Neurofibromatosis (NF)
• NF Is an autosomal-dominant trait manifested
by changes in the skin, nervous system, bones, and endocrine glands. These
changes include a variety of congenital abnormalities, tumors, and hamartomas.
• Two major forms of
NF are recognized: (1) classic von Recklinghausen NF, termed NF1, and (2)
central or acoustic NF, termed NF2. Several less common variants have also
been reported (variants NF3- NF7).
• Both common types
have cafe-au-lait macules and neurofibromas, but only NF2 has bilateral
acoustic neuromas (unilateral acoustic neuromas are a variable feature of NF1).
• An important
diagnostic sign present only in NF1 is pigmented hamartomas of the iris (Lisch
nodules).
Epidemiology
Incidence: NF1:
1:3000 and NF2: 1:50,000.
Sex: Males
slightly more than females.
Heredity: Autosomal dominant; the gene for NF1 is on
chromosome 17 and the gene codes for a protein named neurofibromin. The gene
for NF2 is on chromosome 22 and codes for a protein called merlin.
Neurofibromatosis
Type I
Salient features
|
Updated diagnostic
criteria including recently recognized manifestations (e.g. nevus anemicus,
choroidal nodules) and NF1 gene
testing are under development. When a multistep, comprehensive analysis of
the NF1 gene is performed, an
underlying mutation can be detected in ≥95% of non-founder patients who fulfil
these diagnostic criteria.
The National Institutes of Health (NIH) criteria for NF1
are met in 97% of affected individuals by age 8 years and 100% by age 20 years.
National
Institutes of Health (NIH) criteria for NF1
Two or More Required for Diagnosis
|
1. Six or
more café-au-lait macules over 5 mm in greatest diameter in prepubertal
individuals, and over 15 mm in postpubertal individuals 2. Two or
more neurofibromas of any type or one plexiform neurofibroma 3. Freckling
in the axillary or inguinal regions 4. Optic
glioma 5. Two or
more iris Lisch nodules (iris hamartomas) 6. A
distinctive osseous lesion such as sphenoid dysplasia or thinning of long
bone cortex with or without pseudarthrosis 7. A
first-degree relative (parent, sibling, or offspring) with NF-1 by the above
criteria |
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MAJOR
CLINICAL FEATURES OF NEUROFIBROMATOSIS TYPE 1 |
|
Cutaneous |
|
· Neurofibromas (60–90%)
· Café-au-lait macules
(>90%)
· Axillary and/or
inguinal freckling (~80%)
· Plexiform neurofibroma
(25%)
· Nevus anemicus
(30–50%)
· Juvenile
xanthogranuloma (15–35% in first 3 years of life) |
|
Ocular |
|
· Lisch nodules (~90% by
20 years of age)
· Choroidal nodules
(>80% of adults)
· Neovascular glaucoma,
retinal vasoproliferative tumors |
|
Skeletal |
|
Cranial |
|
· Macrocephaly (20–50%)
· Hypertelorism (25%)
· Sphenoid wing
dysplasia (<5%) |
|
Spinal |
|
· Scoliosis (5–10%)
· Spina bifida |
|
Limbs |
|
· Dysplasia of long bone
cortex (5%), pseudarthrosis (2%) |
|
Other |
|
· Generalized osteopenia
(~50%), osteoporosis (~20%)
· Short stature (~30%
<3rd percentile)
· Pectus deformity
(30–50%) |
|
Tumors |
|
· Optic glioma (10–15%)
(with or without precocious puberty)
· Malignant peripheral
nerve sheath tumors (3–15%)
· Pheochromocytoma (~1%)
· Juvenile
myelomonocytic leukemia
· CNS tumors other than
optic gliomas (~5%)
· Rhabdomyosarcoma,
especially of the genitourinary tract
· Duodenal carcinoid
· Somatostatinoma
· Parathyroid adenoma
· Gastrointestinal
stromal tumors (GIST)
· Breast cancer (~5-fold
increased risk in women <50 years of age) |
|
Neurologic |
|
· Unidentified bright
objects (UBO) on MRI (50–75%)
· Learning difficulties
(30–50%)
· Seizures (~5%)
· Intellectual
impairment (severe in <5%)
· Aqueductal stenosis
and hydrocephalus (~2%) |
|
Cardiovascular |
|
·
Hypertension (~30%): essential > renal artery
stenosis or pheochromocytoma
· Pulmonic stenosis
(~1%)
· Renal artery stenosis
(~2%)
· Cerebrovascular
anomalies (2–5%), including vascular stenoses and aneurysms |
Timing of onset of
clinical manifestations
The
prevalence of various clinical features in patients with NF1 evolves over the
first two decades of life. PNFs and skeletal defects are probably congenital,
and both CALMs and nevus anemicus are congenital or become apparent in the
first few years of life. Intertriginous “freckling”, Lisch nodules, and optic
gliomas usually occur by the school-age years, and multiple CNFs typically
start to develop closer to puberty.
