Rebecca L. Slayton

 Outline

Basic Genetic Concepts

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.

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.

Molecular Basis of Disease

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.

Inheritance Patterns

Dentist as Dysmorphologist

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.