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DD type II is also inherited as an autosomal dominant trait and is associated with mutations in
the DSPP gene. Clinically, this condition presents with similar features as Shield type II DGI, but it
exclusively affects deciduous (baby) teeth, while the permanent teeth appear normal in colour,
shape and height(7).
Management: similar to AI, treatment usually involves using crowns, over- dentures and dental
implants to maintain facial height and improve aesthetics and function(7).
16.2.3 Ectodermal Dysplasia
Ectodermal dysplasias (ED) are a diverse group of approximately 100inherited disorders identified
by aberrations in at least two structures derived from embryonic ectoderm. ED can involve skin
appendages (hair, nails, sweat glands), teeth, inner ear, retina, optic lens, etc. The global prevalence
of ED is approximately 7in 10,000. The most prevalent type is hypohydrotic ED, which is frequently X- linked with full expression seen only in males(17).
Clinical Features: The characteristic feature of ED is hypohidrosis, which is inadequate sweating,
leading to frequent episodes of unexplained fever. Due to the partial or complete absence of
sweat and sebaceous glands, the affected individual has smooth, dry and thin skin. Scalp hair is
usually blonde, fine and short, while axillary and pubic hair is frequently sparse. Eyebrows and
eyelashes are commonly missing(17).
The most important feature of ED is oligodontia of primary and secondary dentition
(Figure16.6). The number of missing dentitions varies widely, with a higher incidence in the
mandible. Moreover, the present dentition has an abnormal crown form, with most anterior
teeth conical(17).
Pathogenesis: The causative gene has been identified in approximately 30 different types of ED
conditions(18). Hyperhidrotic (or anhidrotic) ED (HED) is the most common form of ED and
can be inherited through X- linked, autosomal recessive, or autosomal dominant patterns.
Spontaneous gene mutations are also possible and may occur in families without any syndrome
history. Mutations in the EDA, EDAR and EDARADD genes are responsible for causing
HED. EDA is the sole gene associated with X- linked HED and is present in 95% of patients.
Figure16.6 Panoramic radiograph of a 17- year- old female with ectodermal dysplasia showing missing
first molars and multiple unerupted teeth. Source: UWC Faculty of Dentistry archives.
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EDAR and EDARADD are linked to both autosomal dominant and autosomal recessive forms of
HED, accounting for 5% of HED cases(17).
The EDA, EDAR and EDARADD genes provide instructions for producing proteins, particularly
ectodysplasin A, which play critical roles during embryonic development. Mutations in these
genes result in defective ectodysplasin production. EDA, for instance, encodes ectodysplasin- A
(EDA), a protein crucial for the normal development of ectodermal appendages, including hair,
teeth and sweat glands. EDA also plays a significant role in the NFκβ pathway, which involves
multiple downstream genes essential for embryogenesis(19).
EDAR contains a single transmembrane domain and is likely to function as a multimeric
receptor related to the TNFR family. Mutated EDA or EDAR cannot effectively bind with ectodysplasin. On the other hand, the protein encoded by EDARADD resembles the death domain,
MYD88, a cytoplasmic transducer of Toll/interleukin receptor signalling. It is co- expressed with
the TNF receptor superfamily member EDAR in epithelial cells during hair follicles and teeth
formation. EDARADD interacts with the death domain of EDAR and links the receptor to signalling pathways(20).
WNT10A is a recently discovered gene contributing to the pathogenesis of HED. WNT10A
encodes a peptide with two N- linked glycosylation sites and conserved residues among WNT proteins(21). This protein contains two domains: a signal peptide and a Wnt domain. It encodes a
secreted signalling molecule involved in various developmental processes, such as regulating cell
fate and pattern during embryogenesis. WNT10A and WNT10B are highly expressed in embryonic
skin and the placodes involved in tooth development. The mechanism behind the disease depends
on the specific variant and the resulting protein changes, which can lead to a loss of function or a
dominant- negative effect. EDA pathogenic variants result in a loss of function, EDAR variants
causing autosomal recessive HED exhibit a loss of function, and those associated with autosomal
dominant HED show a dominant- negative effect(22). Pathogenic variants in WNT10A seem to
affect protein folding or stabilisation(21). EDARADDpathogenic variants can lead to a dominantnegative or loss- of- function effect depending on the specific variant(23).
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Management: depends on the severity of ED and is based on age, growth and development of the
stomatognathic system. Denture fabrication may be the initial step to replace missing primary
dentition. Once the secondary dentition has fully developed, the removable prosthesis can be
replaced with a fixed prosthesis, depending on the number and position of the teeth(17). Dental
implant placement is another option for replacement of missing dentition in ED with a high
success rate, especially in children above 13 years of age(24).
