Developmental Disturbances of Oral and Paraoral Structures

Craniofacial Anomalies

Craniofacial anomalies (CFA) are a diverse group of deformities in the growth of the head and facial bones. Anomaly is a medical term meaning ‘irregularity’ or ‘different from normal’. These abnormalities are congenital (present at birth) and have numerous variations: some are mild, others are severe and require surgery.

There is no single factor that causes these abnormalities. Instead, there are many factors that may contribute to their development, including the following:

• Combination of genes. A child may receive a particular combination of gene(s) from one or both parents, or there may be a change in the genes at the time of conception, which results in a craniofacial anomaly.

• Environmental. There is no data that shows a direct correlation between any specific drug or chemical exposure causing a craniofacial anomaly. However, any prenatal exposure should be evaluated.

• Folic acid deficiency. Folic acid is a B vitamin found in orange juice, fortified breakfast cereals, enriched grain products, and green, leafy vegetables. Studies have shown that women who do not take sufficient folic acid during pregnancy, or have a diet lacking in folic acid, may have a higher risk of having a baby with certain congenital anomalies, including cleft lip and/or cleft palate.

Some of the most common types of craniofacial anomalies (Table 1-1) include:

Table 1-1

Examples of most common craniofacial anomalies

Source: Rovin et al, 1964; Temple, 1989; Cohen et al, 1992; Lewanda et al, 1992; Croen et al, 1996; Derijcle et al, 1996; Sampson et al, 1997; Blate et al, 1998.

• Cleft lip and/or cleft palate. A separation that occurs in the lip or the palate or both. Cleft lip and cleft palate are the most common congenital craniofacial anomalies seen at birth.

Cleft lip. An abnormality in which the lip does not completely form. The degree of the cleft lip can vary greatly, from mild (notching of the lip) to severe (large opening from the lip up through the nose).

Cleft palate. Occurs when the roof of the mouth does not completely close, leaving an opening that can extend into the nasal cavity. The cleft may involve either side of the palate. It can extend from the front of the mouth (hard palate) to the throat (soft palate). The cleft may also include the lip.

• Craniosynostosis. A condition in which the sutures in the skull of an infant close too early, causing problems with normal brain and skull growth. Premature closure of the sutures may also cause the pressure inside the head to increase and the skull or facial bones to change from a normal, symmetrical appearance.

• Hemifacial microsomia. A condition in which the tissues on one side of the face are underdeveloped, affecting primarily the ear (aural), mouth (oral), and jaw (mandibular) areas. Sometimes, both sides of the face can be affected and may involve the skull as well as the face. Hemifacial microsomia is also known as Goldenhar syndrome, brachial arch syndrome, facio-auriculovertebral syndrome (FAV), oculo-auriculovertebral spectrum (OAV), or lateral facial dysplasia.

• Vascular malformation. A birthmark or a growth, present at birth, which is composed of blood vessels that can cause functional or esthetic problems. Vascular malformations may involve multiple body systems. There are several different types of malformations, named after the type of blood vessel that is predominantly affected. Vascular malformations are also known as lymphangiomas, arteriovenous malformations, and vascular gigantism.

• Hemangioma. A type of birthmark; the most common benign (noncancerous) tumor of the skin. Hemangiomas may be present at birth (faint red mark) or appear in the first month after birth. A hemangioma is also known as a port wine stain, strawberry hemangioma, and salmon patch.

• Deformational (or positional) plagiocephaly. A misshapen (asymmetrical) shape of the head (cranium) from repeated pressure to the same area of the head. Plagiocephaly literally means ‘oblique head’ (from the Greek ‘plagio’ for oblique and ‘cephale’ for head).

Collectively they affect a significant proportion of the global society (Table 1-1).

The frequency of occurrence of cleft lip, with or without cleft palate, has been computed on a global scale and is estimated to be 1 in every 800 newborn babies (Tables 1-2 and 1-3). A child is therefore born with a cleft somewhere in the world approximately every two-and-half minutes. Accurate data on the frequency of occurrence of these disorders is relevant for implementing strategies aimed at primary prevention and effective management of these disabled children (Table 1-2). Like anywhere else, the epidemiological data in this situation is also inherently handicapped by:

Table 1-2

Cleft lip with or without cleft palate

Source: WHO (1998), World Atlas of Birth Defects (1st Edition).

^*Abortion for birth defect not permitted.

^↑= 99% significantly higher than the mean.

^↓= 99% significantly lower than the mean.

Table 1-3

Cleft palate without cleft lip

Source: WHO (1998), World Atlas of Birth Defects (1st Edition).

^*Abortion for birth defect not permitted.

^↑= 99% significantly higher than the mean.

^↓= 99% significantly lower than the mean.

• The heterogeneity of orofacial clefting,

• The lack of standard criteria for collection of data, and

• In particular, the lack of and/or failure to apply an internationally comparable classification for orofacial clefting.

Defining the affected population is also problematic because, on many occasions, the terminology is so vague that it is not clear whether it denotes all birth, or all live births. The word ‘births’ is again somewhat ambiguous because it usually includes stillbirths, a term which lacks clarity.

Registration of Targeted Craniofacial Anomalies in India

1. Three multicenter studies in India have provided almost similar frequency of CFA: meta-analysis of 25 early studies from 1960–1979, involving 407,025 births, showed:

CL/P = 440 cases, 1.08 per 1,000 births,

CP = 95 cases, 0.23 per 1,000 births.

2. A prospective national study of malformations in 17 centers from all over India from September 1989 to September 1990 involving 47,787 births showed:

CL/P = 64 cases, 1.3 per 1,000 births,

CP = 6 cases, 0.12 per 1,000 births.

