Adams and Victor's Principles of Neurology

Figure 38-8. 
Typical large café-au-lait spot. The presence of 6 or
more hyperpigmented lesions, each larger than 1.5 cm after puberty
(>5 mm prepubertal), is diagnostic of neurofibromatosis type 1.
Figure 38-9. 
Molluscum fibrosum nonneural skin tumors of von
Recklinghausen disease.
Figure 38-10. 
Hamartomas of the iris (Lisch nodules), typical of neu-
rofibromatosis type 1.

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C
HAPTER
38
Developmental Diseases of the Nervous System
 983
leagues; also, pain was a common symptom in adults and
often related to a malignant peripheral nerve sheath tumor.
Other abnormalities associated less consistently with
type 1 (peripheral) NF include bone cysts, pathologic frac-
tures (pseudoarthrosis), cranial bone defects with pulsating
exophthalmos (sphenoid bone dysgenesis), bone hypertro-
phy, precocious puberty, pheochromocytoma, scoliosis,
syringomyelia, nodules of abnormal glia cells in brain and
spinal cord, and macrocephaly, rarely with obstructive
hydrocephalus as a result of overgrowth of glial tissue
around the sylvian aqueduct and fourth ventricle. Some
degree of intellectual impairment is common; it was found
in 40 percent of Riccardi’s series of 133 patients. But in our
experience, the figure is much lower and the impairment is
usually not profound. Learning difficulty, developmental
disorder, and hyperactivity have been more frequent abnor-
malities, occurring in almost 40 percent of patients. Rosman
and Pearce have ascribed mental retardation in NF to con-
genital malformation of the cerebral cortex (cortical dysgen-
esis). The incidence of seizures is about 20 times higher
than that in the general population, but these tend not to be
a very frequent or intractable problem.
Exceptionally, NF is associated with peroneal muscular
atrophy, congenital deafness, and partial albinism (Brad-
ley et al).
In childhood, progressive blindness is a particularly
dire complication from a tumor mass composed mainly of
astrocytes (optic glioma). The tumor may involve one or
both optic nerves. The diagnosis comes to mind at once in
a child with any of the cutaneous manifestations of NF
and this tumor. Uncertainty as to its nature arises from the
fact that the neuropathologist may be unable to decide
between a benign hamartoma and a grade 1 astrocytoma.
Progressive enlargement in a succession of MRI scans may
be needed to affirm its nature.
It needs to be stated that neurofibromas of the spinal
roots occur regularly in patients without NF (see Chap. 44).
Whether multiple such lesions implicate NF is not clear.
Neurofibromatosis Type 2 
(Acoustic, or Central, NF)
This condition is considerably less frequent than NF1.
Here there is an absence or paucity of cutaneous lesions.
Progressive deafness and the demonstration by enhanced
CT or MRI of 
bilateral acoustic neuromas
afford accurate
diagnosis (see Fig. 31-18). Also, an acoustic neuroma
developing before age 30 years is suspect as being caused
by NF2. Other cranial or spinal neurofibromas, meningi-
oma (sometimes multiple), and glioma may be added to
the syndrome of deafness or may occur prior to its emer-
gence. Juvenile cataracts of the subcortical or capsular
variety are seen in some affected patients.
Analysis for the 
NF2
gene has become available from
several laboratories. The genetics and affected protein
(merlin or schwannomin) are discussed in “Cause and
Pathogenesis” above.
Familial Schwannomatosis
As commented in Chap. 31 in the discussion of acoustic neu-
roma, it is now apparent that the propensity to develop mul-
tiple schwannomas can also be inherited as a dominant trait,
without the vestibular tumors characteristic of NF2. This trait
maps to a genetic locus on chromosome 22 that is distinct
from the one for NF2. It has been estimated that 2 to 5 per-
cent of schwannomas requiring resection are from this dis-
ease. The current diagnostic criteria are based on the
presence of two of more schwannomas without vestibular
nerve tumors in an individual older than age 18 years, as
summarized in a thorough review by MacCollin and col-
leagues. Pain is the dominant problem.
Pathology of NF1 and NF2
The cutaneous tumors are characterized by a rather thin epi-
dermis whose basal layer may or may not be pigmented. The
collagen and elastin of the dermis is replaced by a loose
arrangement of elongated connective tissue cells. The lack of
compactness of the normal dermal collagen allows the pal-
pable opening in the skin. The pigmented (café-au-lait)
lesions contain only the normal numbers of melanocytes; the
dark color of the skin is instead the result of an excess of mel-
anosomes in the melanocytes. Some of the abnormally large
melanosomes measure up to several microns in diameter.
The nerve tumors are composed of a mixture of fibroblasts
and Schwann cells (except the optic nerve tumors, which
contain a combination of astrocytes and fibroblasts). Pre-
dominance of one or the other of these cells in the nerve is
the basis of the diagnosis of neurofibroma or schwannoma.
Palisading of nuclei and sometimes encircling arrangements
of cells (Verocay bodies) are features of both (see Chap. 31).
Occasionally, along spinal roots or sympathetic chains, one
may find a tumor made up of partially or completely differ-
entiated nerve cells, a typical ganglioneuroma. Clusters of
abnormal glia cells may be found in the brain and spinal
cord, and, according to Bielschowsky, they imply a link with
tuberous sclerosis that has never been proved. Clinically and
genetically, the two diseases are quite independent.
Malignant degeneration of the tumors is found in 2 to 5
percent of cases; peripherally they become sarcomas and
centrally, astrocytomas or glioblastomas (Fig. 38-11).
Diagnosis
If skin tumors and café-au-lait spots are numerous and Lisch
nodules are present in the iris, the identification of the dis-
ease as type 1 neurofibromatosis offers no difficulty. A his-
tory of the illness in antecedent and collateral family
members makes diagnosis even more certain. Doubt arises
most frequently in patients with bilateral acoustic neuromas
or other cranial or spinal neurofibromas or schwannomas
with no skin lesions or only a few random ones. The ten-
dency for these forms of NF to have few skin lesions is well
known, but differentiation of type 1 from type 2 may be
uncertain unless genetic studies are undertaken. Plexiform
neuromas with muscle weakness because of nerve involve-
ment and abnormalities of underlying bone may be confused
with other tumors, especially in young children, who tend to
have few café-au-lait spots and few cutaneous tumors.
Hypertrophy of a limb requires differentiation from other
developmental anomalies including Klippel-Trenaunay-
Weber Syndrome.

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