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Figure16.16 Axial and 3D cone beam computed tomography of the same patient in Figure16.15. Not the
multilocular appearance of cherubism in the mandible and buccal and lingual expansion. Source: Fadi
Titinchi.
osteoclastogenesis. Most of the missense mutations identified so far are in exon nine(72, 73). The
cherubism locus was mapped to chromosome 4p16(74), with subsequent identification of a single missense mutation in the gene that encodes the adaptor protein 3BP2within this locus(73).
Osteoclasts are the primary bone- resorbing cells and are pivotal in regulating bone morphogenesis and remodelling. One potent cytokine, RANKL (Receptor Activator of Nuclear Factor κB
Ligand), binds to the receptor activator of NFκB (RANK; TNFRSF11β), which is expressed on the
surface of osteoclast progenitor cells. RANKL initiates a series of changes in gene expression
within preosteoclasts, leading to osteoclast differentiation and the formation of mature, boneresorbing osteoclasts. RANKL exerts its effects on osteoclastogenesis primarily through the transcription and activation of NFATc1 (Nuclear Factor of Activated T- cells, cytoplasmic 1), considered
the master regulator of osteoclast formation(75).
NFATc1 is activated by calcineurin, a calcium- calmodulin- dependent phosphatase, through a
dephosphorylation process. This activation facilitates the translocation of NFATc1 into the cell
nucleus, which is crucial in regulating osteoclastogenesis(75).
Management: Cherubism is generally self- limiting and rarely requires surgical intervention. Long-
term observation and follow- up are the initial management strategy in most patients. Surgical
treatment with curettage, recontouring or resection may be necessary for functional or aesthetic
concerns. These procedures are typically employed when the disease process becomes quiescent. Aggressive lesions that cause significant functional complications, such as airway obstruction, necessitate early surgical intervention(71).
16.4.3 Osteopetrosis
Osteopetrosis (marble bone disease) is a group of rare, heritable disorders of the skeleton
characterised by higher bone density. The incidence of autosomal recessive osteopetrosis
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Figure16.17 Panoramic radiograph of a patient with osteopetrosis showing increased density of bone in
the maxilla along with multiple impacted teeth. Also, note previously managed osteomyelitis of the left
mandible. Source: Fadi Titinchi.
(ARO) is 1in 250,000, while autosomal dominant osteopetrosis (ADO) is more common, with
an incidence of 1in 20,000(76).
Clinical Features: Osteopetrosis presentation varies widely in severity, which ranges from life-
threatening complications in neonates with bone marrow failure to incidental discovery on
routine radiography. Classic ARO is characterised by multiple fractures, short stature, compressive neuropathies, hypocalcaemia with seizures and life- threatening pancytopenia.
Patients with ADO are classically present with fractures and osteomyelitis in late childhood or
adolescence(76).
261
Manifestations of osteopetrosis in the jaws include developmental anomalies of the dentition,
cranial nerve palsies and pathological fractures (Figure16.17). Osteopetrosis is frequently complicated by osteomyelitis, which is commonly refractory to treatment due to hypovascularity of the
jaws(77).
Pathogenesis: Osteopetrosis arises from impairment of osteoclast development or function, and the
identification of mutations in at least ten genes has been linked to its causation in humans,
accounting for 70% of all cases. This condition can be inherited through various modes, including autosomal recessive, autosomal dominant, or X- linked traits, with the severe forms typically
manifesting as autosomal recessive. In the case of ‘pure’ autosomal recessive osteopetrosis
(ARO), the disease results from biallelic mutations in one of seven genes. These genes include
TCIRG1, CLCN7, OSTM1, SNX10 and PLEKHM1, which encode proteins involved in processes
such as the acidification of resorption lacunae and vesicular transport (78). Loss- of- function
mutations in these genes lead to osteoclast- rich osteopetrosis, characterised by abundant but
non- functional osteoclasts. Conversely, mutations in TNFSF11 (RANKL) and its receptors
TNFRSF11A (RANK) are associated with osteoclast- poor osteopetrosis, where osteoclastogenesis is inhibited. Autosomal dominant osteopetrosis (ADO) and X- linked osteopetrosis result
from mutations in CLCN7 and hypomorphic mutations in the NEMO (NF- κβ essential modula-
tor) gene, respectively(79).
Management: Treatment of osteopetrosis patients is mainly symptomatic, although stem cell
transplantation is being more frequently utilised for the more severe forms accompanied by
bone marrow failure. This offers the best outcome for more prolonged survival of these patients.