3. The latest three-center study, conducted in 1994–1996, involved 94,610 births in Baroda, Delhi and Mumbai, and showed a frequency of:

CL/P = 0.93 per 1,000 births,

CP = 0.17 per 1,000 births.

This was the most rigorously conducted study and it found the number of infants born every year with CLP to be 28,600; this means 78 affected infants are born every day, or three infants with clefts are born every hour (Table 1-4)!

Table 1-4

Number of infants with common malformations born every year in India

Source: Global registry and database on craniofacial anomalies: Report of a WHO registry on craniofacial anomalies, 2001.

CFA are not lethal but they are disfiguring, and thus cause a tremendous social burden. However, these disorders have an excellent outcome if surgical repair is carried out competently. Recent information regarding the etiology of CFA provides the means to carry out primary or secondary prevention. Maintaining a registry would be very useful as a benefit to the community and in reducing the burden of these anomalies, either by prevention or surgical repair.

Another reason why a registry would be desirable is the changing pattern of morbidity and mortality in India emerging as a result of the achievements in immunization, the success in providing primary health care and the existence of a well-developed health infrastructure. In many university and city hospitals congenital malformations and genetic disorders have become important causes of illness. All these reasons show that starting a registry of these disorders deserves high priority in India.

Existing epidemiological data on CFA

The epidemiological information that exists on CFA anomalies in India needs to be examined to decide what data should be collected for the registry:

• Higher frequency of CL+CP among Indian males is similar to that observed among Caucasians. The ratio is more than that observed in Africans and Japanese.

• The higher prevalence of CL+CP as compared with CL among Indians is like that observed in Africans, and is more than that observed in Caucasians.

• Children born prematurely are more frequently affected in India, as elsewhere.

• About 10.9% of 459 cases of all clefts are syndromic in Chennai. Of these, about 50 % are due to single-gene disorders, about 18% due to chromosomal disorders, and the rest due to undetermined causes.

• Chromosomal studies would be desirable in cases with associated abnormalities.

• Syndromes are more commonly associated with CP than with CL, as elsewhere.

• Lateralization (more clefts on the left side) in India is similar to that observed in other races.

• In one study in India, the intake of drugs was observed in 18% of parents — mostly steroidal compounds (progestogens as tests for pregnancy).

• A greater history of terminated pregnancies has been observed among cases, as compared with controls.

• History of severe vomiting has been observed to be about six times more common among case mothers than among controls.

• There is some difference in the frequency of orofacial clefts in different states in India; however, this needs verification. The state of origin (or mother tongue) of the parents should be recorded.

• Clefts are more commonly found in certain caste groups among Hindus.

• In India CP has less frequency in those with blood group A.

• CL occurs more in those with group O and AB.

• Association of clefts with certain HLA types has been documented in India.

• In a study in Chennai, significantly more consanguinity was observed among couples having children with clefts as compared with controls.

Genetics: Principles And Terminology

Genotype and Phenotype

The science of genetics is concerned with the inheritance of traits, whether normal or abnormal, and with the interaction of genes and the environment. This latter concept is of particular relevance to medical genetics, since the effects of genes can be modified by the environment.

Table 1-5

Genes involved in craniofacial and dental disorders, sorted by acronym gene name

Acronym	Full name
ACTC	Actin, Alpha, Cardiac Muscle
APP	Amyloid Beta A4 Precursor Protein (APP)
ARVCF	Armadillo Repeat Gene Deleted in VCFS
ATP&E	ATPhase, H+ Transporting, Lysosomal, Subunit E
CA1	Carbonic Anhydrase 1
CLTCL1	Clathrin, Heavy Polypeptide-Like 1
COL01A1	Collagen, Type I, Alpha-1
COL01A2	Collagen, Type I, Alpha-2
COL02A1	Collagen, Type II, Alpha-1
COL04A4	Collagen, Type IV, Alpha-4
COL04A5	Collagen, Type IV, Alpha-5
COL05A1	Collagen, Type V, Alpha-1
COL06A1	Collagen, Type VI, Alpha-1
COL10A1	Collagen, Type X, Alpha-1
COMT	Catechol-O-Methyltransferase
CYLN2	Cytoplasmic Linker 2
DCN	Decorin
DGSI	DiGeorge Syndrome Critical Region Gene
ELN	Elastin
FBLN2	Fibulin 2
FBN1	Fibrillin 1
FGF8	Fibroblast Growth Factor 8
FGFR1	Fibroblast Growth Factor Receptor 1
FGFR2	Fibroblast Growth Factor Receptor 2
FGFR3	Fibroblast Growth Factor Receptor 3
GNAS1	Guanine Nucleotide-Binding Protein, Alpha-Stimulating Activity Polypeptide
GOLGA1	Golgi Autoantigen, Golgin Subfamily A, 1
GP1BB	Glycoprotein Ib, Platelet, Beta Polypeptide
GPC3	Glypican 3
GPC4	Glypican 4
GPR1	G Protein-Coupled Receptor 1
GTF2I	General Transcription Factor II-I
HIP1	Huntingtin-interacting Protein 1
HIRA	Histone Cell Cycle Regulation Defective, S. Cerevisiae, Homolog of, A
HOXD10	Homeo Box D10
ITGB2	Integrin, Beta-2
KRT04	Keratin 4
KRT06A	Keratin 6A
KRT06B	Keratin 6B
KRT13	Keratin 13
KRT16	Keratin 16
KRT17	Keratin 17
LAMB1	Laminin, Beta-1
MEOX2	Mesenchyme Homeo Box 2
MSX1	MSH, Drosophila, Homeo Box, Homolog of, 1
MSX2	MSH (Drosophila) Homeo Box Homolog 2
PNUTL1	Peanut-Like 1
PTHR1	Parathyroid Hormone Receptor 1
RO60	Autoantigen Ro/SSA, 60–KD
SCZD	Schizophrenia
SCZD4	Schizophrenia 4
SCZD8	Schizophrenia 8
SRC	V-SRC Avian Sarcoma (Schmidt-Ruppin A-2) Viral Oncogene
SRY	Sex-Determining Region Y
SSA1	Sjögren Syndrome Antigen A1
SSB	Sjögren Syndrome Antigen B
TNFRSF11B	Tumor Necrosis Factor Receptor Superfamily, Member 11B
TTPA	Tocopherol Transfer Protein, Alpha
TWIST	Twist, Drosophila, Homolog of
WBSCR1	Williams-Beuren Syndrome Chromosome Region 1

