Variable Expression of Neurofibromatosis 1 in
Margaret B. Rieley,1David A. Stevenson,2David H. Viskochil,2Brad T. Tinkle,3Lisa J. Martin,3
and Elizabeth K. Schorry3*
1Eastern Maine Medical Center, Bangor, Maine
2Division of Medical Genetics, University of Utah, Salt Lake City, Utah
3Division of Human Genetics, Cincinnati Children’s Hospital Medical Center, Cincinnati, Ohio
Received 22 September 2010; Accepted 24 November 2010
Neurofibromatosis 1 (NF1) is a common autosomal dominant
sion. Monozygotic (MZ) twins with NF1 who have phenotypic
discordances are a useful tool in evaluating which traits are
influenced by non-hereditary influences such as second hit
somatic events, environmental agents, epigenetic modification,
or post-zygotic mutations. We evaluated nine sets of MZ twins
and one set of MZ triplets, ages 4–18 years, for NF1 features and
calculated probandwise concordance (PC) for each feature. MZ
twins were highly concordant in numbers of caf? e-au-lait spots
disabilities and speech disorders were observed. Twin pairs
showed significant discordance for tumors, particularly plexi-
form neurofibromas (PC¼0.40) and malignant peripheral
-hit events were contributing to these features. One set of twins
was concordant for multiple, large paraspinal neurofibromas,
twins were discordant for scoliosis (PC¼0.40); an additional set
was concordant for scoliosis but differed in presence of dystro-
phic features and need for surgery. Our data suggest there are
and causing discordancies between MZ twins. Future studies
may focus on differences in epigenetic changes or somatic
mosaicism whichhave been documented for other disease genes
in MZ twins. ? 2011 Wiley-Liss, Inc.
Key words: neurofibromatosis 1; NF1; monozygotic twins
Neurofibromatosis 1 (NF1) is a common autosomal dominant
gene displays almost complete penetrance, but extreme variability
of expression, with features ranging from mild cutaneous findings
to severe life-threatening complications. With this great variability
which patients are at risk for specific complications, and therefore
to appropriately manage those at highest risk. Pleiotropic features
patients will develop an optic pathway glioma (OPG) [Lewis et al.,
1984; Listernick et al., 1989], 23–40% have one or more plexiform
scoliosis [Crowe, 1956; Carey et al., 1979; Riccardi, 1992; Huson
and Hughes, 1994; Friedman and Birch, 1997], 8–13% develop
malignant peripheral nerve sheath tumor (MPNST) [Evans
et al. 2002], and 30–65% have learning disabilities [North,
2000]. Various mechanisms have been proposed to explain the
genes, second hit somatic mutation events in NF1 or other genes,
environmental agents, epigenetic modification, and post-zygotic
and no modifying genes have been identified thus far [Castle et al.,
2003]. Whole gene deletions have been associated with a higher
tumor burden, greater degree of cognitive impairment, and a
more severe course [Kayes et al., 1994]. A specific single amino
Elizabeth K. Schorry, M.D., Division of Human Genetics, MLC 4006,
Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229-
3039. E-mail: email@example.com
Published online 18 February 2011 in Wiley Online Library
How to Cite this Article:
Rieley MB, Stevenson DA, Viskochil DH,
Tinkle BT, Martin LJ, Schorry EK. 2011.
Am J Med Genet Part A 155:478–485.
? 2011 Wiley-Liss, Inc.
acid deletion in exon 17 (c.2970–2972 delAAT) (GenBank
Reference NM_001042492.1) has been associated with a milder
NF1 phenotype with a deficiency of neurofibromas [Stevenson
et al., 2006a; Upadhyaya et al., 2007]. Second hit and loss of
heterozygosity events have been well documented in several NF1
tumor types and in tibial dysplasia [Stevenson et al., 2006b;
Upadhyaya et al., 2009], but are unlikely to explain the entire
spectrum of variable NF1 features.
Twin studies have historically been a valuable tool for studying
genetic disorders. The study of MZ twins with NF1, who are
assumed to be genetically identical for modifying genes as well as
for the NF1 mutation, can be a valuable tool in determining which
likely influenced by non-heritable factors such as second hit,
epigenetic, or environmental events.
