1Medical Hypotheses Mdd~ W91) 36.9blW 5Lmcrmm~uKLld1991

Role of Programmed Cell Death in Dental Anomalies Associated with Cleft Lip and Palate P. 5. SHARMA*

and 0. P. KHARBANDA

Department of Dental Surgery, All India Institute of Medica\ Sciences, New Delhi 110029, India. f Army Dental Corps 55 APO, India (Reprint requests to OPK)

Abstract - A role of programmed cell death (PCD) is proposed in the production of tooth anomalies occurring in association with cleft lip and palate (Cl + P). Dental anomalies are viewed as a microform of cleft lip and palate, produced by different modulations of the same operating mechanism.

Introduction

strated (15, 16). Neural crest cells are seen in the frontonasal region of the human embryo by the 35th day after conception and they have been observed to travel to the dental lamina by the 37th day, when the discrete elements of the dental lamina fuse with the dental lamina for primary dentition and form tooth buds under the influence of neural crest cells (17). In chick embryo experiments (18), cleft palate has been produced by damaging the mesencephalic portion of the neural crest. The fate of neural crest cells has also been well worked out (19). It has been concluded from studies on neuml crest cells that cells from the mesencephalic part of the neural crest contribute to the growth of mesenchyme in the dorsal (maxillary) portion of the 1st branchial arch. Damage to at least a certain quantity of these cells results in underdevelopment of the mesenchyme in the branchial arch portion, which subsequently develops into cleft palate. A comprehensive role for neural crest cells was presumed by Osborne in his hypothesis (20, 21), which postulates four basic assumptions:

Hyperdontia, hypodontia, malformations of teeth and delayed eruption of teeth, are all associated with cleft lip and palate (l-9). This and the parallelism in sex distribution of cleft lip and palate and hyperdontia in some populations (10) point in the direction of common aetiology. This subject was well discussed by Fogh-Andersen (11). Fukuhara and Saito (12) proposed that traits like anadontia of upper central and lateral incisors, rotation and crowding of maxillary anterior teeth, asymmetric shape of nose and raphe in upper lip are possible microforms of cleft lip and palate. Impaction of canines as a microform of cleft lip and palate has also been proposed. This hypothesis was disputed by Woolf (13) on the basis of his controlled genetic epidemiologic study. But the aetiology of cleft lip and palate is not entirely genetic and the extra-genetic aetiology of cleft lip and palate has also been proposed. A role of neural crest cells in initiating tooth buds and development of the face has been well demonDate received 1 March 1990 Date accepted 5 April 1990

98

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1.

2.

3.

4.

neural crest cells migrate anteriorly through developing jaws and they initiate an induction reaction in the oral ectoderm; the oral ectoderm develops the potential to react to the neural crest cells in three consecutive stages. First the oral ectoderm responds by generating abortive groupings of ectodermal cells, secondly it attains the capacity of organising the underlying mesenchyme to form dentin, and lastly the epithelium becomes enamel forming; the dental lamina is always capable of tooth development as competence is developed progressively in an antero-posterior direction; developing tooth buds inhibit tooth development in their vicinity.

Osborne assumes that growth is intimately related to tooth development. As tooth buds are initiated, they inhibit further growth around them until they are adequately spaced and hyperdontia (supernumerary teeth) occurs as a result of ectopic tooth buds when focal sites of tooth development fail to be inhibitory. Hyp01hesis

We presume that the inhibitory effect is not from the tooth buds but instead the information for initiating, inhibition and maintenance of the integrity of these cells lies in neural crest cells. These ectopic tooth buds die by programmed cell death as happens in the case of presumed fusion epithelium (PFE) covering the palatal shelves at the time of palatal shelf union in normal palatogenesis (22). Studies on normal palatogenesis have confirmed that lysosomes appear in epithelial cells covering the palatal shelves (PPE): the basement lamina separating the epithelium and the mesenchyme gets disrupted and these epithelial cells of the PFE die a programmed death (22). The lysed epithelial cells are ultimately phagocytosed by macrophages from the adjoining mesenchyme. The finding of epithelial rest cells in the area of dental lamina and palatal union (23) supports to some extent our assumption that these abortive ectopic tooth buds die their programmed natural death. In his postulation, Osborne explained the frequent occurence of supernumerary teeth in the lateral incisor area of cleft lip and palate patients as a result of disruption of dental lamina and loss of inhibition from one of the cleft segments, thus allowing an extra tooth bud to appear. But this cannot explain the equally frequent missing teeth, and still more frequent appearance of supernumerary teeth in this area in subjects without clefts, and general&l reduction in decidious teeth dimensions on the side of the cleft.