16.2.4 Cleidocranial Dysplasia
Cleidocranial dysplasia (CCD) is an uncommon but well- recognised autosomal dominant skeletal
disorder. CCD affects the development of both bones and teeth. As high as 40% of patients have no
family history of CCD and seemingly represent new gene mutations. The global prevalence of CCD
is around 1 per million, with no preference for specific gender or ethnicity(25).
Clinical Features: Clavicle hypoplasia and delayed fusion of the anterior fontanelle are
significant features of CCD. The absent/incomplete clavicles allow undue mobility of the
shoulders, leading to anterior displacement (Figure16.7). Affected individuals have characteristic facial features, including an enlarged forehead, hypertelorism and midface
hypoplasia(26).
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teeth (hyperdontia), which can involve primary and
secondary dentition (Figure16.8). Hyperdontia leads to
multiple impactions, overcrowding and malocclusion,
while midface hypoplasia can further exacerbate the
situation. In addition, teeth crowns may appear abnormal, while enamel may be hypoplastic. Dentigerous
cysts and taurodontia are common findings(26).
Pathogenesis: CCD is an autosomal dominant skeletal
Figure16.7 Young female patient known
with cleidocranial dysplasia displaying
absent clavicles. Source: University of the
Western Cape.
CCD patients have characteristic supernumerary
disorder characterised by complete penetrance but
notable phenotypic variability, even among individuals within the same family(27). The range of phenotypes spans from mild cases with dental abnormalities
as the sole manifestation to severe cases encompassing all features of CCD, coupled with generalised
osteoporosis. Researchers have pinpointed the CCD
locus to chromosome 6p21 (28). The primary cause
of CCD has been attributed to heterozygous mutations affecting the Runt- related transcription factor 2
(RUNX2, also known as CBFA1)(29). RUNX2 is critical in a transcription factor complex vital for osteoblast and chondrocyte differentiation and overall
skeletal development(30).
The expression of RUNX2in mesenchymal cell lines leads to the upregulation of genes associated
with osteoblast function, such as osteocalcin, alkaline phosphatase, collagenase- 3 (MMP- 13), bone
sialoprotein and collagen type 1, alpha- 1(31, 32). In patients with CCD, a multitude of RUNX2
mutations have been identified, with the majority falling into categories like missense, nonsense
and frameshift mutations(33, 34). Some individuals also exhibit chromosomal abnormalities, splicing mutations and intragenic deletions/duplications (35). However, in approximately 20– 30% of
CCD cases, no RUNX2 abnormalities are detected, leaving the underlying cause unidentified(36).
Figure16.8 Panoramic radiograph of a male patient with CCD showing multiple supernumerary
and impacted teeth. Source: Fadi Titinchi.
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Management: There are numerous protocols for the dental management of CCD. Multi- disciplinary
care is vitally important and aimed at removing retained primary and supernumerary teeth to
aid the eruption of secondary dentition. Surgical exposure and orthodontic- aided eruption are
often required. Orthodontic alignment and palatal expansion form part of the final treatment
phase, along with prosthodontic rehabilitation of edentulous spaces(26).
16.3 Heritable Diseases Affecting theOro- Facial Soft Tissue
16.3.1 Hereditary Gingival Fibromatosis
Hereditary gingival fibromatosis (HGF) is a rare autosomal dominant disorder denoted by
benign,non- haemorrhagic, fibrous gingival overgrowth that can present sporadically or as part of
a syndrome. The prevalence of HGF is approximately 1in 175,000(37).
Clinical Features: clinical features gingiva has a rosy colour and fibrous texture with significant
stippling but no sign of inflammation (Figure16.9). It can be localised or generalised and may
cover the dentition wholly or partially with variable degrees of severity and may prevent eruption. The underlying alveolar bone is not involved, but HGF usually hinders speech, lip closure
and mastication. Of more significance is the psychological burden the patient suffers, which can
affect their self- esteem(37).
Pathogenesis: HGF is the most prevalent genetic manifestation of gingival fibromatosis, typically
inherited in an autosomal- dominant manner. However, sporadic and autosomal- recessive
inheritance patterns have been documented(38). While HGF can be a standalone condition, it
can also manifest within syndromes such as Cowden’s syndrome (39), Zimmerman- Laband
syndrome(40), Rutherford syndrome(41) and Costello syndrome(42). Additionally, it may arise
due to factors like inadequate oral hygiene leading to gingival inflammation, as well as during
puberty pregnancy, or as a side effect of common medications such as calcium channel blockers
like nifedipine and verapamil(43).
