Case reports
Infantile osteopetrosis: a case report on dental findings
D, Droz-Desprez\ C, Azou^ P, BordigonP and M. Bonnaure-Mallet^ 'Oral Pediatric Department, Nancy, 'Oral Biology Laboratory Faculty of Odontology, Rennes, 'Children's Hospitai, Nancy, France
Droz-Desprez D, Azou C, Bordigoni P, Bonnaure-Mallet M: Infantile osteopetrosis: a case report on dental findings. J Oral Pathol Med 1992; 21: 422-425. In this paper we have described the case of a 7-yr-old Moroccan osteopetrotic boy, who had received a bone marrow transplant (BMT), He was transplanted from his older brother and, despite immunosuppressive therapy, developed chronic graft-versus-host disease and was placed on corticotherapy. Seven months after the bone marrow transplant, graft versus host di,sease (GVHD) was stabilized, but corticotherapy had inhibited growth. There was evidence of normalizing bone, his hearing was better but he had not recovered vision. Dental findings before the bone marrow transplant revealed some missing teeth, failure of teeth to erupt and decayed teeth but no enamel hypoplasia. The patient had developed one carious lesion on one unerupted tooth: bacteria seem to have found a way through the gubernaculum dentate. The scanning electronmicrographs showed decayed tooth and tissues fitted into each other. .Since the bone marrow transplant, no tooth has erupted. We think that, in this case, failure of tooth eruption would be the sign of osteopetrosis.
The infantile malignant osteopetrosis (Alberts-Schonberg or marble bone disease) is an autosomal recessive di.sorder characterized by sclerotic, brittle, radiopaque bones, with associated hematologic and neurologic abnormalities. The major pathologic changes in osteopetrosis seem due to the disturbed osteoclastic function so that the osteoclastic equilibrium is altered and bone apposition continues without normally balanced resorption (13), The result is extremely dense bone, replacing marrow spaces at the endosteal surfaces. This leads to encroachment on the marrow spaces and results in anemia and thrombocytofjenia (3, 4), Extramedullary hematopoiesis, leukoerythroblastosis and a progressive hepatosplenomegaly also become evident. Proliferation of bone surrounding nerve foramina results in optic nerve atrophy, blindness, vestibula nerve dysfunction, deafness, extra-ocular muscle paralysis and other cranial nerve dysfunction ( 1 3 , 5). Dental findings include delayed tooth eruption, absence of some teeth, unerupted and malformed teeth, enamel hypoplasia, abnormal pulp chambers, a tendency to early decay, defects of the periodontal membrane, thickened lamina dura and early tooth loss due to caries. Osteomyelitis of the jaws often oc-
curred after odontogenic infection or oral surgical procedures (1,2, 6). Most patients fail to grow and death occurs at an early age as a result of severe chronic anemia, bleeding or infection. WALKKR (7) documented the restoration of bone remodeling in osteopetrotic mice by parabiotic union and later by bone marrow transplant (BMT). This led to .several attempts at treating infantile osteopetrosis with BMT (3, 4, 8), Few publications describe the dental tissues in osteopetrotic teeth (1, 2, 6, 9, 10) or the destiny of the teeth after a bone marrow transplant (11 13). It appears interesting to report the case of Hassan, a 7-yr-old Moroccan boy who received bone marrow transplant at the Children's Hospital of Nancy.
