ABSTRACT
A. Neurocutaneous Disorders 1. Formerly called phakomatoses 2. Group of diseases with characteristic cutaneous and
neurologic findings and most with familial tendencies 3. Often have dysplasia of other organ systems
B. Overview of Selected Neurocutaneous Disorders (Table 13-1)
A. Neurofibromatosis 1. Most common neurocutaneous disorder 2. Several distinctive types
B. Two Most Common Types: neurofibromatosis 1 (NF1) and 2 (NF2)
C. Less Common Variants 1. Familial café au lait spots 2. Familial schwannomatosis 3. Mosaic (segmental) NF1 and NF2: neurocutaneous
involvement of limited region of body
D. Neurofibromatosis 1 (von Recklinghausen’s disease, “peripheral neurofibromatosis”)
1. Epidemiology a. NF1: 96% of all cases of neurofibromatosis b. Prevalence: 1:3,000
2. Genetics a. Autosomal dominant
1) Variable expression 2) Near complete penetrance 3) Nearly 50% are new mutations
b. NF1 gene
1) Tumor suppressor gene (chromosome 17q11.2) 2) Codes for neurofibromin (protein involved in regula-
tion of Ras signaling pathway) a) Loss of NF1 gene expression: absence of
neurofibromin b) Absence of neurofibromin leads to increased Ras
activity and increased cell proliferation, resulting in neoplasms
c) Neurofibromin may also regulate cyclic adenosine monophosphate levels
3. Presenting symptoms a. May be due to specific tumors, conditions associated
with NF1, or overall disease b. Common symptoms
1) Cognitive deficits and learning disabilities 2) Pain in specific nerve distribution due to presence of a
neurofibroma 3) Visual complaints (may be related to optic glioma) 4) Seizures (may be due to intracranial tumors) 5) Headaches (may be migraine or intracranial pressure
or mass) 6) Pruritus 7) Progressive neurologic deficits (due to neurofibroma
or other tumors) 4. Neurofibromas
a. Are peripheral nerve sheath tumors b. Are one of hallmark findings and most common tumor
in NF1 c. Often present in puberty and increase in number and
size with age d. May be circumscribed (cutaneous or subcutaneous) or
noncircumscribed (plexiform) e. Are typically benign, but plexiform neurofibromas may
undergo malignant transformation f. May be asymptomatic or symptomatic (pain within a
nerve distribution) g. Commonly located near a spinal nerve root h. Plexiform neurofibromas
Table 13-1. Review Table of Neurocutaneous Diseases and Syndromes
Cutaneous Neurologic Syndrome Inheritance Genetics findings findings Other
1) Specific to NF1 and major cause of morbidity a) Irregular, thickened, noncircumscribed (Fig. 13-1) b) Can envelop vital structures, can involve orbit c) May be disfiguring
2) Malignant peripheral nerve sheath tumors may develop from plexiform neurofibromas a) 3% to 5% of NF1 patients develop malignant
peripheral nerve sheath tumors b) Analysis of these tumors has shown epidermal
growth factor receptor amplification and deletion of p16 tumor suppressor gene in addition to NF1 deletion
c) Difficult to treat because of invasive nature 5. Other tumors
a. Optic nerve gliomas 1) Second most common tumor in NF1 2) A low-grade pilocytic astrocytoma arising from optic
nerve or chiasm 3) May be an incidental finding or present as progressive
loss of vision and optic atrophy b. Intracranial tumors
1) Hemispheric astrocytomas 2) Solitary or multicentric meningiomas 3) Pilocytic astrocytoma (hypothalamus, brainstem,
cerebellum) c. Schwann-cell tumors on any nerve d. Pheochromocytoma (not in children) e. Malignant tumors may include
1) Neuroblastoma 2) Ganglioglioma 3) Sarcoma 4) Juvenile chronic myeloid leukemia 5) Rhabdomyosarcoma
6. Other associated conditions and symptoms of NF1
Table 13-1. (continued)
Cutaneous Neurologicv Syndrome Inheritance Genetics findings findings Other
a. Diagnostic criteria require two or more of seven items 1) At least six café au lait spots (hyperpigmented, oval,
light brown skin macules) a) At least 5-mm diameter in prepubertal patients b) At least 1.5-cm diameter in postpubertal patients c) Typically located on trunk
2) Axillary and/or inguinal freckling (usually present between ages 3 and 5 years)
3) At least two Lisch nodules (iris hamartomas) 4) Neurofibromas: more than one cutaneous neurofi-
broma or one plexiform neurofibroma 5) Characteristic bone anomalies 6) Optic nerve glioma 7) Diagnosis of NF1 in first-degree relative
b. Mutation analysis available 8. Imaging
