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Neurofibromatosis type 1 (NF1) is the most common neurocutaneous
disorder, affecting approximately 1 in 3000 people worldwide. The
hallmark features of NF1, café au lait spots and benign
cutaneous neurofibromas, typically arise in early childhood and
adolescence, respectively. Approximately two thirds of individuals
with NF1 have manifestations that generally do not require clinical
intervention, whereas the remaining one third display myriad medical
complications which are unpredictable, both in timing and severity.
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Even though NF1 has been recognized as von Recklinghausen disease
by the medical community since the 19th century, both its variability
and age dependence of clinical manifestations made it essential
to develop a well-accepted set of clinical criteria to establish
the diagnosis (eTable 182.1).1-3 The
typical clinical manifestations allow the diagnosis to be established
in children by 10 years.4 By virtue of full penetrance
in the adult population, diagnosis of NF1 is more straightforward
in familial cases because it requires only one physical manifestation
in addition to an affected first-degree relative. In sporadic cases,
NF1-related associations that are not part of the diagnostic criteria
sometimes appear prior to the development of a second diagnostic
sign.
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The typical pattern of clinical presentation in NF1 is age dependent.
Usually, multiple café au lait spots (CLS) are identified
in the first two years of life (eFig. 182.1).
The observation of more than 5 CLS that are greater than 0.5 cm
in diameter and of thoracic location in toddlers is a classical
presentation. A number of other conditions include multiple CLS
(ie, McCune-Albright syndrome, Noonan syndrome, Bloom syndrome),
although other signs and symptoms generally make exclusion of other
diagnoses fairly straightforward. Familial multiple café au lait
spots without other signs of NF1 is a relatively rare overlap condition,
Legius syndrome, and it is caused by mutations in the SPRED1 gene.5
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Intertriginous freckling, which usually involves the axillae
and groin areas (eFig. 182.1), occurs in
approximately three quarters of individuals with NF1 who present
with multiple CLS, and this sign develops by late childhood.5Lisch
nodules (iris hamartomas) can be identified by slit lamp examination
of the eyes in over 75% of preadolescents.
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Neurofibromas are benign tumors that are a collection of Schwann
cells, fibroblasts, mast cells, and extracellular matrix. Cutaneous
neurofibromas tend to appear at the time of puberty and progress
in number throughout life. They can be difficult to detect at their
outset, and they are often most easily palpated along the flanks and
lower abdomen as slight depressions rather than protruding bumps.
Cutaneous neurofibromas may itch but are not painful and never lead to
malignancy. Plexiform neurofibromas are very different from cutaneous
neurofibromas and arise in sites associated with the peripheral nerve
sheath. They affect about one fourth of the NF1 population and arise
at variable ages, including infancy.7 Actively growing
plexiform neurofibromas in infancy require a significant amount
of medical attention, as these tumors are diffuse and may extensively
entwine internal organs. Plexiform neurofibromas have a propensity
to undergo malignant transformation to sarcoma (malignant peripheral
nerve sheath tumor), but this is rare in the pediatric population.
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Optic nerve pathway tumors (gliomas) are benign pilocytic astrocytomas
that affect approximately 15% of individuals with NF1,
but only half of these are symptomatic. Symptomatic tumors tend
to arise in the toddler and early childhood years, and rarely develop
after puberty. Pediatric ophthalmologists are adept at identifying
optic nerve pallor or visual symptoms associated with these tumors,
and they are extremely helpful in deciding which children should
undergo brain and orbit MRI. Routine brain MRI is generally not
required in the absence of clinical indications.8Like
plexiform neurofibromas, optic pathway gliomas are unpredictable
in their growth patterns; however, NF1-related optic nerve pathway
gliomas (OPGs) have a slower proliferation rate and are less likely
to cause visual impairment than similar tumors that arise in non-NF1
individuals. Other low-grade intracranial gliomas behave in similar
fashion; in the context of NF1, they grow slower and are less likely
to require treatment than their non-NF1 counterparts.
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The skeletal features of neurofibromatosis type 1 (NF1) are also
age dependent. Sphenoid wing dysplasia, long-bone bowing (ie, tibial dysplasia
with or without pseudarthrosis) and dystrophic scoliosis all tend
to present either in infancy or childhood. The pathophysiology of the
various skeletal features is not understood, and it challenges the
paradigm of NF1 being a disorder of neural crest origin. Both dystrophic scoliosis
and pseudarthrosis of long bones are primary defects that require
significant orthopedic management and do not usually arise in the
context of either plexiform or paraspinal neurofibromas. Like cutaneous
neurofibromas, paraspinal neurofibromas tend to arise in later childhood
and adolescence. In general, these tumors are not symptomatic unless
they compress either nerve roots or adjacent spine. A perplexing
finding in NF1 is the connection between sphenoid wing dysplasia
and orbital-temporal plexiform neurofibromas.9 Sphenoid wing
dysplasia affects approximately 1% of NF1 patients and
it is almost always unilateral. At least half of those individuals
will have an ipsilateral orbital-temporal plexiform neurofibroma.
