NEUROFIBROMATOSIS (Type I)
DEFINITION:
A neurocutaneous syndrome transmitted as an autosomal dominant
trait and characterized by pigmentary changes, tumors, and
dysplasias (skeletal and vascular).
EPIDEMIOLOGY:
- incidence: 1/4000
- age of onset:
- variable from infancy to adulthood
- risk factors:
- familial - autosomal dominant (AD)
- 50% frequency of de novo mutation
- mutation rate: 1 in 10,000
- paternally-derived chrom. 17 contains mutation
- ? increased frequency of new mutations with increasing
paternal age
- penetrance of NF-1 mutant gene close to 100%
PATHOGENESIS:
- specific expression of the NF-1 mutation in restricted cell
types (derived from neural crest cells)
- gene at least 290-390 kb in length
- codes for at least 4 genes:
CLINICAL FEATURES:
- at least 6 in number (>1.5 cm in diameter)
- 0.5 -> 50 cm in diameter
- hyperpigmented (uniformly brown) macules
- distinct edges
- deepen with UV exposure
- usually not present at birth, increase with pregnancy
2. Freckling (Crowe Sign)
- axillary freckles are congenital
- axillary > intertriginous regions > areas of friction
- 40% of NF-1 patients have axillary freckling
- later may cover entire body
3. Hyperpigmentation Overlying a Plexiform Neurofibroma (HOPN)
- orange in colour
- less distinct edges with portions raised
- hypertrichosis
- HOPN reaching the midline suggests neuraxis involvement
4. Others
- diffuse hyperpigmentation (suntan)
- patchy hypopigmented macules
2. Tumors (7)
- upper layer of skin (moves with skin)
- soft and fleshy
- initially flat then sessile or pedunculated
- usually appear at 8-12 yrs although as early as 4-5
years (earlier onset - greater number and distribution)
2. Subcutaneous
- subcutaneous - skin glides over tumor
- associated with pain & neurologic compromise if present
in large numbers and over nerves
- usually appear in 2nd decade (teenage years)
3. Nodular Plexiform
- large network collection
- direct involvement of dorsal nerve roots, plexuses, &
primary and secondary radicals
- earlier onset increased likelihood of serious neurologic
compromise
4. Diffuse Plexiform
- involve all levels of skin, adjacent fascia & deeper
tissues (muscles, erode bone, infiltrate visceri)
- may involve the mediastinum & retroperitoneum
- all are of congenital origin
- may be quiescent for long periods but then grow rapidly
5. Common Locations
- head - scalp, pinna
- face - orbit, cheek, buccal pad, oral (tongue, floor of
mouth)
- neck - retropharyngeal, cervical
- supraclavicular - with cervical or brachial plexus
fossae involvement
- mediastinal
- visceral gastrointestinal tract
- retroperitoneal - body wall, visceral involvement
- pelvis & perineum - urinary tract (bladder), internal &
external genitalia
- buttock
- extremities - upper & lower
2. Neurofibrosarcomas
- major risk for NF-1 patients:
- minimum life-time risk - 5%
- 1000-100,000x more risk than general population
- most develop at or after the age of 10
- clinical presentation:
- pain - neurofibrosarcoma until proven otherwise
- enlargement of a previous quiescent neurofibroma
- focal neurologic signs
- footdrop, dysesthesia, local numbness
- may infiltrate the epineurium & adjacent tissue
- diagnosis - by biopsy showing fusiform cells derived from
Schwann cells with evidence of malignancy
- associated with all types of neurofibromas:
- rarely with cutaneous type
- most with diffuse plexiform type
- most often occur in the lower extremities
- treatment - surgery - amputation (TOC) or radical surgery
- ? adjunctive chemo or radiotherapy efficacy
3. Optic Pathway Gliomas
- astrocytomas originating in the optic nerve >> optic
chiasm or in the postchiasmal optic tracts (any part of the
optic pathway)
- represents the most common type of CNS tumor in NF-1
- occurs in about 10% of NF-1 patients
- unilateral or bilateral
- clinical presentation:
- decreased visual acuity +/- restricted visual fields