Key words: dental tissues: osteopetrosis: ultrastructure. Madame D. Droz-Desprez UER Odontologie, rue du Docteur Heydenreicb. BP 3034 54 012. Nancy Cedex-France. Accepted for publication May 14. 1992
anemia), splenomegaly, bilateral optic atrophy and debutant deafness. He received many regular blood transfusions. In 19S8, the medical council suggested a bone marrow transplant. Splenectomy was performed in February 1989 to relieve severe thromboeytopenia and anemia. It was effective, but not for long; the platelet count decreased again after one month dropping to 70 000/1. A BMT was decided on. Physical examination H. looked like a poorly developed boy: he was but 96 cm tall and weighed only I4kgsat age 6. He presented osseous delormaties: genu valgum, bilateral flexum and forearms valgus. Radiographs showed osseous condensation, loss of distinction between the cortex and medullary cortex, clubbing of the long bones with transverse bands at their ends (Fig. 1). His long bones were extremely dense, as were Case report the carpals and phalanges. His heart was Pretransplantation evaluation normal and his chest was clear to ausculFast medical history Osteopetrosis was tation. Vision wasab.sent and hearing rediagnosed when H. was 2 yr of age. He duced. He became very introverted and had a slow development, loss of hearing was extremely shy and withdrawn. and sight. His parents were first cousins. Dentat course All risk of infection There was no history of osteopetrosis in had to be removed before a bone marhis family and none of his three siblings row transplant (BMT), so H. wasexatni(2 brothers and I sister) has osteope- ned by the detital service for a lull astrosis. He walked at age 3. At four, he sessment before a bone marrow transhad bicytopenia (thrombopenia and plant. Dental examination revealed
Osteopetrosis and dental findings 423 extracted. An orifice which looked like a gubernaculum dentale above the pritnary tnandibular left second molar level was observed. A panoratnic radiograph (Fig. 2) revealed one lesion on the tooth bud which evoked a carious lesion and serious bone density renders reading of panoramic radiograph difficult, particularly at the tnaxillary level. Tooth eruption is significantly reduced. It was difficult to recognize and to count the tooth buds: there were some odontomas. The first pertnanent molars, permanent incisors are underdeveloped and cannot erupt. The pritnary second tnolars are under the gingival level. After discussion with the medical service, germeetomy of the mandibular second left primary molar was decided on, as well as a histologic examination. Fig. L Radiograph of pelvis before bone marrow transplantation (BMT) at 6 yr. There is marked sclerosis of hone, obliteration of marrow spaees of long bones, clubbing with transverse bands at the ends of long bones.
poor tooth development: he had only primary incisors, canines and first molars. The prirnary maxillary canines and primary maxillary left eentral incisor were missing. All the maxillary and mandibular ineisors and canines were deeayed, as were the primary mandibular first tnolars. The decay in the mandibular incisors was symptomatic of a particular dental fragility. At the time of general anesthesia, amalgam restorations were placed on the primary mandibular first tnoUtrs and the pritnaiy mandibular central incisors and canines as the primary maxillary incisors were
Bone marrow transplant (BMT)
Bone Marrow was transplanted from the HLA, AB, DR of his 11-yr-old twin brother. On April 17, 1989 H. received 3.9 X 10 cells/kg of his brother's T-cell non-depleted marrow after cytoreduetion with busulfan (16 mg per kg of body weight), etidoxan (200 mg per kg), araeytine (9 grams per m-) and ATG (antithymocyte globulins. Laboratoire Mcrieux. France) (1 vial per 10 kg) for 5 days before BMT. He also received methotrexate and cyciosporin A for prophylaxis of graft-versus-host disease (G-VHD) (14), Post BMT clinical course
extensive chronic graft-versus-host disease diagnosed on day 108 after BMT and treated by methylprednisolone (2,5 mg/kg/day). On day 149 post BMT, cholestasis and cytolysis remained unchanged and a course of intravenous desferal was then continued on a subcutaneous traet with a pump. On day 169, phospho-calcium metabolism was stabilized by three injections of diphosphate type ADP atid it was noticed that H. had grown 5 cm. On day 190, 7 months after bone marrow transplant, graft versus host disease (GVHD) was stabilized by corticotherapy but this therapy had stopped his growth. There was evidence of a stable red blood-cell chimera (80% donor and 20% host) and of normalizing bone: radiographs revealed medullary cavities in the long bones (Fig. 3), Bone marrow transplant (BMT) has permitted bone resorption and active hematopoiesis, but fragility of individual bones remains: H. was admitted twice: in April 1990 and in January 1991, because of a fractured femoral and humoral. Hearing is better: auditory threshold was at 80 dB before BMT and at 40 dB afterwards. He has not recovered his sight but has, however, some luminar perception. KAPLAN (3) said that improvement of neurologic status probably depends on the degree of neural itijury and compression before transplant. H. recovered hearing, but his condition was too advanced before BMT for him to recover anything other than very slight vision.