99

The coincidence of formation of primary den&ion and fusion of incisive bone with the maxillary process forming the incisive suture may be put forward as the possible explanation for the higher prevalence of primary supernumerary teeth in the lateral incisor region. We presume that the quantity of tissue loss as a result of programmed cell death in the abortive and other tooth buds will dictate the final outcome, whether hyperdontia or hypodontia will occur and also will depend on it the shape and form of teeth lying near the lines of fusion. If there is more generalised tissue loss from the tooth buds, there will be general&d diminution of the dimensions of teeth on the side of cleft. Still more severe loss of tissue as a result of this programmed cell death (PCD) death will result in total breakdown of some tooth buds resulting in hypodontia. But if the information for the programmed lysis of epithelial cells of the tooth bud does not reach these tooth buds, abortive groupings of ectodermal cells may develop into supernumerary teeth (hyperdontia). This wave of programmed cell death (PCD), which we presume is shared by the abortive groupings of ectodermal cells and the presumed fusion epithelium (PFE), if it comes in time, will result in normal palatogenesis and a normal set of teeth. The delay in the onset of PCD will result in hyperdontia, because the abortive tooth buds will not be killed once they are well differentiated. But if likewise PFE cells escape lysis at proper time, mesenchyme will fail to invade and the result will be cleft lip or palate. The early onset of this wave of programmed cell death (PCD) will kill the abortive tooth buds and if more severe, more tooth buds, resulting in hypodontia. But the early lysis of cells of PFE will again result in cleft lip or cleft palate. Thus early or delayed onset of PCD will result in hypodontia and hyperdontia respectively but along the fusion line of palatal shelves, the result will be cleft in both cases. Studies on the teratogenic potential of hydrocortisone in palatogenesis (24) show that the m which normally disappears after timely lysis gets stabilized, and similar findings have been found with some other drugs also. It has been observed that epithelial integrity inhibits the palatal processes from joining. Various teratogens like 6-Mercaptopurine (25) and 5Pluorouracil(26) produce cleft lip and palate by early cell death of PFE. The dental lamina, apart from being initiated by the same tissue as initiates palatogenesis, i.e. neural crest cells, has mom in common with PFE, its ectodermal origin and common fate, after their function is over. After the tooth has been fully formed the epithelium

100 part of the tooth bud which was derived from oral ectoderm, is discarded as reduced enamel epithelium and the same is the fate of PPE, which disappears after palatogenesis is completed. So it can be assumed that they might be sharing information for their differentiation, maintenance of integrity and self-killing. Which tooth or teeth will be affected by this wave of PCD will depend on which tooth at that time has a close biochemical identity to the PFE. Because not all the portions of dental lamina are in the same stage of development at a given time, so only a few selected areas are prone to dental anomalies and some areas are more prone because they happen to lie along the lines of fusion. Because the cells of PPE and the epithelial cell rests may lie for quite some time at these sites, so further clearing of these areas by PCD may extend well up to the period of permanent tooth formation thereby involving permanent teeth also. Conclusion Programmed cell death @‘CD) which usually occurs in presumed fusion epithelium (Pm) during normal palatogenesis can kill the tooth forming elements of oral ectoderm also. So, cleft lip and palate can have hyperdontia or hypodontia in addition, depending upon the timing and severity of this PCD wave. References 1. Dixon DA. Abnormalities of teeth and supporting structures in children with Clefts of Lip and Palate. In: Drillen CM, Ingram TTS, Wiiinsat EM, Eds. The Causes and Natural History of Cleft Lip and Palate. Edinburgh, E and S Livingstone, 1966. 2. Ranta R. Correlation of hypodontia in children with isolated Cleft Palate. Cleft Palate Journal 20 (2): 163, 1983. 3. Ranta R et al. Tooth anomalies associated with congenital sinuses of harelip and Cleft Lip/Palate. Angle orthodontist 52(3): 212-21. 1982. 4. Misra FM, Ran RK et al. Dental abnormalities in case of Cleft Lip and Palate. Journal of Indian Dental Association 94: 1-9. 1972. 5. O’Donnell D, Brook AH. Mab. Bilateral assymetrical complete oro ocular facial clefts and supernumerary teeth in a young Chinese female. AS DC Journal of Dentistry for Children 52(3): 191-194, 1985. 6. Poyry M. Ranta R. Anomalies in decidous dentition outside the Cleft region in children with oral Clefts. Proceedings of Finnish Denral Society 81(2): 91-97, 1985. 7. Jorden RE. Kraus BS et al. Dental anomalies associated with

