Congenital Genetic Disorders and Syndromes
Our understanding of genetics and the genetic basis of disease has increased dramatically over the last 20 years. During this time, scientists have ascertained the sequence of the entire human genome (more than 3 billion nucleotides of DNA) and have discovered new ways that diseases and disease susceptibility are inherited.
As health care professionals, we have gained information from the Human Genome Project that provides us with many opportunities as well as challenges. This information has given us the ability to understand diseases at a molecular level. In addition, diseases that were once thought to be influenced primarily by environmental factors are now known to have genetic factors that modulate their severity. More recently, gene-environment interactions and epigenetics have been shown to contribute to disease susceptibility. Access to the sequence of the entire human genome will continue to facilitate the identification of additional disease genes and allow us to understand the complex interactions that occur between genes and regulatory proteins. The ability to identify single-nucleotide changes (referred to as polymorphisms) will help us understand individual risk factors for disease and how to tailor prevention and treatment strategies at an individual rather than a global level. The complete sequencing of microbial genomes will help us understand what makes some strains of bacteria more virulent than others and will aid in the development of more effective therapeutic interventions.
There are also challenges involved in the management and use of information generated by the Human Genome Project. It will be important to anticipate how this information might be used in ways that are unethical or detrimental to individuals or groups of people. Information about genetics and genetic research is reported almost daily in newspapers and magazines and on the radio, television, and Internet. This often means that a patient may hear of a new discovery before it is published in a scientific journal. Health professionals must be prepared to answer patients’ questions and know how and where to refer them for additional information or counseling. Practicing dental clinicians provide the front line as diagnosticians and for referral of patients and families for genetic testing and counseling for many oral health conditions. This requires a basic understanding of the genetics of human disease, knowledge of the types of genetic testing that are available, and sensitivity to the family’s concerns.
Practicing dentists are confronted daily with conditions that are either primarily genetic or have a significant genetic contribution in their etiology. Common conditions such as congenitally missing teeth now are known in many cases to be caused by specific genetic mutations. Many syndromes involve craniofacial structures and have associated dental anomalies. Frequently, other major malformations are present in addition to the craniofacial anomalies. Advances in the Human Genome Project have led to the discovery of the genetic basis of many of these disorders that have craniofacial and dental anomalies as part of the spectrum of the disease. Understanding the disease at this level permits the practitioner to provide more precise diagnosis of the disease, more appropriate treatment, and more accurate prognosis of the outcomes of care.
Dental practitioners are aware of the environmental and behavioral risk factors that contribute to poor oral health. We routinely counsel our patients and their parents about the risks involved with cigarette smoking, smokeless tobacco, alcohol, poor oral hygiene, sweetened beverages, a diet high in carbohydrates, and traumatic injuries to the head and mouth. We know that the two most common dental diseases—dental caries and periodontal disease—are complex and have both environmental and genetic components. As we continue to gain information about the genetic makeup of individuals, there will be additional genetic susceptibility or resistance factors identified that will influence the severity of oral diseases. Once these factors are identified, there will be tests that can be performed well before the occurrence of disease. This will permit practitioners to educate patients about the importance of their behaviors and to tailor their preventive strategies more specifically for each patient. There will be some tests that dentists can perform in their offices, whereas others will require the use of an outside laboratory. The application of appropriate tests and ultimately the interpretation of the test results and the management of the oral disease will be the responsibility of the dentist. Therefore practicing dentists must understand the basis of the test, how it is performed, and how the results are interpreted. Understanding the basis for many of the genetic tests available today requires an understanding of basic genetic concepts as well as the current technologies that are available for testing.
A person’s genome is made up of the DNA in all 46 chromosomes in the nucleus of each cell of the body. Each cell has 23 pairs of chromosomes. One chromosome of each pair is inherited from each parent. Two of the chromosomes are called sex chromosomes (X and Y), whereas the remaining chromosomes (numbered 1 through 22) are called autosomes. Males have one X and one Y chromosome; females have two X chromosomes. In each cell of a female, one of the X chromosomes is randomly inactivated. This is an important determinant of the severity of X-linked genetic disorders, as will be discussed later. The tool used to look at all of the chromosomes in a cell and to determine the sex of a fetus from amniotic fluid is called a karyotype (Figure 16-1). This technique also identifies major chromosomal anomalies such as trisomy (an extra chromosome), translocations of one part of a chromosome to another, or large chromosomal deletions.
FIGURE 16-1 Karyotype of a normal male.
Each chromosome is made up of double-stranded DNA helix composed of a series of four nucleotides and a sugar-phosphate base. Each of the four nucleotides (adenine, thymine, cytosine, and guanine) is paired with a specific complementary nucleotide to form the double helix. Adenine always pairs with thymine, and cytosine always pairs with guanine. The ability of a single strand of DNA to bind to a complementary strand of DNA or RNA forms the basis of many of the diagnostic tests performed today.
Genes are sequences of DNA that are transcribed into messenger RNA and then translated into proteins. Each chromosome contains thousands of genes. The entire human genome is estimated to have between 35,000 and 50,000 genes. The exquisite control of gene expression is essential for the proper growth, development, and functioning of an organism.
