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Case Report
Dermatology 2004;209:223–227
DOI: 10.1159/000079894
Multiple Myofibromas and an
Epidermal Verrucous Nevus in a Child
with Neurofibromatosis Type 1
Sofie De Schepper
a
Sandra Janssens
b
Ludwine Messiaen
b, c
Caroline Van den Broecke
d
Jean-Marie Naeyaert
a
Departments of
a
Dermatology and
b
Medical Genetics, and
d
Pathology, University Hospital Ghent, Ghent, Belgium;
c
Department of Genetics, University of Alabama, Birmingham, Ala., USA
Received: November 26, 2003
Accepted: April 21, 2004
Prof. Dr. Jean-Marie Naeyaert
Department of Dermatology
De Pintelaan 185
BE–9000 Ghent (Belgium)
Tel. +32 9 240 2298, Fax +32 9 240 4996, E-Mail jeanmarie.naeyaert@ugent.be
ABC
Fax + 41 61 306 12 34
E-Mail karger@karger.ch
www.karger.com
© 2004 S. Karger AG, Basel
1018–8665/04/2093–0223$21.00/0
Accessible online at:
www.karger.com/drm
Key Words
Neurofibromatosis type 1
W Myofibroma W
Epidermal nevus
Abstract
Neurofibromatosis type 1 (NF1) is a com-
mon neurocutaneous autosomal dominant
genetic disorder affecting primarily tissues
derived from the embryonic neural crest.
Two hallmark features of NF1 are the wide
range of potentially affected tissues and the
enormous phenotypic variability of disease
traits even among patients from the same
family. We present a boy fulfilling the diag-
nostic criteria for NF1 with two unusual
lesions: infantile myofibromatosis and a
verrucous epidermal nevus. To our knowl-
edge this association has never been de-
scribed before.
Copyright © 2004 S. Karger AG, Basel
Introduction
Neurofibromatosis type 1 (NF1) is an
autosomal dominant neurocutaneous disor-
der with an estimated prevalence of 1 in
3,000–4,000 individuals.
To establish the clinical diagnosis of NF1
at least two of the following NIH criteria [1,
2] must be fulfilled: 6 or more café-au-lait
spots, the greatest diameter of which is 1 5
mm in prepubertal individuals and 1 15 mm
in postpubertal individuals, 2 or more neu-
rofibromas of any type or 1 plexiform neuro-
fibroma, optic pathway glioma, axillary or
inguinal freckling, 2 or more Lisch nodules,
typical skeletal dysplasia (thinning of long
bone cortex with or without pseudarthrosis
or sphenoid wing dysplasia) or a first degree
relative with NF1 by the above criteria.
The causative NF1 gene is localized on
chromosome 17q11.2 and encodes a very
large protein: neurofibromin. The gene is
highly pleiotropic in that there is a diverse
set of manifestations involving various sys-
tems and types of abnormalities that are due
to the gene mutation. Neurofibromin has
homology to the catalytic domain of
GTPase-activating proteins (GAPs). Three
genes are embedded in intron 27b and tran-
scribed from the opposite strand of the NF1
gene. Advances in our understanding of the
NF1 gene and its product neurofibromin
have led to an increase in our knowledge of
the phenotypic aspects and natural history of
NF1. However, many aspects remain to be
explained. The disease is fully penetrant, but
there is a high degree of phenotypic variabili-
ty among individuals, even among affected
members of the same family. The mutation
rate of the NF1 gene is extremely high, which
implicates that about half of all NF1 cases
are de novo.
Here we present a little boy who, with
café-au-lait spots, axillary and inguinal
freckling and an optic pathway glioma, met
the diagnostic criteria for NF1. The diagno-
sis was confirmed at the genetic level using
fluorescent in situ hybridisation (FISH)
analysis of the NF1 gene.
Preceding the NF1 diagnosis, the boy un-
derwent surgical excision of 2 tumors on his
back, with a histopathological diagnosis of
myofibromas. Later he also developed a ver-
rucous epidermal nevus on the right side of
his upper trunk.
To our knowledge this is the first NF1
patient presenting with 2 unusual lesions
(myofibromas and a verrucous epidermal
nevus) of which the relationship to NF1 is
yet to be established.
Case Report
The patient, a 4-year-old male, presented
with 2 deep tumors on his back at the age of
6 weeks (fig. 1). He was the first child of 2
healthy non-consanguineous parents and
was born preterm at 35 weeks of pregnancy
with a birthweight of 2,800 g.
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Dermatology 2004;209:223–227
De Schepper/Janssens/Messiaen/
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Fig. 1.
At the age of 6 weeks the boy present-
ed 2 tumors on his upper back.
