Genetic Mutations in Certain Head and Neck Conditions of Interest to the Dentist

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 the Lyon phenomenon,⁶ in which each cell of a female randomly inactivates one or another of the genes on its X chromosome. Affected males may have a very thin, smooth enamel layer, whereas females may have thicker enamel with vertical grooves. The protein defect is thought to affect amelogenin, which is involved in enamel mineralization. Lau and others,⁷ using DNA from human–mouse hybrid cells, found the locus for hypoplastic amelogenesis imperfecta on the distal portion of the short (p) arm of the X chromosome. Refining the location further, the locus has been assigned to Xp22.3–p22.1.⁸ Lagerstrom and others⁹ demonstrated a deletion in the amelogenin gene extending over a 5-kilobase area. Lagerstrom-Fermer and others¹⁰ discovered that the deletion removed 5 of 7 exons. Additional studies have also indicated deletions of various sizes involving the X chromosome.

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. In 1992, Brueton and others¹¹ described 3 individuals who had characteristics of this condition and rearrangements of chromosome 8, at locus 8q22. Later, Nienhaus and others¹² reported that the defect causing cleidocranial dysplasia may be located somewhere on chromosome 6. Mundlos and others¹³ independently tried to map the mutation assumed to be on the short arm of chromosome 6 and found 4 loci in a region of 6p. For one locus there was a deletion in all affected family members, and the cleidocranial dysplasia gene was therefore assigned to location 6p21. However, the possibility of another locus on a different chromosome has not been excluded. For example, Narahara and others¹⁴ observed cleidocranial dysplasia in association with a translocation involving chromosomes 6 and 18 (Table 1 ).

Nonsyndromic Cleft Lip with or Without Cleft Palate

Nonsyndromic 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. Chung and others¹⁶ performed a comparative gene analysis for cleft lip with and without cleft palate in 2 populations, one Danish and the other Japanese. They concluded that the Danish data were best explained by a combination of major gene actions, which seemed to involve recessive multifactorial inheritance, whereas the Japanese data were best accounted for by the multifactorial threshold model.

Ardinger and others¹⁷ observed an association between 2 restriction fragment length polymorphisms (RFLPs) and the disease, and propose that they could be used as marker loci. The association involved a locus for the transforming growth factor alpha (TGFalpha) and another for the occurrence of clefting, suggesting that the TGFalpha gene or locus in close proximity to it was associated with the condition in certain cases. Chenevix-Trench and others¹⁸ confirmed excess frequency of the TaqI allele. Holder and others¹⁹ also found a significant association between the TaqI RFLP and the occurrence of clefting. Extending their analysis, Chenevix-Trench and others²⁰ found a significant association between the TGFalpha and BamHI restrictions.

Eiberg and others²¹ concluded that a major locus for nonsyndromic cleft lip with or without cleft palate was located on the distal portion of the short arm of chromosome 6 as an autosomal dominant form. However, Hecht and others²² found no evidence of a clefting locus in a region spanning 54 centimorgans of 6p in the families studied by Eiberg and others.²¹ Hecht and others²³ described families with multigenerational involvement of cleft lip with or without cleft palate. Reanalysis of the data by Mitchell and Risch²⁴ revealed that the inheritance was compatible with either a multifactorial threshold model or a model specifying multiple interacting loci.

Davies and others²⁵ investigated 3 unrelated patients with cleft lip and cleft palate who showed abnormalities of 6p. In 2 patients they found translocation and in the third a deletion, suggesting the existence of a locus for orofacial clefting in the 6p region. Finally, after reviewing the genetic and exogenous factors in the causation of facial clefts, Murray²⁶ concluded that the strongest evidence implies a primary gene on 6p, with the TGFalpha locus acting as a modifier of the clefting state.

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.

There are 3 types of dentinogenesis imperfecta. Type I is associated with osteogenesis imperfecta. Type II was previously found to be linked to altered glycosaminoglycan concentrations.²⁷ Among patients with type II dentinogenesis imperfecta, it was noted that dentin soluble in the calcium chelator ethylenediaminetetra-acetic acid (EDTA) had significantly higher concentrations of glycosamino glycan than was the case among patients without the condition. Type III is the brandywine form, named for the city Brandywine, Maryland, where there was a large population of patients with this disorder. Type III tends to be less severe than type II.

