CLINICAL Journal of Chemotherapy, Vol.

00, 2015, 17

Gardners Syndrome revisited: a clinical case and

overview of the literature
1 1
Jadbinder Seehra , Shruti Patel and Catherine Bryant2
1
Department of Orthodontics, Kings College Dental Hospital, Bessemer Road, London SE5 9RS, UK
2
Department of Oral Surgery, Kings College Dental Hospital, Bessemer Road, London SE5 9RS, UK

Gardners syndrome (GS), a variant of familial adenomatous polyposis (FAP), remains a life-threatening condition of
significant dental relevance. Clinicians can play an important role in the identification of this condition as the
dental manifestations often precede the development of intestinal polyposis. This article describes a clinical case in
which identification of the dental features of GS during routine orthodontic assessment resulted in the early
diagnosis of this condition, which was previously unrecognised in a young female patient.

Key words: Dental, Gardners syndrome, Osteomas

Received 31 July 2014; accepted 07 March 2015

Introduction supernumerary and impacted teeth which often precede

Familial adenomatous polyposis (FAP) (OMIN:
#175100) is an autosomal dominant disorder charac-
terised by multiple adenomatous polyps of the colon and
rectum, which increase in number and size and with
increasing age, can undergo malignant transformation
(Gardner et al., 1980). Mutation of the Adenomatous
polyposis coli (APC) tumour suppressor gene on
chromosome 5q21e22 is responsible for APC (Bodmer
et al., 1987) and mutations of this gene have also been
linked to epithelial tumours (Lesko et al., 2014).
First reported in the 1950s (Gardner and Richards,
1953), Gardners syndrome (GS) is a variant of FAP, with
an incidence ranging between 1 in 8,000 and 1 in 14 000
live births, affecting males and females equally and
without specific ethic predilection (Gardner and
Richards, 1953; Bisgaard et al., 1994). The classic triad of
features consists of colonic polyps, osteomas, and both
cutaneous and subcutaneous soft tissue tumours.
Although GS is inherited with complete penetrance, this
condition may result in variable clinical expression
(Gardner and Richards, 1953). This is highlighted by the
finding that only 38% of GS cases present with the classic
triad (Jarvinen et al., 1982). Most patients develop hun-
dreds of colorectal adenomas during childhood and
adolescence. Of greatest significance is that nearly all
patients will develop colorectal adenocarcinoma by
the age of 4050 years, unless surgical intervention is
undertaken following early detection (Cruz-Correa and
Giardiello, 2003; Vasen et al., 2008). The orofacial
features of GS include osteomas of the jaws, odontomas,
the intestinal polyposis. Identification of the orofacial
features of GS can therefore serve as a sensitive marker of
this condition, facilitating early referral, diagnosis and
instigation of life-saving treatment (Wijn et al., 2007;
Katou et al., 1989; Wesley et al., 1987).
History
A medically fit and well 12-year-old female patient was
referred by her general dental practitioner for a routine
orthodontic assessment. Her presenting complaint was
related to the appearance of her top teeth.
Extra-oral assessment
Extra-orally, the skeletal pattern was assessed as class II
with increased vertical proportions, incompetent lips
and no facial asymmetries.
Intra-oral assessment
Intra-orally, the incisor classification was assessed as class II
division 1 and the overjet was recorded at 8 mm (Fig. 1ae).
Mild crowding localised to the upper and lower labial seg-
ments was recorded. The first permanent molar in the lower
right quadrant had drifted forwards as the LR5 was unerupted.
Essentially a Class I buccal segment relationship was evidant
with crowding in the lower right buccal quadrant. The
upper centreline was to the l eft of t he f acial midline.
Clinical examination revealed that the LLC was retained.
Radiographic assessment
Radiographic examination confirmed the presence of the
unerupted LL3 and LR5. Incidental radiographic findings

*Jadbinder Seehra, Department of Orthodontics,

Kings College Hospital NHS Foundation Trust, Bessemer Road, London SE5 9RS.
Email: jadbinder.seehra@nhs.net
# 2015 British Orthodontic Society DOI 10.1179/1465313315Y.0000000008
 2 Seehra et al. Clinical JO 2015

Figure 1 (a e) Pre-treatment intra-oral views of the malocclusion

included the presence of an odontome overlying the LL3.
Regions of dense radiopacity were observed superior to the
impacted LR5, inferior to the LR8, the interadicular region
between the LR7 and LR8, left maxillary antrum and the
left mental foramen (Figs. 2 and 3). To confirm the diagnosis
and facilitate further treatment planning a Cone Beam
Computed tomography (CBCT) (3D Accuitomo 80;
J. Morita, Irvine, CA USA) scan was undertaken. Radio-
logical reporting of these scans confirmed the dense radio-
pacities to be consistent with osteomas. The possibility of a
differential diagnosis of GS was proposed (Figure 4).
Clinical management
The patient was subsequently referred to a Consultant
Paediatrician and Clinical Geneticist for further
investigation. Blood sampling identified a heterozygous
pathogenic nonsense mutation (c.646CwT; p.Arg216X)
in exon 6 of the APC gene. Following the result of this
test, genetic testing was offered to all other first-degree
relatives. The initial medical management of the
affected individual consisted of monitoring with regular
colonscopy examinations with a view to future
bowel resection.

