AMERICAN JOURNAL OF MEDICAL GENETICS (SEMIN. MED. GENET.
) 89:v–viii (1999)
I N T R O D U C T I O N
Neurofibromatosis 1
It is fitting that the premier issue of the
Seminars in Medical Genetics series is
devoted to a heritable condition that
encompasses most all of the essential
principles of human genetics. Neurofi-
bromatosis type 1 (NF1) is an autoso-
mal dominant condition that affects ap-
proximately 1 in 4,000 individuals
worldwide. It was initially introduced
to the medical community in 1882 by
Dr. Von Recklinghausen, who demon-
strated that the tumors in this condition
arose from the nerve. Hence, the names
neurofibroma for the tumor and neu-
rofibromatosis for the condition of
multiple neurofibromas. The heritable
aspect of Von Recklinghausen disease
was demonstrated by Preiser and Dav-
enport [1918], and, as a Mendelian
condition, it was mapped to chromo-
some 17 in 1987 [Barker et al, 1987].
The years between held many publica-
tions of case reports and cohort studies
[i.e., Crowe et al., 1956] that failed to
distinguish central vs. peripheral in-
volvement of Von Recklinghausen dis-
ease, which is now recognized as com-
pletely distinct entities, NF1 (peripheral
NF) and NF2 (central NF). This Semi-
nars issue deals exclusively with NF1.
The confusion surrounding the misno-
mer of NF2 that is carried in the medi-
cal literature is mainly historical; the
neurofibroma-like tumors are
schwannomas and the clinical overlap is
now recognized to be minimal. This
clinically recognized split in NF nosol-
ogy, familial neurofibromatosis (NF1)
vs. familial schwannomatosis (NF2),
was confirmed at the molecular level
when the respective genes were cloned
and characterized in 1990 [Cawthon et
al, 1990; Viskochil et al, 1990; Wallace
et al, 1990] and 1993 [Rouleau et al,
1993; Trofatter et al, 1993].
The NF1 gene spans approxi-
mately 335 kilobases (kb) of genomic
DNA in band 11.2 on the long arm of
chromosome 17 [Li et al, 1995]. Its
© 1999 Wiley-Liss, Inc.
processed transcript is approximately 12
kb long and it encodes a peptide, neu-
rofibromin, of 2,818 amino acids [Ber-
nards et al, 1992; Marchuk et al, 1991].
The only known function of human
neurofibromin is its interaction with
Ras as a negative regulator of the Ras/
Raf/MAPK signaling pathway (see ar-
ticle by Weiss et al., this issue). NF1 has
3 major splice variants that incorporate
small, in-frame peptide segments of un-
known function [Danglot et al, 1995;
Andersen et al, 1993; Gutmann et al,
1993]. It is driven by a weak promoter
that results in low-level expression in
most mammalian cells [reviewed in
Viskochil, 1998]. The highest levels of
expression are in the central nervous
system [Nordlund et al, 1993], which
may explain its involvement in cogni-
tive function in addition to the devel-
opment of intracranial tumors. Its intra-
cellular location is predicted by its in-
teraction with Ras, which is anchored
to the inner membrane, although dif-
ferent studies have demonstrated local-
ization to different regions of the cell
including microtubules [Golubic et al,
1992; Gregory et al, 1993; Roudebush
et al, 1997]. NF1 mutations have been
reported in more than 200 individuals
with NF1 [reviewed in Upadhyaya and
Cooper, 1998], and there are only a few
relative “hotspots” for mutation. The
vast majority of mutations predict inac-
tivation of neurofibromin, which sup-
ports the paradigm of haploinsuffi-
ciency as an explanation for some of the
clinical features of NF1. Intragenic
polymorphisms have been exploited to
perform linkage analysis in familial cases
of NF1. Signposts of the NF1 gene are
depicted in Figure 1.
The NF1 gene has been conserved
through evolution, from yeast to mam-
malian systems, thus cementing its bio-
logically significant role in intracellular
signal transduction. The universal find-
ing of neurofibromas in individuals
with NF1 indicates its role as a “tumor
suppressor gene,” whereas the 10-fold
increased risk of learning problems in
NF1 demonstrates that neurofibromin
plays an important function in cogni-
tion. In addition, the congenital skeletal
dysplasias of NF1 and animal models
show the potential role for NF1 in em-
bryonic development. These different
aspects of NF1 clearly demonstrate that
this condition is more than a disorder
involving the neural crest. Understand-
ing the role of NF1 in various biologi-
cal systems should provide insight to-
ward general principles of human ge-
netics and provide a rationale for the
development of therapeutic modalities
that could be highly effective in treat-
ment protocols.
This volume explores clinical issues
of paramount importance to families
with NF1: peripheral nerve sheath tu-
mors consisting of benign plexiform
neurofibromas and malignant periph-
eral nerve sheath tumors (MPNSTs);
intracranial tumors consisting of optic
nerve gliomas and low-grade astrocyto-
mas; and cognitive dysfunction. To
fully understand these clinical features,
some knowledge of the pathophysiol-
ogy of NF1 is necessary. Articles focus-
ing on the population-based natural
history of the disorder, its variable ex-
pressivity, and the biochemical role of
the NF1 gene product in intracellular
signaling for cell proliferation help to
provide such background.