a. Magnetic resonance imaging (MRI) of head 1) Shows nonenhancing, well-circumscribed hyperin-
tense T2 signal lesions in several locations: basal ganglia (Fig. 13-2), cerebellum, brainstem
2) No known prognostic significance b. Other: cranial and spinal imaging may show incidental
a. Macrocephaly 1) Aqueductal stenosis 2) Hydrocephalus
b. Kyphoscoliosis, often progressive (10% of cases) c. Hypertension d. Arterial occlusive disease
1) Renal artery stenosis 2) Moyamoya disease
e. Intracranial aneurysms (Table 13-2) f. Migraine g. Epilepsy (10% of cases) h. Focal neurologic deficits i. Learning disabilities (40%-60% of cases)
1) Increased incidence of attention-deficit disorder 2) Cognitive disabilities may include visuospatial prob-
lems, spatial-memory problems, and visuomotor integration skills
j. Proptosis k. Glaucoma l. Short stature
m. Constipation 7. Diagnosis
or symptomatic neurofibromas or other tumors 9. Treatment
a. Genetic counseling, anticipatory guidance, surveillance for treatable complications
b. Annual physical examination (including blood pressure screening, growth, and pubertal status) and ophthalmologic examinations during school years
c. Evaluate and treat for learning disabilities early d. Scoliosis and other skeletal abnormalities need observa-
tion, may require treatment
e. Surgical evaluation and treatment for symptomatic neurofibromas or other tumors
E. Neurofibromatosis 2 (bilateral acoustic neurofibromatosis, “central neurofibromatosis”)
1. Overview a. Autosomal dominant disorder b. Typical characteristics: bilateral vestibular schwannoma
(acoustic neuroma), other nervous system tumors, ocular abnormalities
2. Epidemiology a. NF2: 3% of all cases of neurofibromatosis b. Prevalence: 1:40,000
3. Genetics a. Autosomal dominant: penetrance close to 100% by age
60 years b. NF2 gene
1) Tumor suppressor gene (chromosome 22q12) 2) Codes for merlin (also called schwannomin) 3) Merlin
a) Highly expressed in adult Schwann cells, meningeal cells, the lens, and nerve cells
b) Structurally similar to family of proteins that link cytoskeleton to cell surface
4) Patients with nonsense or frameshift NF2 mutations
Table 13-2. Genetic Disorders Associated With Intracranial Aneurysms
Inheritance Disease pattern Locus Gene Gene product
NIH Diagnostic Criteria for Neurofibromatosis Type 1 Two or more of the following: 1. ≥6 café au lait spots 2. ≥2 neurofibromas of any type or ≥1 plexiform
neurofibroma 3. Freckling (Crowe’s sign) in axilla or groin 4. Optic glioma 5. ≥2 Lisch nodules (benign pigmented iris
hamartomas) 6. Distinctive bony lesion 7. First-degree relative with neurofibromatosis type 1
have severe disease; those with missense mutations, in-frame deletions, or large deletions have mild disease
5) Standard mutation detection a) Bilateral vestibular schwannomas
i) Identify mutation in 66% of patients ii) Majority are truncated mutations iii) More severe clinical disease
b) Without bilateral vestibular lesions i) Linkage analysis is test of choice ii) Provides more than 99% certainty iii) Patients tend to harbor missense mutations iv) Milder clinical disease
4. Clinical manifestations a. Symptoms often present in teenage years b. Symptoms depend on associated lesions (see below)
5. Vestibular schwannoma (also called acoustic neuroma) a. Nerve sheath tumor that typically occurs bilaterally in
NF2 b. Clinical presentation often includes progressive hearing
loss, tinnitus, and imbalance c. MRI
1) Technique: thin sections through internal auditory
canals; performed with and without gadolinium contrast
2) Appearance on MRI a) Extra-axial mass at cerebellopontine angle b) Typically hypointense or isointense on T1 images,
with intense enhancement following contrast and mildly increased signal on T2
6. Other associated conditions or symptoms a. Spinal and cranial nerve (CN) schwannomas
(CN V-XII) b. Intracranial meningiomas (often multiple) c. Spinal cord: ependymomas, gliomas d. Posterior subcapsular cataracts (85% of patients) e. Retinal hamartomas f. Occasional café au lait spots (45% of patients) g. Skin plaquelike lesion (70% of patients) h. Mononeuropathy (CN VII most common) i. Seizures j. Antigenic nerve growth factor is increased
7. Clinical criteria for diagnosis-NF2 is diagnosed in patients with one of the following: a. Bilateral vestibular schwannomas b. A first-degree relative with NF2 and
