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Neurofibromatosis Type 1 is a common autosomal dominant
disease. This disease affects 1 of every 3,000/4,000 people worldwide.1
Even though Neurofibromatosis is a genetic disorder, only 50% of cases are due
to inheritance; whereas, the other 50% arise from random mutations in the NF1
gene. Both instances of the disease produce the same spectrum of symptoms. The
main clinical characteristics of Neurofibromatosis Type 1 are café au lait
spots, axillary and inguinal freckling, cutaneous neurofibromas, and Lisch
nodules. Presentation and severity of symptoms vary from one patient to the
next. Less common manifestations include high blood pressure, bone
abnormalities such as scoliosis, malignant peripheral nerve sheath tumors,
optic gliomas, short stature, vasculopathy, and an unusually large head.1
In 50% or more of patients, a learning disability is present.2 By
acquiring a mutant NF1 gene, the risk of developing cancer, in particular
leukemia and brain tumors, is significantly increased.

Symptoms, typically café-au-lait spots, start appearing during
infancy and increase in size and quantity as the child ages. As development
progresses, freckling and Lisch nodules commonly appear. Most individuals are
diagnosed in childhood, usually by age four. When a positive family history is
known, the child is generally identified within the first year of life since
95% of affected infants present with café-au-lait spots. When there is no known
familial history, half of children are not diagnosed in the first year due to a
lack of additional identifiable symptoms.2 Since there is a very
strict diagnostic criterion, few adults are diagnosed with Neurofibromatosis
Type 1. Genetic testing is done on the individual to confirm the diagnosis if
the disease is suspected but there is insufficient symptom presentation, this
frequently occurs in early childhood. Genetic testing is most commonly
practiced when the individual is showing severe symptoms and a diagnosis would
affect illness management. Adults are only genetically tested when pregnancy is
involved. All diagnosing of Neurofibromatosis Type 1 is dependent on the
National Institutes of Health diagnostic criteria in which an individual must
display at least one symptom in the quantity specified.   

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Neurofibromatosis Type 1 is caused by a loss-of-function mutation
in the Neurofibromin 1, NF1, gene. NF1 is a tumor suppressor protein that
negatively regulates cell growth and division by turning off the Ras protein. A
conserved domain in the NF1 gene is RasGap which produces a GTPase activator
protein for Ras-like GTPases.3–4 Since RasGap is conserved, it is
evident that G-protein-coupled receptors are an essential aspect of NF1 and its
ability to properly control the Ras protein, involved in stimulating cell
growth and division. NF1 also plays a role in somatic cell division,
intracellular cyclic-AMP production, and regulation of adenylyl-cyclase
activity, but the exact mechanisms have not been identified yet. The NF1 gene
has 62 exons and 61 introns, is composed of 8,457 nucleotides which code for
2,818 amino acids, and is located on chromosome 17, specifically the 17q11.2
locus.3 There have been three determined alternatively spliced
transcripts of the NF1 gene. A unique characteristic of this gene is that the
coding sequence for at least three different genes is contained in one of NF1’s

Each individual or family line with Neurofibromatosis Type 1 is
typically a unique pathogenic variant. The variations so far identified in the
NF1 gene are common types of mutations: deletions ranging from one base pair to
the entire gene, insertions, nonsense mutations, missense mutations, splicing
errors, modifications to 3′ untranslated regions, and chromosome rearrangement.
In most instances, these mutations create alterations in mRNA splicing
resulting in severe truncation of the NF1 protein. Two allelic variations of
NF1 are .0003 NEUROFIBROMATOSIS, TYPE 1 NF1, LEU348PRO and .0007
NEUROFIBROMATOSIS, TYPE 1 NF1, 1-BP INS, FS1841TER.4 .0003 depicts
a missense mutation where a T in the DNA template is mutated to a G and
transcribed as a C in the mRNA strand. This leads to proline being coded in
place of leucine. .0007 describes an insertion of a thymidine into the coding
sequence resulting in a premature stop codon and nonsense mutation. Both
alterations to the NF1 gene cause a loss-of-function protein and multiple
symptom presentation. An allelic variation that is associated with café-au-lait
spots and the rare neurofibroma as the only manifestations is a three-base pair
deletion of AAT in exon 22. When there is a deletion of the entire NF1 gene,
there are early manifestations of cutaneous neurofibromas, a greater frequency
and severity of cognitive abnormalities, large hands and feet, dysmorphic
facial features, and somatic overgrowth.2

All information about symptom presentation in relation to genotype
and specific alterations on the NF1 gene have been determined through
sequencing the genome of affected individuals and mice models. When a
transgenic NF1 mutant mouse is created, the same expression of symptoms was
seen as in humans, relative to the specific mutant form introduced. This
similarity was indisputable down to the severity of a learning disability.5
Through these models, the exact molecular mechanism of tumor formation in
Neurofibromatosis Type 1 was identified. There is an increased rate of cell
proliferation and over-activation of the Ras pathway.5 This
indicated that NF1 is indeed the main regulator of the Ras protein. When
mutated, Ras will remain in the active state driving the cell cycle forward
whether or not the cell is functioning normally. When homozygous mutant NF1
transgenic mice were formed, all died during embryonic development.5
This observation lead researchers to the conclusion that the function of NF1 is
vital in tissue development and organogenesis. Currently, researchers are using
heterozygous NF1 models to decipher the exact mechanisms being used in nontumor
symptom presentation. NF1 has some interaction with astrocytes and
cytoskeleton-associated processes allowing for some insight into how
abnormalities in these mechanisms result in certain phenotypes.5