The time course of major diagnostic lesions that develop in NF1. During
the first few years of life, a child may have only café-au-lait macules.
Management of NF-1
CT, computed tomography; MRI, magnetic
resonance imaging; PET-CT, positron emission tomography–computed tomography.
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EVALUATION
AND MANAGEMENT OF NEUROFIBROMATOSIS 1 (NF1) PATIENTS |
|
At time of diagnosis and annually during
childhood and adolescence (unless otherwise indicated) |
|
1. Dermatologic
examination (especially if a plexiform neurofibroma [PNF] is present)
· Surgical consultation
if painful or disfiguring neurofibromas
·
PET-CT if rapid growth, increased
firmness, or persistent pain within an established PNF or the development of
a new neurologic deficit*
2. Ophthalmologic
examination with visual assessment (prior to age 8 years)
·
Orbital/brain MRI if signs/symptoms of optic glioma
3. Evaluation for
scoliosis and tibial bowing
·
Referral to orthopedics if scoliosis develops
4. Neurologic
examination, developmental/behavioral evaluation, and (in young children) measurement
of head circumference
· Orbital/brain and/or
spinal MRI if neurologic signs/symptoms develop†
· Comprehensive
developmental assessment prior to starting school and if problems arise
5. Cardiac assessment and
measurement of blood pressure
· Referral to cardiology
if murmur is detected
·
Renal arteriography and 24-hour urine collection for
catecholamines and metanephrines if hypertension develops
6. Assessment for
pubertal development
· Orbital/brain MRI and
referral to endocrinology if precocious puberty develops |
|
Minimum annual evaluation for adults
with uncomplicated disease |
|
1. Dermatologic
evaluation if PNF is present
· PET-CT for indications
described above
2. Neurologic examination
(especially if a PNF is present)
· MRI and/or other
studies as indicated if neurologic signs/symptoms develop
3. Measurement of blood
pressure
· Evaluation as
described above if hypertension develops
4. In women, screening
for breast cancer with clinical examination + mammography ± MRI (beginning by
age 40 years) |
|
Potentially affected family members |
|
1. Dermatologic
examination for cutaneous manifestations of NF1 2. Ophthalmologic
examination for Lisch nodules 3. Consider genetic
testing if a mutation has been identified in the proband * Immediate
assessment is required for any of these findings. † The
role of neuroimaging in asymptomatic patients is controversial. |
Individuals with NF-1 are best
cared for within a multidisciplinary clinic, which has access to a wide range
of subspecialists. Dermatologists are often consulted to assist
in establishing the diagnosis in affected children. Evaluation of individuals
newly diagnosed with NF1 should include a thorough history (personal and
family) and physical examination, with particular attention to signs and
symptoms of disease manifestations. As part of the initial care of NF1
patients, an in-depth educational discussion should include the natural history
of the condition, possible medical complications and neuro developmental
sequelae, and psychosocial considerations; genetic counselling should also be
provided. Goals of longitudinal care include early recognition and
treatment of complications, maximization of academic and vocational
achievement, and minimization of the disease’s psychosocial impact.
All first-degree relatives should
be examined for the cutaneous manifestations of NF-1 and should undergo
slit-lamp examination at the first visit to ascertain the presence of Lisch
nodules. Yearly visits allow the physician to identify NF-1 complications early
while providing counselling and dissemination of information regarding NF-1.
