VON RECKLINGHAUSEN DISEASE:
ONE PATIENT – VARIOUS PROBLEMS
Bergler-Czop B, Miziołek B, Brzezińska-Wcisło L
*Corresponding Author: Associate Professor Beata Bergler-Czop, Department of Dermatology, Silesian
Medical University Katowice, Francuska Street 20/24, 40-027, Katowice, Poland. Tel./Fax: +48-32-284-
0877. E-mail: bettina2@tlen.pl
page: 95
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DISCUSSION
von Recklinghausen disease belongs to a group
of disorders called phakomatosis, which is characterized
by a set of symptoms resulting from the involvement
of the skin, nervous system and eye. However,
there are many possible manifestations of vRD [1].
The disease is a consequence of a mutation within
the NF1 gene located on chromosome 17 in locus
q11.2. An autosomal dominant pattern of inheritance
is a characteristic feature of the disease, however, it
is observed that about 50.0% of affected patients do
not have a family history of the disease [1,5,6]. Sporadic
vRD was speculated to occur as a new mutation
mainly in the germ cells of fathers. Opinions about an
influence of parental age on the risk of occurrence of
NF1 in a child are divergent. Although Bunin et al.
[7] observed that fathers of patients with vRD were
1.5 years older than fathers of control subjects at the birth of the child, the difference was only borderline
statistically significant.
The product of the NF1 gene is a cytoplasmic
327 kDa protein called neurofibromin, which acts
predominantly as tumor suppressor factor. Neurofibromin
modulates the activity of another protein
called RAS which is responsible for regulation of
cell proliferation and differentiation acting through
RAS/MAPK and RAS/PI3K/AKT/mTOR signaling
transduction pathways [3,8]. Briefly, both pathways
mediate a signal from a membrane tyrosine kinase
receptor activated by growth factor. The activation of
such receptor promotes an activation of RAS protein
by binding a GTP (guanosine triphosphate) particle
to this protein that leads to a formation of activated
RAS-GTP complex. This complex subsequently activates
the following pathways dependant on MAPK
and/or PI3K/AKT/mTOR. Both pathways provide a
signal to the nucleus for cellular growth and proliferation
[9].
Neurofibromin converts active RAS-GTP into
its inactive form, thereby inhibiting both downstream
pathways (MAPK and PI3K/AKT/mTOR).
Preserved activity of neurofibromin limits possible
overstimulation by these pathways preventing from
an excessive growth and proliferation of cells. Mutations
within the NF1 gene impair functions of neurofibromin
that cannot properly control the activity
of RAS and, therefore, also of both downstream
pathways. Possible concomitant activating mutations,
which convert the RAS proto-oncogene into
an oncogene, develop a condition that can lead to
uncontrolled cell proliferation with further tumor
formation [10]. Most patients carry (in all their cells)
both normal and dysfunctional copies of the NF1
gene. In accordance with Knudson’s two-hit hypothesis,
vRD patients carrying a heterozygous germline
mutation within the NF1 gene develop neurofibromas
if mutation occurs also in the second, wild-type, NF1
allele. Somatic inactivation of the NF1 gene may
result from different mutational mechanisms and may
involve intragenic mutations, loss of heterozygosity
(LOH) and epigenetic modification of the promoter
region. Biallelic inactivation of the NF1 gene, causing
a complete loss of functional neurofibromin, initiates
the pathogenic process that eventually results in
the formation of tumors. The NF1 gene inactivation
may occur through by relatively subtle mutation that
can affect just a few DNA bases, or may involve
large genomic changes affecting large chromosomal
regions with contiguous genes, or even the entire
chromosome 17 [8].
Regarding to the type and the extent of mutation
within the NF1 gene, a different phenotype can
be developed. Approximately 5.0-20.0% of all vRD
patients carry a heterozygous deletion of usually 1.5
Mb, involving the NF1 gene and contiguous genes
lying in its flanking regions. The loss of other genes,
as well as NF1 haploinsufficiency, is responsible for
more severe than usual phenotypes known as vRD
microdeletion syndrome. This condition is characterized
by earlier onset of classic manifestations of
vRD, additionally complicated by a development
of other pathologies such as dysmorphisms, cardiac
anomalies, mental retardation or greater risk of malignancies
[11,12]. Another observations revealed an
association between mutations at the 5’ end of the
NF1 gene and the development of optic glioma in
patients with vRD [13]. Upadhyaya et al. [14] and
Rojnueangnit et al. [15] found that a 3 bp deletion
(c.2970-2972delAAT) in exon 17, causing Met992del
in neurofibromin protein, was responsible for a development
of phenotype without cutaneous the neurofibromin.
Pinna et al. [16] presented another mild
variant of vRD, also related to a missense mutation
affecting codon 1809 (c.5425C>T) and causing a
substitution of arginine to cysteine (Arg1809Cys) in
neurofibromin. Characteristics for these phenotypes
was an absence of the following abnormalities: cutaneous
neurofibromas, Lisch nodules, typical osseous
lesions or symptomatic optic gliomas. In accordance
with observations by Rojnueangnit et al. [15], this
variant was also associated with a short stature and
features suggesting Noonan syndrome [16].
