- Email: [email protected]
Oral fibromatosis in tuberous sclerosis
Oral fibromatosis in tuberous sclerosis N. A. Lygidakis,a Oxford England
DMD, iUScM, MScD, and R. H. Lindenbaum,b
UNIVERSITY
OF OXFORD,
OF MEDICAL
GENETICS
GENETICS
LABORATORY,
AND
CHURCHILL
MA. MB, ChB, FRCP,
HOSPITAL,
DEPARTMENT
Thirty-six families with tuberous sclerosis (TS) were clinically examined for oral fibromatosis and other previously reported oral anomalies. These consisted of 48 affected persons and 89 apparently unaffected parents and children. Fifty control subjects were also examined. Oral fibromatosis was observed in 56% of patients with typical TS and in none of 9 “atypical” cases. The total prevalence was 46%. Similar lesions were not seen in the control series, and they were rare in the otherwise apparently normal relatives with TS. However, three parents of patients with TS were found to have oral fibromas even though they had no signs of TS. It is suggested that examination for oral fibromatosis should be made in all persons suspected of having TS and in their close relatives, since such examination may identify other unsuspected carriers of the gene within the family. (ORAL SURC ORAL MED ORAL PATHOL 1989;68:725-8)
T
uberous sclerosis (TS) is a multisystem disorder characterized by the formation of hamartomas that are most often composed of byperproliferative hemangioblasts and fibroblasts. TS is an autosomal dominant disorder. Eighty percent of the cases appear to be sporadic. Sporadic cases represent a smaller proportion of the whole when relatives are carefully assessed by means of techniques such as Wood’s light examination and computerized tomographic brain scan.’ Rarely even very careful examination of an obligate carrier fails to reveal any signs of the trait.* Oral lesions have been reported in about 11% of the patients.3 These lesions consist mainly of fibrous growths affecting the whole oral mucosa and particularly the anterior gingivae. They may also be found on the lips, the dorsum of the tongue, and the palate.’ Various other oral abnormalities have been described, including high palate, cleft lip and palate, macroglossia, and hyperostotic alveolar process.4 Pitted enamel hypoplasia is another characteristic oral manifestation of the disease found in 58% of the patients5 The present study sought to collect further clinical data on the oral abnormalities in TS, especially fibromatosis, and involved examination of apparent-
ly normal close relatives as well as patients themselves. MATERIAL
AND METHODS
The present study was set up in the Oxford region concurrently with a prevalence study6 and a study of pitted enamel hypoplasia in TS.5 Thirty-six families contributed a total of 48 patients and 69 apparently unaffected parents and children. The 48 patients included 39 persons with typical TS and 9 persons with few signs of TS but who had secondary diagnostic criteria’ that lead to the diagnosis of TS or who were obligate carriers from the pedigree. These latter conditions we termed atypical TS.
Patients’ ages ranged from 16 months to 62 years. Four patients with typical TS were edentulous. Fifty persons (26 adults and 24 children) seen in genetic outpatient clinics for problems not related to the head and neck served as clinical control subjects. Their age range was similar to that of the patients with TS. The oral examination was part of the general physical examination performed on all the patients. The oral cavity was examined in daylight and in artificial light. RESULTS
aResearch bConsultant 7/13/11124
Registrar Clinical
Geneticist,
Oral fibromatosis was easily indentified on clinical examination. The fibromas were present as discrete, asymptomatic nodules. They were mostly located on the anterior gingivae in both jaws but also occurred 725
726
Lygidakis
and Lidrldenbaum
ORAL
Fig. 1. Typical lesions on the maxillary anterior gingivae. Severely affected female patient, age 23 years.
ORAL
MED
ORAL PATHOL December 1989
Fig. 3. Typical lesions of smaller size on the mandibular gingivae. Mildly affected female patient, age 1 I years.
Table
1. Results of clinical examination Subject
Patients
with
Number
TS (total)
Typical TS Atypical TS Relatives with Parents (24 Siblings (15 Control group Adults Children
Fig. 2. Typical lesions on the palatal affected male patient, age 14 years.