In this study, we evaluated 10 sets of monozygotic (MZ) twins
and triplets, as a tool to determine which NF1 features are
likely influenced by germline modifying genes, and which may be
of patients may help us begin to better understand mechanisms
behind the variable expression of this complex disorder.
MZ twins and triplets were identified from among 1,100 patients
with NF1 followed at two NF Centers (Cincinnati Children’s
Hospital Medical Center and University of Utah Health Sciences
Center). Diagnosis of NF1 was based on NIH diagnostic criteria or
criterion. Patients were typically evaluated in the NF clinic at least
once annually, and detailed records were kept for each patient
of clinical features, tumors, radiographic studies, and learning
difficulties. Cutaneous features and externally visible tumors
were documented on body diagrams in clinic notes; numbers of
caf? e-au-lait spots (CALS) and cutaneous neurofibromas were
recorded for each patient, with rounding to nearest 5 for values
school or clinics, although not all were tested with the same panel
of tests. All patients at the Cincinnati clinic had routine baseline
MRI of the brain performed in early childhood; the Utah Clinic
hadwhole-bodyMRI performed.Nine(9)patients hadMRIofthe
confirmed by blood or buccal swabs using short tandem repeat
Applied Biosystems, Carlsbad, CA). Accuracy of this method is
reported at greaterthan 98% [Frankelet al., 1996].Fiveof the twin
sets had NF1 mutation analysis performed at a clinical laboratory;
and patient assent when appropriate were obtained and patient
records were reviewed for the presence of the accepted
seven diagnostic criteria, osseous complications (scoliosis, tibial
dysplasia, pectus excavatum), MRI findings, learning or speech
disabilities, attention-deficit hyperactivity disorder (ADHD),
mental retardation, and severity score. The Riccardi severity score
was used, ranking severity of symptoms on a scale of 1–4; 1¼mild
and 4¼severe [Riccardi, 1992].
Our primary outcome measure was the probandwise estimate of
concordance (PC). PCis a measure of the probability that both
the pair is affected [McGue, 1992] and is considered an estimator
for recurrence risk. Assuming complete ascertainment, PCis
is the number of discordant twin pairs [McGue, 1992; Witte et al.,
1999]. The variance is given by
as described by Witte et al. . Using the estimate and the
able to be estimated and therefore, 95% Confidence Intervals were
concordant for the features, PCwas not calculated.
Ten sets of multiples from the two NF centers were enrolled. Nine
and records were reviewed. Nine sets were female, and 1 was male.
age at delivery ranged from 32 to 40 weeks, with a median of 35
weeks. Fifty percent of the twins had a family history of NF1. All
were of Caucasian ethnicity. Concordance for clinical features is
reported in Table I.
All sets were concordant for pigmentary findings including
presence and general number of CALS, and presence or absence
of skin fold freckling. However, all were discordant for the general
location and size of CALS. All but one set were concordant for the
presence or absence of Lisch nodules (PC¼0.90?0.18).
numbers, and three sets were discordant (PC¼0.67?0.36). The
cutaneous neurofibromas had different locations in each twin in
a pair. The majority (6/10) were discordant for the presence
of plexiform neurofibromas (PC¼0.40?0.38). All sets with
plexiform neurofibromas were discordant for location, except for
one twin set both of whom had multiple paraspinal and pelvic
neurofibromas. One set was discordant for MPNST.
With respect to neurological findings, all but one set had
undergone brain MRI, and nine individuals had a spinal MRI
performed. One twin pair had identical Chiari I malformations.
Four sets were discordant for OPG, and five sets had no OPG on
MRI. All patients with an OPG were asymptomatic. Seven of nine
sets were concordant for T2 hyperintensities seen on MRI
Skeletal complications were also examined. The presence of
scoliosis was defined as a spinal curvature of at least 10 degrees
RIELEY ET AL.
although one twin in the set had a mild idiopathic curvature and
the other required treatment for dystrophic scoliosis. Three
additional sets were discordant for scoliosis (PC¼0.40?0.54)
(surgery, bracing) had dystrophic radiographic changes including
ing which were not seen in their respective twins, but did not
have evidence of paraspinal tumors. Four sets were concordant
for presence of pectus deformity while two were discordant
(PC¼0.80?0.27). One pair had severe ‘‘mirror image’’ pectus
requiring surgery, one for pectus excavatum and the other for
pectus carinatum. Two sets were discordant for sphenoid wing
dysplasia; one of the affected members of one pair also had an
orbital plexiform neurofibroma in the region of sphenoid wing
All twins were concordant for the presence or absence of mental
Intelligence quotient (IQ) testing was available for three sets
and there was no more than a 10-point difference between twins.
percent of twins had the same score astheir twin and none differed
by more than one point in severity score (PC¼0.67?0.28).
