Download genetic basis of von recklinghausen disease genetyczne podstawy

Nowiny Lekarskie 2013, 82, 3, 259–261
PRZEMYSŁAW KOPCZYŃSKI1, ANNA WAWROCKA2, MACIEJ R. KRAWCZYŃSKI2,3, RAFAŁ FLIEGER1
GENETIC BASIS OF VON RECKLINGHAUSEN DISEASE
GENETYCZNE PODSTAWY CHOROBY VON RECKLINGHAUSENA
1
Centre for Orthodontic Mini-implants at the Department and Clinic of Maxillofacial Orthopaedics and Orthodontics
Poznan University of Medical Sciences, Poland
Head: Przemysław Kopczyński PhD
2
Poznan University of Medical Sciences
Chair and Department of Medical Genetics
Head: Professor Anna Latos-Bieleńska
3
Center for Medical Genetics GENESIS, Poznan, Poland
Head: Professor Anna Latos-Bieleńska
Abstract
The authors present the changes in the mastication organ in the case of a 9-year old girl affected with von Recklinghausen’s disease.
The symptoms included neurofibromatosis of her face, salivary gland and external ear in the form of an extensive tumour. The disease resulted also in acute right hemifacial hypertrophy. The computer-assisted tomography examination identified acute atrophy of
zygomatic bone, maxilla, mandible alveolar ridge and right base of the skull. The clinical intraoral examination of the patient revealed right buccal occlusion and lingual occlusion on the opposite side.
KEY WORDS: neurofibromatosis, hypertrophy of the mandible, computer tomography.
Streszczenie
Autorzy przedstawiają zmiany narządu żucia u 9-letniej dziewczynki dotkniętej chorobą von Recklinghausena. Objawy u niej zaobserwowane to
nerwiakowłókniakowatość twarzy, ślinianek i ucha zewnętrznego w postaci rozległego guza. W ostrej fazie choroba spowodowała także połowiczy przerost prawej części twarzy. W badaniu tomograficznym zidentyfikowano zanik kości jarzmowej, wyrostka zębodołowego szczęki
i żuchwy oraz części prawej podstawy czaszki. Wewnątrzustne badanie pacjenta wykazało prawostronny zgryz przewieszony i zgryz krzyżowy
po stronie przeciwnej.
SŁOWA KLUCZOWE: nerwiakowłókniakowatość, przerost żuchwy, tomograf komputerowy.
Introduction
Medical literature defines von Recklinghausen’s disease, also known as neurofibromatosis type 1 (NF1), as
an autosomal dominant disease characterized by abnormalities affecting tissues derived from the neural crest.
Neurofibromatosis type 1 (OMIM 162200) occurs in the
general population with frequency of approximately 1 in
3,500 livebirths [1]. It is caused by dominant loss of
function mutations of the NF1 gene (OMIM 613113).
NF1 gene is located on chromosome 17q11.2 and encodes neurofibromin – a cytoplasmic protein that is
mostly expressed in neurons, Shwann cells, oligodendrocytes and leukocytem [2]. It is involved in various signaling cascades and one of the best characterized functions
of NF1 protein is its action as a GTPaseactivating protein (Ras-GAP) [3]. NF1 gene shows one of the highest
mutation rates among human genes, therefore about half
of the NF1 cases result from new mutations [4]. Over
1,300 different mutations have been described so far in
the human gene mutation database (HGMD®;
http://www.hgmd.cf.ac.uk/ac/index.php). Majority of
NF1 gene mutations (20-50%) are splicing mutations,
that seriously alter the structure of the protein [5, 6, 7].
Due to extremely big size of the gene and enormous
number of mutations, molecular diagnosis of NF1 is
difficult and routinely limited to analysis of NF1 gene
towards big deletions and duplications using MLPA
analysis [5,6]. Von Recklinghausen’s disease is diagnosed when at least 2 out of the 7 following criteria are
met: first degree relative afflicted with neurofibromatosis
type 1, min. six café-au-lait spots with a diameter exceeding 5 mm (children) and 15 mm (adults), min. 2 neurofibromas of any type or one plexiform neurofibroma,
freckles and/or discolouration found on covered parts of
the body, optic nerve glioma, min. two Lisch nodules as
well as characteristic bone lesion such as sphenoid wing
dysplasia or thinning of long bone cortex [8]. According
to the study carried out in 2007, the differential diagnosis
of NF1 should focus on excluding such disorders as rare
mosaic or segmental neurofibromatosis type 1, neurofibromatosis type 2, schwannomatosis, Noonan syndrome,
Watson phenotype, café-au-lait spots inherited as an
autosomal dominant condition, McCune-Albright syndrome, LEOPARD syndrome, Klippel-Trénaunay syndrome, Proteus syndrome, multiple lipomas, BannayanRiley-Ruvalcaba syndrome, fibromatosis, multiple endocrine neoplasia syndrome type 2B as well as homozygo-
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Przemysław Kopczyński i inni
sity for one of the genes responsible for causing hereditary non-polyposis cancer of the colon [9]. The aim of this
study was to identify changes in the mastication organ and
specify possibilities of orthodontic treatment of a patient
suffering from von Recklinghausen’s disease.
Case study
We present a case of a 9-year-old girl of Polish origin suffering from von Recklinghausen’s disease with
neurofibromatosis of face, salivary gland and external
ear in the form of an extensive tumour. In consequence,
acute right hemifacial hypertrophy was identified. The
extraoral examination of facial features revealed that the
central part of the chin moved towards the unaffected
side of the face, while the angle of the mouth lowered
significantly towards the affected side of the face. The
clinical intraoral examination of the patient revealed
right buccal occlusion and lingual occlusion on the
opposite side. The computer-assisted tomography examination identified acute atrophy of maxilla, zygomatic
bone, mandible alveolar ridge and right base of the skull.
