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Neurofibromatosis 1

Samantha Brenner, Jeffrey Shyu and Sayone Thihalolipavan

Neurofibromatosis (NF) is a genetic disorder of tumor formation on peripheral and central


nervous tissue. It may also affect skin and bone tissue development. Two types of NF have been
identified: Neurofibromatosis 1 (NF1) and Neurofibromatosis 2 (NF2).
NF1, also known as von Recklinghausen’s Disease or Peripheral NF, is the most common of
the neurocutaneous disorders, appearing in 1:3,000 births [Friedman 1999]. Though NF1 is an
autosomal dominant genetic disorder that is heritable, up to 50% of patients with NF1 have de
novo mutations. A mutation in the NF1 gene on chromosome 17 reduces neurofibromin
expression, resulting in a tumor that is comprised of neoplastic Schwann cells, fibroblasts,
perineurial cells, and mast cells in a mucosubstance collagen matrix [Packer 2002].
Characteristics of NF1 include café-au-lait spots and skin or plexiform neurofibromas.
Bone enlargement and deformation, scoliosis, and brain, cranial nerve, optic nerve, or spinal cord
tumors may develop. Individuals may also experience developmental abnormalities; 30 to 50%
of patients with NF1 have learning disabilities, and some have vascular abnormalities
[ninds.nih.gov]. Symptoms can vary tremendously, with many individuals having a milder form
of the disease and others having more severe cases that can lead to cancerous tumors. The life
expectancy of patients with NF1 is reduced by 15 years. Surgery is the most common method of
treatment to control symptoms.
By contrast, NF2 is rarer, with an incidence of 1:40,000 births, and yields distinct
symptoms, most notably bilateral auditory nerve damage by tumor formation [ninds.nih.gov].
Our paper, however, is exclusively concerned with NF1.

Genetics, Biochemistry, And Molecular Biology


Neurofibromatosis 1 is an autosomal dominant disorder. The gene affected is NF1, which
is located on chromosome 17q11.2 (long arm) [ninds.nih.gov]. NF1 is 350 kb long and contains
60 exons, making it a particularly large gene. NF1 codes for three alternatively spliced
transcripts, and one of its introns codes for three other genes. The NF1 gene encodes
neurofibromin (327 kDa), which regulates signal transduction via the ras GTPase pathway.
Neurofibromin controls cellular proliferation and is thus a tumor suppressor. However, other
researchers have found that in Drosophila, neurofibromin is not involved in Ras suppression but
is involved in voltage-gated potassium channel function, suggesting that there may be other
functions of the neurofibromin protein [Guo 1997].
Neurofibromatosis 1 is almost completely penetrant, with over 90% of individuals with a
mutation showing clinical features of the disease by puberty. 1/3,000 infants have a NF1
mutation at birth, making it one of the most prevalent dominantly inherited genetic disorders
[Friedman 1999]. Approximately half of all reported cases are the result of spontaneous, de novo
mutations. This is because the mutation rate for the NF1 gene is extremely high (~1/10,000). The
scientific basis of the high mutation rate is not known.
Over 500 different mutations on this large gene have been identified, with most mutations
being unique to particular families. The most common pathologic alleles make up no more than
a few percent of the total number of cases, making genetic testing problematic. Consistent
genetic transmission of NF1 variants, such as familial spinal neurofibromatosis [Ars 1998]
demonstrates allelic heterogeneity, or a single disorder from variable mutations. Features such as
dysmorphism do not exist in all individuals with whole NF1 deletions [Kayes 1994]. Pathologic
mutations are varied and include stop mutations, substitutions, whole gene deletions, intronic
changes, and chromosomal rearrangements. It is also reported that modifying genes contribute
to the varied phenotypes [Easton 1993]. Some particularly severe cases of NF1 are the result of
random loss of heterozygosity of the gene. Thus a complex interplay of genetic and
environmental elements contribute to the varying phenotypes of NF1 patients.

