This is a publicly funded effort to map the human genome in its molecular detail.¹ This ambitious project initially had a planned completion date of 2003. By April 2000, Human Genome Project director Francis Collins estimated that 2-thirds of the human genetic code had been sequenced.² However, interest in the project has grown to such a degree that the private company Celera Genomics is now competing with the Human Genome Project in the race to map the genome. Celera claimed in 2001 that it had decoded 99% of human genes.³ The stakes are high and include the patenting of human genetic information, which is especially important for the pharmaceutical industry.²

The full scope of human genetic information is immense. The human genome contains approximately 3 billion nucleotides, making up about 100,000 alleles, which in turn are contained on 46 chromosomes. Transcription of these chromosomes releases the information necessary to synthesize some 6000 proteins. These proteins make up the trillion cells giving rise to the nearly 4000 anatomical structures that constitute a single human being.⁴ Mutation, the accidental alteration of the genome, may result in heritable conditions or syndromes affecting any aspect of growth and development.

Inherited syndromes discussed here are some of the anomalies that a practising dentist may encounter. In addition to describing each syndrome, this article discusses known genetic inheritance and causative mutations. Some of the syndromes have additional clinical or radiographic features, but only selected head and neck anomalies are discussed here. Table 1 summarizes the syndromes under consideration. This area is developing rapidly, and the current body of knowledge is expected to expand and change quickly.

Hypoplastic Amelogenesis Imperfecta

Hypoplastic amelogenesis imperfecta is characterized by enamel that is very hard but abnormally thin and irregular, giving rise to the microdontic appearance of affected teeth (Fig. 1). In most cases of amelogenesis imperfecta, the condition is inherited as an autosomal dominant trait, but the hypoplastic type is inherited as an X-linked dominant trait.⁵ Differences in manifestations between males and females in the hypoplastic forms may be based on random inactivation in females of genes on the normal or affected X chromosome, known as the Lyon phenomenon.⁶ Researchers have identified the locus for hypoplastic amelogenesis imperfecta on the distal portion of the short (p) arm of the X chromosome.^7-10

Cleidocranial Dysplasia

Cleidocranial dysplasia, previously known as cleidocranial dysostosis, includes features such as brachycephaly, frontal bossing, a metopic suture groove, hypoplasia or aplasia of the clavicles permitting abnormal approximation of the shoulders, delayed exfoliation of the deciduous teeth, delayed eruption of the permanent teeth, ectopic tooth position, and multiple supplemental and supernumerary teeth (Fig. 2). Cleidocranial dysplasia is inherited as an autosomal dominant condition. Three possible defects have been identified, on the long arm of chromosome 8 or the short arm of chromosome 6. There is also a possible trans location between the 2 arms of chromosome 6.^11-14

Nonsyndromic Cleft Lip with or Without Cleft Palate

Cleft lip with or without cleft palate (Fig. 3) appears to be associated with complex genetic changes. Carter and others¹⁵ concluded on the basis of a multigenerational study that the most plausible explanation was the multifactorial threshold model and that a single mutant gene was unlikely. However, Eiberg and others¹⁶ proposed a deletion on the short arm of chromosome 6. Others have suggested that the inheritance is compatible with either a multifactorial threshold model or a model specifying multiple interacting loci.¹⁷

Dentinogenesis Imperfecta

Dentinogenesis imperfecta is an entity clearly distinct from osteogenesis imperfecta with opalescent teeth. Dentinogenesis imperfecta affects only the teeth, with no associated increase in fractures of the long bones. The teeth are blue–grey or amber–brown and opalescent. Radiographically, the roots are narrow with little or no evidence of a pulp chamber or canal (Fig. 4). The crowns are bulbous with a wide emergence profile. The enamel may split readily from the dentin when subjected to occlusal or other forces.

Dentinogenesis imperfecta has an autosomal dominant pattern of inheritance. Roulston and others¹⁸ concluded that the locus for type I dentinogenesis imperfecta is located on chromosome 4, at position q13-q21.

Osteopetrosis

Osteopetrosis (also known as marble bone disease or Albers-Schonberg disease) is characterized by excessive formation of dense trabecular bone and calcified cartilage, especially in the long bones, which leads to obliteration of marrow spaces (Fig. 5). The resulting anemia is accompanied by myeloid metaplasia and hepatosplenomegaly. Patients experience progressive deafness and blindness due to pressure on the cranial nerves at their exiting foramina. Osteopetrosis results from defective resorption of immature bones, because the osteoclasts are hypofunctional or absent.

The inheritance of osteopetrosis is mainly autosomal recessive, although there are mild autosomal dominant forms. The exact location of the causative gene is unknown. However, Coccia and others¹⁹ performed bone marrow transplants from an unaffected sibling to another sibling with malignant osteopetrosis. In the infant with the condition, the disease was greatly ameliorated when Y-bearing osteoclasts were transferred, and monocyte-macrophage function, previously defective, was restored.