Of interest, the above data included a set of MZ triplets (set #4,
Table I) conceived spontaneously, a rare event occurring in 1 in
50,000 pregnancies [MacGillivray et al., 1975]. The triplets were
concordant for the presenceor absence of freckling, Lisch nodules,
OPG, T2 hyperintensities, scoliosis, pectus deformity, learning
who required intervention
of cutaneous neurofibromas (with only one triplet displaying
a small number of cutaneous neurofibromas), and sphenoid wing
dysplasia (with one triplet affected).
There are at least 30 case reports of MZ twins with NF1 in the
[Easton et al., 1993; Sabbagh et al., 2009]. Twin sets have been
reported with concordance for CALS, epilepsy, non-dysplastic
scoliosis, spongioblastoma, Dandy–Walker malformation, renal
vascular hypertension and unilateral ptosis (Table II). Non-
neurofibromas as well as the presence of OPG, MPNST,
ulnar pseudarthrosis, and congenital glaucoma (Table II). Easton
concluded that NF1 features varied to a greater degree with
may have a role in the phenotypic variability of NF1 [Easton et al.,
patients (1,132 individuals from 313 NF1 families, including 6 sets
a correlation between phenotypic discordance and mitochondrial
mutation orpolymorphism variation betweenfour twinpairswith
The majority of the NF1 twin literature has focused on case
reports (Table II). Lubinsky  reported twin pair concordan-
reports of concordance include twin pairs with CALS, freckling,
FIG. 1. Scoliosis X-rays of twin pair 5, discordant for scoliosis.
480 AMERICAN JOURNAL OF MEDICAL GENETICS PART A
TABLE I. Concordant Features of NF1 in 10 Sets of Multiples
Caf? e-au-lait spots #
Cutaneous neurofibroma #
Plexiform neurofibroma #
Optic pathway glioma
Sphenoid wing dysplasia
exons 4, 5
Note that for features where there were no concordant twins for the trait (i.e., MPNST, optic pathway glioma), a probandwise concordance could not be calculated.
CI, confidence interval; MPNST, malignant peripheral nerve sheath tumor; Unk, unknown; del, deletion.
aSet 4 is a set of monozygotic triplets.
bNo twins concordant for feature.
cSet 2 was discordant for velopharyngeal insufficiency.
RIELEY ET AL.
Lisch nodules [Bauer et al., 1988], epilepsy [Easton et al., 1993],
developmental delay [Koul et al., 2000], and central nervous
system abnormalities including agenesis of the corpus callosum,
subependymal spongioblastoma, suprasellar astrocytoma, hippo-
campal involvement [Tubridy et al., 2001], OPG [Dresner
and Montgomery, 1949; Cartwright, 1982; Crawford and
Buckler, 1983; Pascual-Castroviejo et al., 1988], ophthalmic vein
thrombosis, and Dandy–Walker malformation [Koul et al., 2000].
Reportsof discordance include
cutaneous and mesenteric neurofibromas [Bauer et al., 1988;
OPG [Vaughn et al., 1981; Akesson et al., 1983; Kelly et al., 1998;
Tubridy et al., 2001], congenital glaucoma [Payne et al., 2003],
of twins with OPG [Crawford and Buckler, 1983] or plexiform
of MZ twins reported by Kaplan et al.  who were discordant
forclinical diagnosis ofNF1.The affectedtwinwasfoundtohave a
pathogenic NF1 mutation in three different cell types tested; the
clinically unaffected twin was mosaic for the NF1 mutation, with a
mutation present in blood and buccal cells, but not in fibroblasts.