- distortions of binocular vision or strabismus
- others: optic atrophy, proptosis, nystagmus, headaches,
nausea and vomiting, anorexia, diencephalic syndrome
- thought of as congenital hamartomas which are either
static or aggressive although tumor growth is generally slow -
diagnosis:
- MRI or CT - begin MRI screening q yearly from 1st year
- ? electrophysiologic studies (ERG, visual EP)
- treatment:
- both surgery and irradiation can be used with variable
results with the potential for chemotherapy
4. Other Intracranial Tumors
- involve the optic pathway (optic gliomas), brain stem,
and posterior fossae
- are the most common intracranial tumors seen in NF-1
- vary between benign & malignant
2. Others
- medulloblastomas, ependymomas, hamartomas
5. Spinal and Paraspinal Tumors
- most common type of tumor involving the spinal cord in
NF-1
- usually arise off dorsal root or adjacent autonomic
ganglia and extend into the spinal column or along major
nerves
- usually occur in multiple sites
- cervical neurofibromas secrete excessive catecholamines
resulting in hypertension
2. Astrocytomas
- usually arise in the cervical and upper thoracic regions
of the spinal cord but can involve the entire cord
6. Pheochromocytomas
- occur in about 0.1-15% of patients with NF-1
- usually present in the adrenal medulla
- may present in a variant non-secreting form: paraganglioma
- clinical presentation:
- intermittent autonomic s/s: anxiety, agitation,
hypertension, tachycardia, sweating, headache
- screen for only if patient symptomatic
- treatment: surgical removal
7. Leukemias and Other Malignancies
- usually CML and highly associated with xanthomas or
xanthogranulomas
- rarely ALL
2. Acoustic Neuromas
- ataxia, hearing loss, tinnitis, vertigo
- early auditory assessment
3. Others
- neuroblastomas, Wilms' tumor, rhabdomyosarcoma, soft
tissue sarcomas, lymphoma, systemic mastocytosis, pancreatic
carcinoma, breast cancer, gastrointestinal tumors
3. Dysplasias (2)
- developmental defects of the skull & facial bones
- range from simple skull asymmetry to localized defects
(usually parietal or occipital)
- may lead to impingement on the brainstem or upper spinal
cord
- sphenoid wing dysplasias:
- most consistent craniofacial dysplasia in NF-1
- usually unilateral
- may lead to orbital wall defects -> pulsating
enophthalmos or brain herniation into orbits
- neurofibroma of scalp may lead to areas of cranial wall
hypoplasia or aplasia
2. Vertebral (5)
- mildest form of vertebral involvement
- a radiologic-detected defect involving the dorsal
surface of the vertebral bodies
- lumbar vertebral scalloping seen in 10% of NF-1
2. Dystrophic Scoliosis (10%)
- usually develops between ages 6-10 years of age
- rapidly progressive
- involves lower cervical & upper thoracic regions with
a sharp anterior angulation (kyphoscoliosis)
- Tx: bracing, surgery (internal fixation)
3. Secondary Vertebral Destruction
- due to paravertebral neurofibromas particularly in the
cervical region
4. Vertebral Dysplasia
- usually associated with dystrophic scoliosis and
paraspinal neurofibromas
- involves one or a group of vertebrae with varying
degrees of severity
- clinical presentation:
- spinal cord or nerve root compression
- GA problems if 1 & 2 cervical vertebrae affected
5. Meningeal Defects
- range from dural ectasia to meningoceles
- may distort one or more vertebrae leading to spinal
cord comprimise
3. Sternal
- occurs in about 50% of NF-1 patients
- congenital with variable severity
- pectus carinatum is rare
4. Extremities
- occurs in 1% of NF-1 patients, M > F
- sites: tibia >> radius, ulna, clavicle
- usually limited to one site
- medial/lateral deviation of the distal aspect of the
affected bone resulting in bowing at the site - a primary
lesion of unknown nature representing a congenital defect
of bone formation
- Tx: surgery - local excision, bone graft, amput.