Fig. 2.
The boy has multiple café-au-lait
spots.
Fig. 3.
Two consecutive excisions of myofi-
bromas left a large atrophic scar on his
shoulder.
Fig. 4.
The pedigree of the boy shows no other cases of NF1 or of
consanguinity. Legend: ) = male, [ = female, open symbols = unaf-
fected, filled symbol = affected, X = sex unknown.
Fig. 5.
· Smooth muscle actin staining of the recurrent tumor at the
age of 6 months. Scale bar = 100 Ìm. Vimentin and calponin also
stained the tumor tissue. Neurofilament, S100 protein and desmin
staining were negative.
The tumors were resected and the histo-
logical examination suggested myofibroma.
Infantile myofibromatosis was suspected
and for this reason an abdominal ultrasound
was performed to exclude internal or visceral
myofibromas. No additional tumors were
found and the boy remained in good health
until the age of 6 months. At that time the 2
tumors re-emerged. They were again re-
sected, resulting in the same histological
diagnosis of myofibroma.
By the age of 13 months the boy present-
ed with numerous café-au-lait spots (fig. 2).
Physical examination at that time showed no
major dysmorphic features, no axillary or
inguinal freckling, no cutaneous or subcuta-
neous neurofibromas and a normal neuro-
motor development. His back displayed a
large atrophic scar resulting from the pre-
vious myofibroma surgery (fig. 3). In view of
the large number of café-au-lait spots a mu-
tation analysis of the NF1 gene was per-
formed using an optimized protein trunca-
tion test, which detects the pathogenic muta-
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Neurofibromatosis Type 1 and
Myofibromas
Dermatology 2004;209:223–227
225
tion in approximately 80% of patients fulfill-
ing the NIH diagnostic criteria [3], as the
first test of choice. The protein truncation
test turned out negative and at that time no
further tests were performed to detect a mis-
sense mutation or total gene deletion. There
was no family history of NF1 (fig. 4).
At the age of 21 months the boy was seen
again with complaints of nausea and vomit-
ing. His head circumference had increased
significantly, from a value around the 50th
percentile to one around the 95th percentile.
An MRI of the brain showed a glioma of the
chiasm and right optical tract. Physical ex-
amination also revealed axillary and ingui-
nal freckling. At that time the boy met the
diagnostic criteria for NF1 and a blood sam-
ple was taken in order to perform the next
steps in the cascade of testing developed [3].
FISH analysis using PACs 926B9 and
1002G3 revealed absence of one copy of the
NF1 gene in 20 metaphases counted.
The diagnosis of NF1 was now finally
established and the optic glioma was closely
observed, with magnetic resonance imaging
and ophthalmologic follow-up every 6
months.
More than 1 year later, at the age of 4
years, the parents noticed a verrucous struc-
ture on the right flank of the child. A verru-
cous epidermal nevus, of which the possible
link with NF1 is yet to be established, was
diagnosed and treated with topical retinoids
in anticipation of possible carbon dioxide
laser treatment.
Discussion
The fluorescence in situ hybridization
(FISH) analysis, using the probes PAC22
(926B9, 5) end of the NF1 gene) and PAC 13
(1002G3, 3) end of the gene), showed no sig-
nal for both probes on 1 copy of chromo-
some 17, confirming the diagnosis of NF1
caused by a total gene deletion.
In NF1 a wide variety of mutation types
have been reported. While the majority of
cases are caused by subtle private mutations
that predict truncation of neurofibromin, an
estimated 5–10% are heterozygous for a
germline deletion, predominantly maternal
in origin, encompassing the 350-kb NF1 lo-
cus [4–8]. Until now, no definite genotype-
phenotype correlations have been found, ex-
cept for a more or less distinct severe pheno-
type associated with deletions of the entire
NF1 gene locus. The features of reported
patients include a large number of dermal
neurofibromas with an earlier age at onset,
developmental delay or mental retardation
and a dysmorphic but not entirely character-
istic facies with hypertelorism, ptosis and/or
a Noonan-like appearance [9–17]. Recently
an elevated risk for the development of ma-
lignant peripheral nerve sheath tumors was
described in NF1 microdeletion patients
[18]. It is unclear how consistently this phe-
notype is actually associated with deletion of
the entire NF1 locus. Families have been
reported in which large deletions segregate
not only with NF1 but also with associated
features of the phenotype [12, 14]. On the
other hand many patients with a severe NF1
phenotype do not have large deletions [10,
16], and large deletions have been observed
in patients without this unusual phenotype
[19]. It is hypothesized that the phenotype
associated with a total gene deletion may be
a consequence of the co-deletion of genes
flanking the NF1 gene and/or of the 3 genes
(EVI2A, EVI2B and OMGP) embedded in
exon 27b [13]. Our patient did not display
the distinct total gene deletion phenotype,
suggesting the influence of modifier loci or
the variation in somatic mutations that may
determine the progression and severity of
the disease in different tissues [20]. He has a
normal neuromotor development, no typical
dysmorphic craniofacial features (except for
a macrocephaly) and no early onset of cuta-
neous neurofibromas.