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Researchers have identified four specific loci (2p22.1, 2p23.3- p22.3, 5q13- q22 and 11p15)
associated with HGF(44– 46). The underlying pathophysiological mechanisms of HGF remain
Figure16.9 A patient with hereditary gingival fibromatosis. Source: Professor T. Roberts, UWC Faculty
ofDentistry archives.
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largely unclear. However, the condition may be attributed to excessive production of extracellular matrix components, notably collagen type I (COL1A1), contributing to the overgrowth of
gingival fibroblasts(47). Overexpression of TGF- β1 and IL- 6in gingival fibroblasts could poten-
tially play a pivotal role in enhancing COL1A1 synthesis alongside other specific growth
factors(48).
Furthermore, a transcriptomic analysis conducted on HGF patients and controls by Han etal. in
2019 revealed that the regulatory network connection between the TGF- β/SMAD signalling path-
way and craniofacial development processes contributes to the molecular mechanism underlying
the clinical- pathological manifestations of HGF.
Management: The treatment of choice for HGF is gingivectomy, as this condition does not resolve
spontaneously. The ideal timing to perform surgery is following the eruption of the secondary
dentition to prevent recurrence. However, performing surgery at earlier ages may be warranted
to avoid adverse psychological effects and functional difficulties(41).
16.3.2 Neurofibromatosis
Neurofibromatosis (NF) is a collection of autosomal dominant disorders identified by numerous
cutaneous lesions and tumours of the nervous system. NF is divided into two genetically distinct
entities, namely NF type- 1 (NF- 1) and NF type- 2 (NF- 2). NF- 1 or von Recklinghausen disease is
the most frequent subtype of NF, with a prevalence of approximately 1 in 3500 individuals
globally(49).
Clinical Features: patients with NF- 1 classically display brown, ovoid cutaneous macules of
approximately 10– 40 mm. The presence of six or more macules is one of the diagnostic criteria
for NF- 1 (Table 16.2). Almost 90% of patients with NF- 1 display characteristic axillary and
inguinal freckling following cutaneous macules’ development. Other classical features of
NF- 1include neurofibromas around peripheral nerves and Lisch nodules (pigmented hamartomas of the iris)(49).
NF- 2 is less prevalent than NF- 1, with an estimated frequency of 1in 25,000individuals. Abrupt
hearing loss due to the development of vestibular schwannomas is frequently an early sign in
patients with NF- 2. These tumours can cause nerve compression and result in a significant amount
of pain, nerve dysfunction and raised intracranial pressure(49).
Table16.2 Diagnostic criteria forNF- 1 according toNIH consensus development conference 1988.
Criteria (two or more features are diagnostic for NF- 1)
● Six or more café au lait macules >5 mm in greatest diameter in children and >15 mm in greatest
diameter in adults
● Freckling in the axillary or groin regions
● Two or more neurofibromas of any type or one plexiform neurofibroma
● Optic pathway glioma
● Two or more Lisch nodules on slit lamp examination
● Bony dysplasia in the sphenoid wing, bowing of long bones, or pseudarthrosis
● First- degree relative with NF- 1
Source: Stumpf etal.(50)/U.S. Department of Health and Human Services / Licensed under CC BY 4.0.
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Figure16.10 Patient with neurofibromatosis involving the right peri- orbital and facial tissues and the
right maxilla. Source: UWC Faculty of Dentistry archives.
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Figure16.11 Panoramic radiograph of another patient showing neurofibroma involving the left mandible.
Source: UWC Faculty of Dentistry archives.
Approximately 72% of patients with NF- 1 present with oral manifestations, including gingival
enlargement, supernumerary teeth, impacted teeth, missing teeth and overgrowth of the alveolus.
The development of neurofibromas is a distinctive feature of NF- 1 and, to a lesser extent, NF- 2. In
the oral cavity, neurofibromas commonly involve the tongue and are nodular. Involvement of
facial bones is also part of the diagnostic criteria for NF- 1 (Figure16.10). Bony lesions such as
neurofibromas may involve sphenoid wing, orbits, maxilla and mandible (Figure16.11)(49).