The patietit"s hospital course was complicated by severe hypercalcemia and by
Fig. 2. Panoramic radiograph reveals of lesion which resembles a carious lesion on primary niandibiiUir left second molar bud.
Eig. .1 Radiograph of forearms utter B.M.T. shows evidence of normalizing bone with medullary cavity.
424
DROZ-DESPREZ et al.
washing in the same cacodylate buffer, sample was ethanol-dehydrated in progressive alcohol solutions. It was kept in pure acetone and sliced for scanning electronmicroscopy. Fragments were critical point dried and metallized with gold and were observed under a JEOL JSM 35 scanning electron microscope.
Results
Eig. 4. A. B. Radiographs shows poor osseous healing at extraction site, no more root development for permanent first molar and odontoma on site of mandibular left second premolar.
He will be transferred to an institution for blind and partially-sighted children. Dental examination did not show any improvement; none of the permanent incisors or permanent molars had erupted. Radiographs showed poor healing at the extraction levels, with no more root development of buds. The buds are malformed. Some odontoma appeared on a retroalveolar radiograph on the site of the second mandibular left premolar (Fig. 4A, B). HIttologic procedure
After extraction, the tooth was fixed in a cacodylate buffered 3% glutaraldehyde solution (0.1 M pH 7.2). After
Eig. 5. Extracted tooth. TEM, x 20
The crown has a primary molar globular shape. The roots are underdeveloped, short and squat (Fig. 5). The enamel observation of proximal surfaces shows normal perikymatia with alternating strips. On the occlusal face enamel is normal or decayed. At the dentin-enamel junction, it is difficult to differentiate dentin from enamel: dentin and enamel are strongly intricated and present a foliated aspect (Fig, 6), But in the deep dentin, the tubular dentin is recognizable. A carious lesion is characterized by lack of odontoblastic process, an altered intertubular dentin and a dentinar selerosis (Fig. 7). Bacteria can be seen in dentin tubuli and surfaces. A magnificant of root shows a particular aspect with numerous apical foramina. A study of one detail allows us to observe cementum with classieal organization, but the cellular and accellular parts are irregular. Around a seeondary apical foramina, resorption pictures are demonstrated. A majority of the root surface is covered by bone. The cementum-enamel junction is normally scalloped, but the cementum is covered by bone (Fig. 8). To sum up, the tooth has normal constituants, but their repartition is anarchic. Each element is strongly intricated with its neighbors. The alveolar ligament is absent. Collagen extrinsic fibers were not observed.
Eig. 6. Occlusal enamel surface with carious lesions. TF-M, x40()
Eig. 7. Carious dentin. I hM, x 2000
Discussion
In osteopetro,sis dentition is greatly affected by the disease process. At 6 yr of age, the intraoral examination of our patient revealed a constricted, underdeveloped maxillary arch and H. showed the absence of some temporary teeth as well as many decayed teeth. On a panoramic radiograph, dental structures were difficult to identify because of the increased density of the bone: we could see unerupted and tnalformed teeth and the permanent first molars and the permanent incisors showed no propensity for eruption, as in other studies (2, 5). For FRIHDI: (5), the poor development of dental structures, resulting from increased bone density, is probably cau.sed by progressive inadequacy of the supply of nutrients to the developing tooth germs, DotJRov & PuiLii'i'ARi (II) have studied tooth eruption in osteopetrotic rats: they have described a gubernaculum dentale opening, but without eruption or root formation. For them, fai-
Eig. fl. Under bone alveolar, cementum. TEM, < 1000.