Source: Report of the National Institutes of Dental and Craniofacial Research Genetics Workgroup, Meeting held November 14–16, 1999.

Consideration of the heritability of a particular feature or trait requires a consideration of the relationship between genotype and phenotype. Genotype is defined as the genetic constitution of an individual, and may refer to specified gene loci or to all loci in general. An individual’s phenotype is the final product of a combination of genetic and environmental influences. Phenotype may refer to a specified character or to all the observable characteristics of the individual. The proportion of the phenotypic variance attributable to the genotype is referred to as heritability.

Genetic variation in man may be observed at two levels:

In specific traits, individual genotypes are readily identified and differences are qualitative (discrete), for example, the ABO blood antigen system. Gene frequencies can be estimated and the Mendelian type of analysis can be applied.

In continuous traits such as height, weight or tooth size, differences are characterized quantitatively between individuals. These quantitative traits in man are more elusive to study because they are determined by the alleles of many gene loci, and therefore, the Mendelian type of analysis is not appropriate. They are further modified by environmental conditions which obscure the genetic picture. If the genetic variation of a particular phenotypic trait is dependent on the simultaneous segregation of many genes and affected by environment it is referred to as being subject to multifactorial inheritance. Genetic differences caused by the segregation of many genes is referred to as polygenic variation and the genes concerned are referred to as polygenes. These genes are, of course, subject to the same laws of transmission and have the same general properties as the single genes involved in qualitative traits, but segregation of genes is translated into genetic variations seen in continuous traits through polygenes.

Different types of genetic ‘product’ can be thought of as being different distances from the fundamental level of gene activity. Enzymes, for instance, are almost direct products of gene action, and in most cases where genetic variation of enzyme structure has been demonstrated, it has been shown that a single locus is responsible for the structure of a single enzyme. The structure, and consequently, the activity of an enzyme is therefore usually simply and directly related to allele substitutions at a single locus.

Morphological characters, on the other hand, such as the numerous dimensions used to describe the shape of the face and jaws, are furthest removed from the fundamental genetic level and are the end results of a vast complexity of interacting, hierarchical, biochemical, and developmental processes. Each gene is therefore likely to influence many morphological characters so that a deleterious mutation, although producing a unitary effect at the molecular level, almost always results in a syndrome of morphological abnormalities. When a gene is known to affect a number of different characters in this way its action is said to be pleiotropic. A reverse hierarchy also exists, making each morphological character dependent on many different genes (Mossey, 1999).

Modes of Inheritance

Population genetics deals with the study of the mode of inheritance of traits and the distribution of genes in populations.

All chromosomes exist in pairs so our cells contain two copies of each gene, which may be alike or may differ in their substructure and their product. Different forms of genes at the same locus or position on the chromosome are called alleles. If both copies of the gene are identical, the individual is described as homozygous, while if they differ, the term used is heterozygous.

The exception to the rule that cells contain pairs of chromosomes applies to the gametes, sperm and ovum, which contain only single representatives of each pair of chromosomes, and therefore, of each pair of genes. When the two gametes join at fertilization, the new individual produced again has paired genes, one from the father and one from the mother. If a trait or disease manifests itself when the affected person carries only one copy of the gene responsible, along with one normal allele, the mode of inheritance of the trait is called dominant (Fig. 1-1A). If two copies of the defective gene are required for expression of the trait, the mode of inheritance is called recessive (Fig. 1-1B).

Figure 1-1 (A) Autosomal dominant pedigree. (B) Autosomal recessive pedigree. (C) X-linked recessive pedigree. Courtesy of PA Mossey, 1999.

The special case of genes carried on the X chromosome produces yet different pedigrees. Since male-to-male transmission is impossible and since females do not express the disease when they carry only one copy of the diseased gene (since it is modified by the homologous X chromosome), the usual pedigree consists of an affected male with clinically normal parents and children, but with affected brothers, maternal uncles, and other maternal male relatives (Fig. 1-1C). This mode of inheritance is described as X-linked recessive.

It has been long appreciated that many normal traits, such as height, intelligence, and birth weight, have a significant genetic component, as do a number of common diseases, such as diabetes mellitus, schizophrenia, hypertension, and cleft lip and palate. However, the pattern of inheritance of these traits does not follow the simple modes just described. Mathematical analysis of many of these has led to the conclusion that they follow the rules of polygenic inheritance, i.e. determined by a constellation of several genes, some derived from each parent.