1) Unilateral vestibular schwannoma or 2) Any two of meningioma, schwannoma, glioma, neu-
rofibroma, posterior subcapsular lenticular opacities c. Unilateral vestibular schwannoma and any two of
meningioma, schwannoma, glioma, neurofibroma, posterior subcapsular lenticular opacities
d. Multiple meningiomas and 1) Unilateral vestibular schwannoma or 2) Any two of schwannoma, glioma, neurofibroma,
cataract 8. Clinical management
a. Genetic counseling b. Anticipatory guidance and surveillance for treatable
complications c. Baseline MRI of brain and spinal cord: reimage and
monitor, especially if symptomatic d. Hearing and speech evaluation and augmentation e. Ophthalmologic evaluation f. Annually
1) Neurologic evaluation 2) Cranial MRI 3) Audiography
9. Management of acoustic neuroma a. Observation b. Surgical management c. Stereotactic radiosurgery d. Fractionated radiotherapy
A. Features 1. Rare form of neurofibromatosis characterized by multi-
ple pathologically proven schwannomas on cranial, spinal, and peripheral nerves
2. Vestibular schwannomas or other kinds of tumors or manifestations of NF1 and NF2 do not develop
B. Genetics: autosomal dominant with incomplete penetrance and variable expression
C. Symptom: pain 1. In distribution of the schwannoma 2. Can occur in any part of the body 3. Only a single part of the body may be affected
D. Management 1. Surgical removal of symptomatic schwannoma if
possible 2. If inoperable, multidisciplinary pain management
A. Overview 1. Autosomal dominant 2. Often referred to as the tuberous sclerosis complex
(TSC) because of involvement of multiple organ systems by development of distinctive tumors or hamartomas
3. Organs commonly involved: brain, kidney, skin, eye, heart
4. Classic triad (Vogt’s triad): seizures, mental retardation, and adenoma sebaceum (less than 1/3 of patients display all three features)
B. Epidemiology 1. Prevalence: 1:6,000 to 1:9,000 2. Second most common neurocutaneous disorder
C. Genetics 1. Autosomal dominant disorder with almost complete
penetrance 2. Characterized by a wide phenotypic spectrum, even
within same family 3. Mutations of two different genes can cause TSC 4. New mutations occur in 65% to 75% of cases
a. Severely affected patients often have a new mutation b. No feature that distinguishes which of the two genes is
defective 5. TSC1 gene
a. Tumor suppressor gene (chromosome 9q34.3) b. Codes for hamartin c. If this gene is affected, patient may have less risk of cog-
nitive impairment than if TSC2 gene is affected 6. TSC2 gene
a. Tumor suppressor gene (chromosome 16p13.3) b. Codes for tuberin
1) Guanosine triphosphatase-activating leucine zipper protein
2) Contiguous with adult polycystic kidney disease type 1 gene : may explain development of multiple renal cysts
7. Hamartin and tuberin bind to form a complex, explaining why a mutation in either gene may result in similar phenotype
D. Pathology 1. Hamartias, hamartomas, hamartoblastomas
a. Hamartia 1) Characterized by misaligned groups of dysplastic cells
appropriate for the organ or tissue 2) These undifferentiated cells do not multiply or grow
more rapidly than normal cells of that particular organ
b. Hamartoma 1) Well-circumscribed group of dysplastic cells 2) These cells have a propensity to multiply excessively,
thus growing as benign tumors that may or may not become symptomatic
c. Hamartoblastoma: rare malignant tumor derived from hamartoma
d. Development and growth of hamartomas: age-dependent
e. Brain hamartias and hamartomas include 1) Most patients with TSC have at least one supratento-
rial brain lesion (infratentorial lesions less common) 2) Cortical tubers (Fig. 13-3 and 13-4): common
hamartia found in cortical gyri; may calcify over time 3) White matter abnormalities: dysplastic changes of
Hallmark Findings in Tuberous Sclerosis Complex Mental retardation
Seizures
Adenoma sebaceum
white matter may occur; may have white matter linear migration lines
4) Subependymal nodules a) Hamartoma along ventricular surface b) Commonly located near caudate nucleus and just
posterior to foramen of Monro c) May have the appearance of melting candle wax,
so-called candle guttering, pathologically (Fig. 135) and on radiographs
d) May be calcified 5) Subependymal giant cell astrocytoma (SEGA) (Fig.