Theoretically, substitution of a single nucleotide
of the Arg1809 codon CGC can result in six different
missense variants. Arg1809 resides at the C-terminal
α helix of the Pleckstrin Homology (PH) domain
of neurofibromin, however, its functions have not
been fully elucidated [15]. Presumptively, the domain
interacts with the Sec-14 domain, thus targeting neurofibromin
to facilitate colonization with RAS [17].
Amino acid changes at position 1809 were found
to cause a significant rearrangement of the secondary
structure of the PH domain that severely disrupt
interactions between the above reported domains
within the protein. The presence of only cutaneous
pigmentary manifestations of rVD would be deprived of cutaneous neofibromas or Lisch nodules, with a
special tendency to occurrence of dysmorphic features
characteristic for the Noonan Syndrome [18].
The diagnosis of vRD is based on clinical criteria
and genetic analysis is not required. To recognize the
disease, it is necessary to fulfill at least two out of
seven following criteria established at the National
Institutes of Health Consensus Conference in 1988
[1,19,20]: 1) >6 CAL (café au lait) spots (>5 mm in
size at pre-puberty and >15 mm in adults); 2) axillary
or groin freckling (Crowe’s symptom ); 3) >2
neurofibromas of any type or one plexiform neurofibromas;
4) optic pathway glioma; 5) a presence of
>2 Lisch nodules (iris hamartomas, best observed in
a slit lamp); 6) detection of characteristics for vRD
bone abnormalities (bony dysplasia of the sphenoid
wing; thinning of the long bone cortex with or without
pseudarthrosis of the long bones); 7) first degree
relative with vRD.
Our male patient fulfilled four of these seven
criteria: multiple neurofibromas, freckles in axillary
areas, Lisch nodules and the presence of bone abnormalities
within the left shin. Another suspicious
findings could enhance the clinical diagnosis of vRD:
presumptive vRD of the patient’s mother, a suspicion
of the right optic glioma and spotty hyperpigmentations
of the skin. Interestingly, patients with vRD
may experience CAL spots for a period of time, with
the onset of such lesions usually in early childhood.
Their numbers tend to increase into the early teens
and then CAL spots may fade or even disappear in
some adults [1,5].
The majority of patients with vRD can be diagnosed
by careful analysis of clinical symptoms of the
disease. Recommendations for considering NF1 gene
testing involve [5]: 1) young children with >6 CAL
spots as the sole disease manifestation with negative
family history towards vRD – other features (including
cutaneous neurofibromas) may not develop until
early adulthood; 2) children over 3 years old with 3-5
CAL spots and no other manifestations of Vrd; 3)
families with CAL patches and freckling but without
neurofibromas – unusual phenotypes of the disease.
Indeed, some clinical variants may provide difficulties
in proper diagnosis and recently, Kehrer-
Sawatzki [17], inspired by Rojnueangnit et al. [15],
postulated the importance of mutation testing in vRD
patients. This management would allow for a proper
recognition of less evident cases involving the above
mentioned phenotypic variants. Such genetic analysis
can also provide great psychological relief to those
patients with the above presented clinical variants of
the disease due to the absence of the greater risk of
vRD-associated tumors [15,17]. Santoro et al. [18]
also advised the necessity of combined vRD testing
together with SPRED1 (sprouty-related, EVH1 domain
containing protein 1) analysis. Essentially, mutations
of the SPRED1 gene lead to the development
of Legius syndrome, which is a disorder with a pigmentary
phenotype overlapping with vRD syndrome,
but with a much better long-term prognosis [21]. Molecular
analysis of the NF1 gene based on genomic
DNA is challenging due to its large size (more than
50 exons and 300 kb of genomic sequence), as well as
the presence of NF1 pseudogenes on the other chromosomes
[22]. Abramowicz and Gos [3] suggested
combining several methods to analyze the NF1 gene
that allows the detection of mutations in up to 95.0%
of patients with a clinical diagnosis of the disease.
There is a superiority of multiplex ligation-dependent
probe amplification (MLPA) over fluorescent in situ
hybridization (FISH). Multiplex ligation-dependent
probe amplification allows for both quantitative assessment
of specific DNA fragments, as well as for
detection of duplications or deletions (even of a single
exon) within the NF1 gene. In contrast to MLPA,
FISH detects mainly deletions involving large portions
of the NF1 gene, and furthermore, there is a
risk of hybridization of the probe to false NF1 pseudogenes.
Another inadequate technique for analysis
used to be the protein truncation test. Undoubtedly,
a very useful technique comprises sequencing of the
NF1 gene based on the analysis of cDNA synthesized
by reverse transcription from mRNA. This analyzes
only a small portion of the NF1 gene without its introns.
This technique was estimated to detect approximately
90.0% of mutations in patients with a
clinical diagnosis of vRD. However, some doubts
result from a fact that a large number of the NF1
genes involve splicing abnormalities, and therefore,
it is more reasonable to combine sequencing based
on both mRNA and genomic DNA [4].
Treatment of vRD has still been only a symptomatic
striving for reduction of the most disfiguring
or life-threatening complications of the disease.
Plexiform neurofibromas, tumors pressing peripheral
nerves or those causing other neurological symptoms
and suspected malignancies, should be referred for mandatory surgical treatment. Repeated removal of
disfiguring cutaneous lesions with cryo-surgery or
laser therapy may significantly improve individual
quality of life, allowing for achievement of selfacceptance
[1].
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