The determination of heritability for polygenic or multifactorial characters is difficult, as a feature of continuous variation is that different individuals may occupy the same position on the continuous scale for different reasons. Using mandibular length as an example, micrognathia can occur in chromosomal disorders, such as Turner’s syndrome, in monogenic disorders such as Treacher Collins syndrome or Stickler syndrome, or due to an intrauterine environmental problem, such as fetal alcohol syndrome. Combined with this the concept of etiological heterogeneity encompasses the principle of the same gene defect producing different phenotypic anomalies, and syndromes can be due to defective gene activity in different cells. Conversely, different gene defects or combinations of defective genes can produce a similar phenotypic abnormality. Genetic lethality or reduced reproductive fitness can also complicate the diagnostic picture and genomic imprinting can result in a gene defect ‘skipping’ a generation. These complexities serve to hamper progress in the understanding of polygenic or multifactorial disorders such as orofacial clefting (Mossey, 1999).

Multifactorial Inheritance

In contrast to single-gene inheritance, either autosomal or sex-linked, the pedigree pattern does not afford a diagnosis of multifactorial inheritance. In multifactorial traits, the trait is determined by the interaction of a number of genes at different loci, each with a small, but additive effect, together with environmental factors (i.e., the genes are rendering the individual unduly susceptible to the environmental agents). Many congenital malformations (Table 1-6) and common diseases of adult life are inherited as multifactorial traits and these are categorized as either continuous or discontinuous.

Table 1-6

Causes of deformations

Extrinsic

Mechanical

Unstretched uterine and abdominal muscles

Small maternal size

Amniotic tear

Unusual implantation site

Uterine leiomyomas

Unicornuate uterus

Bicornuate uterus

Twin fetuses

Intrinsic

Malformational

Spina bifida

Other central nervous system malformations

Bilateral renal agenesis

Severe hypoplastic kidneys

Severe polycystic kidneys

Urethral atresia

Functional

Neurologic disturbances

Muscular disturbances

Connective tissue defects

Source: MM Cohen Jr, The Child with Multiple Birth Defects. Raven Press, New York, 1982, p 10. Cited by RJ Gorlin, MM Cohen, LS Levin. Syndromes of the Head and Neck, 3rd Ed, Oxford University Press; 1990, New York.

Molecular Genetics in Dental Development

The first sign of tooth development is a local thickening of oral epithelium, which subsequently invaginates into neural crest derived mesenchyme and forms a tooth bud. Subsequent epithelial folding and rapid cell proliferation result in first the cap, and then the bell stage of tooth morphogenesis. During the bell stage, the dentine producing odontoblasts and enamel secreting ameloblasts differentiate. Tooth development, like the development of all epithelial appendages, is regulated by inductive tissue interactions between the epithelium and mesenchyme (Thesleff, 1995).

There is now increasing evidence that a number of different mesenchymal molecules and their receptors act as mediators of the epithelial-mesenchymal interactions during tooth development. Of the bone morphogenetic proteins (BMPs) 2, 4, and 7 mRNAs shift between the epithelium and mesenchyme in the regulation of tooth morphogenesis (Aberg et al, 1997). The fibroblast growth factor (FGF) family have also been localized in epithelial and mesenchymal components of the tooth by immunohistochemistry (Cam et al, 1992); and in dental mesenchyme tooth development and shape is regulated by FGF8 and FGF9 via downstream factors MSX1 and PAX9 (Kettunen and Thesleff, 1998).

Control of Tooth Development

Homeobox genes have particular implications in tooth development. Muscle specific homeobox genes Msx-1 and Msx-2 appear to be involved in epithelial mesenchymal interactions, and are implicated in craniofacial development, and in particular, in the initiation developmental position (Msx-1) and further development (Msx-2) of the tooth buds (MacKenzie et al, 1991; Jowett et al, 1993). Further evidence of the role of Msx-1 comes from gene knock-out experiments which results in disruption of tooth morphogenesis among other defects (Satokata and Maas, 1994). Pax-9 is also transcription factor necessary for tooth morphogenesis (Neubuser et al, 1997). BMPs are members of the growth factor family (TGF) and they function in many aspects of craniofacial development with tissue specific functions. BMPs have been found to have multiple roles not only in bone morphogenesis, (BMP 5, for example, induces endochondral osteogenes is in vivo), but BMP 7 appears to induce dentinogenesis (Thesleff, 1995).

Table 1-7

Classification of cleft lip

Type	Occurrence (%)
Unilateral incomplete	33
Unilateral complete	48
Bilateral incomplete	7
Bilateral complete	12

Source: V Veau: Division palatine; anatomie, chirurgie, phonetique. Paris, Masson et Cie, 1931.

Stem cells

Stem cells are clonogenic cells that have the capacity for self-renewal and multilineage differentiation. The microenvironment in which stem cells reside is called a stem cell niche and is composed of heterologous cell types, extracellular matrix and soluble factors to support the maintenance and self-renewal of the stem cells. Stem cells have been isolated and characterized from a wide variety of sources. Adult progenitor cellular populations have been isolated from distinctive tissues and fluids, such as bone marrow, peripheral blood, umbilical cord blood, Wharton’s jelly, placenta, amniotic fluid and membrane, adipose tissue, dermis, hair follicles, synovial membrane, skeletal muscle, central nervous system, olfactory bulb, retina, and liver among others. From these biological sources, progenitors of the mesenchymal, epithelial, hematopoetic (discussed elsewhere), neural, endothelial and trophoblastic lineages have been identified (Fig. 1-2).

Figure 1-2 Mandibular micrognathia. Courtesy: Prof Anil Sukumaran, Prof R Rajendran. King Saud University, Riyadh, KSA.

