NEUROFIBROMATOSIS
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| CUTANEOUS MANIFESTATIONS OF NEUROFIBROMATOSIS |
There are eight distinct clinical forms of neurofibromatosis. The two most studied and clinically important forms are type I and type II. Neurofibromatosis type I (von Recklinghausen disease) and neurofibromatosis type II are autosomal dominant disorders involving the skin, the central nervous system, and various other organ systems. Type II has many overlapping features that are also seen in patients with type I disease. The genetic bases for type I and type II neurofibromatosis have been determined, and the specific gene for each type has been isolated. The skin findings can be instrumental in the diagnosis of neurofibromatosis type I.
Clinical Findings: Type I neurofibromatosis is usually diagnosed
in early childhood. It has an estimated incidence of 1 per 3000 births and
occurs world-wide. There is no gender or race predilection, and type I accounts
for 85% to 90% of all cases of neurofibromatosis. There is wide clinical
variability in neurofibromatosis. Diagnostic criteria have been established by
the U.S. National Institutes of Health. Two or more of the following seven
criteria are needed for diagnosis: (1) six or more café-au-lait macules (≥5 mm in size
in prepuberty patients; >1.5 cm in postpuberty patients); (2) one plexiform
neurofibroma or two or more neuro-fibromas; (3) axillary or inguinal freckling;
(4) optic glioma; (5) two or more Lisch nodules of the iris; (6) sphenoid
dysplasia or other distinctive bone abnormality, such as pseudarthrosis of a
long bone; or (7) a first-degree relative with neurofibromatosis.
The
cutaneous findings, and in particular the café- au-lait macules, are often the
presenting sign of the disease. Solitary café-au-lait macules are seen in a
large percentage of the normal population, and the diagnostic criteria for
neurofibromatosis require the presence of at least six such lesions. Spinal
dysraphism may be present if the skin overlying the spine is involved with a
café-au-lait macule. The onset of axillary and inguinal freckling is often
during puberty. Axillary freckling is also known as Crowe’s sign. Cutaneous
neurofibromas are the most common benign tumor found in patients with
neurofibromatosis. The tumors tend to be plentiful and to increase in number
and size with time. They are soft and often exhibit the “buttonhole” sign when
compressed. These tumors may have an overlying pink to light violet coloration.
Plexiform neurofibromas are large dermal and subcutaneous tumors specific to
type I neurofibromatosis. They can cause compression of underlying structures
and wrap themselves around nerves. Compared with the typical neurofibroma, they
are firm and larger and have an ill-defined border. Both forms of neurofibromas
can produce varying amounts of pruritus. Patients with plexiform neurofibromas
have hypertrichosis with and without hyperpigmentation. The presence of
multiple neurofibromas can cause psychological disease.
Lisch
nodules are hamartomas of the iris. They are observed under slit-lamp
examination and can be seen by approximately 6 years of age. Optic gliomas are
seen in about 1 of every 8 patients with neurofibromatosis. Optic gliomas may
be asymptomatic, or they may cause compression of the pituitary gland,
resulting in precocious puberty. Gliomas can also cause visual disturbance
and proptosis. The best method to detect an optic glioma is with brain magnetic
resonance imaging (MRI). Other ophthalmological findings that may be present
include hypertelorism and congenital glaucoma.
Type
II neurofibromatosis has a completely different phenotype than type I disease,
with some overlap. Onset of disease is often not until the second or third
decade of life. The main aspect of type II neurofibromatosis is the
formation of bilateral acoustic neuromas (vestibular schwannomas). These tumors
can lead to headaches, vertigo, and various degrees of hearing loss.
Schwannomas may occur in any cranial nerve. The criteria used to establish the
diagnosis are (1) the presence of bilateral schwannomas; (2) the combination of a
first-degree relative with type II neurofibromatosis and a unilateral
vestibular schwannoma; or (3) a first-degree relative with type II
neurofibromatosis and any two of the following tumors: neurofibroma,
glioma, schwannoma, meningioma, or juvenile posterior subcapsular lenticular
opacity.
Cutaneous
findings in type II neurofibromatosis include neurofibromas and café-au-lait
macules. Although both findings are less numerous than in type I
neurofibromatosis, most patients have only one or two café-au-lait macules.
Cutaneous schwannomas are common in type II disease but are not seen in type I
disease. A unique form of cataracts can be seen in neurofibromatosis type II;
these are termed juvenile posterior subcapsular lenticular cataracts.
Histology: Skin biopsies of café-au-lait macules show epidermal
hyperpigmentation. There is no increase in the number of melanocytes, and no
nevus cells are present. Macromelanosomes can be seen. Neurofibromas can be
located within the dermis or subcutaneous tissue. Histological evaluation shows
a well-circumscribed tumor composed of uniform-appearing spindle cells of nerve origin.
Special immune histochemical stains can be performed to confirm the nerve
derivation of the tumors. Many mast cells are seen intermingled within the
spindle cell tumor.
Pathogenesis: Type I neurofibromatosis is caused by a mutation in
the NF1 gene. This gene is located on the long arm of chromosome 17 and
encodes the protein neurofibromin. Defects in NF1 are responsible for
most cases of neurofibromatosis, making type I neurofibromatosis the most
common type of neuro- fibromatosis. Because of the large size of the NF1 gene,
many spontaneous mutations occur and result in cases of neurofibromatosis. The
neurofibromin protein has been determined to be a tumor suppressor protein. It
regulates the ras family of protooncogene. When neurofibromin is
defective, the ras protooncogene loses its negative regulatory protein
and is able to signal continuously.
Type
II neurofibromatosis is caused by a genetic defect in the SCH (NF2) gene
on the long arm of chromosome 22. The NF2 gene is approximately one
third the size of NF1. It encodes the schwannomin (merlin) protein, a
tumor suppressor protein that helps act as a go-between in the interactions
between the cell cytoskeleton/membrane and the extracellular matrix. Loss of
function of the protein results in abnormal cell signaling and unabated cell
growth in various tissues.
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| CUTANEOUS AND SKELETAL MANIFESTATIONS OF NEUROFIBROMATOSIS |
Treatment: Once the diagnosis has been established, patients need
lifelong monitoring for the development of various complications related to
their disease. Family members should be screened for the disease, and genetic
counseling should be offered to affected patients. Adolescents and young adults
may benefit from annual physical examinations, and routine ophthalmological
examinations should be recommended. Screening in childhood for the development
of scoliosis should be recommended. Patients should be screened for
hypertension at each visit because of the increased incidence of
pheochromocytoma. Patients with neuro-fibromatosis are at increased risk for
development of malignant transformation of their neurofibromas into
neurofibrosarcomas. These rare sarcomas can be located anywhere, and any major
change, pain, or growth of a preexisting neurofibroma should make the
clinician consider performing a biopsy to rule out malignant degeneration.
Optic gliomas are best surgically excised if indicated, even though removal of
the optic glioma typically results in blindness.
Patients
with type II disease should have screening MRI studies of the brain and the
rest of the central nervous system to look for schwannomas. Type II disease,
because of the presence of bilateral schwannomas, is a much more serious and
life-altering disease than type I. The follow-up management of type II
neurofibromatosis requires a multidisciplinary approach. Ophthalmology,
otolaryngology, neurosurgery, and internal medicine physicians need to
coordinate care for these patients. Neurosurgery and localized radio-therapy
have been used to treat the brain tumors.