SURG
TS (total) families) families) (total)
48 39 9 69 43 26 50 26 24
Oral fibromas 22 22 0 3 3 0 0 0 0
(46%) (56%) (4%) (7%)
mucosa. Severely
on other places such as lips, buccal mucosa, palate, and tongue (Figs. 1 and 2). They were usually covered by normal mucosa and were of normal color, occasionally whitish grey. They were quite easily differentiated from other oral lesions. Their number and shape varied with age and the severity of the disorder. Severely affected patients had many large fibromas (up to 1 cm in diameter), whereas the mildly affected had fewer of smaller size (up to 0.5 cm in diameter, Fig. 3). Within the group of severely affected patients, the older ones appeared to have a larger number of fibromas. Of 39 patients with typical TS examined, 22 had oral fibromatosis (56%; see Table I). None of the nine patients with atypical TS showed the defects. The youngest patient with oral fibromas was 11 years old. A further six patients had a high arched palate. Three patients had macroglosia, and in one patient a thickened alveolar process was found as a result of a
large cavernous hemangioma. Oral clefts were not seen in any of the patients. Forty-three apparently unaffected parents were examined. (See Table I). In this group three parents showed apparently typical TS fibromas, located in the anterior gingivae. One parent, who had three children with atypical TS, showed two gingival fibromas in her maxilla. Another parent, an obligate carrier because his mother and sister had typical TS, and his son atypical TS, had many small gingival fibromas in the mandible. The third parent, who had a son with apparently sporadic atypical TS, had oral fibromas in his maxilla and mandible. None of the 26 unaffected children (from 15 families) had any signs of oral fibromatosis. Oral fibromas were not found in any of the 50 individuals examined as control subjects. DISCUSSION It is clear that oral fibromatosis is often found in patients with TS. In our series of 39 patients previously known or suspected of having typical TS, we found oral fibromas in 56%. We also saw nine
Oraljibromatosis
Volume 68 Number 6
patients whom we classified as having atypical TS; none of them had oral fibromas. With the inclusion of this atypical group, the prevalence of oral fibromatosis in the whole series of TS falls to 46%. This percentage can be compared with other signs listed’ (e.g. facial angiofibromas 70%, hypomelanotic macules 57%, retinal hemangioma 50%, shagreen skin 36%, etc.). The percentage of patients with TS who have oral fibromatosis found in our study is much different from the 11% reported before.3 The reported lesions were noted as appearing either at 4 to 10 years of age or at puberty. In our study none of the 20 patients under the age of 11 years showed any oral fibromas. Older patients with fibromas recalled the first appearance of the defects in their mouth during the second decade of their lifes. The location and clinical appearance of the oral fibromas in our study confirm the findings in the few reports on isolated cases found in the literature.7-1’ In these reports the lesions appear histologically to be either fibromatous or papillomatous hyperplasias. It has been suggested that the oral fibromas might not be true TS lesions but could result from phenytoin treatment for the neurologic manifestations of the disease. Phenytoin is known to produce fibrous gingival hyperplasia.‘* This suggestion does not seem sufficient for the following reasons: (1) Phenytoin affects only gingivae and particularly interdental papillae12 and not buccal mucosa, tongue, lips and palate, where TS fibromas can quite frequently be found. (2) Phenytoin produces homogeneous generalized gingival hyperplasia’* and not the fibrous nodule8 that are observed in TS. (3) Finally, in the case of phenytoininduced fibrous hyperplasia, only 20% of patients treated with the drug may manifest the condition,13 and it has been suggested that patients with adequate oral hygiene may not manifest gingival hyperplasia at a11.14 In contrast, 46% of the patients with TS in the present study had oral fibromas, some of whom had never been treated with phenytoin or any other antiepileptic drug. However, phenytoin treatment may mask, modify, or augmerit the gingival lesions in TS. Whether the high arched palate and the macroglosia found in some of the patients in this study and also reported by other authors4 are significant findings is not yet clear, since no detailed study of their prevalence in the normal population has been done. In the present study, done with exactly the same subjective clinical criteria, macrogiosia was found in
in tuberous sclerosis
727
