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17
Non-heritableDevelopmentalDisorderswithExamples
InvolvingtheOral-MaxillofacialComplex
John Anthony Ozolek
Department of Pathology, Anatomy, and Laboratory Medicine, West Virginia University, Morgantown, WV, USA
17.1 Introduction
In this chapter, we will cover select pathologies of the oral- maxillofacial (OMF) complex that
currently have no known specific genetic or heritable cause yet seem to be aberrations of development or, in the case of a tumour, for example, appear or manifest at birth. We admit that other
pathologies could be included here and even the ones discussed here could be afforded more
comprehensive attention. However, given space constraints, we will attempt to cover as much
important pathology as necessary within current literature. Pathologies with well- defined genetic
mutations or syndromic associations will not be covered in this chapter as they are addressed
proficiently elsewhere in this book. However, some pathologies discussed here may occur in
association with syndromes (e.g. branchial cleft cyst [branchial- oto- renal syndromes], oro- facial- digital,
etc.) or occur sporadically without a known syndromic association. It is likely that entities discussed here as ‘non- heritable’ may eventually be shown to have a genetic basis and may be ‘heritable’. Approximately 75% of all human malformations occur in the head and neck/craniofacial
region(1, 2). The cranial neural crest is ultimately responsible for the skeleton (mandible and
maxilla, middle ear bones, temporal bone, hyoid and laryngeal cartilages), muscle (tongue and
masticatory muscles notably) and connective tissue and dental tissues (ameloblasts, odontoblasts,
fibroblasts [pulp], alveolar bone, dentin). Increasing knowledge of the complicated and specific
signalling pathways that affect craniofacial bone and skeletal development, tooth development
and craniofacial soft tissue development may shed light on genetic and epigenetic mechanisms.
Recent advances have shown the importance of circular and microRNAs, signalling pathways,
particularly bone morphogenic factor (BMP), fibroblast growth factor (FGF), Wnt/Shh, Indian
Hedgehog, matrix metalloproteinases and matricellular proteins, gap junctions, cell death
andmany other complex molecular pathways in craniofacial and tooth development(3–14). In
reality, many, perhaps, if not most, head and neck pathologies are ‘multifactorial’; an interplay
between environmental influences/cues mingling with a complex cascade of molecular interactions orchestrated progressively in the developing human craniofacial region. The study of ciliopathies is fascinating as mutations in specific proteins related to the ciliary body complex are
continually defined, and the spectrum of diseases related to defects in ciliary proteins expands.
Pathological Basis of Oral and Maxillofacial Diseases, First Edition. Editedby S. R.Prabhu, Syed AliKhurram,
OmarKujan andMervaSoluk Tekkesin.
© 2025John Wiley & Sons Ltd. Published 2025 by John Wiley & Sons Ltd.
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17.2 Acquired Non-heritable Developmental Pathologies of the OMF
Cranioectodermal dysplasias are part of the ciliopathies associated with a wide spectrum of
craniofacial and tooth anomalies (hypoplastic teeth, hypodontia). Others include primary ciliary
dyskinesia (PCD), Bardet–Biedl syndrome, oral- facial- digital syndrome (OFDS), Joubert syndrome, Ellis van Creveld syndrome and Curry Hall syndrome. As part of their phenotype, these
also have multiple dental anomalies that include an increase or decrease in the number and size
of teeth, shape of teeth and mineralisation abnormalities(15, 16). These will not be discussed here
as many have a defined genetic basis and rightly deserve an entire book; however, the reader
should know these entities as they relate to your practice. In this review, we will cover aspects of
the developmental aberrations seen in the soft tissues, bone and teeth that have no apparent
genetic basis and mention those that may be acquired due to teratogenic or other prenatal exposures. In the area of tumours, the discussion will primarily focus on tumours present at birth (i.e.