With 10 sets of MZ twins/triplets with NF1, ours is the largest
sample set described to date. Our population of 10 sets of MZ
based on a population incidence of MZ twinning of 1/250, and is
clinically significant (c2¼7.156, P¼0.0075). Possible explana-
tions could include older maternal age with increased rate of
twinning; alternatively, presence of an NF1 mutation with activa-
tion of Ras in the early zygote might increase the chance of MZ
twinning. The skewed sex ratio with 90% female in our report is
likely due to the small sample size since this ratio has not been
cases where gender was reported, 6 of 13 pairs (46%) of MZ NF1
twins were of male gender, not different from the population ratio
[Vaughn et al., 1981; Cartwright, 1982; Akesson et al., 1983;
Crawford and Buckler, 1983; Pascual-Castroviejo et al., 1988;
Craigen and Clarke, 1995; Kelly et al., 1998; Koul et al., 2000;
2010]. Fifty percent of twin pairs in our study were de novo
mutations, as expected with the known new mutation rate of the
NF1 gene. Five of our twin pairs had NF1 mutations confirmed
molecularly; the others did not undergo testing as it was not
or a whole gene deletion.
This study’s data agree with previous reports of very high MZ
twin concordance rates of overall numbers of CALS, axillary and
inguinal freckling, and Lisch nodules. As pigmentary features have
varied more among more distant relatives in the same family
[Easton et al., 1993; Sabbagh et al., 2009], it is likely that there are
germline modifying genes affecting expression of these features.
However, the location of CALS was discordant between the twin/
triplet sets. This suggests that the development of individual
CALS is influenced by somatic events, but that there is a germline
Tumors in twins with NF1 have shown significantly less
concordance than other features both in previous reports and in
our data. Since many NF1-related tumors have been found to
require a second hit in the other NF1 allele, the sporadic nature of
the second hit event could explain the discordance of tumors in
twins. Alternatively, there could be other non-hereditary factors
influencing tumor initiation and growth such as epigenetic
changes, somatic mutations in other tumor-related genes, or
environmental events. When looking at OPG in the combined
pairs discordant. The four concordant pairs are somewhat higher
than expected if OPG occurred randomly in 15% of patients
with NF1, suggesting that modifying genes may play some role
in susceptibility to OPG. Alternatively, there may have been
ascertainment bias in literature reports, as twin pairs concordant
for a rare tumor might be more likely to be published than those
Cutaneous and plexiform neurofibromas occur in a large
percentage of patients with NF1. Numbers of cutaneous neuro-
fibromas were similar in 70% of our MZ twin pairs, suggesting
that tumor burden for cutaneous neurofibromas is strongly
influenced by germline genetic factors. However, our study
neurofibromas, which are often congenital lesions, were much
more discordant among our patients, and all except one pair were
TABLE II. Concordance in NF1 Twins in Literature
Optic pathway glioma
Renal vascular HTN
A, F, J, O
36 A, H, I, J, K, O
A, B, C, D, E, F, G
K, M, O
C, D, E
MPNST, malignant peripheral nerve sheath tumor; HTN, hypertension.
Authors: A¼Easton et al., B¼Pascual-Castroviejo et al., C¼Cartwright et al.,
D¼Crawford et al., E¼Kelly et al., F¼Vaughn et al., G¼Tubridy et al., H¼Lubinsky et al.,
I¼Payne et al., J¼Akesson et al., K¼Bauer et al., L¼Brady et al., M¼Koul et al.,
N¼Cragen et al., O¼Sabbagh et al., #¼number of.
482AMERICAN JOURNAL OF MEDICAL GENETICS PART A
discordant for specific location of the plexiform neurofibromas.
This would be consistent with studies showing second hit muta-
formneurofibromas likelyhave beenunderdiagnosed,asfull-body
MRI was not performed on any of the participants, and small or
asymptomatic tumors may have been missed. Of interest, the one
question of whether paraspinal neurofibromas have different fac-
tors influencing their development than do plexiform neurofibro-
twins could be helpful in determining if paraspinal tumors exist in
other twin pairs and if they are concordant. Malignancy, particu-
pair with extensive paraspinal tumors) as well as one pair reported
in the literature [Akesson et al., 1983], again supporting a random
is therefore difficult to draw conclusions.
CNS malformations, including Chiari malformation, Dandy–
features of NF1, and the high concordance suggests a heritable
influence in their pathogenesis.