Although each cell contains the same DNA and therefore the same genes, only a small percentage of those genes are active or expressed depending on the time of development and the type of cell. Cells in the epidermis need different proteins than cells in the developing tooth or in the kidney, and each cell type has a complex regulatory process to ensure that the right genes are expressed and translated into the necessary proteins at the proper time.
Traditionally, genetic diseases have been thought of in terms of Mendelian inheritance patterns. This means that a mutation present in a gene transmitted to a child from one or both parents results in the child’s either having the disease or being a carrier of the disease. As we have learned more about genetics, additional mechanisms of inheritance have been identified that make it more challenging to predict both the occurrence and the severity of disease. It is not uncommon for a genetic disease to be the result of a new mutation. In this case, there would be no history of the disorder on either side of the family. Other types of nonmendelian inheritance patterns include imprinting, DNA triplet repeat expansion, mitochondrial DNA defects, and complex disorders in which multiple genes may be involved and in which sequence changes increase or decrease a person’s susceptibility to disease.
In autosomal dominant inheritance, the transmission is vertical from parent to child. An affected parent has a 50% chance of passing along the defective gene to either sex child. It may occur in the family initially as a new mutation or may have been present in the family for multiple generations. Dentinogenesis imperfecta is an example of an autosomal dominant disorder. The gene for type I dentinogenesis imperfecta has been identified (dentin sialophosphoprotein) and is located on chromosome 4. Other autosomal dominant disorders include achondroplasia (short-limbed dwarfism), some forms of amelogenesis imperfecta, and Marfan syndrome.
An autosomal recessive disorder is only manifest when an individual has two copies of the mutant gene. Most frequently, each parent has one copy of the defective gene and is a carrier, and there is a 25% chance that both mutant genes will be passed on to their offspring. It is equally likely that males and females will be affected. Fifty percent of the time the offspring will get one copy of the mutant gene from one parent and will be a carrier, and 25% of the time the offspring will get two normal copies of the gene. Although autosomal recessive disorders are relatively uncommon, the carrier status in certain populations can be significant. For example, 1 in 25 people of northern European descent are carriers of cystic fibrosis.1
Mutations in genes located on the X chromosome result in X-linked genetic disorders. Since females have two X chromosomes and one is randomly inactivated in each cell, they are carriers and do not normally manifest the disorder. Males, on the other hand, only have one X chromosome, which is inherited from their mother. A son has a 50% chance of inheriting the defective gene from his mother and manifesting the disease. A daughter also has a 50% chance of inheriting the defective gene from her mother but will then be a carrier. X-linked disorders often appear to skip a generation because an affected male will only pass the affected X chromosome to a daughter and she will serve as a carrier to the next generation. Disorders with X-linked inheritance include factor VIII deficiency (hemophilia), X-linked hypohydrotic ectodermal dysplasia, fragile X syndrome, and X-linked amelogenesis imperfecta. Occasionally, as a result of nonrandom X inactivation, females may have mild symptoms of an X-linked disorder.
In the previous examples, defects in one or both copies of a gene were responsible for the occurrence of a genetic disorder. Some disorders result from defects in chromosomes that result in extra copies of one or more genes, entire deletions of one or more genes, or translocation of one part of a chromosome with another. Generally, chromosomal anomalies result in multiple physical defects as well as mental and developmental delay. Down syndrome is the result of a trisomy (three copies) of all or part of chromosome 21. The duplicated part of the chromosome leads to an extra copy of all the genes on that part of the chromosome. The dosage of gene products in each cell is highly regulated. Extra copies of genes lead to excess gene products that interfere with the necessary balance in the cell. Extra or missing chromosomal material frequently results in miscarriages and/or multiple birth defects.
Most common diseases of adulthood (such as diabetes, hypertension, and manic depression) as well as most congenital malformations (cleft lip/palate and neural tube defects) are the result of multiple genes and gene-environment interactions, rather than a single gene defect. This is also true for the most common dental diseases (periodontal disease and dental caries). Multifactorial traits are thought to result from the interaction between multiple genes with multiple environmental factors. The most convincing evidence for this type of inheritance comes from twin studies. If a trait is multifactorial with a significant genetic component, monozygotic (identical) twins will both have the disease significantly more frequently than dizygotic (fraternal) twins. This has been demonstrated in multiple studies for dental caries among twins raised apart and provides strong evidence that there is a genetic component to dental caries susceptibility.2,3 More recently, researchers have completed a genome-wide association study to identify genetic loci associated with the susceptibility or resistance to dental caries.4
Other types of inheritance patterns that do not fit the traditional Mendelian patterns and that have been identified fairly recently are imprinting and triplet repeat expansion. Imprinted genes are turned off by methylation of the gene. This process controls the level of expression of a particular gene in the offspring. Depending on whether the imprinted gene is inherited from the mother or father determines if the child has a particular disease. In some cases, if the imprinted gene is inherited from the father, the child has one disease, but if the same imprinted gene is inherited from the mother, he or she has a different disease.