Figure 2 Pre-treatment Orthopantogram radiograph

 JO 2015 Clinical
Figure 3 Periapical radiograph of impacted LR5 and
overlying radiopacity
Given the wider implications of the patients condition
on her general health, the ideal correction of her mal-
occlusion understandably became less of a priority to
her and her family. The patient was concerned about the
spacing and prominence of her upper incisors so a
compromised treatment involving an upper fixed appli-
ance and extra-oral headgear was prescribed, to address
this specific concern. The presence of increased alveolar
bone density, hypercementosis and odontomas in GS
patients has been suggested as potential obstacles to
orthodontic tooth movement. In this case however,
orthodontic treatment was uneventful (Figure 5).
Figure 4 CBCT images of odontome overlying the LL3 and osteoma overlying the impacted LR5 (a, d) Frontal; (b, e) and
Sagittal (c, f)
Gardners syndrome revisited 3
Discussion
The primary role of the APC tumour suppressor gene is
regulation of intestinal tissue development and homo-
eostasis. At a cellular level this entails regulation of apical-
basal polarity, cell cycle, DNA replication and repair and
apoptosis (Lesko et al., 2014). Adenomatous polyposis coli
is also a well known negative regulator of the Wnt/b-
catenin pathway. Wnt proteins have a major role in cell
formation, specification and self-renewal of stem cells
(Anastas and Moon, 2013). Wnt proteins activate at least
four discrete intracellular signalling pathways including
the Wnt/b-catenin pathway (Xi and Chen, 2014; Nelson
and Nusse, 2004). Importantly, Wnts and their down-
stream effectors regulate several processes that are specific
for tumourigenesis. Dysregulation of Wnt signalling has
been reported to lead to the development of defects and
conditions affecting either tissue development or homo-
eostasis within humans. Furthermore, unregulated func-
tion of this pathway has been implicated in the
development of hyperdontia (Fleming et al., 2010).
Familial adenomatous polyposis develops as a result
of mutation in the APC tumour suppressor gene.
The mutation itself follows a two-hit model, in that
individuals inherit one germline mutation. A subsequent
additional somatic mutation results in the loss of the
wild-type APC allele and tumour development. The
clinical phenotype can vary and is a direct consequence
of the location of the mutation. Mutations at the 59 and
39 ends of the coding sequence are associated with a
weakened FAP phenotype. In contrast, mutation of the
 4 Seehra et al.
Figure 5 Near end treatment orthopantomogram (OPT) radiograph with upper fixed appliance in situ
middle portion of APC is associated with sporadic
colorectal cancers. This mutation cluster region (MCR)
has been identified as a location where b-catenin
binding and down-regulation takes place (Kinzler and
Vogelstein, 1996; Lesko et al., 2014). In this clinical case,
sequence analysis of exon 6 of the APC gene identified a
heterozygous C to T base substitution at nucleotide
position 646 (c.646CwT). This results in the replace-
ment of the amino acid arginine at position 216 with a
stop codon (p.Arg216X) and is therefore considered to
be pathogenic.
Gardners syndrome is a genetic disorder of significant
dental relevance. As highlighted in this clinical case the
identification of the oral manifestation of GS on an
orthopantomogram (OPT) radiograph and further
special investigations led to the diagnosis and instigation
of appropriate treatment. The initial management
involves confirmation of the diagnosis of GS; identifi-
cation of other affected family members and the
reduction of future mortality risk. Diagnosis may
involve consideration of the following factors: family
history, presenting clinical features, intestinal examin-
ation and genetic testing. In the majority of FAP cases a
strong family history is often reported. However, almost
a third of cases are a result of a new mutation within a
family member as exemplified in this case (Bussey et al.,
1978). Following the identification of the mutated gene
in the index patient, predictive testing for the mutation
is commonly offered to the first-degree relatives
(Vasen et al., 2008). Adenomatous polyposis coli
mutations can be identified in 7085% of individuals
following blood sample analysis (Vasen et al., 2008;
Armstrong et al., 1997). If the mutation cannot be
identified by blood test in an apparently affected
individual then bowel screening is indicated. The stan-
dard clinical diagnosis of typical/classical FAP is based
Clinical JO 2015
on the identification of w100 colorectal adenomatous
polyps (Vasen et al., 2008). Approximately 75% of FAP
patients may present with congenital hypertrophy of the
retinal pigment epithelium (CHRPE). Identification of
multiple or bilateral patches of CHRPE has been