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The infantile variants of osteopetrosis are associated with reduced life expectancy, whereas life
expectancy is normal in the adult- onset variant(76).
16.4.4 Gardner Syndrome
Gardner syndrome (GS) is a subtype of familial adenomatous polyposis (FAP), an autosomal dominant syndrome encompassing a triad of colorectal polyps, multiple osteomas and a variety of soft
tissue tumours. GS develops due to mutation in the adenomatous polyposis coli (APC) tumour
suppressor gene. The reported incidence of GS ranges between 1in 8000– 14,000with no ethnic or
gender predilections(80).
Clinical Features: Patients with GS have a high risk of developing colorectal cancer at a younger
age. Almost all colorectal polyps will undergo malignant transformation if left untreated, with
59% of patients dying from colorectal cancer as a result of extensive metastasis. Osteomas in the
jaws become clinically apparent around puberty and are usually detected before intestinal polyps. They commonly present at the mandibular angle and can cause significant facial deformity
and reduced mouth opening without pain (Figure16.18). Supernumerary and impacted teeth
are also frequent findings in the jaws. Common soft tissue manifestations of GS include epidermoid cysts and desmoid tumours(81).
Pathogenesis: Familial adenomatous polyposis (Gardner’s syndrome) is an autosomal dominant
disorder characterised by mutations in the Adenomatous polyposis coli (APC) tumour suppressor gene on chromosome 5q21(82). The primary role of the APC tumour suppressor gene
revolves around the regulation of intestinal tissue development and homeostasis. At the cellular
level, this encompasses the control of apical- basal polarity, cell cycle progression, DNA replication and repair and apoptosis(83).
Additionally, Adenomatous polyposis coli is a negative regulator of the Wnt/β- catenin pathway.
Wnt proteins play a pivotal role in cell differentiation, specification and the self- renewal of stem
cells(84). Wnt proteins activate distinct intracellular signalling pathways, including the Wnt/βcatenin pathway(85). Importantly, Wnt signalling and its downstream effectors govern several
processes specifically relevant to tumorigenesis. Dysregulation of Wnt signalling has been
Figure16.18 Panoramic radiograph of a patient with Gardner syndrome displaying multiple osteomas
of the mandible bilaterally. Source: Fadi Titinchi.
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associated with the development of defects and conditions affecting tissue development and
homeostasis in humans. Furthermore, uncontrolled activation of this pathway has been implicated in the pathogenesis of hyperdontia(86).
Familial adenomatous polyposis results from mutations in the APC tumour suppressor gene.
These mutations follow a ‘two- hit’ model, where individuals inherit one germline mutation, and
additional somatic mutations lead to the loss of the wild- type APC allele and the development of
tumours. The clinical phenotype can vary and is directly influenced by the location of the mutation. Mutations at the 5′ and 3′ ends of the coding sequence are associated with a milder FAP
phenotype. In contrast, mutations in the middle portion of the APC gene are linked to sporadic
colorectal cancers. This region, known as the mutation cluster region (MCR), has been identified
as a site where β- catenin binding and down- regulation occur(83, 87).
Management: Oral health professionals play a critical role in detecting GS as gnathic features gen-
erally develop before the malignant transformation of colorectal polyps. This facilitates appropriate referral of these patients to reduce morbidity and mortality. Osteomas in the maxillofacial
region can be surgically excised to improve aesthetics and can aid in creating space for the eruption of impacted teeth(81).
16.4.5 Apert Syndrome
Apert syndrome is a craniosynostosis (premature fusion of cranial sutures) syndrome with an incidence ranging between 1in 65,000 and 200,000 births. While incidence significantly increases with
paternal age, it equally affects both genders(88).
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Clinical Features: Patients with Apert syndrome present with the classical triad of craniosynosto-
sis, midface hypoplasia (Figure16.19) and symmetric syndactyly (fusion) of the hands and feet
(Figure 16.20). Craniosynostosis in Apert syndrome (Figure 16.21) is more severe than in
Crouzon syndrome, while the additional feature of syndactyly in Apert syndrome assists in differentiating it from other craniosynostosis syndromes(88).
Figure16.19 Four- year- old female with Apert syndrome showing brachycephaly, hypertelorism, midface
hypoplasia and syndactyly. Source: Fadi Titinchi.
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Figure16.20 The same patient in Figure16.19 with symmetric syndactyly of the hands.