Mandibulofacial Dysostosis

Mandibulofacial dysostosis, also known as Treacher Collins syndrome or Treacher Collins-Franceschetti syndrome, presents with antimongoloid slant of the eyes, coloboma of the lower eyelids, cleft palate, micrognathia, microtia and other deformities of the ears, hypoplasia of the zygomatic arches and macrostomia (Fig. 6).

Mandibulofacial dysostosis is inherited as an autosomal dominant trait that can vary in severity. The allele is also known as the Treacle gene and may consist of a balanced translocation.²⁰

Hypodontia

Hypodontia is a condition in which the affected individual develops fewer than the normal complement of teeth. In oligodontia, a severe form of hypodontia, at least 6 permanent teeth, excluding the third molars, do not develop (Fig. 7). Few dental conditions have been studied more extensively than hypodontia. To a geneticist, hypodontia represents one of the most widespread abnormalities in humans. To an orthodontist, it presents as malocclusion. To an archaeologist, it represents an anomaly that can link 2 or more fossil remains.

Most investigators have considered hypodontia the result of a single dominant gene.²¹ However, Suarez and Spence²² showed, through 2 multiple threshold models, that hypodontia data fit a polygenic model better than a single major gene model, which indicates that the condition is caused by both environmental and genetic factors. The gene responsible for oligodontia or hypodontia has not yet been located.

Nevoid Basal Cell Carcinoma Syndrome

Nevoid basal cell carcinoma syndrome, also known as Gorlin-Goltz syndrome, is an autosomal dominant condition characterized by multiple basal cell carcinomas of the skin and other tumours, including medulloblastoma, rhabdomyosarcoma, ovarian fibroma and meningiomas. Affected individuals experience a number of structural malformations, including pitting of the palms and soles, spine and rib abnormalities, ectopic calcifications and midline brain malformations, and they have characteristic coarse facies with frontal bossing.²³ This syndrome (Figs. 8 and 9) is also characterized by the development of odontogenic keratocysts of the jaws, often multiple.²⁴ This presentation contrasts with sporadic odontogenic keratocysts occurring outside the syndrome, which are more likely to be solitary.

The clinical features of nevoid basal cell carcinoma syndrome have long suggested that the underlying genetic disorder is a mutation in a tumour suppressor gene. The gene for the syndrome was first identified by positional cloning, which defined the minimum region of deletion on chromosome 9 as 9p22.3, where the gene was likely to reside.²⁵ Interestingly, the importance of this gene in the development of sporadic (nonsyndromic) keratocysts has been supported by the finding of gene loss in the 9p22.3 region in DNA extracted from biopsy samples of these cysts.²⁶

Conclusions

Our knowledge of the loci of many genetic mutations is rapidly increasing. For example, mutation of the fibroblast growth factor gene has recently been implicated in Crouzons syndrome.²⁷ Localization of defects within the genome is an essential step in understanding and possibly correcting genetic disorders. Once the locations are known, therapeutic changes may be possible through specific identification of causative sites.

Gene therapy and genetic engineering are still in their earliest phases, and there are many hurdles to overcome. Characteristics common to the disorders that have been discussed here include their low prevalence and the complexity of accurately locating the defective gene.

Although great strides continue to be made, most work has been on animal models, and there are still many gaps in human genetic knowledge. Of significant concern are the ethical ramifications of permanently altering an individual’s genetic makeup. For the future, many techniques in nanotechnology^28,29 remain to be perfected and, at a philosophical level, many issues remain to be debated and reconciled. 

Dr. Sàndor is coordinator, oral, maxillofacial surgery, Hospital for Sick Children and Bloorview MacMillan Children’s Centre; and director, graduate residency program in oral and maxillofacial surgery, The Toronto General Hospital; and associate professor, faculty of dentistry, University of Toronto.

Dr. Carmichael is coordinator, prosthodontics, Hospital for Sick Children and Bloorview MacMillan Children’s Centre; and assistant professor, faculty of dentistry, University of Toronto.

Dr. Coraza was formerly a dental intern, The Toronto General Hospital.

Dr. Clokie is associate professor and head, oral and maxillofacial surgery, University of Toronto and The Toronto General Hospital; and director, Orthobiologics Research Group, oral and maxillofacial surgery, University of Toronto.

Dr. Jordan is associate professor of oral pathology and pathology in the school of dentistry and medicine, University of California, San Francisco, California.

Correspondence to: Dr. George K.B. Sàndor, Hospital for Sick Children, 555 University Ave., Toronto, ON M5G 1X8. E-mail: gsandor@sickkids.ca. 

The authors have no declared financial interests.

1. Beardsley T. Vital data. Sci American 1996; 274(3):100-5.

2. Friend T. Investors rejoice in Celera promise: Complete human genetic blueprint expected this year. USA TODAY, Friday April 7, 2000.

3. Venter JC, Adams MD, Myers EW, Li PW, Mural RJ, Sutton GG, and others. The sequence of the human genome. Science 2001; 291(5507):1304-51.

4. Spurder GH. Personal communication. American Cleft Palate and Craniofacial Association Meeting, New Orleans, April 1997.

5. Schultze C, Lenz FR. Ueber Zahnschmelzhypoplasi von unvollstandig dominatem geschlechtsgebundenen Egrgang. Z. Menschl. Vererb. Konstitutions. 1952; 31:104-14.

