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(von Recklinghausen disease/Watson disease)

What is Neurofibromatosis?
Neurofibromatosis is a genetic defect that causes
neural crest cells to develop abnormally. This
results in numerous tumors and malformations of
the nerves, bones, and skin.
Target population
There are 2 form of NF : NF-1 and NF-2
Both forms of neurofibromatosis are caused by a
defective gene.
NF-1 is caused by a defect on chromosome 17
NF-2 results from a defect on chromosome 22.
Both are inherited as a dominant trait.
This means that anybody who receives just one defective
gene will have the disease. However, a family pattern of NF
is only evident for about half of all cases of NF. The other
cases of NF occur due to a spontaneous mutation.
The chance of a person with NF passing on the NF
gene to their child is 50%.
Neurofibromatosis-I is one of the most common
genetic disorders that is dominantly inherited
Neurofibromatosis type I (NF1) is caused by
mutation in the neurofibromin gene

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

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

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
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
A distinctive osseous lesion, such as
sphenoid dysplasia or thinning of the long
bone cortex, with or without
A first-degree relative with NF-1 according
to the above criteria
More Clinical Features of NF-1
Pseudarthrosis of the tibia
Acoustic neuroma
Optic neuroma
Mental retardation
Fibromas in Iris
Glaucoma - rare
Most common benign tumor of NF-1

These tumors are made of Schwann cells,

fibroblasts, mast cells, and vascular

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

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

There are no cure for the
The symptoms of NF-1 and NF-2 can be
treated individually.
Skin tumors can be surgically removed.
Some brain tumors, and tumors along the
nerves, can be surgically removed, or
treated with drugs or x-ray treatments.
S. L. Blachford, The Gale Encyclopedia of Genetic Disorders.
Detroit: Gale. Retrieved from|0OLG&v=2.1&u=cary
Gulli, L. F. (2005). Neurofibromatosis. In B. Narins (Ed.), The
Gale Encyclopedia of Genetic Disorders (2nd ed., Vol. 2, pp.
909-911). Detroit: Gale. Retrieved from