Diagnosis
Symptoms of NF1 can vary greatly in different patients, and the expressivity of the disease
is difficult to predict. In mild NF1 cases, the only adulthood signs may be multiple café-au-lait
spots and a few dermal neurofibromas. Roughly 60% of patients with NF1 have a milder form
of the disorder. In more severe cases, complications that are usually present at birth or that
develop during childhood accompany the milder symptoms [ninds.nih.gov].
The clinical diagnosis of NF1 is formally defined by the NIH as the observation of two or
more of the following indicators:
1. café-au-lait spots ( ≥ 6 )
• before puberty – largest spot must be greater than 5 mm in diameter
• after puberty – largest spot must be greater than 15 mm in diameter
2. axillary or inguinal freckles
3. any type of neurofibroma ( ≥ 2 ) or plexiform neurofibroma ( 1 )
4. Lisch nodules (iris hamartomas) ( ≥ 2 )
5. optic glioma
6. sphenoid dysplasia or thinning of long bone cortex with or without pseudarthrosis
7. a first degree relative with NF1 [ninds.nih.gov]
The most common sign of NF1 is the café-au-lait spots. These flat spots are named for their
light tan color. In darker-skinned patients, the café-au-lait spots are darker than the rest of the
skin. The size of the spots has clinical relevance, as their diameter has to be greater than 5 mm
in children and 15 mm in adults for NF1 to be diagnosed or considered in a differential
diagnosis. The café-au-lait spots, usually present at birth, change over time, increasing in size
and number, and growing darker.
In unaffected individuals, freckles are the product of sun exposure; however NF patients can
develop freckles in areas of the body, such as the axilla, that are not regularly exposed to the sun.
Therefore, axillary freckling and freckling of the groin are useful indicators that the patient is
affected with neurofibromatosis.
Neurofibromas are the most common tumors in NF, and can affect virtually any organ in the
body. Finding multiple neurofibromas is considered diagnostically important, because single
neurofibromas occur in patients without the disease. Neurofibromas are benign growths which
develop subcutaneously from both nervous and fibrous tissues, often causing disfigurement of
the affected individual. An individual affected with NF can have anywhere from a few to
thousands of neurofibromas. Pregnant women have been known to experience a rapid increase
in the number and size of neurofibromas [Tonsgard 1997].
Deep neurofibromas, which may also develop, are called plexiform neurofibromas.
Plexiform neurofibromas can be nodular or diffuse. In the face and neck, diffuse plexiform
neurofibromas rarely appear after one year of age. Diffuse plexiform neurofibromas in other
parts of the body usually develop up until the end of adolescence. Contrastingly, deep nodular
neurofibromas are more commonly found in adults. In general, plexiform neurofibromas are
more likely to develop into cancerous tumors. However, malignant transformation is extremely
rare for either type of neurofibroma [Dugoff 1996]
Lisch nodules are clumps of pigment in the iris, and they usually appear around puberty.
These iris hamartomas do not affect vision, and require a slit-lamp examination by an
ophthalmologist to be distinguished from iris freckles.
Optic gliomas are characterized by a thickening of the optic nerve. They typically develop
in the first six years of life. Optic gliomas may remain asymptomatic or conversely, they may
lead to blindness [Thiagalingam 2004].
NF1 patients can also develop a rapidly progressive form of scoliosis. Their scoliosis
usually develops between six and ten years of age, although milder forms of scoliosis without
vertebral anomalies have been known to occur during adolescence.
Although not diagnostically relevant, learning disabilities have been associated with
neurofibromatosis in roughly half of the cases. The learning disabilities in NF are mild or
moderate learning disabilities, as well as mental retardation in very rare cases. In particular,
visual-spatial performance and attention deficits are most often seen. These disabilities usually
persist into adulthood, and are often accompanied with poorer social skills.
Studies have also found that NF1 is associated with vascular abnormalities such as
coarctation of the aorta, as well as stenoses of the renal artery, inferior carotid artery, middle
cerebral artery, anterior cerebral artery, or pulmonary valve [Guttman 1999, Fossali 2000].

Prognosis
The prognosis for NF1 is varied. In mild cases, the prognosis is good. The life expectancy
is shortened by 15 years, mostly as a result of vasculopathy or malignant peripheral nerve sheath
tumors [Zoller 1995]. Since there is no way to currently predict how severe an individual’s
manifestation of the disease will be, it is difficult for physicians to make accurate predictions
until symptoms begin to surface [Zoller 1995].

Treatment
There is no known cure for NF1. Currently, surgical removal of tumors is the
predominant method of treatment. Cutaneous or subcutaneous tumors can be removed
surgically; the physical disfigurement caused by the disease is often distressing to patients.
Removal of plexiform tumors is often unsuccessful because these neurofibromas often grow
back and are intimately associated with nerves. Plexiform lesions can grow quite large, leading
to impingement of other structures and disfigurement [Neville 2001]. Most patients with optic
gliomas are asymptomatic and the lesions progress very slowly; therefore, most people with this
condition do not require surgery. There is no determined remedy for visual deterioration caused
by optic nerve gliomas [Astrup 2003]. Cerebellar and brainstem astrocytomas are less
aggressive in NF1 individuals than those without the disease. Regression of tumors has
occasionally been seen in people with NF1, therefore this should be taken into consideration
when considering treatment of astrocytomas [Leisti 1996].
Clinical trials have studied the efficacy of antihistamines (ketotifen fumarate), anti-
angiogenic agents (thalidomide and α-interferon), and anti-fibrotic drugs (Pirfenidone) to target
some of the symptoms of the disease and reduce the size and symptoms of progressive plexiform
tumors [Packer 2002]. To date, no drug has been able to reduce tumors by ≥ 50 % (as
determined by radiographic images). Chemotherapy is not advised since it may stimulate benign
neurofibromas to become malignant peripheral nerve sheath tumors.
Those with the disease are suggested to have annual physical examinations by a
physician familiar with NF1. For children, an ophthalmological exam is advised every year; for
adults, less frequently. A questionnaire should be filled out regularly to assess the development
of the disease. Blood pressure should be monitored regularly. If symptoms are clinically
apparent, other studies should be performed.

Risks For Family Members


NF1 is an autosomal dominant disorder, and people are heterozygotes for the disease.
50% of people with NF1 have an affected parent and 50% have a de novo mutation. Both
parents, siblings, and children of a person with NF1 should be tested. However, if neither parent
has the disease, alternate paternity is possible. Each child of the patient has a 50% chance of
inheriting the mutant allele. Penetrance is almost 100%, but expressivity is highly variable. If
neither parent has the allele and alternate paternity has been ruled out, then the risk to siblings is
low. Prenatal testing for NF1 is available but uncommon since the severity and age of onset are
very variable. Prenatal testing is done for those with increased risk by amniocentesis at 15-18
weeks’ gestation and analysis of extracted DNA [genereviews.org].

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