6. Rushton MA. Hereditary enamel defects. Proc Roy Soc Med 1964; 57:53-8.

7. Lau EC, Mohandas TK, Shapiro LJ, Slavkin HC, Snead ML. Human and mouse amelogenin gene loci are located on the sex chromosomes. Genomics 1989; 4(2):162-8.

8. Lau EC, Mohandas TK, Slavkin HC, Snead ML. Chromosomal localization of amelogenin gene on the S and/or Y chromosomes. (Abstract) J Cell Biol 105:241a only, 1987.

9. Lagerstrom M, Dahl N, Nakahori Y, Hakagome Y, Backman B, Landegren U, Pettersson U. A deletion in the amelogenin gene (AMG) causes X-lined amelogenesis imperfecta (AIH1). Genomics 1991; 10(4):971-5.

10. Lagerstrom-Fermer M, Pettersson U, Landegren U. Molecular basis and consequences of a deletion in the amelogenin gene, analyzed by capture PCR. Genomics 1993; 17(1):89-92.

11. Brueton LA, Reeve A, Ellis R, Husband P, Thompson EM, Kingston HM. Apparent cleidocranial dysplasia associated with abnormalities of 8q22 in three individuals. Am J Med Genet 1992; 43(3):612-8.

12. Nienhaus H, Mau U, Zang KD, Henn W. Pericentric inversion of chromosome 6 in a patient with cleidocranial dysplasia. Am J Med Genet 1993; 46(6):630-1.

13. Mundlos S, Mulliken JB, Abramson DL, Warman ML, Knoll JHM, Olsen BR. Genetic mapping of cleidocranial dysplasia and evidence of a microdeletion in one family. Hum Molec Genet 1995; 4(1):71-5.

14. Narahara K, Tsuji K, Yokoyama Y, Seino Y. Cleidocranial dysplasia associated with a t(6;18)(p12;q24) translocation. Am J Med Genet 1995; 56(1):119-20.

15. Carter CO, Evans K, Coffey R, Roberts JA, Buck A, Roberts MF. A three generation family study of cleft lip with or without cleft palate. J Med Genet 1982; 19(4):246-61.

16. Eiberg H, Bixler D, Nielsen LS, Conneally PM, Mohr J. Suggestion of linkage of a major locus for nonsyndromic orofacial cleft with F13A and tentative assignment to chromosome 6. Clin Genet 1987; 32(2):129-32.

17. Mitchell LE, Risch N. Mode of inheritance of nonsyndromic cleft lip with or without cleft palate: a reanalysis. Am J Hum Genet 1992; 51(2):323-32.

18. Roulston D, Schwartz S, Cohen MM, Suzuki JB, Weitkamp LR, Boughman JA. Linkage analysis of dentinogenesis imperfecta and juvenile periodontitis: creating a 5 point map of 4q. Am J Hum Genet 1985; 37(Abstr):A206.

19. Coccia PF, Krivit W, Cervenka J, Clawson C, Kersey JH, Kim TH, and others. Successful bone-marrow transplantation for infantile malignant osteopetrosis. New Eng J Med 1980; 302(13):701-8.

20. Balestrazzi P, Baeteman MA, Mattei MG, Mattei JF. Franceschetti syndrome in a child with a denovo balanced translocation of (5;13)(q11;p11) and significant decrease of hexosaminidase B. Hum Genet 1983; 64(3):305-8.

21. Alvesalo L, Portin P. The inheritance pattern of missing, peg-shaped and strongly mesio-distally reduced upper lateral incisors. Acta Odontol Scand 1969; 27(6):563-75.

22. Suarez BK, Spence MA. The genetics of hypodontia. J Dent Res 1974; 53(4):781-6.

23. Gorlin RJ. Nevoid basal cell carcinoma syndrome. Dermatol Clin 1995; 13(1):113-25.

24. Kimonis VE, Goldstein AM, Pastakia B, Yang ML, Kase R, DiGiovanna JJ, and others. Clinical manifestations in 105 persons with nevoid basal cell carcinoma syndrome. Am J Med Genet 1997; 69(3):299-308.

25. Goldstein AM, Stewart C, Bale AE, Bale SJ, Dean M. Localization of the gene for the nevoid basal cell carcinoma syndrome. Am J Hum Genet 1994; 54(5):765-73.

26. Lench NJ, High AS, Markham AF, Hume WJ, Robinson PA. Investigation of chromosome 9p22.3-q31 DNA marker in odontogenic keratocysts. Eur J Cancer B Oral Oncol 1996; 32B(3):202-6.

27. Everett ET, Britto DA, Ward RE, Hartsfield JK Jr. A novel FGFR2 gene mutation in Crouzon syndrome associated with non penetrance. Cleft Palate Craniofac J 1999; 36(6):533-41.

28. Yeager AL. Where will the genome lead us? Dentistry in the 21st century. J Am Dent Assoc 2001; 132(6):801-7.

29. Slavkin HC. The human genome, implications for oral health and diseases, and dental education. J Dent Educ 2001; 65(5):463-79.