Neurofibromatosis

By Shannon Weeks

What is Neurofibromatosis?
Neurofibromatosis type I (NF1) is caused by mutation in
the neurofibromin gene
AKA von Recklinghausen disease , Watson disease
An autosomal dominant neurogenetic disorder
Characterized by the presence of multiple benign
neurofibromas
Affects the bone, the nervous system, soft tissue, and
the skin
Clinical symptoms increase over time
Neurologic problems and malignancy may develop

Neurofibromatosis-1
NF-1 occurs in approximately 1 of 2500-3300 live births
This disease can involve various body systems over time
Signs can range from benign cutaneous manifestations to
extreme disfigurement
The mortality rate is higher than that of the healthy
population because of the increased potential for
malignant transformation of diseased tissues and the
development of neurofibrosarcoma
Patients with NF-1 have about a 3-15% additional risk of
malignant disease in their lifetime
All racial groups are affected equally
Women and men are affected equally

Genotype/Phenotypeect
Increased concentrations of nerve growth stimulating activity
have been linked with the development of neurofibromatosis
NF-1 is a disorder with variable phenotypic expression
Some patients may mainly have cutaneous expression, and
others may have life-threatening or sever disfigurement
The variation of this disease is even shown within families
The spontaneous mutation rate is 100 times greater than for
many genes, and it is thought to contribute to approximately
30-50% of neurofibromatosis cases.
A genotype- phenotype analysis suggests that there is no
clear relationship between specific NF1 mutations and clinical
features of Neurofibromatosis type 1.

Diagnostic criteria for NF-1

(The diagnostic criteria are met

if 2 or more of the features listed
are present.)

Six or more caf au lait macules

larger than 5 mm in greatest
diameter in prepubertal
individuals and those larger than
15 mm in greatest diameter in
postpubertal individuals
Two or more neurofibromas of
any type or 1 plexiform
neurofibroma
Freckling in the axillary or
inguinal regions
Optic glioma
Two or more Lisch nodules (iris
hamartomas)
A distinctive osseous lesion,
such as sphenoid dysplasia or
thinning of the long bone cortex,
with or without pseudoarthrosis
A first-degree relative with NF-1
according to the above criteria

More Clinical Features of NF-1

Scoliosis
Pseudarthrosis of the tibia
Pheochromocytoma
Meningioma
Glioma
Acoustic neuroma
Optic neuroma
Mental retardation
Hypertension
Hypoglycemia
Fibromas in Iris
Glaucoma - rare

Neurofibromas

Most common benign tumor of NF-1

These tumors are made yp ofof

Schwann cells, fibroblasts, mast
cells, and vascular components

They can form at any place along a

nerve

Three subtypes of neurofibroma

exist: cutaneous, subcutaneous, and
plexiform

Cutaneous lesions and

subcutaneous lesions are
circumscribed. These nodules may
be brown, pink, or skin colored. They
may be soft or firm to the touch

Plexiform neurofibromas are

noncircumscribed, thick, and
irregular, and they can cause
disfigurement by entwining
important supportive structures

Cellular loss of wild type NF1 allele is

associated with neurofibromas

Protein Function/Biochemistry

Neurofibromin is a cytoplasmic protein that is expressed in neurons, Schwann

cells, oligodendrocytes, astrocytes and leukocytes

It is encoded by the gene NF1

It is located on chromosome 17, at the band q11.2

It has several biochemical functions, including association to microtubules and

participation in several signaling pathways

Alterations in the protein are responsible for a phacomatosis named

neurofibromatosis type 1

Neurofibromin has a guanosine triphosphatase (GTPase) region that binds to Ras

and positively modulates conversion of guanosine triphosphate (GTP) to
guanosine diphosphate (GDP)

The protein is necessary for the negative regulation of Ras protein signal; telling
us that neurofibromin acts as a tumor suppressor

Needed for the negative regulation through the cell cycle

3-D Visualization

Ball and Stick

Analysis of mutations

Many different mutations in the neurofibromatosis gene have been

described.

In 95% of NF1 individuals, a mutation is found in the NF1 gene

5% of the patients, the germline mutation consists of a microdeletion

that includes the NF1 gene and several other genes

45 mutations within the NF1 gene are associated with neurofibromatosis

type 1

Mutations are found in exon 2

Mutations in this exon involves an insertion of cytosine into codon 5662

and resulted in an early stop codon.

Another mutation in exon 2 is from the insertion of the amino acid

thymidine at nucleotide 5678, which also creates an early stop codon.

Mutations in NF1 can also lead to juvenile myelomonocytic leukemia

References
http://www.ncbi.nlm.nih.gov/entrez/
viewer.fcgi?
db=nucleotide&val=109826563
http://www.ncbi.nlm.nih.gov/Structu
re/mmdb/mmdbsrv.cgi?
form=6&db=t&Dopt=s&uid=38151
http://www.ncbi.nlm.nih.gov/entrez/
dispomim.cgi?id=162200