proposed as a strong identifier of the GS phenotypic
gene carriers (Lyons et al., 1988). Following diagnosis,
genetic counselling and mutation analysis are offered to
all patients with FAP. Family members that are found
to carry the mutation are advised to undergo periodic
examination of the rectosigmoid colon (from their early
teens) and of the upper gastrointestinal tract to monitor
adenoma development. Prophylactic total colectomy or
subtotal colectomy with an ileorectal anastomosis is
however usually performed because of the potential
for these ademonas to undergo rapid malignant
transformation (Cruz-Correa and Giardiello, 2002).
The clinical features of GS can be divided into both
extra-colonic and colonic features. Extra-colonic features
include osteomata, fibromata, epidermal and sebaceous
cysts and desmoid tumours (Jarvinen et al., 1982; Lyons
et al., 1988; Gurbuz et al., 1994). Reported dental
abnormalities associated with GS include: odontomas,
supernumerary teeth, impacted and ectopic teeth and
hypercementosis (Wijn et al., 2007; Carl and Her-
rera, 1987). Osteomas are the most common skeletal
abnormality associated with GS and probably have the
most significant relevance from a dental perspective.
The frequent sites for these tumours within the facial
complex include: the outer cortex of the skull, paranasal
sinuses and the alveolus of mandible and maxilla
(Lew et al., 1999; Oner and Pocan, 2006; Ida et al., 1981).
Osteomas tend to increase in size and number with
increasing age (Takeuchi et al., 1993). Radiographically
they appear as a well-defined radiopacaity with no
involvement of the root apices. Two distinct patterns of
 JO 2015
osteoma distribution have been described in FAP: focal
(80%) and widespread (20%). The latter is often seen
associated with other abnormalities (Kubo et al., 1989).
Clinically, osteomas are usually asymptomatic but
can cause disfigurement, asymmetry and restricted
mandibular movements depending on their location
within the craniofacial complex (Wijn et al., 2007; Lew
et al., 1999). Almost 50% of FAP patients are reported to
have three or more osteomas present (Ida et al., 1981).
In addition, the highest incidence of supernumerary teeth
and odontomas has been reported to occur in FAP
patients with three or more osteomas (Wolf et al., 1986).
The detection of three or more osteomas in the
maxillofacial complex is suggestive of GS and may
contribute to early diagnosis but has no prognostic value
regarding the development of colonic cancer (Ida et al.,
1981; Takeuchi et al., 1993).
Orthopantomogram radiographs are often requested to
assess the developing dentition as part of a routine
orthodontic assessment. This investigation often alerts the
clinicians to the presence of additional dental pathology.
Previous authors have highlighted the diagnostic value of
OPTs in the identification of the maxillofacial features of
GS (Jarvinen et al., 1982; Utsunomiya and Nakamura,
1975). An association between localized radiopacities
detected on OPTs and FAP has been reported.
Radiopacities are seen in almost 95% of patients with FAP
(Utsunomiya and Nakamura, 1975). Orthopantomo-
grams provide limited information however regarding the
localization, extension and relationship of a tumour mass
in relation to adjacent anatomical structures. In addition,
OPT radiographs may underestimate the exact numbers of
osteomas in GS patients (Halling et al., 1992). The
identification of multiple osteomas is pivotal in the
diagnosis of GS. Cone beam computed tomography scans
are considered the gold standard modality for the
diagnosis of osteomas (DelBalso and Werning, 1986).
The importance of the role that clinicians may play in
the early diagnosis of GS cannot be underestimated.
Orthopantomogram radiographs are commonly taken
during an orthodontic assessment. Maxillofacial path-
ology such as osteomas always appears to precede the
presentation of intestinal polyps. The presence of
abnormal bone and dental findings, in particular
patients who present with three or more osteomas of
the jaws should alert the clinician to initiate further
investigations and instigate appropriate referral, as this
is suggestive of GS.
Disclaimer Statements
Contributors Each of the authors contributed in the
following manner: substantial contributions to the
Clinical Gardners syndrome revisited 5
design of the article, drafting the article or revising it
critically; and final approval of the version to be pub-
lished. The guarantor is Jadbinder Seehra.
Funding None.
Conflicts of interest None.
Ethics approval None.
Acknowledgements
This case report was not funded by any external body.
The authors would like to thank Dr Suk Y. Ng,
Consultant in Dental & Maxillofacial Radiology for
providing the reporting of the radiological images
described in this case.
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