In tissue engineering applications, mesenchymal stem cells are among the most used populations because of the wide variety of sources from which they can be harvested, their ability to self-renew, and their multilineage potential following adequate induction. Moreover, the vast majority of the tissues relevant in surgical repair / regeneration are of mesenchymal origin. This is of particular relevance in the craniofacial area because during development cells originating from the neural crest are known to migrate, differentiate, and participate in the morphogenesis of virtually all structures of the region including muscle, ligament, bone, cartilage, periodontal tissues and teeth.

There are two major categories of stem cells, which are of relevance to dentistry:

1. Embryonic stem cells

2. Adult or somatic stem cells.

Totipotent embryonic stem cells are derived from the inner cell mass of mammalian blastocyst and can be maintained indefinitely in culture. Somatic stem cells have a limitation in their potential of differentiation. The differentiation potential of dental stem cells lies in the formation of dentin or periodontium associated tissues, whether these cells are derived from pulp, periodontal ligament or dental follicle. It is obvious that dental ectomesenchymal stem cells can be classified into two different groups with respect to their differentiation potential. The first group is associated with the dental pulp, consisting of dental pulp stem cells (DPSCs), stem cells from exfoliated deciduous teeth (SCEDs), and stem cells from apical papilla (SCAPs); the second group contains periodontal ligament stem cells (PLSCs) and dental follicle progenitor cells (DFPCs), related to the periodontium.

The odontogenic stem cells are further divided into:

1. Epithelial stem cells (ESCs)

2. Mesenchymal stem cells (MSCs).

Dental epithelial stem cells

Embryonic dental epithelium is capable of inducing the development of a tooth germ in combination with non-dental ectomesenchymal tissue. However, oral ectomesenchyme in combination with non-dental epithelium did not induce tooth development. Later steps in tooth development are driven by a complex interaction of both ectodermal and ectomesenchymal tissues along with growth promoting factors of bone morphogenic protein-4 (BMP-4) and fibroblast growth factor-8 (FGF-8), produced by the oral ectoderm for the initiation of tooth development.

Oral ectoderm derived ameloblasts are unable to proliferate or regenerate once they have reached the maturation stage of development. Continuously growing mouse incisors and molars in some mammalian species show replenishing populations of enamel organs composed of stellate reticulum, stratum intermedium and enamel epithelial cells which provide models for dental epithelial stem cells. Mice have an epithelial stem cell niche located at their incisor labial apical ends, known as the cervical loop. The cervical loop has been considered to be a determinative region in odontogenesis due to its ability to produce enamel and dentin. One specialized structure found at the apical region of the labial cervical loop in mouse incisors, “apical bud” (Ohshima H et al, 2003), is suggested as stem cell compartment that could differentiate into ameloblast through interaction with mesenchymal cells and growth factors.

In humans, these dental epithelial stem cells are lost after tooth eruption; therefore, are not available for studies on dental development. In contrast to dental epithelial stem cells, undifferentiated cells of the oral ectomesenchyme are not entirely lost after tooth eruption in humans. It became possible to isolate precursor cells from the dental pulp and ectomesenchymal stem cells were isolated from the dental pulp of extracted wisdom teeth.

Dental mesenchymal stem cells

They are a heterogeneous population of multipotent self-renewal cells that possess clonogenic competence and the capacity to differentiate into all cell lineages of the mesenchymal and connective tissue elements. They also seem to be able to differentiate into epithelial cells and lineages derived from neuroectoderm. Mesenchymal stem cells have been shown to produce a wide range of bioactive molecules capable of immunomodulatory functions along with the ability to modulate the regenerative processes in the human body (Ohshima H et al, 2001).

Developmental Disturbances of Jaws

Agnathia (Otocephaly, holoprosencephaly agnathia)

Agnathia is a lethal anomaly characterized by hypoplasia or absence of the mandible with abnormally positioned ears having an autosomal recessive mode of inheritance. More commonly, only a portion of one jaw is missing. In the case of the maxilla, this may be one maxillary process or even the premaxilla. Partial absence of the mandible is even more common. The entire mandible on one side may be missing, or more frequently, only the condyle or the entire ramus, although bilateral agenesis of the condyles and of the rami also has been reported. In cases of unilateral absence of the mandibular ramus, it is not unusual for the ear to be deformed or absent as well. It is probably due to failure of migration of neural crest mesenchyme into the maxillary prominence at the fourth to fifth week of gestation (postconception). The prevalence is unknown and less than 10 cases are described. The prognosis of this condition is very poor and it is considered to be lethal.

Micrognathia

Micrognathia literally means a small jaw, and either the maxilla or the mandible may be affected. Many cases of apparent micrognathia are not due to an abnormally small jaw in terms of absolute size, but rather to an abnormal positioning or an abnormal relation of one jaw to the other or to the skull, which produces the illusion of micrognathia.

True micrognathia may be classified as either congenital, or acquired. The etiology of the congenital type is unknown, although in many instances it is associated with other congenital abnormalities, including congenital heart disease and the Pierre Robin syndrome (q.v.) This form of the disease has been discussed by Monroe and Ogo. It occasionally follows a hereditary pattern. Micrognathia of the maxilla frequently occurs due to a deficiency in the premaxillary area, and patients with this deformity appear to have the middle third of the face retracted. Although it has been suggested that mouth-breathing is a cause of maxillary micrognathia, it is more likely that the micrognathia may be one of the predisposing factors in mouth-breathing, owing to the associated maldevelopment of the nasal and nasopharyngeal structures.

True mandibular micrognathia of the congenital type is often difficult to explain. Some patients appear clinically to have a severe retrusion of the chin but, by actual measurements, the mandible may be found to be within the normal limits of variation. Such cases may be due to a posterior positioning of the mandible with regard to the skull or to a steep mandibular angle resulting in an apparent retrusion of the jaw. Agenesis of the condyles also results in a true mandibular micrognathia.