All children with NF-1 who are
6-years-old and younger should have yearly complete ophthalmologic examinations
looking for signs of an optic pathway tumor. These should include assessment
of visual acuity, color vision, visual fields, fundoscopy, and slit-lamp
examination. As almost all optic pathway tumors arise in children in this age
group, the frequency of ophthalmologic examinations can be reduced in children
over 10 years of age. Yearly measurements of weight and height should be
plotted on standardized growth charts, as the earliest indication of precocious
puberty may be accelerated linear growth. Blood pressure measurements should be
obtained at each visit to look for signs of renovascular hypertension. In
addition, the spine should be examined each year for early signs of scoliosis.
Café-Au-Lait Spots
Café-au-lait spots on the face
are unusual in individuals with NF-1. On occasion, they do occur and affected
individuals may seek to improve cosmesis.
Café-au-lait spots can be removed with laser therapy such as Q-switched
ruby laser (694 nm), the continuous mode copper vapor laser (511 nm) or the
erbium: YAG laser (2,940 nm). Although total disappearance of the lesion may
occur, some studies cite a recurrence rate as high as 67%. Multiple treatments
of a single lesion may be more effective.
Cutaneous Neurofibromas
Discrete cutaneous neurofibromas
may be removed surgically to improve cosmesis or to prevent local irritation,
for example, in the hairline while brushing or on the foot rubbing against the
shoe. Deeper neurofibromas may require surgical removal when pushing on vital
structures, such as a dorsal root neurofibroma that infiltrates the neural
foramen and compresses the spinal cord. Complications of surgery include
regrowth of the original tumor and nerve damage. In individuals who have
severe pruritus from a large burden of cutaneous neurofibromas, antihistamines
may provide symptomatic relief. ketotifen, an antihistamine and mast cell
stabilizer, has provided relief from pruritus and pain and prevented the rapid
growth of new neurofibromas. Use of the CO2 laser under general anaesthesia
to remove hundreds of cutaneous neurofibromas has resulted in markedly
increased patients’ quality of life and decreased pain and pruritus.
Plexiform Neurofibromas
Until recently, the treatment of
plexiform neurofibromas was limited to surgical debulking either to improve
cosmesis or to prevent loss of function (e.g., upper airway obstruction,
blindness). Such surgery was highly limited in its efficacy; complete resection
was impossible given the highly infiltrative nature of these tumors and tumor
regrowth was common. Thus, there has been considerable interest in the
development of non-traditional chemotherapy for use against these tumors. Plexiform
neurofibromas are quite different biologically from more conventional solid
neoplasms. Lack of growth following treatment may be part of the natural
history of the tumor rather than a true therapeutic response. In addition, tumor
burden may be difficult to quantify radiographically; plexiform neurofibromas
may “spread” along nerve roots sending out multiple finger-like projections,
quite different than a single, solid tumor mass.
Several chemotherapeutic agents
are used. Pirfenidone, an antifibrotic agent that decreases proliferation of
fibroblasts and collagen matrix synthesis, and a farnesyl
transferase inhibitor which down regulates the ras oncogene did not
yield promising results. Based on the role of mast cell c-kit receptor signaling,
administration of imatinib to a 3-year-old with an
unresectable airway plexiform neurofibroma led to 70% diminution in size during
3 months of therapy. Other newer agents are also currently being studied. These
include: (1) AZD2171, which is a potent inhibitor of vascular endothelial
growth factor receptor tyrosine kinases; (2) sirolimus, an mTOR pathway inhibitor; (3)
PEG interferon-α-2b; and (4) photodynamic therapy. If any of these studies
demonstrate potential efficacy, the role of screening imaging to detect
“hidden” plexiform neurofibromas would need to be readdressed.
Optic Pathway Tumors
Once identified, OPT should be
followed by serial MRI and ophthalmologic examinations. Treatment should be
initiated only after demonstration of clear radiographic progression or
deterioration of vision. The goal of treatment should be preservation of vision
while minimizing the side effects of therapy. Chemotherapy with carboplatin and vincristine has proven effective in the
management of these tumors. Radiation therapy, while a mainstay of treatment
of progressive CNS neoplasms not associated with NF-1, is not appropriate for NF1-associated
OPTs because of the risk of vasculopathy, second malignancies, and detrimental
neurocognitive and endocrinologic side effects in very young children.