Dentinogenesis imperfecta has an autosomal dominant pattern of inheritance. Roulston and others²⁸ found cosegregation between this condition and localized juvenile periodontitis in certain families, which indicated that the loci were separate but perhaps closely linked. Using the genetic mapping technique known as chromosome walking and the study already described,²⁸ it was concluded that the type I locus is located on chromosome 4, at position q13–q21.²⁸ A deficiency of dentin phosphoprotein was suggested as a causative factor, given that the locus for this protein was postulated to be near the dentinogenesis imperfecta gene. However, MacDougall and others²⁹ discovered that the gene for dentin phosphoprotein is not located on chromosome 4, excluding it as a candidate. Osteopontin, a bone glycoprotein, is also expressed in dentin. However, Crosby and others³⁰ showed no association between a type of polymorphism at the osteopontin locus and type II dentino genesis imperfecta.

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 the 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. For mice with osteopetrosis, Yoshida and others³¹ demonstrated that the defect resides in the gene for macrophage colony-stimulating factor (GM-CSF1). In this organism, the condition cannot be cured by transplantation of normal bone marrow cells, which suggests that the defect consists of an abnormal hematopoietic microenvironment rather than an intrinsic defect in progenitors or mature macrophages and osteoclasts. Yoshida and others³¹ found insertion of a single base pair in the coding region that generated a stop codon, 21 base pairs from the GM-CSF1 gene. However, it has not yet been proven that a mutation in the GM-CSF1 gene is responsible for osteopetrosis in humans. In this regard, Orchard and others³² found that the serum of 13 patients with malignant osteopetrosis showed radioimmunoassay levels of GM-CSF1 equal to or greater than the levels in 6 control patients.

Coccia and others³³ 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, which may vary in severity. The allele for the condition is also known as the Treacle gene. Balestrazzi and others³⁴ described this disorder in a girl with a de novo balanced translocation involving chromosomes 5 and 13 — t(5;13)(p11;q11) — and decreased hexosaminidase B. Hexosaminidase B has its locus HEXB at the 5q13 position. The suggestion that the balanced translocation results in mandibulofacial dysostosis was based on the observed decrease in hexosaminidase B. Dixon and others³⁵ identified a family with this condition who had a balanced translocation involving chromosomes 6 and 16 — t(6;16)(p21.31;p13.11). These findings later led to linkage of the mandibulofacial dysostosis locus to a balanced translocation of certain markers in the region of 5q31–q34, and further refinement of the location to 5q32–33.2. Jabs and others³⁶ found a patient with a de novo chromosomal deletion in the region of 4p14–p15.32 with severe manifestations of mandibulofacial dysostosis. These results were corroborated independently by Edery and others.³⁷

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.³⁸ However, Suarez and Spence³⁹ showed, through 2 multiple threshold models, that hypodontia data fit a polygenic model better than a single major gene model. It is now well accepted that the mode of inheritance for hypodontia is polygenic, that is, it is caused by both environmental and genetic factors.

In a study by Eidelman and others,⁴⁰ 21,384 children ages 12 to 18 were examined for general signs of hypodontia and then specifically for hypodontia of the maxillary lateral incisors, the second premolars and the mandibular incisors. The prevalence of any type of hypodontia in the general population was 4.61%, and there was no significant difference between males and females in the sample. The prevalence of absence of the maxillary lateral incisors was 2.11% overall and was significantly lower in males than females. The prevalence of absence of the second premolars was 1.87% for the general population, with no significant difference between males and females. The prevalence of absence of the mandibular incisors was 0.68% in the general population and was significantly higher in males than in females (Table 2).

In a study, by the same researchers,⁴¹ of families of 305 probands with diagnosed hypodontia, 14.8% of siblings and 9.4% of parents of probands with hypodontia also expressed the condition. More females than males were affected. The authors concluded that 11.8% of first-degree relatives of probands with hypodontia showed hypodontia of the same teeth (Table 2).