Osteopetrosis and dental findings 425 lure of eruption results frotn fragmenting atid dispersion of the tooth germ in the osteopetrotic bone (15). For CAHILL & MARKS (16), root formation does not have a direct influence, but is pertnitted by tooth eruption. YouNAi et at. (2) suggest that failure of teeth to erupt is not due to mechanical obstruction alone but to bone ankylosis as well. These authors also describe a defective periodontal ligament. The histologic finditigs illustrate this opinion: examination of the cetnentutn interface of the root of the unerupted extracted tooth showed areas of ankylosis and the absence of alveolar ligament. Bands of resorption were observed around a secondary apical forameti. Dental findings concerning osteopetrosis include enatnel hypoplasia, abnormal pulp chambers, a tendency to early decay, and early tooth loss due to caries ( 1 2 , 6), In the present case no enamel hypoplasia was demonstrated but there was one particularity: tissues fitted into each other: dentin into enamel, enamel into cetnentutn and dentin into cementum. We had no alteration in dentin mineralization, as des-
(11) have described different treatments by op/op rats. In osteopetrotic op/op rats, the incisors and the molars do not erupt. In op/op rats who reeeived at day 3, intraperitoneally medullary cells, aetive hetiiatopoiesis and nortnal osteous resorption were observed. The tnolars erupt in the oral cavity but the incisors never erupt. Resumption of osteoclasis began too late to allow eruption of incisors. This failure of incisor ertiption in op/op treated rats could be explained by the early interruption of the periodontal membrane and by the mechanical lock caused by the growing odontomas. The proliferation of the apical odontogenic tissue of the incisors led to the fortnation of odontonias composed of disorganized pulp, dentin and enamel. In most cases, the shape of the root of the maxillary first tnolar was atypical (13), PHILIPPART
In the present case, a bone marrow transplant (BMT) was given too late to allow tooth eruption. Perhaps corticotherapy, as treatment for graft versus host disease (GVHD), could explain the occurtencc of delayed teeth. The verdict is not yet final, but it could be that osteopetrosis will leave its mark in the cribed by SYMONS (9) and no abnormal pulp chatnber as described by CR(K- failure of tooth eruption. KI:TT (6). Many authors have described Acknowledgements The authors thank early tooh loss due to caries in osteope- PKTtR Rt:Ai). BILL COURTNHV and MICHEL trosis (6, 10) but we have found no refe- BLIQUK for their helpful review of the manurences reporting that an unerupted script and Dr. BoRDKiONi for hi,s permission tooth can be decayed. Some articles to refer to medical records of the patient. have described unerupted decayed References teeth, but there was always hypoplasia 1. GoMKZ LSA, TAYLOR R , COHKN M , S H or resorption whieh looked like earies KLAR G. The jaws in osteopetrosis (Al(17-19). In the present case, real decay bers-Schonberg disease): report of case. was present. Scanning electrontiiicroJ Orat Surg 1966; 24: 67 74. graphs showed decayed enamel and al2. YOUNAI F, ElSENBUD L, SCIUBBA JJ. Ostered dentin, as well as sclerosis in tuteopetrosis: a case report including gross buli, disorganized interglobular dentin and microscopic fmdings in the mandible and bacteria iti dentin tubuli. As in the at autopsy. Orat Surg Orat Med Orat Pattiot 1988; 65: 214 21. case described by DotiROV & PUILIP3. KAPLAN FS, Auciusr CS, FALLON MD, PAR r (11), gubernaculum dentale was DAtiNKA M, AxKL L, HAODAO JG. Sucopened, but there was no eruption and cessful treatment of infantile malignant bacteria may have found a way through osteopetrosis by bone marrow transplangubernaculum dentale to reach the untation. J Bone Joint Surg 1988; 70: erupied tooth. Perhaps this could ex617 2^. plain the osteomyelitis, related to the 4. SiEFF CA, LEVINSKV RJ, RcKitRS DW, et eruption of the dentition. at. Allogenic bone-marrow transplantation in infantile malignant osteopetrosis. After BMT, H. had no teeth eruption, Lancet 1983; 26: 437-41. but there are some odontomas, other leeth are ankylosed. MARKS (20) has de-
5. FRiEt>t H, MANALIGOD JR, ROSENTHAL
scribed the dependence of tooth eruption on bone resorption by direct application of some of Walker's original observation to the ia mutation.
