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Neurofibromatosis
Described in 1882 by von Recklinghausen
DEFINITION
 neurofibroma - benign growth of multiple cellular elements of a peripheral
nerve
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neurofibromatosis - a hereditary autosomal dominant disorder that
produces pigmented spots and tumours of the skin; tumours of the
peripheral, optic and acoustic nerves; and subcutaneous and bony
deformities
There is marked clinical and genetic heterogeneity. Nine types of
neurofibromatosis are recognised:
CLASSIFICATION
Neurofibromatosis-1 (NF-1)
von Recklinghausen’s disease or peripheral neurofibromatosis
Incidence
 1 of 2500-3300 live births, regardless of race, sex, or ethnic background
 Autosomal dominant; 50% of cases represent new mutations
 85% of subtypes
 Diagnostic criteria (two or more)
1. 6 or more café-au-lait macules
 >5mm in greatest diameter in pre-pubertal children
 >15mm in post-pubertal individuals
2. 2 or more neurofibromas of any type or one plexiform neurofibroma
3. freckling in the axillary or inguinal region (Crowe’s sign)
4. optic glioma
5. two or more Lisch nodules (iris hamartomas)
6. a distinctive osseous lesion, such as sphenoid dysplasia (typically
aplasia of the greater wing of the sphenoid) or thinning of long bone
cortex, with or without pseudoarthrosis
7. a first degree relative with NF-1 by the above criteria
Aetiology
 linked to a large gene on band 17q1
 encodes a protein termed neurofibromin, which has a guanosine
triphosphatase (GTPase) region that binds to Ras
 protein is produced in nerve cells and in oligodendrocytes and Schwann cells
 acts as a tumor suppressor
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Mutations in the NF1 gene lead to the production of a nonfunctional version of
neurofibromin that cannot regulate cell growth and division
Neurofibromatosis-2 (NF-2)
central neurofibromatosis / bilateral acoustic neurofibromatosis
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10% of subtypes
usually diagnosed within the first decade of life
most common tumor associated with the syndrome is the vestibulocochlear
schwannoma
common tumors - mnemonic MISME
1. Multiple Inherited Schwannomas
2. Meningiomas
3. Ependymomas
Skin lesions unusual
Diagnostic criteria:
1. patient has bilateral VIII nerve masses (seen on CT or MRI) or,
2. patient has a first degree relative with NF-2 and:
 unilateral VIII nerve mass or,
 two of the following:
i. neurofibroma (rare)
ii. meningioma
iii. glioma
iv. schwannoma
v. juvenile posterior subcapsular lenticular opacity
Aetiology
 chromosome 22q
 neurofibromin 2 gene encodes for a protein known as merlin
 This protein is found in the brain, nerves, eyes, and in Schwann cells
 Functions as a tumor suppressor protein
Neurofibromatosis-3 (NF-3)
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Combined features of NF1 and NF-2
Neurofibromatosis-4 (NF-4)
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Characterized by diffuse neurofibroma and cafe-au-lait pigmentation. Other
features of NF-1are not present.
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Neurofibromatosis-5 (NF-5)
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segmental neurofibromatosis with disease is restricted to one area of the
body.
the CLS accompanying the tumour(s) are restricted to the side of the body
ipsilateral to the tumour, with no crossing of the midline
believed to represent a somatic mutation during embryonic development.
Neurofibromatosis-6 (NF-6)
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café-au-lait neurofibromatosis
CLS and other non-specific features such as pectus excavatum, but no
neurofibromas are present
Neurofibromatosis-7 (NF-7)
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late-onset neurofibromatosis
many of the manifestations of NF-1 do not become apparent until the end of
the third decade of life or later
NO familial cases
neurofibromas may be cutaneous, subcutaneous or both, and can be
localized or diffused over the entire body
Neurofibromatosis-8 (NF-8)
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gastro-intestinal neurofibromatosis
NF involvement limited to the gastro-intestinal tract
onset in middle or late adult years
risk of bleeding / intussusception / obstruction
Neurofibromatosis-9 (NF-9)
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neurofibromatosis / Noonan type
features of both NF and Noonan syndrome
OVERVIEW OF VON RECKLINGHAUSEN’S DISEASE
Progression
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Neurofibromas can begin as early as 16 weeks of intra-uterine development
or become manifest at any time in the life of the patient.