Our NF centers have a particular interest in skeletal compli-
evidence from animal models and human data that the hetero-
zygous NF1 state can cause generalized bone abnormalities such
as osteopenia [Kuorilehto et al., 2004; Lammert et al., 2005;
Stevenson et al., 2007; Brunetti-Pierri et al., 2008]. Other skeletal
some such as tibial dysplasia/pseudarthrosis occur very rarely,
with an incidence of only 3–5% of NF1 patients. Scoliosis occurs
in between 15% and 30% of NF1 patients, depending on the type
of population surveyed [Crawford and Schorry, 1999]. Pectus
deformities of the chest wall appear quite common in NF1,
particularly when one looks for subtle manifestations. It is of
interest that four sets of our twins were concordant for the
presence of a pectus deformity, implying heritable control rather
than stochastic events. Although second hit events in NF1 have
been demonstrated in pseudarthrosis tissue from NF1 tibias
complications such as scoliosis, sphenoid wing dysplasia, or
pectus require a second hit event. Some cases of dystrophic
scoliosis in NF1, with an acute sharply angulated curve, may be
impacted by closely located tumors, which would be expected to
occur randomly; likewise, a second hit event in vertebrae could
contribute to a focal dysplastic scoliosis. Our twin pairs showed
mixed concordance and discordance for presence of scoliosis
(PC¼0.67) but the affected pairs were discordant for degree of
curvature, presence of dystrophic features, and need for surgery.
This implies both heritable and non-heritable factors contribut-
ing to the pathogenesis of scoliosis in NF1, but with dystrophic
curvatures likely requiring a non-hereditary event such as a
closely located tumor or a second-hit event in local bone cells
leading to the underlying vertebral dysplasia.
Easton et al.  proposed that modifying genes could
account for the phenotypic variability of NF1 based on phenotypic
concordance in MZ twins and discordance between family mem-
bers with the same mutation. Our data support that for many
features of NF1, there is evidence for heritable modifiers. It can
be speculated that in addition to transcribed genes, other
heritable areas to investigate could include regulatory genes,
etc., which have all been found to modify phenotype in other
disorders. These areas have not yet been fully explored for NF1.
There is also evidence for non-heritable factors involved in many
NF1 complications. Besides second hit events, other non-heritable
factors which could potentially modify the NF1 phenotype could
include epigenetic changes such as methylation differences, and
somatic mosaic events. Recent studies have demonstrated that MZ
twins may not be as ‘‘genetically identical’’ as originally assumed.
Fraga et al.  demonstrated that MZ twins acquire epigenetic
changes throughout their lifetimes. Specifically, epigenetic
differences occurred in different tissue types, increased with age,
differences have been demonstrated in MZ twins discordant for
schizophrenia and in twin pairs discordant for birth weight and
differences in the methylation of the COMT gene promoter region
[Petronis et al., 2003; Mill et al., 2006]. Additionally, Bruder et al.
 recently reported that MZ twin pairs who were discordant
for Parkinson disease showed differences in copy number variants
for future exploration in NF1.
the literature to date, is small. In addition, there has likely been
incomplete ascertainment for certain complications of NF which
young age, and it is unknown whichadditional NF1 complications
they will develop in the future. It will be important to follow
this group into adulthood. Despite these limitations, we have
documented unique concordancies and discordancies within this
of etiology of NF1 complications.
In summary, pigmentary features, numbers of cutaneous
neurofibromas, pectus deformity, and cognitive disabilities seen
have a primary germline genetic etiology. When combined with
data from others showing these features to be less concordant in
more distant relatives [Easton et al., 1993; Sabbagh et al., 2009],
our data support the existence of heritable modifying genes for
these traits. Complications that show high rates of discordance
such as plexiform neurofibromas and malignancies appear to
be influenced by non-heritable or somatic factors, such as a
second hit event in the NF1 allele or other genes. Paraspinal
other plexiform neurofibromas. Skeletal complications were
more difficult to interpret, with evidence for both heritable and
non-heritable contributors to the skeletal phenotype. With the
recent research into methylation discrepancies between MZ
twins, investigation into methylation patterns affecting NF1
warrants future exploration. Prospective multi-center twin
studies will be helpful in elucidating those factors which influence
NF1 complications, including epigenetic, ‘‘second hit,’’ and
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