IM. Craniofacial abnormalities in osteopetrosis with precocious manifestations: report of a case with .serial cephalometric roentgenograms. J Craniofac Genet Dev Biot 198,S; 5: 247 57.
LAMKNDIN et at. (12) and DOUROV &
6. CROtKETT DM, STANLEY RB, LUBKA R .
Osteomyelitis of the maxilla in a patient with osteopetrosis (Albers Schonberg disease). Ototarvngot Head Neet< Surg 1986; 95: 117 2i. 7. WALKER DG. Spleen cells transmit osteopetrois in mice. Science \915: 190: 785-7. 8. BAt LET J J , GRISCELLt C , COUTRIS C , et
at. Bone marrow transplant in osteopetrosis. Lancet 1977; 2: 1137 (only). 9. SYMONS AL, POWELL R N , SEYMOUR GY,
HARBROW DJ. Disturbances of tooth form and eruption in the microphtalmic (mi) mouse: a light and electron microscopic study. Areh Orat Biot 1989; 34: 71-6. 10. Dt( K HM, SIMPSON WJ. Dental changes in osteopetrosis. Orat Surg Orat Med Orat Pathot 1972: 34: 408-16. 11. DotiROv N, PHit.ippART C. Acquisitions nouvelles sur Teruption dentaire en relation avec Ies interactions osteodontaires chez le rat osteopetrotique op/op. Effet curatif des greffes precoces de la moelle osseuse. Butt Mem Aead R .Med Betg 1987; 142: 297 303. 12. L A M E N D I N H , MOUTIER R, TOYAMA K ,
BERENHOLC S. A propos de la guerison de l'osteopetrose par injection de cellules de moelle osseuse allogenique chez le rat double mutant osteopetrotique athymique: observation des signes bucco-dentaires. Chir Dent E 1980; 65: 49 50. 13. PHU.tppART C, ARYS A , DOUROV N . Ef-
fects of bone marrow transplantation on impacted dental germs in osteopetrotic op/op rats. J Oral Pathol .Med 1989; 18: 163 6. 14. STORB R , DEEG HJ, PEPE M , et at.