The acquired type of micrognathia is of postnatal origin and usually results from a disturbance in the area of the temporomandibular joint. Ankylosis of the joint, for example, may be caused by trauma or by infection of the mastoid, of the middle ear, or of the joint itself. Since the normal growth of the mandible depends to a considerable extent on normally developing condyles as well as on muscle function, it is not difficult to understand how condylar ankylosis may result in a deficient mandible.

The clinical appearance of mandibular micrognathia is characterized by severe retrusion of the chin, a steep mandibular angle, and a deficient chin button (Fig. 1-3).

Figure 1-3 Mandibular micrognathia Courtesy of Dr G Thaddeus Gregory and Dr J William Adams.

Micrognathia may be caused by or may be a feature of several conditions (Table 1-8).

Table 1-8

Causes of micrognathia

Congenital conditions

• Catel-Manzke syndrome

• Cerebrocostomandibular syndrome

• Cornelia de Lange syndrome

• Femoral hypoplasia—unusual facies syndrome

• Fetal aminopterin-like syndrome

• Miller-Dieker syndrome

• Nager acrofacial dysostosis

• Pierre Robin syndrome

• Schwartz-Jampel-Aberfeld syndrome

• van Bogaert-Hozay syndrome

Intrauterine acquired conditions

• Syphilis, congenital

Chromosomal abnormalities

• 49, XXXXX syndrome

• Chromosome 8 recombinant syndrome

• Cri du chat syndrome 5p

• Trisomy 18

• Turner’s syndrome

• Wolf-Hirschhorn syndrome

Mendelian inherited conditions

• CODAS (cerebral, ocular, dental, auricular, skeletal) syndrome

• Diamond-Blackfan anemia

• Noonan’s syndrome

• Opitz-Frias syndrome

Autosomal dominant conditions

• Camptomelic dysplasia

• Cardiofaciocutaneous syndrome

• CHARGE syndrome

• DiGeorge’s syndrome

• Micrognathia with peromelia

• Pallister-Hall syndrome

• Treacher Collins-Franceschetti syndrome

• Trichorhinophalangeal syndrome type 1

• Trichorhinophalangeal syndrome type 3

• Wagner vitreoretinal degeneration syndrome

Autosomal recessive conditions

• Bowen-Conradi syndrome

• Carey-Fineman-Ziter syndrome

• Cerebrohepatorenal syndrome

• Cohen syndrome

• Craniomandibular dermatodysostosis

• De la Chapelle dysplasia

• Dubowitz syndrome

• Fetal akinesia-hypokinesia sequence

• Hurst’s microtia-absent patellae-micrognathia syndrome

• Kyphomelic dysplasia

• Lathosterolosis

• Lethal congenital contracture syndrome

• Lethal restrictive dermopathy

• Marden-Walker syndrome

• Orofaciodigital syndrome type 4

• Postaxial acrofacial dysostosis syndrome

• Rothmund-Thomson syndrome

• Smith-Lemli-Opitz syndrome

• ter Haar syndrome

• Toriello-Carey syndrome

• Weissenbacher-Zweymuller syndrome

• Yunis-Varon syndrome

X-linked inherited conditions

• Atkin-Flaitz-Patil syndrome

• Coffin-Lowry syndrome

• Lujan-Fryns syndrome

• Otopalatodigital syndrome type 2

Autoimmune conditions

• Juvenile chronic arthritis

Source: www.diseasesdatabase.com, Health on the Net Foundation, 2005.

Macrognathia

Macrognathia refers to the condition of abnormally large jaws. An increase in size of both jaws is frequently proportional to a generalized increase in size of the entire skeleton, e.g. in pituitary gigantism. More commonly only the jaws are affected, but macrognathia may be associated with certain other conditions, such as:

• Paget’s disease of bone, in which overgrowth of the cranium and maxilla or occasionally the mandible occurs,

• Acromegaly, in which there is progressive enlargement of the mandible owing to hyperpituitarism in the adult, or

• Leontiasis ossea, a form of fibrous dysplasia in which there is enlargement of the maxilla.

Cases of mandibular protrusion or prognathism, uncomplicated by any systemic condition, are a rather common clinical occurrence (Fig. 1-4). The etiology of this protrusion is unknown, although some cases follow hereditary patterns. In many instances the prognathism is due to a disparity in the size of the maxilla in relation to the mandible. In other cases the mandible is measur-ably larger than normal. The angle between the ramus and the body also appears to influence the relation of the mandible to the maxilla, as does the actual height of the ramus. Thus prognathic patients tend to have long rami which form a less steep angle with the body of the mandible. The length of the ramus, in turn, may be associated with the growth of the condyle. It may be reasoned, therefore, that excessive condylar growth predisposes to mandibular prognathism.

Figure 1-4 Macrognathia (prognathia) of the mandible. (A) The protrusion of the mandible is obvious. (B) The same patient after surgical correction (ostectomy) (Courtesy of Dr G Thaddeus Gregory and Dr J William Adams.

General factors which conceivably would influence and tend to favor mandibular prognathism are as follows:

• Increased height of the ramus

• Increased mandibular body length

• Increased gonial angle

• Anterior positioning of the glenoid fossa

• Decreased maxillary length

• Posterior positioning of the maxilla in relation to the cranium

• Prominent chin button

• Varying soft-tissue contours.

Surgical correction of such cases is feasible. Ostectomy, or resection of a portion of the mandible to decrease its length, is now an established procedure, and the results are usually excellent from both a functional and a cosmetic standpoint.

