Chief complaint and medical history
A 29-year-old male patient visited for the overall evaluation and treatment regarding
the underdevelopment of the maxilla, and multiple impacted teeth. The patient had
no medical history or disease except tonsillectomy at ENT.
Clinical features
The height of the patient was less than the average height for the age, approximately
170Â cm. An 8-unit bridge fixed prosthesis replaced a large number of unerupted maxillary
permanent teeth (#11, 21, 22, 23) (Fig. 1). The patient showed hypertelorism but no hypermobility of the scapula. His shoulders
could not be brought closer together and did not meet in the middle of the body (Fig. 2). The patient also did not show any sign of mental retardation or physical disability.
And there was no family history of vertical or horizontal inheritance of the disease.
Fig. 1. Panoramic radiographs at the age of 11 and 29 show unerupted maxillary permanent teeth.
a At the age of 11. b At the age of 29
Fig. 2. Shoulder mobility test shows that the patient’s shoulders cannot be brought closer
together
Radiographic features
Chest PA revealed thick and short clavicles with a bell-shaped thoracic cage (Fig. 3).
Fig. 3. Chest PA images show a bell-shaped thorax and a short and thick clavicle
PA cephalogram confirmed a large amount of wormian bone at the lambdoidal sutures,
aplasia of the frontal sinus, and the dysplasia of the zygomatic bone (Fig. 4). The temporal bone was so compact that the mastoid cell of the petrous potion was
barely observable.
Fig 4. PA chephalogram shows a large amount of wormian bone at the lambdoidal sutures, aplasia
of the frontal sinus, and the dysplasia of the zygomatic bone
Lat cephalogram at the age of 11 and 29 is shown in Fig. 5. The cephalometric analysis of the same patient at the age of 11 and 29 is listed
in Table 1. The tendency of maxillary hypoplasia and short cranial base length compared to the
others is shown.
Fig 5. Lat cephalometric radiographs at the age of 11 and 29 show the tendency of maxillary
hypoplasia and pseudo-mandibular prognathism due to midface deficiency. a At the age of 11. b At the age of 29
Table 1. Cephalometric analysis at age 11 and at age 29
A panoramic radiography revealed multiple unerupted permanent teeth (#11, 21, 22,
23, 38) and the parallel-sided borders of the ascending ramus. The coronoid process
was directed to the postero-superior, not to the antero-inferior, and the density
of the ascending ramus was increased between the anterior border of the mandible and
the inferior dental canal.
Gene analysis
The patient was referred to the medicine laboratory of Samsung Hospital in Seoul for
gene sequencing of the runt-related transcription factor 2 (RUNX2) gene. A missense
mutation of the 1259th nucleotide C being replaced with T was discovered from the
analysis, and it caused this mutation of the 420th amino acid Thr (thyrosine) substituted
with isoleucine. A similar result of the gene mutations has been reported previously
in other literatures (Table 2).
Table 2. Gene mutation analysis. It shows a missense mutation of the 1259th nucleotide C being
replaced with T, and it causes the mutation of the 420th amino acid, Thr (thyrosine),
being substituted with isoleucine
Treatment
Multiple maxillary and mandibular impacted teeth and the retained root of #36 were
extracted under general anesthesia in February 2013. On the 7th postoperative day,
the patient revisited the Department of Oral and Maxillofacial Surgery with left mandibular
coronoid process fracture, which occurred as the patient was chewing on hard food
and had experienced pain with a crack sound (Fig. 6). No additional treatment was performed, but the patient was regularly followed up
for the next 9Â months, and it was evident from a panoramic radiograph that the left
coronoid process fracture was healed successfully. Osstem TS III 4.0?×?11.5 mm implant
was installed for tooth #36. Finally, he was treated with fixed prosthesis for the
restoration of partially edentulous maxilla and tooth #36 (Fig. 7).
Fig 6. Panoramic radiography shows the fracture of the left mandibular coronoid process
Fig 7. The patient was successfully treated with fixed prosthesis for the restoration of
partially edentulous maxilla and tooth #36
Discussion
Cleidocranial dysplasia (CCD) follows an autosomal dominant pattern of inheritance.