Despite a number of surgical procedures aimed at removing the tumour (first procedure when the patient was
6 years old), the tumour kept recurring.
Discussion
According to literature, neoplasia is an inherent characteristic of a phenotype seen in patients suffering from
von Recklinghausen’s disease - therefore, it is the main
factor influencing the selection of a therapy. Although
there are certain single attempts of pharmacological
treatment of ganglioneurofibromas at their early development stage, it is agreed that, in fact, no preventive
actions are possible. Hence, in the case of neurofibromatosis type 1, reconstruction and aesthetic procedures are
widely applied in treating the disease [10]. The orthodontic appliance used in the case of the analysed patient
aimed, among others, at improving facial features by
means of making a functional change in the position of
the mandible. Von Recklinghausen’s disease in the oral
cavity often manifests itself by gingival overgrowth,
erosions, increased proneness to caries and to attachment
loss due to problems with maintaining proper hygiene.
Another phenomenon noticed in the case of the disease
is the lack of teeth buds, teeth migration or intrusion. It
is often underlined that until the skeletal development is
complete, prosthetic restorations which could impact
bone growth should not be used. The best solution seems
to be the one offered by temporary restorations, the use
of which should be consulted with an orthodontist. It was
also suggested that in many cases orthodontic treatment
suffices, as restoration may be combined with the treatment of existing malocclusion with the use of orthodontic appliances. The appliances should be constructed
with consideration to the missing teeth and they should
restore them, prevent teeth migration, maintain space for
erupting permanent teeth, restore correct articulation and
occlusal conditions and stimulate maxilla’s and mandi-
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ble’s bone development [11]. In the case of the described
patient, orthodontic treatment with the use of removable
appliance prevented further intensification of the malocclusion and it was not necessary to introduce any
other elements to the Metzelder’s appliance.
Surgical treatment of a patient with a hemimandibular hyperplasia was conducted in the Maxillo-Facial
Surgery Department in Poznań. The 18-year old patient
with right hemimandibular hyperplasia underwent (based
on pre-operative and operative measurements) a correction procedure - sagittal mandibular osteotomy at the
side of the hyperplasia combined with dissection of inferior alveolar nerve and genioplasty. Additionally, sagittal
split osteotomy of the mandible was conducted on the
opposite side. The correction of the occlusion involved
Le Fort I osteotomy [12]. In the analysed case, the hyperplasia was caused by a neoplastic tumour. The surgical action consisted in its enucleation, but despite the
procedure relapses occurred requiring repeated surgical
procedures. Studies conducted in 2007 suggested that in
the case of children suffering from von Recklinghausen’s disease deciduous teeth erupt earlier. Researchers
explained this phenomenon with the activity of osteoclasts, which are more prone to migrate and proliferate in
comparison with the cells of healthy individuals. This
leads to faster alveolar process bone resorption around
deciduous teeth buds and thus earlier eruption of the
teeth [9]. The applied orthodontic appliance, owing to its
construction, could have been used by the patient during
the entire process of the functional treatment, regardless
of the presence of particular teeth during teeth replacement stage and did not inhibit the functioning of the
mastication organ. During visits at the orthodontic surgery, special surfaces in the acrylic mass of the appliance
were prepared to enable uninhibited eruption of permanent teeth. Finnish authors made a groundbreaking discovery of a sex-dependent characteristic in the case of
patients suffering from neurofibromatosis type 1. Based
on an analysis of pantomographic images of 55 patients
(29 women and 26 men), the scientists proved that cement dysplasia around lower teeth root apexes affects
only women. Additionally, they also pointed to the fact
that 85% of cases showed enlargement of mandibular
foramen and canal. Although the changes often accompany plexiform tumours located in this area, it is a characteristic of von Recklinghausen’s disease and may be
taken into consideration in differential diagnostics also
in cases in which neoplastic changes are not present in
those anatomical areas [10]. Radiological testing of the
patient showed no dysplastic cement changes around
teeth roots, but it did show slightly enlarged mandibular
foramens and canals. Neurofibromatosis type 1 is characterised by highly variable expression, even within the
same family [4]. A recent study of monozygotic twins
reported by Rieley et al. confirmed the opinion that
different phenotype expression is observed not only in
family members with the same mutation but also in individuals who have inherited the same NF1 germinal
Genetic basis of von Recklinghausen disease
mutations [13]. This variability is not well understood.
Genotyp/phenotype correlation studies showed that the
type of mutations in the NF1 gene does not have much
influence on phenotype variability. Easton and Sabbagh
et al. confirmed the impact of the modifier genes (including protein-coding genes, microRNA and long noncoding RNA) and environmental factors on the phenotypic variability [2, 14, 15]. Easton at al. concluded that
the genotype at modifier loci determines the phenotypic
expression [14]. A better understanding of the naturally
occuring genetic modifiers, may contribute to improve
the prediction and treatment (new therapeutics) of neurofibromatosis.
Summary
Considering the malocclusion they are suffering
from, children diagnosed with von Recklinghausen’s
syndrome should undergo orthodontic consultation and,
if necessary, should be treated with the use of removable
appliances, so that the malformation of the mastication
organ does not intensify.
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Adres do korespondencji:
Rafał Flieger
ul. Bukowska 70
Poznań
tel: 660446872
e-mail: [email protected]
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