These disfiguring tumors tend to be raised and pigmented, and their
unchecked growth can obscure vision.
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Individuals with NF1 are prone to a number of medical complications
that are quite varied, although it is rare that any one individual
has more than one major complication. Approximately 40% to
50% have speech and language delays as preschoolers and/or
learning problems in school, which are not specific to NF1.10 Early recognition
and treatment within the educational environment can effectively
deal with NF1-related learning problems, and is one reason to provide
a provisional diagnosis of NF1 in sporadic cases who only have multiple
café au lait spots. Short stature, macrocephaly, hypertension,
constipation and chronic headaches are other NF1-related features.
Dystrophic scoliosis, deep plexiform neurofibromas, low-grade astrocytomas
of the posterior fossa, spinal neurofibromas, malignant peripheral
nerve sheath tumors, pheochromocytomas, rhabdomyosarcomas, and myelogenous
leukemia are a few of the more serious medical complications associated
with NF1.
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The NF1 gene spans approximately 335 kilobases
of genomic DNA and is ubiquitously expressed. It encodes neurofibromin,
a GTPase activating protein that downregulates ras signaling through
the mitogen-activated protein kinase (MAPK) pathway. NF1 mutations
are generally inactivating, and double inactivation of both alleles
in NF1-related tissues classifies this gene as a tumor suppressor.11,12
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Approximately half of individuals with neurofibromatosis type
1 (NF1) seen in North American and European clinics are sporadic
cases, which indicates that the gene is highly mutable. The high
germ-line NF1 mutation rate likely carries over
to somatic mutation, which supports the tumor suppressor model for
NF1 and provides one explanation for the variable and progressive
nature of some clinical features. Random acquisition of somatic
mutation that inactivate the normal NF1 allele
(second hit) in tissue showing abnormal growth could explain the age-related
clinical presentation of many NF1 features, that is, neurofibromas,
optic nerve pathway tumors, and tibial dysplasia. Leukemia cells,
neurofibromas, malignant peripheral nerve sheath tumors, and pheochromocytomas
have all demonstrated double inactivation of NF1.
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As a prototype for other neurocutaneous disorders, counseling
issues surrounding NF1 relate to its heritability, variable expressivity,
age-related penetrance of myriad clinical features, and pleiotropy.
Even though there is a high sporadic incidence, once it is established
within a family it behaves as any other autosomal dominant condition,
whereby there is a 50% risk for occurrence in each child
conceived. However, unlike many other dominant conditions, the lack
of a genotype–phenotype correlation means that affected family
members who have the same NF1 mutation usually
have different manifestations. This is one reason clinical mutation
analysis on a routine basis is generally not needed. To date, there
are only two clear genotype–phenotype correlations. Those
with a large, whole-gene deletion (~5% of all NF1 patients)
share a phenotype marked by an unusually large number of neurofibromas
that present at an earlier age, distinctive facial features differing
from family background, and decreased level of intellectual functioning.13 Those
with a specific 3 base-pair deletion leading to loss of a methionine
residue generally have multiple café au lait spots without
other serious clinical manifestations.14This group
of patients may be indistinguishable from those who have mutations
in SPRED1, thus suspicion of Legius syndrome is pretense
for NF1/SPRED1 mutation
analysis because lack of tumors alters the approach to clinical
management.
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Most tumor-related complications of NF1 are managed surgically;
however, there is clearly a role for watchful waiting in this condition,
especially with the development of medical therapies targeted to
the RAS-MAPK signal transduction pathway. Clinical trials with various
RTK (receptor tyrosine kinase), MAPK, and mTORC (mammalian target
of rapamycin complexes, see below) pathway inhibitors are underway,
thus medical therapies might be available to complement the surgical
management of NF1-related tumors. Treatment of symptomatic or progressive
optic nerve pathway tumors in NF1 is nonsurgical, and biopsies are
not needed to begin therapy with either carboplatin or carboplatin plus
vincristine chemotherapy protocols. Radiation therapy is generally
contraindicated in the treatment of NF1-related central nervous
system (CNS) tumors because of significant side effects and heightened
risk for secondary, radiation-induced malignancy years after treatment.
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Anticipatory guidance for NF1 includes the recognition of the
age-related occurrence of many manifestations, some of which are quite rare and not included
in the diagnostic criteria (eTable 182.2).
Common issues to be addressed on a regular basis are school performance,
tumors, bone abnormalities, and psychosocial adaptation. Annual
clinical assessments using a multidisciplinary approach are important
to determine appropriate imaging protocols on an individualized
basis.
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