Pathogenesis: NF1 is typically inherited in an autosomal dominant manner; however, as many as
50% of cases result from de novo mutations(51). The NF1 gene is located on chromosome locus
17q11.2, and its gene product is known as neurofibromin(52). Neurofibromin functions as a
tumour suppressor gene within the RAS- mediated signalling pathway. By deactivating RASGTP, neurofibromin downregulates pathways related to cell proliferation, including mitogenactivating protein kinase (MAPK), MAPK/extracellular signal- regulated kinase (ERK) and the
cyclic adenosine monophosphate (cAMP)- mediated protein kinase A pathway(53). Individuals
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with NF1have impaired neurofibromin function, leading to uncontrolled activation of RASGTP pathways. Furthermore, the mTOR pathway is upregulated, which promotes malignant
development(54, 55).
NF2 follows an autosomal dominant inheritance pattern and arises from a loss- of- function
mutation in the NF2 gene on chromosome 22. This gene encodes a tumour suppressor protein
known as merlin, a member of the band 4.1 family of cytoskeleton- associated proteins called the
ERM family(56). Tumourigenesis is initiated only when both copies of the gene are inactivated,
aligning with the classic ‘two- hit’ hypothesis of tumorigenesis proposed by Knudson in 1971.
Merlin, the NF2 protein, is expressed in various tissues, including neurons, Schwann cells and
meningeal cells. Under normal circumstances, merlin plays a crucial role by binding to transmembrane adhesion molecules like CD44 (hyaluronate receptor) and cytoskeleton components
(β- actin, microtubules, β- spectrin)(57). Consequently, NF2 protein disrupts cell adhesion, motility and spreading properties, all essential for tumour formation.
Management: The goal of NF management is early recognition of the condition and treatment of
potential complications. Surgical excision of disfiguring or uncomfortable cutaneous or subcutaneous neurofibromas is usually indicated. Neurofibroma arising within the oro- facial usually
requires excision to prevent further destruction of adjacent structures and avoid malignant
transformation. Treatment of optic gliomas is unnecessary, mainly as the lesions are frequently
asymptomatic and clinically stable. Annual physical examination is essential, as well as ophthalmologic examination in children annually(58).
16.4 Heritable Diseases Affecting theOro- Facial Hard Tissue
16.4.1 Naevoid Basal Cell Carcinoma Syndrome
Nevoid Basal Cell Carcinoma syndrome (NBCCS) is a rare autosomal dominant entity first
described by Gorlin and Goltz in 1960. It features multiple basal cell carcinomas (BCCs), odontogenic keratocysts (OKCs) and skeletal anomalies. The estimated prevalence is 1in 57,000– 1 in
164,000with no gender predilection(59).
Clinical Features: BCCs typically develop early (during puberty) and frequently affect the face, trunk
and limbs (Figure16.12). Multiple OKCs are a distinct feature of NBCCS and may be the first
presenting feature which can be an incidental finding (Figure16.13). OKCs may develop as early
as the first decade of life, and patients tend to develop newer lesions with increasing age. Other
common skeletal features include palmar and plantar pits, bifid ribs (Figure16.14), spine abnormalities and calcification of falx cerebri(60).
Diagnostic criteria for NBCCS necessitates the presence of two major or one major and two
minor criteria (Table16.3). The presence of one major criterion with molecular confirmation is
also diagnostic. Diagnostic work- up for patients suspected of having NBCCS should include a complete dermatological exam and panoramic radiograph, MRI brain, cardiac ultrasound, pelvic ultrasound (if female) and spine radiograph(61).
Pathogenesis: NBCCS is inherited as an autosomal dominant pattern(61, 62). The causative gene
for this disorder is PTCH1, which serves as a human homologue of the Drosophila segment
polarity gene known as patched (PATCH1). PTCH1 is mapped to chromosome 9q22.3- q31 and
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Figure16.12 Basal cell carcinoma on the patient’s trunk with NBCCS. Source: University of the
Western Cape.
Figure16.13 Panoramic radiograph showing multiple radiolucencies of the OKCs in the maxilla
andmandible. Source: Fadi Titinchi.
Figure16.14 Cropped chest radiograph showing bifid rib (arrow) in patient with NBCCS. Source: Fadi Titinchi.
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Table16.3 Diagnostic criteria forNBCCS adapted fromthe first international colloquium
onbasal cell nevus syndrome.