four of 50 control subjects and high arched palate in five. Therefore the& findings in TS as well as the previously reported oral clefts (none found in our study) appear to be well within the normal range. However, the large cavernous hemangioma found in the maxillary alveolus of a 3-year-old patient with TS could be a significant finding because this association has never been reported before. A pedunculated hemangioma of the tongue in a 24-year-old patient with TS has once been reportedq9 Congenital hemangiomas of the mouth are very rarely reported. Since TS is an autosomal dominant disorder, it is assumed that in the sporadic cases the problem arose from a new mutation and neither parent carries the mutant gene. If so, then the recurrence risk for children after the sporadic case woild be zero. However, pairs of affected children with normal parents have been described, as have other family patterns in which apparently unaffected persons are obligate carriers of the TS gene.2~6~15-17 The more clinical or special tests that are applied to such “unaffecttid” carriers, the more likely it is that some abnormality will be detected. Although interpretation of the findings in parents was difficult, the type of oral fibromas strongly suggests that these persons were carrying the gene. Therefore examination for oral fibromas may reveal “abnormality” in an apparently unaffected relative of a patient with TS and so identify unsuspected carriers in larger families with obvious transmission. REFERENCES
1. Comez MK, ed. Tuberous sclerosis. New York: Raven Press. 1979:211-4, 11-3. 2. Baraitser M, Patton MA. Reduced penetrance in tuberous sclerosis. J Med Genet 1985;22:29-3 1. 3. Schuermann H, Greitehn A, Hornstein 0, eds, Kranheiten der mund-schleimhaut und der lippen. Berlin: Urban Schwarzenberg, 1966:47-g. 4. Gorlin RJ, Pindborg JJ, Cohen MM, eds. Syndromes of head and neck. London: McGraw-Hill, 1976:587. 5. Lygidakis NA, Lindenbaum RH, Enamel defects in tuberous sclerosis patients and first degree relatives. Clin Genet 1987; 32:216-21. 6. Hunt A, Lindenbaum RH. Tuberous sclerosis: a new estimate of prevalence within the Oxford region. J Med Genet 1984; 211272-J.
I. Butterworth T, Wilson J Jr. Dermatologic aspects of tuberous sclerosis. Arch Dermatol Syph (Chic) 1941;43:1-41. 8. Gorlin RJ, Chaudhry AP, Kelln EE. Oral manifestations of the Fitzgerald-Gardner, Pringle-Bourneville, Robin, adrenogenital and Hurler-Pfaundler syndiomes. ORAL SURG ORAI. 9.
MED ORAL
PATHOL
1960;13:1233-44.
Davis RK, Bear PN, Archard HO, Pulmer JH. Tuberous sclerosis with oral manifestations. ORAL SURG ORAL MED ORAL PATHOL
1964;17:395-400.
10. Mackler SB, Shoulars HW, Burker EJ. Tuberous sclerosis with gingival lesions. ORAL SURC ORAL MED ORAL PATHOL 1912;34:619-24.
Lygidakis and Lindenbaum
728
ORAL
SURG ORAL
MED
ORAL
December 11. Papanayotou lesion. ORAL
P, Vezirtzi SURG
F. Tuberous
ORAL
MED
ORAL
sclerosis
with
PATHOL
1975;39:578-
gingival
82. 12. Shaffer W, Hine MK, Levy BM, eds. A textbook of oral pathology. Philadelphia: WB Saunders Co, 1983:786-7. 13. Zegarelli EV, Kutschev AH, Human GA eds. Diagnosis of diseases of the mouth and jaws. Philadelphia: Lea and Febiger, 1978:211. 14. Nuki K, Cooper SH. The role of inflammation in the pathogenesis of gingival enlargment during the administration of diphenylhydantoin sidium in cats. J Periodont Res 1972;7:102. 15. Wilson J, Garter C. Genetics of tuberous sclerosis. Lancet
1978;1:340.
BOUND
VOLUMES
AVAILABLE
PATHOL
1989
16. Rushton AR, Shaywits BA. Tuberous sclerosis: possible modifications of phenotypic expression by an unlinked dominant gene. J Med Genet 1979;16:32-5. 17. Lowry RB, Dunn HE, Paris RP. Inheritance of tuberous sclerosis. Lancet 1979; I:21 6.
Reprint requests to: Dr. N. A. Lygidakis Dental Faculty, University of Athens 2 Thivon St. Athens 115 27 Greece
TO SUBSCRIBERS
Bound volumes of ORAL SURGERY, ORAL MEDICINE and ORAL PATHOLOGY are available to subscribers (only) for the 1989 issues from the Publisher, at a cost of 40.00 ($52.00 international) for Vol. 67 (January-June) and Vol. 68 (July-December). Shipping charges are included. Each bound volume contains a subject and author index and all advertising is removed. Copies are shipped within 60 days after publication of the last issue in the volume. The binding is durable buckram with the journal name, volume number, and year stamped in gold on the spine. Payment must accompany all orders. Contact The C. V. Mosby Company, Circulation Department, 11830 Westline Industrial Drive, St. Louis, Missouri 63146, USA, phone (800) 325-4177, ext. 351. subscriptions mustbe in force to qlllhlfy. Bound volumes are not available in place of a regular jam& subscription.