Intra-uterine development of NFs tends to occur in the orbits or peri-orbital
regions, and are classically plexiform NFs.
However, discrete cutaneous and subcutaneous neurofibromas are not
usually apparent in infancy and early childhood; congenital neurofibromas
begin to develop with the onset of puberty, heralding a major increase in the
size and number of NFs. Although the development of neurofibromas is
usually gradual, there may be a sudden eruption of miliary neurofibromas
(erupted neurofibromatosis) over a period as short as a few months.
Pregnancy is also associated with an increase in both number and size of
neurofibromas, often with inflammation and vascular engorgement
superimposed. Delivery usually brings with it only partial resolution.
Middle and late adulthood are characterised by a progressive and unrelenting
increase in the size and number of neurofibromas.
With advancing age the neurofibromas tend to become more quiescent.
Morbidity related to:
i. visual prognosis is related predominantly to the presence or the absence of
an optic pathway glioma or congenital glaucoma
ii. Cosmetic disfigurement from neurofibroma
iii. Spinal cord tumors causing rogressive paraplegia or quadriplegia
iv. Malignant transformation of neurofibromas and schwannomas (3-15%)
a. 34 times more likely to have a malignant connective or other soft tissue
neoplasm than normal population
v. Hypertension
a. Usually essential but may be due to vascular dysplasias (ie renal artery
stenosis, coarctation) or phaechromacytoma
vi. Seizures, mental retardation
vii. Life span approximately 20 years shorter
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Clinical Features
i.
café-au-lait spots
 consistent manifestation of NF
 earliest clinical finding
 number, size and definition tend to increase during the first year of life
 occur anywhere except scalp, eyebrows, palms, soles
 clinically and histologically they resemble a large freckle (excess melanin
is present in the basal layer of the epidermis); the hyperpigmentation is
due to the melanocytes containing giant melanosomes / melanin
macroglobules.
 co-incidental pigmented naevi may be superimposed
 six or more CLS greatly heightens the chance of a patient have NF
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ii. Axillary freckles
 Axillary or inguinal freckles are rarely present at birth but appear during
childhood through adolescence
iii. neurofibromas
 Neurofibromas comprise cells derived from three lineages: Schwann cells,
perineurial cells and fibroblasts.
 rarely in young children
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matrix is rich in mucopolysaccharides and is usually myxomatous. The
lesion may be well circumscribed, or it may be diffuse with no apparent
margins. Mast cells are usually scattered within the specimen.
Nerve fibers are found scattered throughout the body of the tumor unlike
in Schwannoma
cell of origin for neurofibroma has not been definitively identified.
Some believe it arises from the Schwann cell.
Perineural fibroblasts are neuroectodermal tissue cells that synthesize
collagen and create a network that envelops the individual axis cylinders
of the nerves with their associated Schwann cells. Some investigators
believe that perineural fibroblasts give rise to the neurofibroma.
uniformly positive for S-100 protein
may be dermal, subcutaneous or subfascial
Puberty or pregnancy may be associated with an increased number of
neurofibromas as well as more rapid growth of preexisting lesions.
Basically 4 types of neurofibromas found in NF1:
i. Cutaneous neurofibromas
1. occurring within the dermis and epidermis; tumour attached
to skin
2. multiple, soft tan to light brown , appearing over the entire
body surface
3. soft and non-painful
4. at a later stage, they become pedunculated and have a
reddish or bluish hue
5. Histologically indistinguishable from the solitary
neurofibroma, they appear as well-circumscribed,
nonencapsulated spindle cell tumors of the dermis
ii. Subcutaneous neurofibroma
1. deep in the subcutaneous tissues
2. skin mobile over them
3. discrete and spheric, round or ovoid in shape
4. firm; may be tender and painful
iii. nodular plexiform neurofibromas
1. arise along the course of a nerve trunk, nerve fibres are
entrapped by the tumour making it impossible to separate
the tumour from the nerve (unlike a Schwannoma).
iv. Diffuse plexiform neurofibromas (elephantiasis
neurofibromatosa)
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1. diffuse, elongated fibromas coursing along the nerves.
2. These lesions frequently involve the trigeminal or upper
cervical nerves.
