NEUROFIBROMATOSIS TYPE 1

Neurofibromatosis Type 1
Christina Fingerlow
State University of New York Polytechnic University

NEUROFIBROMATOSIS TYPE 1

Neurofibromatosis type 1 is a condition characterized by changes in skin pigmentation

and the growth of tumors along nerves in the skin, brain, and other parts of the body. The tumors
are most commonly benign. Symptoms vary greatly and change from childhood through
adulthood. Fortunately symptoms may be managed and patients living with neurofibromatosis
type 1 may live an active life with minimal complication.
Neurofibromatosis type 1 was first described in 1882 by a physician von Reckling.
Neurofibromatosis type one is a microdeletion syndrome involving recombination between low
copy repeat sequences, located at 17q11.2. The rearrangement is 1400 kb while the repeat length
is 85 kb. Neurofibromatosis type 1 is an autosomal dominant disease of the nervous system, eye
and skin (McInnes & Willard, 2007). The gene is mapped to the proximal long arm of
chromosome 17. Many different mutations have been found in the neurofibromatosis type one
gene, all of which cause loss of function of its gene product, neurofibromin. Neurofibromin is a
protein expressed in almost all tissue but most abundantly in the brain, spinal cord and peripheral
nervous system; which regulates several intracellular processes. Half of the patients with
neurofibromatosis type one have de novo mutations (McInnes & Willard, 2007). The mutation
rate of this disease is one of the highest known for any human gene, it is 1 mutation per 10,000
live births. 80% of de novo mutations are paternal in origin but there is no evidence for a
paternal age effect increasing the mutation rate. Neurofibromatosis type one is a large gene that
which has over 500 identified mutations. Neurofibromatosis type one is sometimes segmental,
affecting only one part of the body (McInnes & Willard, 2007). Segmental neurofibromatosis
type one is caused by mosaicism for a mutation that occurred after conception. In such cases, the
patient has normal parents, but it is he or she who has an affected child, the child's phenotype is
typical for neurofibromatosis type one (McInne & Willard, 2007). Interpretations of

NEUROFIBROMATOSIS TYPE 1

neurofibromatosis type one point mutations are often difficult, the effects of DNA substitution on
mRNA or protein levels cannot be correctly predicted. In a study conducted by Okumura, Ozaki
and Niida, it was concluded that one patient had two unexpectedly contained splicing mutations
both of which may be responsible for in frame deletion of neurofibromin. These results clearly
indicate that both DNA and RNA level analysis are required to understand the consequences of
neurofibromatosis mutation (Okumura, et al. 2014).
Neurofibromatosis type one is a clinical diagnosis. Identification of mutations is not done
routinely due to the size of the gene and the extreme allelic heterogeneity (McInnes & Willard,
2007). Diagnosis is complicated in children as signs develop gradually over time during
childhood. Throughout the newborn period, less than half of affected newborns show even subtle
symptoms of the disease. Penetrance is age dependent. Half of the cases of neurofibromatosis
type one result from a new rather than an inherited mutation. Genetic counseling may be
problematic for families, for two reasons: the disease may be in the proband sporadic due to a
new mutation or the disease may have been inherited from a parent whose symptoms are not
expressed (McInnes & Willard, 2007). A diagnosis can be made after the patient meets two or
more of the following conditions: six or more caf au lait spots measuring at least 5 mm in
diameter, two or more neurofibromas of any type, one plexiform neurofibroma, axillary or
inguinal freckling; optic glioma, two or more Lisch nodules; a distinctive osseos phenotype or a
first degree relative with neurofibromatosis type one. Patients with no family history of NF1 will
most likely meet criteria before the age of eight (McInnes & Willard, 2007).
Neurofibromatosis type one is a multisystem disorder with neurological, musculoskeletal
and ophthalmological and skin abnormalities and predisposition of neoplasia. Clinical
manifestations result from loss of function of the gene product, 80% of the mutations cause