DMD, iUScM, MScD, and R. H. Lindenbaum,b
UNIVERSITY
OF OXFORD,
OF MEDICAL
GENETICS
GENETICS
LABORATORY,
AND
CHURCHILL
MA. MB, ChB, FRCP,
HOSPITAL,
DEPARTMENT
Thirty-six families with tuberous sclerosis (TS) were clinically examined for oral fibromatosis and other previously reported oral anomalies. These consisted of 48 affected persons and 89 apparently unaffected parents and children. Fifty control subjects were also examined. Oral fibromatosis was observed in 56% of patients with typical TS and in none of 9 “atypical” cases. The total prevalence was 46%. Similar lesions were not seen in the control series, and they were rare in the otherwise apparently normal relatives with TS. However, three parents of patients with TS were found to have oral fibromas even though they had no signs of TS. It is suggested that examination for oral fibromatosis should be made in all persons suspected of having TS and in their close relatives, since such examination may identify other unsuspected carriers of the gene within the family. (ORAL SURC ORAL MED ORAL PATHOL 1989;68:725-8)
T
uberous sclerosis (TS) is a multisystem disorder characterized by the formation of hamartomas that are most often composed of byperproliferative hemangioblasts and fibroblasts. TS is an autosomal dominant disorder. Eighty percent of the cases appear to be sporadic. Sporadic cases represent a smaller proportion of the whole when relatives are carefully assessed by means of techniques such as Wood’s light examination and computerized tomographic brain scan.’ Rarely even very careful examination of an obligate carrier fails to reveal any signs of the trait.* Oral lesions have been reported in about 11% of the patients.3 These lesions consist mainly of fibrous growths affecting the whole oral mucosa and particularly the anterior gingivae. They may also be found on the lips, the dorsum of the tongue, and the palate.’ Various other oral abnormalities have been described, including high palate, cleft lip and palate, macroglossia, and hyperostotic alveolar process.4 Pitted enamel hypoplasia is another characteristic oral manifestation of the disease found in 58% of the patients5 The present study sought to collect further clinical data on the oral abnormalities in TS, especially fibromatosis, and involved examination of apparent-
ly normal close relatives as well as patients themselves. MATERIAL
AND METHODS
The present study was set up in the Oxford region concurrently with a prevalence study6 and a study of pitted enamel hypoplasia in TS.5 Thirty-six families contributed a total of 48 patients and 69 apparently unaffected parents and children. The 48 patients included 39 persons with typical TS and 9 persons with few signs of TS but who had secondary diagnostic criteria’ that lead to the diagnosis of TS or who were obligate carriers from the pedigree. These latter conditions we termed atypical TS.
Patients’ ages ranged from 16 months to 62 years. Four patients with typical TS were edentulous. Fifty persons (26 adults and 24 children) seen in genetic outpatient clinics for problems not related to the head and neck served as clinical control subjects. Their age range was similar to that of the patients with TS. The oral examination was part of the general physical examination performed on all the patients. The oral cavity was examined in daylight and in artificial light. RESULTS
aResearch bConsultant 7/13/11124
Registrar Clinical
Geneticist,
Oral fibromatosis was easily indentified on clinical examination. The fibromas were present as discrete, asymptomatic nodules. They were mostly located on the anterior gingivae in both jaws but also occurred 725
726
Lygidakis
and Lidrldenbaum
ORAL
Fig. 1. Typical lesions on the maxillary anterior gingivae. Severely affected female patient, age 23 years.
ORAL
MED
ORAL PATHOL December 1989
Fig. 3. Typical lesions of smaller size on the mandibular gingivae. Mildly affected female patient, age 1 I years.
Table
1. Results of clinical examination Subject
Patients
with
Number
TS (total)
Typical TS Atypical TS Relatives with Parents (24 Siblings (15 Control group Adults Children
Fig. 2. Typical lesions on the palatal affected male patient, age 14 years.