Facial Hemihypertrophy (Hyperplasia)

Hemihyperplasia is a rare developmental anomaly characterized by asymmetric overgrowth of one or more body parts. Although the condition is known more commonly as hemihypertrophy, it actually represents a hyperplasia of the tissues rather than a hypertrophy. Hemihyperplasia can be an isolated finding, but it also may be associated with a variety of malformation syndromes (Table 1-9). Almost all cases of isolated hemihyperplasia are sporadic.

Table 1-9

Malformation syndromes associated with hemihyperplasia

• Beckwith-Wiedemann syndrome

• Neurofi bromatosis

• Klippel-Trenaunay-Weber syndrome

• Proteus syndrome

• McCune-Albright syndrome

• Epidermal nevus syndrome

• Triploid/diploid mixoploidy

• Langer-Giedion syndrome

• Multiple exostoses syndrome

• Maffucci’s syndrome

• Ollier syndrome

• Segmental odontomaxillary dysplasia

Source: HE Hoyme et al, 1998.

Hoyme et al (1998) provided an anatomic classification of hemihyperplasia:

• Complex hemihyperplasia is the involvement of half of the body (at least one arm and one leg); affected parts may be contralateral or ipsilateral,

• Simple hemihyperplasia is the involvement of a single limb, and

• Hemifacial hyperplasia is the involvement of one side of the face.

Etiology

The cause is unknown, but the condition has been variously ascribed to vascular or lymphatic abnormalities; CNS disturbances; and chromosomal abnormalities.

Clinical Features

Patients affected by facial hemihypertrophy exhibit an enlargement which is confined to one side of the body, unilateral macroglossia and premature development, and eruption as well as an increased size of dentition. Familial occurrence has been reported on a few occasions, according to the excellent review of the condition by Rowe, who described four additional cases. Of all reported cases, females are affected somewhat more frequently than males (63% versus 37%), according to the review by Ringrose. There is an almost equal involvement of the right and left sides.

Oral Manifestations

The dentition of the hypertrophic side, according to Rowe, is abnormal in three respects: crown size, root size and shape, and rate of development. Rowe has also pointed out that not all teeth in the enlarged area are necessarily affected in a similar fashion. There is little information about the effects on the deciduous dentition, but the permanent teeth on the affected side are often enlarged, although not exceeding a 50% increase in size. This enlargement may involve any tooth, but seems to occur most frequently in the cuspid, premolars, and first molar. The roots of the teeth are sometimes proportionately enlarged but may be short.

Characteristically, the permanent teeth on the affected side develop more rapidly and erupt before their counterparts on the uninvolved side (Fig. 1-5). Coincident to this phenomenon is premature shedding of the deciduous teeth. The bone of the maxilla and mandible is also enlarged, being wider and thicker, sometimes with an altered trabecular pattern.

Figure 1-5 Facial hemihypertrophy.
The difference in the eruption pattern of the teeth on each side is apparent. The teeth on the affected side, where all deciduous teeth have already been lost, are not appreciably larger than those on the unaffected side (Courtesy of Dr John B Wittgen.

The tongue is commonly involved by the hemihypertrophy and may show a bizarre picture of enlargement of lingual papillae in addition to the general unilateral enlargement and contralateral displacement. In addition, the buccal mucosa frequently appears velvety and may seem to hang in soft, pendulous folds on the affected side.

Histologic Features

Tissue examination has been infrequently reported but is generally uninformative. In those cases reported, true muscular hypertrophy was not found.

Treatment and Prognosis

There is no specific treatment for this condition other than attempts at cosmetic repair. Cosmetic surgery is advised after cessation of growth. Effect on life expectancy is not certain, but in some cases patients have lived a normal life span. Periodic abdominal ultrasound/ MRI is recommended to rule out tumors.

Differential Diagnosis

There are certain diseases of the jaws, such as neurofibromatosis and fibrous dysplasia of the jaws, that may give the clinical appearance of facial hemihypertrophy, but these can usually be differentiated readily by the lack of effect on tooth size and rate of eruption.

Facial Hemiatrophy (Parry-Romberg syndrome, Romberg-Parry syndrome, progressive facial hemiatrophy, progressive hemifacial atrophy)

Hemifacial atrophy remains almost as much an enigma today as it was when first reported by Romberg in 1846. Hemifacial atrophy, originally described by Parry and Henoch and Romberg consists of slowly progressive atrophy of the soft tissues of essentially half the face, which is characterized by progressive wasting of subcutaneous fat, sometimes accompanied by atrophy of skin, cartilage, bone and muscle. Although the atrophy is usually confined to one side of the face and cranium, it may occasionally spread to the neck and one side of the body and it is accompanied usually by contralateral Jacksonian epilepsy, trigeminal neuralgia, and changes in the eyes and hair. Evidence of a mendelian basis is lacking. Lewkonia and Lowry reported the case of a 16-year-old boy who developed facial changes at age seven and had localized scleroderma on one leg and the trunk. The presence of antinuclear antibodies in his serum suggested that the Parry-Romberg syndrome may be a form of localized scleroderma. Hemifacial atrophy is a form of localized scleroderma and is supported by its concurrence with scleroderma.

Hemifacial atrophy is a rare condition that occurs sporadically although some familial distribution has been found. The majority of cases are sporadic with no definite inheritance being proven in the literature.