congenital) and presumably ‘developmental’. Since developmental aberrations in the craniofacial
region often do not just affect one compartment (i.e. bone, tooth, soft tissue), this review will
divide pathologies (albeit probably naively) by whether they are congenital (developmental without an apparent genetic or environmental cause) or acquired (environmental/exogenous agent
affecting development). It should be noted that most of the pathologies associated with development, whether congenital or acquired, do not necessarily generate specimens that a pathologist
will examine microscopically, for example. This means that the development aberrations are those
determined upon a patient’s external or visual exam and do not proceed further to excision or
biopsy for subsequent microscopic diagnosis. Most developmental lesions (excluding odontogenic), cysts, pits, hyperplasias, hypoplasias, dysplasias and tooth and enamel developmental
anomalies do not require biopsy or pathologic microscopic examination on a routine basis for
diagnosis. However, these entities have been examined histologically for definition and characterisation. Common specimens received by surgical pathologists, particularly paediatric pathologists, would include branchial anomalies (cysts and sinuses), thyroglossal duct cysts, dermoid
cysts, vascular tumours, odontogenic lesions, intraoral choristomas/hamartomas/heterotopias
and of course any tumour/neoplasm. This review will not address odontogenic cysts and tumours,
as these will be addressed elsewhere in this book.
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17.2 AcquiredNon-heritableDevelopmentalPathologiesoftheOMF
17.2.1 ExogenousandEnvironmentalFactorsinDevelopmentalDisordersofCraniofacial
DevelopmentandOdontogenesis
Increasingly, evidence shows that maternal health status and prenatal environment are particularly
essential for enamel development. Here, we will look at two important nutritional conditions that
impact odontogenesis: vitamin D deficiency (VDD) and hyperglycemia.
Multiple factors have been identified that cause developmental defects in enamel that cluster
into a few general categories. (i) Toxins/exposures: This group includes xenobiotics (dioxins
particularly), fluoride (fluorosis), tobacco, alcohol, chemoradiation and antibiotics. (ii) Infections:
congenital infections such as syphilis, cytomegalovirus, rubella (TORCH infections) and other
infections. (iii) Prenatal/neonatal: neonatal hypoxia, low birth weight/prematurity, maternal prenatal factors (nutritional status, medications, gestational diabetes). (iv) Metabolic: VDD, starvation, hypocalcemia. Virtually all of these can result in a hypoplasia/hypomineralised phenotype,
with entities such as congenital syphilis and rubella resulting in hypoplasia as the primary
phenotype(17).
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276
17.2.1.1 Vitamin D
Vitamin D is a hormone with activity that promotes serum calcium and phosphate homeostasis via
intestinal absorption regulation. It has multiple cellular functions, including regulation of cell
differentiation, cell maturation and innate immunity mediated through the Vitamin D receptor.
Assuch, Vitamin D modulates an estimated 5–10% of the entire genome. The main sources of
Vitamin D are exposure to ultraviolet B and nutritional sources. Regarding OMF pathologies, VDD
is increasingly linked to caries and periodontal disease, the two most prevalent diseases worldwide. Here, we will focus on Vitamin D’s role in odontogenesis, specifically tooth mineralisation
and subsequent increased risk of dental caries. Severe VDD results in hypocalcemia and hypophosphatemia, secondary hyperparathyroidism, elevated one α, 25- dihydroxyvitamin D, increased
bone turnover, hypercalcemia and low serum inorganic phosphate levels. Loss of vitamin D signalling pathways, hypocalcemia and hypophosphatemia result in defective tooth mineralisation.
Signalling initiated by vitamin D through the vitamin D receptor (VDR) controls gene expression
via vitaminD receptor elements (VDRE) that regulate gene expression related to mineral metabolism, bone, cell life cycle and energy metabolism. Vitamin D upregulates VDR, which can induce
structural gene products that include calcium- binding proteins and extracellular matrix proteins
such as enamels, amelogenins, dentin sialoglycoproteins and dentin phosphoproteins all necessary
for dentin and enamel production(18, 19).
Deciduous dentition is also affected by maternal vitamin D [25(OH)D] levels. Foetal mineralisation patterns depend on the time during gestation when maternal VDD occurs. Maternal VDD at
12–16, 20–32 and 36–40weeks results in mineralisation defects at the incisal third, middle third
and cervical third, respectively. Women with low (<15 ng/ml) vitamin D levels have a 14% higher
risk of enamel defects, and supplementation produced a 50% reduced odds of enamel defects(18, 19).
17.2.1.2 PrematurityandLow-birthWeight
It is worth a brief mention that developmental defects of enamel are associated with low birth
weight resulting from prematurity independent of socioeconomic factors that may predispose to
premature birth. In the Brazilian study by Massoni etal., they demonstrated that enamel defects
(diffuse, demarcated opacity, hypoplasia of reduced enamel thickness or absence, or both opacity
and hypoplasia) of the primary incisors were significantly associated with premature and
low- birth weight, intrauterine growth restriction, non- breast- fed children and children with a
nutritional deficiency at presentation. Nelson etal. demonstrated similar findings that very- lowbirth- weight infants (birth weight < 1500 g) had a markedly increased number of demarcated
enamel opacities(20, 21).