CCD is caused by mutations in the RUNX2 gene which is critical for osteoblast differentiation
and function. Prevalence of CCD is about 1/1,000,000 without any gender or racial
difference 8].
The skeletal features of CCD are short stature, hypoplasia or aplasia of the clavicle,
and, consequently, hypermobility of the scapula. A bell-shaped small thoracic cage
and dysplasia of the scapula are also seen in patients with CCD 9].
The CCD patients exhibit pseudo-mandibular prognathism due to midface deficiency and
higher incidence of paranasal sinus infection caused by maxillary sinus hypoplasia
and otitis media compared to other patients without the condition 10].
A delayed closure of the cranial sutures and the frontanelles is observed in the cephalographic
radiography. Especially the presence of wormian bones in the coronal suture and the
lambdoidal suture is often observed because the area acts as a secondary center of
the compensatory ossification for bone union 11].
Prolonged retention of deciduous teeth, multiple unerupted supernumerary teeth, and
delayed eruption of the permanent teeth are detected from the panoramic radiograph.
Additionally, the radiograph shows the characteristics of the parallel-sided borders
of the ascending ramus and coronoid process in posterior inferior direction 12]. McNamara et al. reported a morphological abnormality of the maxilla and mandible
of the patient with CCD in panoramic radiograph as follows [Table 3].
In this case, both clavicles were short and thick. Most of the intraoral features
of CCD were recognized from the patient’s clinical examination and radiographs.
The RUNX2 gene is essential for mesenchymal cells to differentiate into osteoblast.
It is composed of runt domain, proline/serine/threonin-rich (PST) activation domain,
and N-terminal (Q/A domain) with continuous repetition of glutamine and alanine 13]
There are many studies reporting the mutation of RUNX2 to cause CCD. Inactivation
of the RUNX2 gene of mice completely deteriorates the bone generation 14]. It was also reported that RUNX2 knockout mouse died immediately after birth as a
result of respiratory failure. A mouse with a mutated heterozygous RUNX2 gene had
open frontanelles and hypoplasia of the clavicle which are the typical features of
CCD 15].
In this patient, the missense of the 1259th nucleotide, C replaced by T, in PST domain
ultimately introduced incorrect 420th amino acid change, Ile instead of Thr. And it
was already reported that T420I mutation of RUNX2 is associated with CCD 16]. Therefore, T420I mutation in PST domain caused CCD by affecting transcriptional
activation of target genes.
Numerous experiments on the mutation of RUNX2 have been carried out, and the opinions
on the correlation of the mutation of the RUNX2 gene and the phenotypic variabilities
are still controversial. Quack et al. said that there is no difference between the
phenotypes of missense, deletion, insertion, and frameshift mutation, but only haploinsufficiency
is caused by the mutations 17]. The truncated protein which resulted from the mutated gene may be unstable in intracellular
environment and can be degraded rapidly 18]. Thus, different intracellular concentration levels of the RUNX2 protein can affect
the manifestations of the disease. Yoshida et al. suggested that if the runt domain
is intact, the mild short stature is observed and that there is also a significant
correlation between short stature and number of supernumerary teeth from gene analysis
of 17 patients with CCD 19]. He also confirmed hypoplasia of the clavicle and open frontanelle from all of his
patients. He mentioned that cleidocranial bone formation by intramembranous ossification
requires a higher level of RUNX2 gene compared to skeletal bone formation by endochondral
ossification and the tooth formation by odontogenesis.
Most mutations of the RUNX2 gene usually occur in runt domain and may cause haploinsufficiency
which generates a classic phenotype of CCD. However, mutation outside the runt domain
can result in a hypomorphic phenotype with clinical variability that is different
from the typical CCD. In the case of this patient, mutation of the RUNX2 gene in PST
domain was identified. His clavicles were short and thick, and his height was close
to the average. Also, no intraoral supernumerary teeth existed, but multiple impacted
permanent teeth were only observed in the maxilla.