NEUROFIBROMATOSIS TYPE 1

protein truncation. This is a disease which can be identified for more than 95% of individuals
with neurofibromatosis type one (McInnes & Willard, 2007). Clinical presentation can be
characterized by growth of multiple benign fleshy tumors, neurofibromas in the skin; presences
of multiple flat, irregular pigmented skin lesion known as caf au lai spots, growth of small
benign tumors called hamartomas or Lisch nodules on the iris of the eye and less frequently
mental retardation, central nervous tumors, diffuse plexiform neurofibromas, and the
development of cancer of the nervous system and muscle tissue (McInnes & Willard, 2007). This
condition has a pleiotropic phenotype. Caf au lai spots are hyper pigmented spots on the skin,
and are used a diagnostic sign in family members who otherwise may appear unaffected. Most
patients have six or more spots at least 15mm in diameter and usually located on the lower
backside. Freckling is seen on 90% of patients (McInnes & Willard, 2007). Numerous
neurofibromas are present in adults with NF1. Ocular manifestations can also include optic
gliomas. The most serious complication is in the bone and includes: scoliosis, vertebral
dysplasia, pseudarthrosis, and overgrowth. Other organ complications may include: stenosis of
pulmonic, renal, and cerebral vessels and hypertension. Neurofibromatosis type one effects 1 in
3500 births with no variation between ethnic groups (McInnes, & Willard, 2007). Glomas tumors
have been found with a strong correlation in patients with neurofibromatosis type one, they may
occur as part of the cancer disposition syndrome. Glomas tumors are painful hamartomas
(Kumar, et al. 2014).
Founded in 1982 by Dr. Robert Martuza, the Massachusetts General Hospital
Neurofibromatosis Clinic was one of the first to acknowledge the unique multi-disciplinary
problems that the neurofibromatosis patient and family face and the vital role that a dedicated
clinic plays in the research community. The Neurofibromatosis Clinic offers a comprehensive

NEUROFIBROMATOSIS TYPE 1

initial evaluation to all persons in whom a diagnosis of neurofibromatosis has been suggested or
confirmed. In addition to a neurological examination this includes a dermatological evaluation
and referral for neuro-ophthalmological evaluation and imaging studies (Owen, 2006). Many
patients come to the clinic with a diagnosis of rule out neurofibromatosis and the role of the
clinic is to clarify whether or not that diagnosis can be made. Others come because they are a
first degree relative of a neurofibromatosis patient and are thus at 50-50 risk for the disease.
Because so much is now known about the natural history and genetic risks of these diseases, it is
always important to make a clear diagnosis at the onset in any one person (Owen, 2006).
No curative treatments are available, and therefore treatment focuses on symptomatic
management. Ongoing surveillance in an individual with NF1 should include an annual
examination conducted by someone familiar with neurofibromatosis type one, annual
ophthalmological evaluation in childhood, regular developmental assessments, and regular blood
pressure measurements. The deformities caused by neurofibromatosis type one are the most
distressing manifestation (McInnes & Willard, 2007). Discrete cutaneous and subcutaneous
neurofibromas can be surgically removed if they are disfiguring or inconveniently located.
Plexiform neurofibromas causing disfigurement or impingement can also be surgically managed.
However, surgical intervention for these neoplasms can be problematic as they are often involved
with nerves and have a tendency to grow back at the site of removal (McInnes & Willard, 2007).
Patients coping with pain which are not candidates for surgical intervention may benefit from
other therapies, such as stereotactic radiosurgery, or medicinal to control pain or physical therapy
for symptom management (Mayo Clinic, 2013).
Neurofibromatosis is a genetic disorder which effects cell growth in the nervous system.
Symptoms may range from non-life threatening hyper pigmentations in the skin to more serious

NEUROFIBROMATOSIS TYPE 1

hypertension or predisposition to some types cancer. Fortunately symptoms may be managed

and patient can live close to normal lives.

NEUROFIBROMATOSIS TYPE 1

Reference
Kumar, M., Emmett, R., Bayliss, S., & Gutmann, D. (2014). Glomus tumors in individuals with
neurofibromatosis type 1. American Academy of Dermatology, 44-48. Retrieved from
MEDLINE database.
Mayo Clinic. (2013, January). Neurofibromatosis. Retrieved April 26, 2015, from
http://www.mayoclinic.org/diseases-conditions/neurofibromatosis/basics/definition/con20027728
McInnes, R., & Willard, H. (2007). Genetics in Medicine (7th ed.) (R. Nussbaum, Ed.).
Philadelphia, PA: Thompson & Thompson.
Okumura, A., Ozaki, M., & Nidda, Y. (2014). Development of a practical NF1 genetic testing
method through the pilot analysis of five Japanese families with neurofibromatosis type
1. Retrieved from MEDLINE database
Owen, C. (2006). The Neurofibromatosis Clinic at MGH. Retrieved April 26, 2015, from
http://neurosurgery.mgh.harvard.edu/NFclinic/