SURG
TS (total) families) families) (total)
48 39 9 69 43 26 50 26 24
Oral fibromas 22 22 0 3 3 0 0 0 0
(46%) (56%) (4%) (7%)
mucosa. Severely
on other places such as lips, buccal mucosa, palate, and tongue (Figs. 1 and 2). They were usually covered by normal mucosa and were of normal color, occasionally whitish grey. They were quite easily differentiated from other oral lesions. Their number and shape varied with age and the severity of the disorder. Severely affected patients had many large fibromas (up to 1 cm in diameter), whereas the mildly affected had fewer of smaller size (up to 0.5 cm in diameter, Fig. 3). Within the group of severely affected patients, the older ones appeared to have a larger number of fibromas. Of 39 patients with typical TS examined, 22 had oral fibromatosis (56%; see Table I). None of the nine patients with atypical TS showed the defects. The youngest patient with oral fibromas was 11 years old. A further six patients had a high arched palate. Three patients had macroglosia, and in one patient a thickened alveolar process was found as a result of a
large cavernous hemangioma. Oral clefts were not seen in any of the patients. Forty-three apparently unaffected parents were examined. (See Table I). In this group three parents showed apparently typical TS fibromas, located in the anterior gingivae. One parent, who had three children with atypical TS, showed two gingival fibromas in her maxilla. Another parent, an obligate carrier because his mother and sister had typical TS, and his son atypical TS, had many small gingival fibromas in the mandible. The third parent, who had a son with apparently sporadic atypical TS, had oral fibromas in his maxilla and mandible. None of the 26 unaffected children (from 15 families) had any signs of oral fibromatosis. Oral fibromas were not found in any of the 50 individuals examined as control subjects. DISCUSSION It is clear that oral fibromatosis is often found in patients with TS. In our series of 39 patients previously known or suspected of having typical TS, we found oral fibromas in 56%. We also saw nine
Oraljibromatosis
Volume 68 Number 6
patients whom we classified as having atypical TS; none of them had oral fibromas. With the inclusion of this atypical group, the prevalence of oral fibromatosis in the whole series of TS falls to 46%. This percentage can be compared with other signs listed’ (e.g. facial angiofibromas 70%, hypomelanotic macules 57%, retinal hemangioma 50%, shagreen skin 36%, etc.). The percentage of patients with TS who have oral fibromatosis found in our study is much different from the 11% reported before.3 The reported lesions were noted as appearing either at 4 to 10 years of age or at puberty. In our study none of the 20 patients under the age of 11 years showed any oral fibromas. Older patients with fibromas recalled the first appearance of the defects in their mouth during the second decade of their lifes. The location and clinical appearance of the oral fibromas in our study confirm the findings in the few reports on isolated cases found in the literature.7-1’ In these reports the lesions appear histologically to be either fibromatous or papillomatous hyperplasias. It has been suggested that the oral fibromas might not be true TS lesions but could result from phenytoin treatment for the neurologic manifestations of the disease. Phenytoin is known to produce fibrous gingival hyperplasia.‘* This suggestion does not seem sufficient for the following reasons: (1) Phenytoin affects only gingivae and particularly interdental papillae12 and not buccal mucosa, tongue, lips and palate, where TS fibromas can quite frequently be found. (2) Phenytoin produces homogeneous generalized gingival hyperplasia’* and not the fibrous nodule8 that are observed in TS. (3) Finally, in the case of phenytoininduced fibrous hyperplasia, only 20% of patients treated with the drug may manifest the condition,13 and it has been suggested that patients with adequate oral hygiene may not manifest gingival hyperplasia at a11.14 In contrast, 46% of the patients with TS in the present study had oral fibromas, some of whom had never been treated with phenytoin or any other antiepileptic drug. However, phenytoin treatment may mask, modify, or augmerit the gingival lesions in TS. Whether the high arched palate and the macroglosia found in some of the patients in this study and also reported by other authors4 are significant findings is not yet clear, since no detailed study of their prevalence in the normal population has been done. In the present study, done with exactly the same subjective clinical criteria, macrogiosia was found in
in tuberous sclerosis
727
four of 50 control subjects and high arched palate in five. Therefore the& findings in TS as well as the previously reported oral clefts (none found in our study) appear to be well within the normal range. However, the large cavernous hemangioma found in the maxillary alveolus of a 3-year-old patient with TS could be a significant finding because this association has never been reported before. A pedunculated hemangioma of the tongue in a 24-year-old patient with TS has once been reportedq9 Congenital hemangiomas of the mouth are very rarely reported. Since TS is an autosomal dominant disorder, it is assumed that in the sporadic cases the problem arose from a new mutation and neither parent carries the mutant gene. If so, then the recurrence risk for children after the sporadic case woild be zero. However, pairs of affected children with normal parents have been described, as have other family patterns in which apparently unaffected persons are obligate carriers of the TS gene.2~6~15-17 The more clinical or special tests that are applied to such “unaffecttid” carriers, the more likely it is that some abnormality will be detected. Although interpretation of the findings in parents was difficult, the type of oral fibromas strongly suggests that these persons were carrying the gene. Therefore examination for oral fibromas may reveal “abnormality” in an apparently unaffected relative of a patient with TS and so identify unsuspected carriers in larger families with obvious transmission. REFERENCES
1. Comez MK, ed. Tuberous sclerosis. New York: Raven Press. 1979:211-4, 11-3. 2. Baraitser M, Patton MA. Reduced penetrance in tuberous sclerosis. J Med Genet 1985;22:29-3 1. 3. Schuermann H, Greitehn A, Hornstein 0, eds, Kranheiten der mund-schleimhaut und der lippen. Berlin: Urban Schwarzenberg, 1966:47-g. 4. Gorlin RJ, Pindborg JJ, Cohen MM, eds. Syndromes of head and neck. London: McGraw-Hill, 1976:587. 5. Lygidakis NA, Lindenbaum RH, Enamel defects in tuberous sclerosis patients and first degree relatives. Clin Genet 1987; 32:216-21. 6. Hunt A, Lindenbaum RH. Tuberous sclerosis: a new estimate of prevalence within the Oxford region. J Med Genet 1984; 211272-J.