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Cleft Lip/or Palate.. Cleft Palate Journal 3: 22. 1966.

8. Abdulht A. Decidous tooth dimensions in Cleft LipandPalate. Cleft Palate Joumal21(4): 301307,1984. 9. Foster TD, Laville CL The size of dentition in complete cleft lip and palate Cleft Palate Joumal8: 177-184, 1971. 10. Hurlen B, Humerfelt D. Characteristics of premaxillaty hypcrdcntia - A radiographic study. Acta Odontologica Scandanavica. 43: 75-81, 1985. 11. Fogh-Andersen P. Inheritance of hare tip and palate.NYT Nordisc Forlag A Busdt, Copenhagen, 1942 12. Fukuhara T. Saito S. Possible Carrier status of hereditary cleft palate with clefi lip. Repott of cases. Bulletin of Tokyo Medi&aland Dental U&e&y. 10: 333. 1963. 13. Woolf CM. Woolf RM. Broadbent TR. Lateral incisor anomalies, microforms of cleft lip and palate. Plastic and Rec~nst~ctive Surgery. 350: 543-547, 1965. 14. Sadove R et al. Cartilagenous histology of cleft lip, nose: Proving the extrinsic aetiology. Plastic and Reconstructive Surgery 81 (5): 655-661, 1988. 15. De Beer GR. The differentiation of neural crest cells into visceral cartilages and odontoblasts in Amblystoma and a reexamination of germ layer theory. Proceedings Royal Society London (Series B) 134: 377-398. 1947. 16. Sellman S. Some experiments on determination of larval teeth in Amblystoma mexicanum. Odontologica Tidskr. 54: l-28, 1946. _ 17. Limborgh Junior, Song SLK et al. Cleft lip and palate due to deficiencv of mesenceohalic neural crest cells. cleft Palate Journal 20:251-259, 1983. 18. Johnston MC. A radioautographic study of migration and fate of neural crest cells in chick embryo. Anatomic Records. 156: 143-156, 1966. 19. Miller SM. Waterman RE Congenital craniofacial abnormalities P 888 in Text Book of Oral Biology 1st Ed (Shaw JH, Sweeney EA. Cappuccino CC and Meller SM eds). W B Saunders Company, Philadelphia, 1978. 20. Osborne JW. The ontogeny of tooth succession in Lacerta Vivi para Jacquin. Proceedings of Royal Society London (Series B) 179: 261-289. 1971. 21. Osborne JW. The evolution of dentitions. American Science. 62: 548-559, 1973. 22. Shah RM, Choudry Ap. Light microscopic and histochemical observations on the development of palate in the Golden Syrian Hamsrer. Joumal of Anatany 117: 1-15, 1974. 23. Kitamura H. Epithelial remanants and pearls in the secondary palate in human abortus: a contribution to the study of mechanism of cleft palate formation. Cleft Palate Joumal 3: 240-257. 1966. 24. Shah RM, Traivill AA. Light and electron microscopic observations on Hydrocomsone induced cleft palate in hamsters. American Journal of Anatomy 145: 149-166. 1976. 25. Burdett et aL Gross and cellular analysis of 6-mercapapurine induced cleft palate in hamsters. American Journal of Anatomy, 181 27: 179-194. 1988. 26. Shah RM, Wong TW et al. uhrastmctural and cytochemical observations on 5-fluorouracil induced cleft palate develcpment in hamsters. Cleft Palate Journal 170.567-580: 1984.

Role of programmed cell death in dental anomalies associated with cleft lip and palate.

A role of programmed cell death (PCD) is proposed in the production of tooth anomalies occurring in association with cleft lip and palate (Cl + P). De...
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