3. often appear within the first 2 years of life
4. an extensive network of tumour parts, including multiple
cellular elements of the peripheral nerve
5. deep involvement of skin and subcutaneous tissues
6. tumour extends into deeper tissues including the craniofacial
region, perispinal area, mediastinum, retroperitoneum and
viscera (eg GIT)
7. may be extensive intra-thoracic, mediastinal or
retroperitoneal involvement
8. hyperpigmentation and hypertrichosis of the overlying skin
are common
9. rapid growth may suggest sarcomatous change
iv. Lisch nodule of the iris
 small, translucent masses punctuated by melanin-containing cells usually
imparting a gray-tan hue
 unique to NF, virtually all patients with NF-1 have Lisch nodules by age 20
years
 histopathologically characterized as melanocytic hamartomas,
histologically identical to iris nevi
v. Sphenoid dysplasia
 Found in 7%
 aplasia of the greater wing of the sphenoid (Harlequin sign on XRay)
 likely secondary to the presence of adjacent tumor.
 associated with enlargement of the middle cranial fossa in primarily the
anteroposterior dimension
 often occurs in conjunction with plexiform neurofibroma of the ipsilateral
eyelid
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Bilateral facial soft-tissue tumor infiltration, bilateral enlarged middle cranial fossae (arrowheads),
bilateral large globes (buphthalmos), and infiltration of both optic nerve sheaths.
progression of sphenoid bone abnormalities over 10 years
vi. Optic nerve glioma
 occur primarily in children younger than 5 years.
 most common intracranial tumor associated with neurofibromatosis type 1.
 occurs in 12% of patients and is bilateral in 4%
 Asymmetric, noncorrectable visual loss is the most common presenting
symptom
 Usually managed conservatively although radiation treatment is used by
some
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Malignancy
Neurofibrosarcoma
 commonest malignancy
 also called malignant schwannoma, neurogenic sarcoma
 life-time risk = 5%
 about half of all patients with neurofibrosarcomas are estimated to have
NF
Other neural crest tumours:
 phaeochromocytoma (5-10% of pheochromocytomas are in NF patients)
 melanoma
Embryonal tumours
 neuroblastoma
 Wilm’s tumour
 rhabdomyosarcoma
Eyelid Involvement
Problems:
(1) brow ptosis secondary to infiltration
a. debulk
b. brow lift
(2) upper lid infiltration with ptosis (classically an S-shaped deformity)
a. debulking
b. full thickness pentagonal wedge excision
c. levator resection/advancement
d. frontalis suspension for poor levator function
(3) lower lid infiltration
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(4) lateral canthal disinsertion
a. reinsertion
(5) lacrimal gland infiltration.
(6) functional nasolacrimal duct obstruction.
Orbitotemporal neurofibromatosis
Jackson’s classification (PRS; 1993)
I
Orbital soft tissue involvement with a seeing eye
II
Orbital soft tissue and significant bony involvement with a seeing eye
III
Orbital soft tissue and significant bony involvement with a blind or absent
eye
Description
I
Orbital soft tissue involvement with a seeing eye
 eyelid involvement (usually upper lid although lower may be
involved)
 neurofibroma present within the orbit
 absence of greater wing of sphenoid (partial / complete)
 variable proptosis
 orbital size normal / close to normal
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Orbital soft tissue and significant bony involvement with a seeing eye
 eyelid and intra-orbital soft tissue involvement
 severe proptosis of a seeing eye
 absence of greater wing of sphenoid (partial / complete)
 posterior wall defect is variable (actually an enlargement of the
superior orbital fissure)
 variable degree of temporal lobe prolapse into the orbit causing
pulsatile proptosis
 may be an associated arachnoid cyst of the temporal lobe
 a subgroup may have enophthalmos
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due to enlargement of the inferior orbital fissure
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there is escape of orbital contents through this defect into
the temporal fossa
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III
this escape of contents, together with the increase in bony
orbital volume, results in enophthalmos
there is no pulsation of the eye
Orbital soft tissue and significant bony involvement with a blind or absent
eye
 neurofibroma in the orbit and the temporal area
 severe pulsating exophthalmos - posterior wall defect is large and
therefore there is a large prolapse of the temporal lobe (or arachnoid
cyst) into the orbit
 eye is blind and enlarged due to involvement with neurofibroma (or
may have been previously removed)
 gross involvement of upper lid leading to complete ptosis with no lid
movement
 orbit is considerably enlarged and typically egg-shaped
 hypoplastic zygoma
 usually widespread NF infiltration of the temporalis muscle