Figure16.21 3D computed tomography of the same patient in figure showing early fusion of coronal
suture and copper beaten skull.
Hypertelorism, proptosis and downward- slanting of palpebral fissures are common facial features present in a number of craniosynostosis syndromes but cannot be utilised to differentiate
between the syndromes. Oral findings include dental crowding, high- arch palate, narrow palate
and clefts. Mild to moderate intellectual disability may also occur(89).
Pathogenesis: Most cases of Apert syndrome are typically sporadic, arising from new mutations.
However, there have been reports of autosomal dominant transmission with complete penetrance(29). In approximately 98% of Apert syndrome cases, the condition results from one or
two heterozygous mutations in exon IIIa of the fibroblast growth factor receptor 2 (FGFR2)
gene, leading to amino acid substitutions, specifically Ser252Trp or Pro253Arg(90). FGFR2 is
one of four transmembrane protein receptors that play a crucial signalling role in cranial sutures
and embryological development (90). The signalling activities mediated by FGFR2 regulate
various processes, including stem cell proliferation affecting different cell lineages such as
osteoblasts and chondroblasts(91).
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These mutations, S252W and P253R, result in increased affinity and altered specificity
in FGFR- ligand binding. The S252W mutation is the most common and is associated
with severe craniofacial anomalies, while the P253R mutation contributes to severe
syndactyly(92).
Management: Similar to other syndromes of craniosynostoses, management is based on a multidisciplinary team- based approach. Cranial vault surgery may be indicated early to release premature cranial suture closure and allow brain development. Midface advancement may be necessary
to relieve upper airway obstruction and correct orbital proptosis(88).
16.4.6 Crouzon Syndrome
Crouzon syndrome (CS) is an autosomal dominant disorder caused by mutations in the fibroblast
growth factor (FGFR- 2) gene leading to premature closure of cranial sutures. Its incidence is
approximately 1in 25,000 births(1).
Clinical features: this syndrome has widely variable phenotypes in cranial and facial manifesta-
tions. Some patients display a mild form of this syndrome with an almost normal lifestyle.
On the other hand, patients may show a severe form of the condition, leading to poor quality
of life(1).
The most common features that define the crouzonoid face include brachycephaly, hypertelorism, globe proptosis, a flattened forehead, a beaked nose and midface hypoplasia. These
patients can also suffer from functional issues, including raised intracranial pressure, upper airway
obstruction, hearing loss and cleft lip and palate. The prevalence of exorbitism and strabismus
(misaligned eyes) are very high. A defining feature of CS from other craniosynostosis syndromes is
the normal hands and feet. This is in contrast to patients with Apert syndrome, where there is
noticeable syndactyly of the extremities and Pfeiffer syndrome, which is characterised by short,
broad, big toes and thumbs(88).
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Pathogenesis: Craniosynostosis follows an autosomal dominant inheritance pattern with com-
plete penetrance, but it exhibits variable expressivity, leading to a range of phenotypic presentations within the same family (29). Among craniosynostosis cases, approximately 70%
have an affected parent, while the remaining cases result from de novo mutations. Notably, a
gain- of- function mutation can be identified in 50– 60% of cases(93). Mutations in the gene
fibroblast growth factor receptor two and fibroblast growth factor receptor 3 (FGFR2 and
FGFR3), located on chromosome 10q26, have been identified in both syndromic and nonsyndromic cases of craniosynostosis(94, 95). FGFR2 and FGFR3 are two of four transmembrane protein receptors that mediate signalling downstream of fibroblast growth factor
ligands, playing critical roles in skeletal development and related diseases (as seen in Apert
syndrome). Missense mutations in these receptor genes result in gain- of- function signalling,
which subsequently accelerates the differentiation of osteoblasts, leading to premature
fusion of cranial sutures(96).
As With Other Craniosynostosis Syndromes, A Multi- disciplinary Approach to Managing CS is
Essential: When cranial vault abnormalities are timely corrected, patients with CS will have
near- normal cognitive function, vision, hearing and life expectancy. Although not all patients
will need surgical intervention, a team- based approach to monitor these patients is essential to
intervene when complications develop(88).
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16.4.7 Treacher Collins Syndrome
Treacher- Collins syndrome (TCS), or Mandibulofacial Dysostosis, is a congenital autosomaldominant craniofacial disorder characterised by malar and maxillo- mandibular hypoplasia and
periorbital anomalies. The estimated frequency is approximately 1in 50,000 births with no gender
predilection(97).