Etiology

The etiology has been the subject of considerable debate. Wartenburg considered the primary factor to be a cerebral disturbance leading to increased and unregulated activity of sympathetic nervous system, which in turn produced the localized atrophy through its trophic functions conducted by way of sensory trunks of the trigeminal nerve. Other workers suggested extraction of teeth, local trauma, infection and genetic factors could also be a cause. In a paper published in 1973, Poswillo attributed the development of facial deformities to the disruption of the stapedial artery. Poswillo fed pregnant rats with triazine and pregnant monkeys with thalidomide and showed the consistent maldevelopment of first and second branchial arch structures. Robinson, in 1987, supported Poswillo’s theory by demonstrating carotid flow abnormalities in two and defects related to vascular disruption in a third child with craniofacial microsomia.

Clinical Features

Hemifacial atrophy is a syndrome with diverse presentation. The most common early sign is a painless cleft, the ‘coup de sabre,’ near the midline of the face or forehead. This marks the boundary between normal and atrophic tissue. A bluish hue may appear in the skin overlying atrophic fat.

The affected area extends progressively with the atrophy of the skin, subcutaneous tissue, muscles, bones, cartilages, alveolar bone and soft palate on that side of the face. In addition to facial wasting that may include the ipsilateral salivary glands and hemiatrophy of the tongue, unilateral involvement of the ear, larynx, esophagus, diaphragm, kidney and brain have been reported.

It starts in the first decade and lasts for about three years before it becomes quiescent. The final deformity varies widely, burning itself out in some patients with minimal atrophy, while in others progressing to marked atrophy.

Neurological disorders are found in 15% of patients, while ocular findings occur in 10–40%, the most common being enophthalmos.

Rarely, one half of the body may be affected. This condition may be accompanied by pigmentation disorders, vitiligo, pigmented facial nevi, contralateral Jacksonian epilepsy, contralateral trigeminal neuralgia and ocular complications.

The disease occurs more frequently in women; female to male ratio is 3 : 2. It has a slight predilection for the left side and appears in the first or second decades of life. It progresses over a period of two and 10 years, and atrophy appears to follow the distribution of one or more divisions of the trigeminal nerve. The resulting facial flattening may be mistaken for Bell’s palsy (Fig. 1-6).

Figure 1-6 Facial hemiatrophy.

Oral Manifestations

Dental abnormalities include incomplete root formation, delayed eruption and severe facial asymmetry, resulting in facial deformation and difficulty with mastication. Hemiatrophy of the lips and the tongue is reported, as are dental effects. Foster has reported that growth of the teeth may be affected just as other tissues are involved. Eruption of teeth on the affected side may also be retarded.

In the preceding sections the conditions discussed are those in which there is an actual or apparent abnormal variation in size of one or both jaws. Of far greater importance than a simple disparity in size is the disparity in relation of one jaw to the other and the difficulties in occlusion and function that result.

A great many different types of malocclusion exist, and many classifications have been evolved in an attempt to unify methods of treatment. The classification of Angle, proposed in 1899, is the most universally known and used. That classification, with the approximate percentage occurrence as determined by Angle in a large group of orthodontic patients, is as follows:

Class I. Arches in normal mesiodistal relations 69.0%.

Class II. Mandibular arch distal to normal in its relation to the maxillary arch.

Division 1. Bilaterally distal, protruding maxillary incisors 9.0.

Subdivision. Unilaterally distal, protruding maxillary incisors 3.5.

Division 2. Bilaterally distal, retruding maxillary incisors 4.0.

Subdivision. Unilaterally distal, retruding maxillary incisors 10.0.

Class III. Mandibular arch mesial to normal in its relation to the maxillary arch.

Division.Bilaterally mesial 3.5.

Subdivision.Unilaterally mesial 1.0.

Since these abnormal jaw relations constitute a separate course of study, no further allusion to this subject will be made here.

Developmental Disturbances of Lips And Palate

Congenital Lip and Commissural Pits and Fistulas

Congenital lip pits and fistulas are malformations of the lips, often following a hereditary pattern, that may occur alone or in association with other developmental anomalies such as various oral clefts. Both Taylor and Lane and McConnel and his associates have emphasized that in 75–80% of all cases of congenital labial fistulas, there is an associated cleft lip or cleft palate, or both. The association of pits of the lower lip and cleft lip and/or cleft palate, termed van der Woude’s syndrome, has been reviewed by Cervenka and his associates.

Commissural pits are an entity probably very closely related to lip pits, but occur at the lip commissures, lateral to the typical lip pits. Everett and Wescott have described this entity and noted that it is also frequently hereditary, possibly a dominant characteristic following a Mendelian pattern, and may be associated with other congenital defects.

Etiology

Many theories of the etiology of congenital lip pits have been offered, but none has been universally accepted. Pits may result from notching of the lip at an early stage of development, with fixation of the tissue at the base of the notch, or from failure of complete union of the embryonic lateral sulci of the lip, which persist and ultimately develop into the typical pits.

Commissural pits are also difficult to explain, but they occur at the site of the horizontal facial cleft and may represent defective development of this embryonic fissure.

Clinical Features

The lip pit or fistula is a unilateral or bilateral depression or pit that occurs on the vermilion surface of either lip but far more commonly on the lower lip (Fig. 1-7A). In some cases a sparse mucous secretion may exude from the base of this pit. The lip sometimes appears swollen, accentuating the appearance of the pits.

Figure 1-7 (A) Congenital lip pits. (B) Congenital commissural pits. Courtesy of Dr Spencer Lilly, Meenakshi Ammal Dental College, Chennai.

Commissural pits appear as unilateral or bilateral pits at the corners of the mouth on the vermilion surface (Fig. 1-7B). An actual fistula may be present from which fluid may be expressed. Whether this tract, either in lip or commissural fistulas, represents a true duct is not clear. Interestingly, in several cases preauricular pits have been reported in association with commissural pits.