I Durand-Zaleski, J. C. Moreno, et a. “Cost Evaluations of Medical
Management of Neurofibromatosis 1.” British Journal of Dermatology. 142.6 (2000)
1166.
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