Clinical Features: TCS is characterised by marked malar hypoplasia, bilateral down- slanting of
palpebral fissures, micrognathia and ear abnormalities (Figure16.22). Mandibular and zygoma
hypoplasia can lead to substantial feeding and respiratory challenges. Approximately 40– 50% of
patients have conductive hearing loss due to malformation of ear ossicles. Less frequent anomalies include cleft palate and choanal stenosis or atresia. Classically, intellect is unaffected(97).
Pathogenesis: TCS follows an autosomal dominant inheritance pattern with varying degrees of expres-
sivity. Approximately 60% of TCS cases do not have a family history and are believed to arise from
de novo mutations, while the remaining 40% are familial. The responsible gene for TCS is located
on the chromosome 5p32- 33.1locus(98). This gene encodes a nucleolar phosphoprotein known as
Treacle or TCOF1, which plays a crucial role in regulating ribosome biogenesis(99). Ribosome
biogenesis is essential for neuroepithelial survival and neural crest cell proliferation, which are central processes in normal craniofacial development. Several hypotheses have been proposed to
explain the cellular basis of TCS, including abnormal patterns of neural crest cell migration, altered
cell death patterns, improper cellular differentiation during development, or abnormalities in the
extracellular matrix. Recent advancements in molecular biology, cell biology, mouse genetics and
experimental embryology have provided new insights into the molecular pathogenesis of TCS,
shedding light on both the cellular and genetic bases of the condition(100).
On the cellular level, neural crest cells, which originate from the neuroepithelium during
early embryogenesis, give rise to a significant portion of the cartilage, bone and connective
tissue in the head and face. While it was initially assumed that defects in neural crest cell
Figure16.22 Patient with Treacher Collins syndrome displaying malar hypoplasia, beaked nose, microtia
and down- slanting of palpebral fissures. Source: UWC Faculty of Dentistry archives.
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References
formation, proliferation, migration or differentiation were responsible for craniofacial abnormalities in TCS, research using mouse models of TCS with severe craniofacial hypoplasia and
dysplasia did not reveal migratory or pathfinding defects in cranial neural crest cell migration.
Instead, it was observed that TCS embryos had 25% fewer migrating neural crest cells compared
to their wild- type counterparts, resulting in the general cranio- skeletal hypoplasia seen in
TCS. The reduction in neural crest cell numbers stemmed from extensive neuroepithelial apoptosis, highlighting the critical role of Treacle/TCOF1in neuroepithelial survival and neural
crest cell proliferation(101).
At the genetic level, mutations in TCOF1 often result in a truncated protein, leading to
haploinsufficiency(29). This haploinsufficiency of Treacle/TCOF1 protein impairs ribosome
biogenesis, rendering it inadequate to meet the demands of the highly proliferative neuroepithelium. This deficiency in ribosome biogenesis triggers nucleolar stress activation and
stabilisation of the p53 protein, which, in turn, transcriptionally activates numerous proapoptotic genes, including Ccng1, Trp53inp1, Noxa, Perp and Wig1 within the neuroepithelium.
This cascade of events leads to neuroepithelial apoptosis, resulting in the loss of neural crest
cells(100).
As with other craniofacial syndromes, a multi- disciplinary team approach is needed. Neonates
with airway difficulties may need early interventions, including tracheostomy, to improve ventilation. Hearing aids and speech therapy are initiated early to address hearing loss. Cleft palate
closure is usually performed at one year, while zygomatic and orbital reconstruction is done
between 5 and 7 years of age. Orthognathic surgery to correct jaw relationship is typically
performed between 16 and 18 years of age(102).
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16.5 Summary
Numerous heritable disorders involve the oro- facial region with variable presentations. These phenotypic traits largely depend on the level of penetrance of the gene mutation, which can range
from very mild features to severe disfigurement. Knowledge of these disorders and the tissue types
they affect becomes vitally essential for diagnostic and therapeutic purposes. Heritable disorders
involving the oro- facial complex should be divided into those that affect the dentition, the soft tissues, the hard tissues or a combination. As oral healthcare providers, recognising the oro- facial
features of these disorders will not only aid in detecting what may otherwise be non- symptomatic
characteristics but also prevent life- threatening complications.
Acknowledgement
The authors sincerely thank Professor T. Roberts and the staff of the archives division of the
Faculty of Dentistry, University of the Western Cape, for supplying some of the clinical images and
radiographs.
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