17.2.1.3 DiabetesMellitus(DM)andHyperglycemia
Hyperglycemia is the phenotype associated with the group of disorders termed Diabetes Mellitus
(DM) and is due to reduced insulin secretion, decreased glucose utilisation and increased glucose
production. DM, as a group, is a prevalent and potentially severe and chronic health condition. The
clinical phenotype comes in three main types: type I (juvenile), type II (adult onset) and pregnancyassociated or gestational diabetes(22). Few publications have directly addressed the direct effects
of hyperglycemia on the molecular pathways involved in odontogenesis. The most relevant studies
were either using animal models of diabetes or invitro studies with dental pulp and apical papillae
stem cells. These studies demonstrated that high glucose environments activated the TLR4/NF- κβ
pathway, leading to activation of pro- inflammatory cytokines that result in decreased cell proliferation and increased apoptosis in dental epithelial stem cells of molar tooth germ and dental pulp
cells, resulting in odontodysplasia. In addition, DM causes epigenetic silencing of Oct4 and Nanog
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17.2 Acquired Non-heritable Developmental Pathologies of the OMF
through DNA hypermethylation and APEX1 (apurinic/apyrimidinic endonuclease1) downregulation,
resulting in decreased cell proliferation of dental epithelial cells of the labial cervical loop.
Highglucose environments also inhibit the differentiation of dental papilla cells to odontoblasts
through inhibition of SMAD1/5/9 phosphorylation of dental pulp cells (DPCs) and decreased
BMP/SMAD signalling but enhance the osteo/odonto differentiation of stem cells from the
apicalpapilla while also reducing their proliferation. Even less knowledge is available regarding
translating these findings to humans and the resulting phenotypes from perturbations in these
molecular pathways(23).
17.2.1.4 AntidepressantMedications
Depression is an increasingly common psychological condition that affects the general population,
and depression in women during (antenatal) and after delivery (postpartum) is well- known.
According to the Centres for Disease Control, approximately 10–15% of the US population has a
diagnosis of depression in their medical record (https://www.cdc.gov/nchs/fastats/depression.htm).
Maternal or antenatal depression, along with postpartum depression, are significant health issues,
and estimates of the prevalence of maternal depression vary greatly, but 10–65% of mothers experience depression antenatally. According to some estimates, approximately one- third of pregnant
mothers are treated pharmacologically with antidepressant medications. These medications, known
as serotonin reuptake inhibitors (SSRIs), block the serotonin transporter (SERT), increasing extracellular serotonin. The most commonly prescribed SSRIs are sertraline (Zoloft), fluoxetine (Prozac) and
citalopram (Celexa). As the use of these medications continues to increase, interest in their effects on
foetal development is being investigated, including how these SSRIs affect craniofacial/OMF development. Serotonin receptors are expressed at early stages in mouse embryos, and antagonists to serotonin receptors result in inhibited migration of neural crest malformed embryos and block expression
of mandibular proteins. Similarly, SERT is expressed in different regions of the mouse craniofacial
mesenchyme. Serotonin uptake and degradation are found in the mouse tooth germ. In animal models, SSRIs inhibit osteoblast proliferation and ameloblast differentiation, increase neural crest cell
migration, and decrease tooth germ epithelial proliferation. Collectively phenotypic defects in cranial
bones, including hypoplastic maxilla/mandible, delayed development of frontoparietal bones and
nasal cartilage, have been identified with SSRI exposure during embryonic development. Combined,
serotonin levels seem to regulate cell proliferation, differentiation and migration of neural crest and
progenitor cells that form bone, cartilage, tooth germ, salivary gland and palate. Several extensive
clinical studies in humans have shown an association between SSRI use and increased craniofacial
defects, most notably craniosynostosis and anencephaly. Further investigations into the pathogenetic
mechanisms of serotonin regulation/deregulation in the craniofacial region of the developing
embryo will need to be continued as thesemedications will be used to treat a prevalent and perhaps
increasingly prevalent health condition(24).