Currently, no environmental factors have been identified as a
factor in disease expression. Researchers know the microenvironment plays a
very important role in the genotype-phenotype correlation, but no definitive
associations have been made. It is the interaction of the microenvironment with
the NF1 gene that lead to specific phenotypes. Each individual with
Neurofibromatosis Type 1 will receive one nonfunctional copy of the tumor
suppressor gene. The specific mutations made to the functioning NF1 protein,
consequently knocking it out, is what leads to unique tumors in a variety of
locations.2 The second hit mutation will control the specific
characteristics of the tumor growth. Most of these mutations are caused by
nucleotide exchanges or small deletions. It has been noted that pregnancy
accelerates cutaneous neurofibroma growth.2 A possible explanation
for this rapid increase in tumor growth is the dramatic alteration of hormone
levels once a pregnancy is initiated. Differences in gender play a role in
phenotypic presentation. Learning disabilities are mainly seen in men whereas
women are more likely to present with optic gliomas resulting in vision loss.
The disease progression between males and females is different. Males have a
reduced level of DARPP32 phosphorylation, an increased level of ERK1/2
phosphorylation, and an increased amount of Ras protein activation in the
hippocampus as seen in NF1 transgenic mice.6 It is hypothesized that
the AZI1 protein influences phenotypes through its involvement in genome
stability regulation.7 Mutations in the AZI1 protein has been
identified as a factor in tumorigenesis. It has also been determined that
variations in the PTPN11 protein, which regulates the Ras pathway of cell
growth and proliferation, result in the Noonan Syndrome phenotype. Individuals
with Neurofibromatosis-Noonan Syndrome develop low-set ears, neck webbing,
ocular hypertelorism, down slanted palpebral fissures, and pulmonic stenosis.2
The complexity and diversity in NF1 pathogenic variants in Neurofibromatosis
Type 1 will continue to make identifying the genotype-phenotype correlation
exceptionally difficult.

   There is still not cure for Neurofibromatosis
Type 1. Suffering individuals have life expectancy eight years lower than the
general population. Early death is caused by malignant tumors. Current
treatment is symptom management. Neurofibromas are mainly treated with surgery.
Laser ablation is preferred over invasive surgery techniques because it can
rapidly and effectively remove numerous cutaneous neurofibromas with minimal
scarring. Surgical treatments of plexiform neurofibromas is commonly deficient
because in most cases the tumor will recur and neurological deficits are a possible
side effect due to the intracity of the tumor in the nerve. Radiotherapy should
not be used to treat tumors in patients with Neurofibromatosis Type 1 because
of the high risk of developing malignant peripheral nerve sheath tumors. MRI,
PET, and CT scans are used to identify benign versus malignant peripheral nerve
sheath tumors. The only possible cure for these tumors is complete surgical
extraction, but adjuvant chemotherapy has been used and produced positive
results in a small quantity of patients. Optic gliomas are discovered via MRI
and do not require treatment as long as they remain asymptomatic. Typically,
treatments include chemotherapy with carboplatin and vincristine. Surgery is
only used when the patient is already blind. Bone abnormalities, such as
scoliosis, require difficult and complex surgical management. Methylphenidate
is used to treat neurobehavioral problems, specifically ADHD.2

All individuals with Neurofibromatosis Type 1 should have annual
physicals with a physician familiar with both the patient and the disease. It
is essential for disease management to have regular blood pressure monitoring
and additional medical testing when indicated. In early childhood, there needs
to be regular screening to measure development and annual ophthalmologic
examinations. When women with this disease become pregnant additional
precautions need to be taken. In addition to a dramatic increase in
neurofibromas, hypertension becomes apparent and large pelvic and genital
neurofibromas complicate delivery causing a cesarean section to frequently be

There are currently 119 clinical studies underway for
Neurofibromatosis accordingly to the U.S. National Library of Medicine.8
In a clinical trial for plexiform neurofibromas, a 20% or more decrease in
tumor volume was observed in 17 out of 24 children who received long-term
treatment with selumetinib. None of the children showed an increase in tumor
size with long-term treatment.2 Radiofrequency therapy has shown
promising results in treating facial diffuse plexiform neurofibromas and
café-au-lait spots.2 Everolimus is being used to reduce the size of
cutaneous lesions. No statistically significant results were collected. Some of
the side effects include gastrointestinal upset, weight loss, tooth infections,
and urinary tract infections.8 Lamotrigine is currently being tested
as a means to improve cognitive and neurophysiological deficits.8
Additional clinical studies are also being performed on malignant peripheral
nerve sheath tumors and optic pathway gliomas.

In the future, doctors are hoping to be able to make treatment
plans tailored to each patient’s specific pathogenic variant of NF1. This
includes taking the individual’s gender into consideration to determine the
expected disease progression.6 Since so much about NF1 is still
unknown, researchers are continuing to use mice models to discover the exact
pathways both wildtype and mutant NF1 interacts with. They aim to use genome
sequencing to gather additional information about gene interactions. Minimizing
regulatory requirements for clinical trials will maximize availability to
patients and allow for recently diagnosed patients to be studied.9
The creation of a central database containing genomic, genetic, histologic,
molecular, immunohistochemical, treatment, radiographic, and relevant clinical
data would be extremely beneficial to NF1 discoveries.9 Data sharing
among researchers is essential for a rapid breakthrough. Additional knowledge
on Neurofibromatosis Type 1 and NF1 will allow for the development of more
effective drugs to manage symptoms, targeted treatments, and hopefully one day
a cure.

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