These data show significant differences between the sexes and among the family members of probands. It is therefore possible that differences in the type of hypodontia may be caused by, or associated with, different gene loci or 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.⁴² This syndrome (Figs. 8 and 9) is also characterized by the development of odontogenic keratocysts of the jaws, often multiple.⁴³ 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. In other syndromes involving an inherited mutation in a tumour suppressor gene, cancer also occurs at a very early age. For example, Li-Fraumeni syndrome is due to an inherited mutation in the tumour suppressor gene p53 and is characterized by early onset of multiple neoplasias.⁴⁴ People with nevoid basal cell carcinoma syndrome exhibit basal cell carcinomas at a far younger age than those with sporadic basal cell carcinomas of the skin; this difference supports the concept that a germ-line mutation in a tumour suppressor gene is the cause of the syndrome.⁴⁵

The causative gene 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.⁴⁶ Subsequent isolation and characterization of the gene showed that it was homologous to the Drosophila gene called patched (PTCH), which is essential for early embryonic development.^47-49 In Drosophila, the protein product of the PTCH gene is a component of the hedgehog signalling pathway. The PTCH gene actually represses the activity of the hedgehog protein, a protein that acts on a number of other genes including the protein product of the smoothened gene. In humans this pathway is similar, with the PTCH gene normally acting to repress the activity of the human homologue of the hedgehog gene, termed the sonic hedgehog gene. Studies in mice have shown that if the PTCH gene is not functioning, there is overexpression of the smoothened gene, which leads to increased proliferation of several embryonic cell types. Furthermore, overexpression of either the sonic hedgehog or the smoothened gene has the same net effect as loss or mutation of the repressor gene PTCH.^50,51

Studies in humans have shown that mutations of the PTCH gene are involved in the development of basal cell carcinomas in the syndrome. Furthermore, mutations of this gene are also present in a proportion of sporadic basal cell carcinomas, further strong evidence for the crucial role of PTCH as a tumour suppressor in human keratinocytes.⁵²

Despite compelling evidence that PTCH gene mutations are the cause of the abnormalities seen in nevoid basal cell carcinoma syndrome, few studies have directly examined its role in odontogenic keratocysts. Lench and others⁵³ identified novel mutations of the PTCH gene in families who exhibited multiple odontogenic keratocysts. Interestingly, the importance of the PTCH 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.⁵⁴

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.⁵⁵ 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^56,57 remain to be perfected and, at a philosophical level, many issues remain to be debated and reconciled. 

References

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 JH, 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. Chung CS, Bixler D, Watanabe T, Koguchi H, Fogh-Andersen P. Segregation analysis of cleft lip with or without cleft palate: a comparison of Danish and Japanese data. Am J Hum Genet 1986; 39(5):603-11.

17. Ardinger GG, Buetow KH, Bell GI, Bardach J, VanDemark DR, Murray JC. Association of genetic variation of the transforming growth factor-alpha gene with cleft lip and palate. Am J Hum Genet 1989; 45(3):348-53.

18. Chenevix-Trench G, Jones K, Green A, Martin N. Further evidence for an association between genetic variation in transforming growth factor alpha and cleft lip and palate. Am J Hum Genet 1991; 48(5):1012-3.

19. Holder SE, Vintiner GM, Farren B, Malcolm S, Winter RM. Confirmation of an association between RFLPs at the transforming growth factor-alpha locus and non-syndromic cleft lip and palate. J Med Genet 1992; 29(6):390-2.

20. Chenevix-Trench G, Jones K, Green AC, Duffy DL, Martin NG. Cleft lip with or without cleft palate: associations with transforming growth factor alpha and retinoic acid receptor loci. Am J Hum Genet 1992; 51(6):1377-85.

21. 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.

22. Hecht JT, Wang Y, Connor B, Blanton SH, Daiger SP. Nonsyndromic cleft lip and palate: no evidence of linkage to HLA or factor 13A. Am J Hum Genet 1993; 52(6):1230-3.

23. Hecht JT, Yang P, Michels VV, Buetow KH. Complex segregation analysis of nonsyndromic cleft lip and palate. Am J Hum Genet 1991; 49(3):674-81.

24. 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.

25. Davies AF, Stephens RJ, Olavesen MG, Heather L, Dixon MG, Magee A, and others. Evidence of a locus for orofacial clefting on human chromosome 6p24 and STS content map of the region. Hum Molec Genet 1995; 4(1):121-8.

26. Murray JC. Face facts: genes, environment, and clefts. Am J Hum Genet 1995; 57(2):227-32.

27. Sauk JJ Jr, Witkop CJ Jr, Brown DM, Corbin KW. Glycosaminoglycans of EDTA soluble and insoluble dentin in dentinogenesis imperfecta type I. Oral Surg Oral Med Oral Pathol 1976; 41(6):753-7.

28. 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.