DNA triplet repeat expansion is a phenomenon where strings of repeated nucleotides increase in number. For example, within a particular gene, there may be 200 copies of the trinucleotide repeat “TAG.” Smaller numbers of repeats are often referred to as a premutation, but when the repeats are expanded in an offspring, they may cause the gene to be inactivated (often by methylation). Diseases caused by this type of defect include Huntington chorea and fragile X syndrome.
Epigenetic mechanisms affect the expression of genes and can be caused by environmental chemicals, developmental processes, drugs, or aging. These changes are not the result of DNA sequence alterations but rather are caused by factors such as DNA methylation and histone acetylation. Although the term epigenetics was coined in 1942, its relevance to inheritance of disease susceptibility has attracted substantial attention in recent years.
The word dysmorphic describes faulty development of the shape or form of an organism. Facial features in a child are frequently referred to as dysmorphic when they vary from what is considered normal. Features such as the spacing between the eyes, the position and shape of the ears, and the relative proportions of the maxilla and mandible either are within the range of normal or vary enough to be considered dysmorphic. Many genetic syndromes result in dysmorphic facial features that frequently help to diagnose the syndrome. For example, children with Down syndrome have inner epicanthal folds, up-slanting palpebral fissures, and maxillary hypoplasia. This causes unrelated children with Down syndrome to have a similar appearance to each other.
There are four basic mechanisms that result in structural defects during development. The first is malformation, the second is deformation due to mechanical forces, the third is disruption where there is a breakdown of tissues that were previously normal, and the fourth is dysplasia. Dysplasia is caused by a failure of normal organization of cells into tissues. It is not uncommon for humans to have at least one “minor” malformation. This includes things such as hair whorls, inner epicanthal folds, aberrant positioning of oral frenula, or preauricular pits. Although the occurrence of single anomalies such as these are relatively common and often present as a familial trait, there are a number of studies that have demonstrated that a child who has three minor anomalies has a much greater chance of having a major anomaly such as a defect in brain or heart development.5-7 This illustrates why it is important for health care professionals to be careful observers of their patients and to be familiar with the facial features that are considered to be normal or aberrant.
In general, the children seen in a dental practice fit into one of three categories. They may be normally developed in every way; they may have been diagnosed with a developmental anomaly of some type (either physical or mental); or they may have a developmental anomaly that has not been diagnosed. Pediatric dentists and general dentists are in the unique position of seeing their patients regularly, even when the patient does not perceive a dental problem. This is in contrast to the typical physician who may only see patients when they are ill. This frequent interaction between dentists and their patients gives the dentist the opportunity to observe a child’s growth and development and to note changes that are not within the range of normal. As health care professionals, it is incumbent on all dentists to recognize disease in their patients and to make the appropriate referral for definitive diagnosis and treatment.
Dentists are trained to observe and examine the mouth, face, and other craniofacial structures. Coincidentally, many inherited diseases in humans involve malformations of the craniofacial region. Accurate diagnosis of developmental anomalies and their related disorders relies on the ability of the clinician to recognize and differentiate between normal and dysmorphic physical characteristics. According to the text Smith’s Recognizable Patterns of Human Malformation, 12 of the 26 categories of malformations used for diagnostic purposes involve features of the head or neck.8 Several are limited to oral structures, such as hypodontia, microdontia, micrognathia, and cleft lip/palate. In addition, having an understanding of the full spectrum of malformations associated with certain syndromes is essential for the safe and effective treatment of patients with these disorders.
Because dentists concentrate their diagnostic expertise on the face and mouth, they may be more likely to observe anomalies that are suggestive of major developmental malformations. Dentists who can recognize potential genetic disorders can also provide a valuable service to their patients by offering appropriate referral to a medical geneticist or a genetic counselor.
Minor anomalies that affect the eyes and ocular region include widely spaced eyes (hypertelorism) (Figure 16-2), inner epicanthal folds (Figure 16-3), slanting of the palpebral fissures (upward or downward) (Figures 16-4 and 16-5), a single eyebrow (synophrys), blue sclera, and coloboma of the iris (cat-eye) (Figure 16-6).
FIGURE 16-2 Hypertelorism.
FIGURE 16-3 Inner epicanthal fold.
FIGURE 16-4 Up-slanting palpebral fissures.
FIGURE 16-5 Down-slanting palpebral fissures.
There are a number of minor anomalies that affect the outer ear (auricle) and the preauricular region. These include preauricular tags or pits (Figure 16-7), low-set and malformed ears (Figure 16-8), protruding ears, and slanted ears.
FIGURE 16-7 Ear tag.
Cleft lip alone or combined with a cleft palate, although not a minor anomaly, can occur independently from other malformations and is then considered nonsyndromic. Other anomalies in this region include lower lip pits (Figure 16-9), bifid uvula, macroglossia, and prominent or full lips. Attached frenula as is seen with ankyloglossia (Figure 16-10) is also a fairly common anomaly/>