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17.2.1.5 DentalandOMFAbnormalitiesRelatedtoTherapy:Chemoradiation-related
AbnormalitiesandMedication-relatedOsteonecrosisoftheJaw(MRONJ)
17.2.1.5.1 Chemoradiation- related Abnormalities
As a disease group, a cancer diagnosis is much less frequent in the paediatric population when
compared to adults. For example, in 2020, the incidence rate of cancer in children <15 years of
age was 17.1/100,000 compared to 4282/100,000 for those >15 years of age (https://seer.cancer.
gov/statfacts/). The types of cancers also vary significantly in children compared to adults. By far,
acute lymphoblastic leukaemias (ALL) are the most common malignancy in children, followed
by primary central nervous system tumours. Other tumours include neuroblastoma, Wilms
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tumour, rhabdomyosarcoma, Ewing sarcoma/primitive neuroectodermal tumour, retinoblastoma, osteosarcoma and lymphomas (Hodgkin and non- Hodgkin types). Of these, rhabdomyosarcoma occurs much more commonly in the head and neck region, and leukaemias are more
likely to require bone marrow transplantation (BMT), which necessitates chemotherapy and total
body irradiation (TBI) before transplantation(25). However, cancer in the paediatric population
is not without significant morbidities due to factors related to the cancer itself and more factors
related to the treatment. Chemoradiation for cancer therapy in children increases the risk of subsequent secondary malignancies. Additional adverse and often irreversible effects on proper tissue development can occur, not sparing the OMF. Numerous studies have documented the dental
and OMF findings in childhood cancer survivors, particularly in those who had rhabdomyosarcoma of the head and neck or who received chemotherapy and TBI before BMT. These studies,
when taken together, show similar dental and OMF anomalies. The first reports of dental anomalies in children post- cancer therapy came in the late 1960s, but it was not until the 1980s that the
frequency of publications in this area began to increase as chemoradiation protocols for childhood cancers increased and improved(26–31). The review by Carrillo etal. included 13 published
studies from 1987 to 2006 that documented dental anomalies in childhood cancer survivors.
Dental anomalies within several categories: (i) Tooth shape (microdontia, macrodontia and taurodontia), (ii) Tooth number (hypodontia), (iii) Root formation (blunted, tapered, delay) and (iv)
Enamel (discolourations, hypoplasia). They noted several key points: (i) The severity of anomalies was related to age at diagnosis and stage of tooth development. Children treated before five
years of age had the most severe anomalies; (ii) The type of treatment. Children subjected to head
and neck radiation or combined chemotherapy and TBI had the highest prevalence and most
severe dental anomalies. Still, the threshold total dose of radiation necessary to induce permanent
damage to ameloblasts and other cellular components of the developing tooth is unclear. Likewise,
while animal studies have shown aberrations in dental development when exposed to vincristine,
vinblastine, doxorubicin and cyclophosphamide (most used agents in treating childhood cancer),
it is again unclear what dosages and even which agents are the most egregious in this regard.
Radiation appears to induce quantitative and qualitative changes in enamel and dentin formation, while chemotherapy induces qualitative changes. (iii) Children with ALL seem to be more
severely affected, perhaps due to the age at presentation and duration of therapy during critical
periods of tooth ontogenesis(25). A large study published in 2009 from the Childhood Cancer
Survivor Study was conducted using surveys to identify patients, followed by medical record
review. This study included 8522 survivors and a cohort of 2831 siblings. They also showed a significantly higher prevalence of microdontia, hypodontia, caries, abnormal roots, enamel hypoplasia and xerostomia compared to non- treated siblings. Key points from this study: (i)
Radiotherapy to the teeth significantly increased the risk of developing one or more dental abnormalities in a dose- dependent fashion. (ii) Microdontia and enamel hypoplasia had a significant
interactive effect between radiation to the teeth and the use of alkylating agents. (iii) Children
under five years old exposed to higher doses of alkylating agents had the highest prevalence of
dental abnormalities(28). Dental practitioners should be particularly attuned to any significant
dental abnormality in children (or adults) and inquire regarding a history of childhood cancer.
17.2.1.5.2 Medication- related Osteonecrosis of the Jaw (MRONJ)
MRONJ is a relatively ‘new’ pathologic entity first described 20 years ago. MRONJ is defined as
exposed or fistulous bone in the OMF persisting for more than eight weeks in patients currently
or previously treated with anti- resorptive medication used to treat osteometabolic disease alone
or in combination with immune modulators or anti- angiogenic therapy (used in cancer therapy)
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