Management
Group 1
 upper eyelid (bleph) approach is usually sufficient
 dissect tumour out completely if possible; plexiform neurofibromas with
involvement of neuromuscular structures are best excised incompletely
 small posterior orbital wall defects may be left; significant defects should
be closed with bone grafts (split-thickness rib or split-skull)
 upper lid skin and levator resection should be conservative - rather underexcise
Group 2
 upper eyelid plus bicoronal approaches
 infero-lateral orbital osteotomy is done in order to remove any intracranial
extension of the tumour, and to facilitate replacement of the temporal lobe
 split-thickness carvarial graft is wired or plated into position to close the
posterior orbital wall defect
 infero-lateral segment replaced and lateral canthal ligament re-attached
 ptosis surgery is again conservative
Group 3
 the blind eye must be sacrificed
 approach determined by the skin involvement
 plane of resection depends on temporalis muscle involvement - if it is
involved the plane of resection must be sub-periosteal
 orbital contents dissected out at the sub-periosteal level, and the
ophthalmic vessels are ligated
 cranial bone graft is preferred as it shows less resorption
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the eyelids are sutured together and used to cover the interior of the orbit
(defect is later reconstructed with a total eye/eyelid prosthesis)
if the temporalis muscle is excised, the defect may reconstructed
subsequently by inserting a contoured silicone block or
methylmethacrylate
Generally treatment recommended in cases with significant orbital deformities
and associated defects of the orbital walls.
Reconstruction via transcranial approach
Jackson recommends complete tumor resection where possible, zygomatic
osteotomies to reduce the orbital aperture, and sacrifice of the blind globe
Tumor or soft-tissue eyelid resection is conservative to prevent exposure
problems, and secondary eyelid adjustment is frequently necessary
Timing of surgery controversial
i. Advocates of conservative surgery recommend selective conservative,
nerve sparing, resection of functionally impairing or cosmetically
deforming masses, with multiple excisions over a period of years.
ii. Proponents of more aggressive surgery claim that repeated debulking
procedures to remove the main bulk of the tumours offered the best
chance of avoiding further deformities
Poole (BJPS 1989)
 stresses the high complication rate and the modest improvement in
appearance that should be expected.
 transcranial repair of the sphenoidal bony defect and orbital debulking
surgery produced disappointing results unless the eye was removed
 Patients who have a seeing eye and wish to retain it should undergo a
two-stage procedure with conservative debulking of intraorbital soft-tissue.
Australian Craniofacial Unit (Snyder PRS 1998)
 bone graft used to reconstruct the greater wing of the sphenoid in four
cases resorbed (? due to pulsation of the temporal lobe, tumor erosion, or
the nature of the local environment (i.e., abnormal dura associated with
the primary dysplasia) ) - led to recurrence of globe pulsation.
 began using either split calvarial or inner cortical iliac bone grafts
supported by titanium mesh in the reconstruction.
Surgical Management
“It is unrealistic, inappropriate, and often unnecessary to remove neurofibromas
surgically in many patients.” (Spira, Riccardi)
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Only loose guidelines exist.
multidisciplinary assessment with thorough paediatrician, geneticists,
neurosurgical, ophthalmological, orthopaedics, and craniofacial evaluation.
CLS do not need treatment
Neurofibromas
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o sessile-type skin neurofibroma is usually best left alone. When it
becomes large and pedunculated, and a source of irritation, simple
excision can be performed.
o Excision of the lesion with primary closure is better than shave
excisions with cauterization of the base - this leaves unacceptable
scarring. When there are multiple tumours associated with skin
redundancy, it may be appropriate to do repeat, multiple debulking
procedures.
o Subcutaneous neurofibromas can often be shelled out. Some
plexiform neurofibromas may also be amenable to a subcutaneous
excision or shelling out. Liposuction has been used and found by
some to be of value.
o Plexiform neurofibromas tend to recur, so excision of a neurofibroma
strictly because of its presence generally is not advised, unless the
lesion is causing functional impairment and/or pain.
CLS do not need treatment
Gross facial disfigurement due to multiple tumours requires multiple staged
excisions, with or without fascia lata support to elevate paretic soft tissue.
Ablation may be the only option for massive involvement of the extremities.