To set the stage, Jan Friedman ex-
plores the prevalence, fitness, and dis-
ease burden of NF1. In addition, he re-
views issues of mortality which suggest
that there may be a reduced survival of
NF1 patients, although usually after the
reproductive years. John Carey and I
use NF1 as a model condition to ex-
plore the molecular basis of variability
of clinical expression in genetic disor-
ders. We examine segmental NF, famil-
ial spinal NF, familial café-au-lait spots,
 vi
AMERICAN JOURNAL OF MEDICAL GENETICS (SEMIN. MED. GENET.)

Fig. 1. Schematic diagram representing the NF1 exons as rectangular boxes and important signposts as lettered circles. Introns are not shown to scale. Scale in lower left corner is for the size of exons. The
transcription start site is depicted as a horizontal arrow upstream of exon 1. a: Not I restriction enzyme site. b: Single-nucleotide polymorphism as an Rsa I restriction site [Hoffmeyer and Assum, 1994] or adapted
as mutagenically separated PCR [Purandare et al., 1996]. c: Site of truncation of a cDNA isolated from human placenta cDNA library [Suzuki et al., 1992]. d: Single-nucleotide polymorphism site adapted for MS-PCR
[Purandare et al., 1996]. e: Approximate location of the t(1;17) balanced translocation breakpoint and nearby site of GXAlu, a tetranucleotide repeat within an Alu-repetitive element [Xu et al., 1992]. f: Dinucleotide
repeat polymorphism [Lazaro et al., 1994]. g: Insertion/deletion polymorphism of an L1-element [Bleyl et al., 1994]. h: Site of the most common NF1 mutation, a C5839T substitution resulting in an Arg1947 to
termination [Upadhyaya and Cooper, 1998]. i: Site of the t(17;22) translocation breakpoint. j: Dinucleotide polymorphism [Lazaro et al., 1993]. k: Site of a processed AK3 (adenylate kinase 3) pseudogene [Xu et al.,
1992]. l: Single-nucleotide polymorphism site adapted for MS-PCR [Purandare et al., 1996]. m: Polyadenylation site representing the 3⬘-end of the NF1 gene. The GAP-related domain, Ras-GRD, is shown spanning
exons 21 to 27a [Scheffzek et al., 1998]. The asterisk in exon 23-1 represents a site of mRNA processing, C3916U, which leads to premature truncation at codon 1303 [Skuse et al., 1996]. The alternative splice forms
are in-frame insertions of exons 9a, 23a, and 48a, and they are hash-marked. The embedded genes are shown in bold in intron 27b.

and Noonan NF as paradigms of disease
heterogeneity. The NF1 whole-gene
deletion phenotype is also reviewed.
The third article is devoted to the as-
sessment of the role of neurofibromin
in the Ras pathway and a review of the
role of hyperactive Ras in NF1. Brian
Weiss et al. focus on Ras processing,
activation, and down modulation as tar-
gets for drug design. They present some
preliminary results of animal models
treated with anti-Ras agents and specu-
late on future studies. With that as the
background, both Bruce Korf and
James Woodruff take on the natural his-
tory and pathology of peripheral nerve
sheath tumors in NF1. Dr. Korf ad-
dresses the natural history and manage-
ment issues surrounding plexiform neu-
rofibromas, whereas Dr. Woodruff
focuses on the manifestations of
MPNSTs. The significance in these tu-
mors of NF1 morbidity and mortality is
substantial. Benign plexiform neurofi-
bromas affect 25% and MPNSTs affect
approximately 2–5% of individuals with
NF1. On the theme of clinically diffi-
cult tumors, Listernick et al. review a
relatively low frequency but pathologi-
cally important finding in NF1, intra-
cranial gliomas. The authors are expert
in their review of what is known about
the natural history of optic nerve glio-
mas. They also explore the molecular
biology of NF1-associated astrocyto-
mas. The issue is rounded out by the
review of Ozonoff on cognitive impair-
ment. As a psychologist who is most
familiar with the field of executive
function testing in autism, Dr. Ozonoff
has extensively reviewed the ever-
accumulating neuropsychological lit-
erature related to NF1 to compile a
table that identifies the different mea-
sures used in various studies. She gives
credit to the need to further clarify the
cognitive phenotype of NF1, and she
recommends that all children with NF1
should have thorough cognitive work-
ups at least by the beginning of school
entry.
It is the sincere hope of all the au-
thors involved in this series that the cu-
mulative articles provide an up-to-date
account of a few of the most relevant
AMERICAN JOURNAL OF MEDICAL GENETICS (SEMIN. MED. GENET.)
issues surrounding the clinical manage-
ment of NF1.
Dave Viskochil
Guest Editor
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