Major criteria
● Basal cell carcinoma before 20 years of age or excessive numbers of basal cell carcinomas out of
proportion to prior sun exposure and skin type
● Odontogenic keratocyst before 20 years of age
● Palmar or plantar pitting
● Lamellar calcification of the falx cerebri
● Medulloblastoma, typically desmoplastic
● First- degree relative with nevoid basal cell carcinoma syndrome
Minor criteria
● Rib abnormalities
● Other specific skeletal malformations and radiologic changes (i.e. vertebral anomalies, kyphoscoliosis,
short fourth metacarpals, postaxial polydactyly)
● Macrocephaly
● Cleft lip or palate
● Ovarian or cardiac fibroma
● Lymphomesenteric cysts
● Ocular abnormalities (i.e. strabismus, hypertelorism, congenital cataracts, glaucoma)
Source: Adapted from Ref.(61).
comprises 23 exons encoding a protein of 1447 amino acids(63). The PTCH1 protein functions
as a receptor for Sonic Hedgehog (SHH) and consists of 12 transmembrane domains. Sonic
hedgehog is a secreted molecule implicated in forming embryonic structures and tumourigenesis(62). Individuals affected by NBCCS inherit one non- functional copy of PTCH1 and subsequently acquire a ‘second- hit’ mutation, activating the Sonic Hedgehog pathway and developing
basal cell carcinoma(60).
In the absence of the hedgehog ligand protein, PTCH1, a membrane- bound protein, maintains
smoothened transmembrane protein (SMO), which resembles a G protein- coupled receptor- like
molecule, in an active and unphosphorylated state(64, 65). This condition renders SMO susceptible to endocytosis and subsequent degradation, making it incapable of activating glioma- derived
transcriptional factor (GLI1) proteins. These GLI1 proteins are transcription factors necessary for
activating or repressing pathway- dependent genes. Negative regulation of GLI1 factors is further
facilitated by the suppressor of fused (SUFU), a protein encoded by the SUFU gene, which is an
integral part of the corepressor complex(66).
Upon the binding of hedgehog (SHH) to PTCH1, repression of SMO is released, leading to SMO
becoming hyperphosphorylated. Consequently, this allows GLI1 to translocate into the nucleus. In
normal physiological circumstances, this results in transcriptional modulation and various downstream effects, including the proliferation, migration and differentiation of progenitor cells
throughout vertebrate development(67).
However, under pathological conditions, constitutive activation of the hedgehog signalling pathway occurs due to mutations in critical regulatory proteins, resulting in uncontrolled tumour cell
proliferation. Loss of function mutations in PTCH1 can occur through various mechanisms, such
as deletions, insertions, nonsense and missense mutations (67), and are estimated to affect
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approximately 70% of patients who meet the diagnostic criteria for NBCCS. Additionally, loss of
function SUFU germline mutations have recently been reported in a subset of NBCCS patients.
However, these patients tend to exhibit a lower incidence of major NBCCS criteria, including OKC
but may have an increased risk of developing desmoplastic medulloblastoma(68).
Management: Frequent dermatological examination is essential for NBCCS patients, and sun pro-
tection is a vital preventative measure. Radiological screening for medulloblastomas and OKCs
is usually performed yearly. Treatment options for BCCs include surgical excision or application
of topical agents such as 5- fluorouracil (5- FU) and imiquimod. Surgical management of OKCs
includes enucleation or marsupialisation with adjuvant therapies, including peripheral ostectomy and topical application of Carnoy’s solution or 5- FU to reduce recurrences(69). Recent
advancements in personalised medicine have introduced the utilisation of hedgehog pathway
inhibitors (HPI), such as Sonidegib, for treating patients with NBCCS(70).
16.4.2 Cherubism
Cherubism is an autosomal dominant skeletal dysplasia characterised by bilateral and symmetric
fibro- osseous lesions confined to the jaws. The name of the disorder is derived from the swollen,
rounded cheeks and the upward positioning of the eyes, giving a cherubic (angel) appearance portrayed in Renaissance art. The prevalence of this rare condition is unknown, with approximately
350 cases reported in the literature(71).
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Clinical Features: clinical features of children appear normal at birth, and enlargement of the jaws
typically starts between the ages of two and seven years. These lesions continue to proliferate
and increase in size until puberty. Radiographically, the lesions appear as expansile multilocular
radiolucencies in the mandible and maxilla (Figures16.15 and16.16). These lesions are asymptomatic but can disturb the development or eruption of secondary dentition. The lesions subsequently ‘burn out’ or regress, filling with bone and remodelling until around 30, when they are
commonly no longer detectable(71).
Pathogenesis: Cherubism is inherited as an autosomal dominant trait, although there are indications
that a recessive form may also exist. Cherubism is primarily caused by heterozygous germline
gain- of- function mutations in the Sh3bp2 gene, which encodes the adaptor protein 3BP2.
This protein is potentially involved in signal transduction and plays a role in regulating
Figure16.15 Panoramic radiograph of a young patient with cherubism showing bilateral mandibular
multilocular radiolucencies. Source: Fadi Titinchi.
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