Some of the NF1 deletion patients may
be at increased risk for connective tissue
abnormalities and/or neoplasms, possibly
caused by deletion of an unknown gene in
the NF1 region, which may affect tumor ini-
tiation or development.
At the age of 6 weeks our patient devel-
oped 2 deep nodules in the shoulder region, 1
situated paravertebral and the other more
towards the right scapula. The tumors were
surgically excised and microscopic and im-
munohistochemical studies revealed a diag-
nosis of myofibroma (fig. 5).
A few months later local recurrence of
the 2 tumors occurred. Re-excision was per-
formed with curative results. The recurrence
rate of myofibromas is reported to be as high
as 7–10% but spontaneous resolution of the
tumors has also been described [21].
Infantile myofibromatosis is one of the
most common types of soft-tissue tumors of
infancy and early childhood. It can present
as solitary or multiple lesions, most com-
monly situated in the head and neck region
and shoulder girdle [22]. Visceral tumors
have also been observed in multicentric
form. More than half of the cases of infantile
myofibromatosis appear at or soon after
birth. Most lesions are (sub)cutaneous but
deeper intramuscular, intraosseous or viscer-
al tumors are possible. The lesions are sug-
gested to originate from the myofibroblast
[21–23].
To our knowledge the association of NF1
and myofibromas has never been reported.
There have, however, been several reports
concerning the association of granular cell
tumors [24–27], originally called ‘granular
cell myoblastomas’ by Abrikossoff in his
original description in 1926 [28], and NF1
[29–32]. In addition the malignant rhabdo-
myosarcomas, usually of skeletal muscle ori-
gin as opposed to smooth muscle myofibro-
mas, have also been known to appear in NF1
[33–36]. In one study, as much as 1% of NF1
individuals had rhabdomyosarcoma.
Some studies point to a role for neurofi-
bromin as a growth regulator for muscle
cells. This could explain a mutation in the
NF1 gene favoring muscle cell proliferation,
but formal proof is still lacking [37, 38].
At the age of 4 years, the boy presented
with a linear verrucous epidermal nevus on
the right side of his upper trunk.
Epidermal nevi are organoid nevi arising
from pluripotent germinative cells in the
basal layer of the embryonic epidermis and
are classified according to their predominant
component, in this case (nevus verrucosus)
keratinocyte. Although epidermal nevi are
often present at birth, they may develop dur-
ing childhood and are claimed to be caused
by somatic mosaicism, with a breakpoint
localized in a number of patients to the long
arm of chromosome 1, where the genes of
important epithelial structure proteins such
as profillagrin, involucrin, loricrin and tri-
chohyalin, as well as the two forms of cellular
retinoic acid binding protein are situated
[39–42].
In cases where the epidermal nevi are
associated with abnormalities in other organ
systems, the term ‘epidermal nevus syn-
drome’, originally described by Salomon in
1968, is used [42]. At present 5 epidermal
nevus syndromes are distinguished: (1) seba-
ceous nevus syndrome (Schimmelpenning-
Feuerstein-Mims), (2) comedo nevus syn-
drome, (3) Becker’s nevus syndrome, (4)
Proteus syndrome and (5) CHILD syndrome
[43].
The association of NF1 and epidermal
nevi has been described in the past and was
sometimes classified as epidermal nevus
syndrome [43–46].
In the case presented here the genetic
diagnosis of NF1 was established before the
epidermal verrucous nevus appeared, and it
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Dermatology 2004;209:223–227
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Van den Broecke/Naeyaert
is most probable that they have different
genetic origins since chromosomal aberra-
tions in chromosome 17 have not yet been
identified in epidermal nevi.
In summary, we present an unusual case
of sporadic NF1 caused by a total NF1 gene
deletion and associated with recurrent soft-
tissue tumors and an epidermal nevus.
Acknowledgments
S.D.S. is a research fellow of the Fund for
Scientific Research, Flanders, which sup-
ported this work (grant number G.0292.02).
This work was partially supported by
The Interuniversity Attraction Poles (IUAP)
grant from the Federal Office for Scientific,
Technical and Cultural Affairs, Belgium
(2002–2006, P5/25) to L.M.
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