2. Bowing
- genu valgum or varum
- occurs in 5-15% of NF-1 patients
- may be mild form of pseudoarthoses
- may present as gross motor developmental delay - a
delay in ambulation
- Tx: braces or surgery
5. Short Stature
- average height of NF-1 patients is less than that of
age-matched controls
- only a portion of NF-1 patients manifest short stature
6. Macrocephaly
- no significant difference between controls and NF-1
patients at birth
- F - macrocephaly at 1 year only
- M - macrocephaly begins & persists after 4 years of age
2. Vascular Dysplasias (4)
- one or more cell types of the arterial wall are capable of
expressing an NF-1 mutation directly and primarily
- proliferation of spindle cells, whether of Schwann cell or
muscle cell origin, appear to be the disruptive element
- the entire arterial tree from the proximal aorta to the
small arteries may show involvement
- two types of anomalies:
- external compression - by adjacent tumor mass
- internal compression - intramural thickening, aneurysms,
dysplasia
- congenital heart disease marginally increased in NF-1:
- pulmonary stenosis, mitral valve prolapse, cardio
myopathy, coarctation of the aorta
- involves stenosis or occlusion
- affects carotids, middle & anterior cerebral and
sometimes L posterior cerebral arteries
- internal carotid stenosis and obstruction at the siphon
level is the most prevalent lesion
- clinical presentations:
- seizures and/or hemiparesis most common
- severe headache or other neurologic deficits of abrupt
onset
2. Gastrointestinal Vascular Compromise
- stenosis or occlusions can occur at all levels of GI
circulation especially at and proximal to major vessel
origins
- clinical presentation:
- abdominal pain (angina) with bowel infarcts
- GI bleed
3. Renovascular Compromise
- arterial thickening and aneurysms can occur especially
renal artery stenosis
- clinical presentation:
- hypertension
- seen in at least 6% of NF-1 patients
- may present during pregnancy
- other causes: pheochromocytomas, cervical
neurofibromas, essential hypertension
- Tx: medical vs surgery
- revascularization, nephrectomy
4. Others
- coronary artery involvement - ischemic heart disease
- vessels affected by external compression:
- pulmonary vasculature
- rarely lymphatics or veins
- angiomas
- may be seen with a large number of cutaneous
neurofibromas; common in NF-1 adults
4. OTHER CLINICAL FEATURES
- mental retardation (8%)
- learning disabled (25-45%)
- developmental delay (21%) - motor, speech & language
- motor dysfunction
- generalized muscular hypotonia
- uncoordination (40-50%)
- partial paralysis, hemiparesis, paraparesis, spastic
quadriplegia
- sensory dysfunction
- dysesthesia (touch)
- tenderness/pain
- seizures (10%)
- hearing deficits
- auricular neurofibromas can occlude the external
auditory meatus
- can have unilateral or bilateral sensorineuronal hearing
loss
2. Endocrine
- premature or delayed puberty, incomplete sexual
maturation
- CNS tumors, especially chiasmal optic gliomas
encroaching on the hypothalamus, may be responsible
3. Gastrointestinal
- neurofibromas, leiomyomas, ganglioneuromas
- may evolve into neurofibrosarcomas
- sites: stomach, jejunum, ileum, colon
- presentation: abdominal pain, hematemesis, melena
- minor - constipation, abdominal mass +/- distension,
obstruction, megacolon, perforation
2. Neuronal Hyperplasia
- diffuse hyperplasia of the myenteric and submucosal
plexuses
INVESTIGATIONS:
- Lisch Nodules, optic gliomas
2. Imaging Studies
- skull - sphenoid wing dysplasias, craniofacial defects
- spine - paraspinal neurofibromas, scalloping, scoliosis,
vertebral dysplasias
- chest - neurofibromas in chest cavity or mediastinum
2. MRI/CT
- intracranial, orbital, spine, paraspinal, vascular
dysplasia
3. Vascular
- arteriography, radionucleotide scans
4. Spinal
3. Neurologic
- EEG
- Auditory Evaluation
- audiogram, brainstem auditory evoked potentials to rule
out acoustic neuromas and to assess hearing
- Cognitive and Learning Abilities
MANAGEMENT:
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