29. MacDougall M, Zeichner-David M, Murray J, Crall M, Davis A, Slavkin H. Dentin phosphoprotein gene locus is not associated with dentinogenesis imperfecta types II and III. Am J Hum Genet 1992; 50(1):190-4.

30. Crosby AH, Edwards SJ, Murray JC, Dixon MJ. Genomic organization of the human osteopontin gene: exclusion of the locus from a causative role in the pathogenesis of dentinogenesis imperfecta type II. Genomics 1995; 27(1):155-60.

31. Yoshida H, Hayashi S, Kunisada T, Ogawa M, Nishikawa S, Okamura H, and others. The murine mutation osteopetrosis is in the coding region of the macrophage colony stimulating factor gene. Nature 1990; 345(6274):442-4.

32. Orchard PJ, Dahl N, Aukerman SL, Blazar BR, Key LL Jr. Circulating macrophage colony-stimulating factor is not reduced in malignant osteopetrosis. Exp Hematol 1992; 20(1):103-5.

33. 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.

34. 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.

35. Dixon MJ, Haan I, Baker E, David D, McKenzie N, Williamson R, and others. Association of Treacher Collins syndrome and translocation 6p21.31/16p13.11: exclusion of the locus from these candidate regions. Am J Hum Genet 1991; 48(2):274-80.

36. Jabs EW, Cross CA, Hayflick SJ, Whitmore TE, Pauli RM, Kirkpatrick SJ, and others. Chromosomal deletion 4p15.32-p14 in a Treacher Collins syndrome patient: exclusion of the disease locus from and mapping of anonymous DNA sequences to this region. Genomics 1991; 11(1):188-92.

37. Edery P, Manach Y, Le Merrer M, Till M, Vignal A, Lyonnet S, and other. Apparent genetic homogenicity of the Treacher Collins-Franceschetti syndrome. Am J Med Genet 1994; 52(2):174-7.

38. 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.

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

40. Eidelman E, Chosack A, Rosenzweig KA. Hypodontia prevalence among Jewish populations of different origin. Am J Phys Anthrop 1973; 39(1):129-33.

41. Chosack A, Eidelman E, Cohen T. Hypodontia: a polygenic trait - a family study among Israeli Jews. J Dent Research 1975; 54(1):16-9.

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

43. 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.

44. Malkin D. p53 and the Li-Fraumeni syndrome. Biochim Biophys Acta 1994; 1198(2-3):197-213.

45. Bale AE. The nevoid basal cell carcinoma syndrome: genetics and mechanism of carcinogenesis. Cancer Invest 1997; 15(2):180-6.

46. 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.

47. Wicking C, Bale AE. Molecular basis of the nevoid basal cell carcinoma syndrome. Curr Opin Pediatr 1997; 9(6):630-5.

48. Chidambaram A, Goldstein AM, Gailani MR, Gerrard B, Bale SJ, DiGiovanna JJ, and others. Mutations in the human homologue of the Drosophila patched gene in Caucasian and African-American nevoid basal cell carcinoma syndrome patients. Cancer Res 1996; 56(20): 4599-601.

49. Wicking C, Shanley S, Smyth I, Gilles S, Negus K, Graham S, and others. Most germ-line mutations in the nevoid basal cell carcinoma syndrome lead to a premature termination of the PATCHED protein, and no genotype-phenotype correlation are evident. Am J Hum Genet 1997; 60(1):21-6.

50. Hahn H, Wojnowski L, Miller G, Zimmer A. The patched signaling pathway in tumorigenesis and development: lessons from animal models. J Mol Med 1999; 77(6):459-68.

51. Hahn H, Wicking C, Zaphiropoulous PG, Gailani MR, Shanley S, Chidambaram A, and others. Mutations of the human homologue of Drosophila patched in the nevoid basal cell carcinoma syndrome. Cell 1996; 85(6):841-51.

52. Aszterbaum M, Rothman A, Johnson RL, Fisher M, Xie J, Bonifas JM, and others. Identification of mutations in the human PATCHED gene in sporadic basal cell carcinomas and in patients with the basal cell nevus syndrome. J Invest Dermatol 1998; 110(6):885-8.

53. Lench NJ, Telford EA, High AS, Markham AF, Wicking C, Wainwright BJ. Characterization of human patched germ line mutations in nevoid basal cell carcinoma syndrome. Hum Genet 1997; 100(5-6): 497-502.

54. 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.

55. 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.

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