I. Butterworth T, Wilson J Jr. Dermatologic aspects of tuberous sclerosis. Arch Dermatol Syph (Chic) 1941;43:1-41. 8. Gorlin RJ, Chaudhry AP, Kelln EE. Oral manifestations of the Fitzgerald-Gardner, Pringle-Bourneville, Robin, adrenogenital and Hurler-Pfaundler syndiomes. ORAL SURG ORAI. 9.
MED ORAL
PATHOL
1960;13:1233-44.
Davis RK, Bear PN, Archard HO, Pulmer JH. Tuberous sclerosis with oral manifestations. ORAL SURG ORAL MED ORAL PATHOL
1964;17:395-400.
10. Mackler SB, Shoulars HW, Burker EJ. Tuberous sclerosis with gingival lesions. ORAL SURC ORAL MED ORAL PATHOL 1912;34:619-24.
Lygidakis and Lindenbaum
728
ORAL
SURG ORAL
MED
ORAL
December 11. Papanayotou lesion. ORAL
P, Vezirtzi SURG
F. Tuberous
ORAL
MED
ORAL
sclerosis
with
PATHOL
1975;39:578-
gingival
82. 12. Shaffer W, Hine MK, Levy BM, eds. A textbook of oral pathology. Philadelphia: WB Saunders Co, 1983:786-7. 13. Zegarelli EV, Kutschev AH, Human GA eds. Diagnosis of diseases of the mouth and jaws. Philadelphia: Lea and Febiger, 1978:211. 14. Nuki K, Cooper SH. The role of inflammation in the pathogenesis of gingival enlargment during the administration of diphenylhydantoin sidium in cats. J Periodont Res 1972;7:102. 15. Wilson J, Garter C. Genetics of tuberous sclerosis. Lancet
1978;1:340.
BOUND
VOLUMES
AVAILABLE
PATHOL
1989
16. Rushton AR, Shaywits BA. Tuberous sclerosis: possible modifications of phenotypic expression by an unlinked dominant gene. J Med Genet 1979;16:32-5. 17. Lowry RB, Dunn HE, Paris RP. Inheritance of tuberous sclerosis. Lancet 1979; I:21 6.
Reprint requests to: Dr. N. A. Lygidakis Dental Faculty, University of Athens 2 Thivon St. Athens 115 27 Greece
TO SUBSCRIBERS
Bound volumes of ORAL SURGERY, ORAL MEDICINE and ORAL PATHOLOGY are available to subscribers (only) for the 1989 issues from the Publisher, at a cost of 40.00 ($52.00 international) for Vol. 67 (January-June) and Vol. 68 (July-December). Shipping charges are included. Each bound volume contains a subject and author index and all advertising is removed. Copies are shipped within 60 days after publication of the last issue in the volume. The binding is durable buckram with the journal name, volume number, and year stamped in gold on the spine. Payment must accompany all orders. Contact The C. V. Mosby Company, Circulation Department, 11830 Westline Industrial Drive, St. Louis, Missouri 63146, USA, phone (800) 325-4177, ext. 351. subscriptions mustbe in force to qlllhlfy. Bound volumes are not available in place of a regular jam& subscription.