Methotrexate and cyclosporine versus cyclosporine alone for prophylaxis of graft-versus-host disease in patients given HLA-identical marrow grafts for leukemia: long-term tbllow-up of a controlled trial. Blood 1989; 73: 1729 34. 15. PHiLiPPARr C, ARYS ,\. DOUROV N . His-
topathology of the interactions between alveolar bone and impacted dental germs in osteopetrotic op/op rats. J Orat Pathol Med \989. 18: 157 62. 16. CAHILL D , MARKS JR. Tooth eruption:
evidence for the central role of the dental follicle. J Orat Pathot 1980; 9: 189 200. 17. Wcx)DEN KuETiNEC. Decay of unerupted premolar. Orat Surg Orat Med Oral Pattiot 1974; 38: 491 2. 18. MtlELLER BH, LirHTY GC, TALLERICO ME, BuGG JL. Caries like resorption of unerupted permanent teeth. J Pedod 1980; 4: 266 72. 19. RANKOW H , CROLL T P , MILLER AS. Pre-
eruptive idiopathic coronal resorption of permanent teeth in children. J Endo 1986; 12: ,16 9. 20. MARKS SC. Tooth eruption depends on bone resorption: experimental evidence from osteopetrotic rats (ia). Metahot Bone Dis Ret Res 1981; 3: 107-15,
Infantile osteopetrosis: a case report on dental findings
D, Droz-Desprez\ C, Azou^ P, BordigonP and M. Bonnaure-Mallet^ 'Oral Pediatric Department, Nancy, 'Oral Biology Laboratory Faculty of Odontology, Rennes, 'Children's Hospitai, Nancy, France
Droz-Desprez D, Azou C, Bordigoni P, Bonnaure-Mallet M: Infantile osteopetrosis: a case report on dental findings. J Oral Pathol Med 1992; 21: 422-425. In this paper we have described the case of a 7-yr-old Moroccan osteopetrotic boy, who had received a bone marrow transplant (BMT), He was transplanted from his older brother and, despite immunosuppressive therapy, developed chronic graft-versus-host disease and was placed on corticotherapy. Seven months after the bone marrow transplant, graft versus host di,sease (GVHD) was stabilized, but corticotherapy had inhibited growth. There was evidence of normalizing bone, his hearing was better but he had not recovered vision. Dental findings before the bone marrow transplant revealed some missing teeth, failure of teeth to erupt and decayed teeth but no enamel hypoplasia. The patient had developed one carious lesion on one unerupted tooth: bacteria seem to have found a way through the gubernaculum dentate. The scanning electronmicrographs showed decayed tooth and tissues fitted into each other. .Since the bone marrow transplant, no tooth has erupted. We think that, in this case, failure of tooth eruption would be the sign of osteopetrosis.
The infantile malignant osteopetrosis (Alberts-Schonberg or marble bone disease) is an autosomal recessive di.sorder characterized by sclerotic, brittle, radiopaque bones, with associated hematologic and neurologic abnormalities. The major pathologic changes in osteopetrosis seem due to the disturbed osteoclastic function so that the osteoclastic equilibrium is altered and bone apposition continues without normally balanced resorption (13), The result is extremely dense bone, replacing marrow spaces at the endosteal surfaces. This leads to encroachment on the marrow spaces and results in anemia and thrombocytofjenia (3, 4), Extramedullary hematopoiesis, leukoerythroblastosis and a progressive hepatosplenomegaly also become evident. Proliferation of bone surrounding nerve foramina results in optic nerve atrophy, blindness, vestibula nerve dysfunction, deafness, extra-ocular muscle paralysis and other cranial nerve dysfunction ( 1 3 , 5). Dental findings include delayed tooth eruption, absence of some teeth, unerupted and malformed teeth, enamel hypoplasia, abnormal pulp chambers, a tendency to early decay, defects of the periodontal membrane, thickened lamina dura and early tooth loss due to caries. Osteomyelitis of the jaws often oc-
curred after odontogenic infection or oral surgical procedures (1,2, 6). Most patients fail to grow and death occurs at an early age as a result of severe chronic anemia, bleeding or infection. WALKKR (7) documented the restoration of bone remodeling in osteopetrotic mice by parabiotic union and later by bone marrow transplant (BMT). This led to .several attempts at treating infantile osteopetrosis with BMT (3, 4, 8), Few publications describe the dental tissues in osteopetrotic teeth (1, 2, 6, 9, 10) or the destiny of the teeth after a bone marrow transplant (11 13). It appears interesting to report the case of Hassan, a 7-yr-old Moroccan boy who received bone marrow transplant at the Children's Hospital of Nancy.
Key words: dental tissues: osteopetrosis: ultrastructure. Madame D. Droz-Desprez UER Odontologie, rue du Docteur Heydenreicb. BP 3034 54 012. Nancy Cedex-France. Accepted for publication May 14. 1992
anemia), splenomegaly, bilateral optic atrophy and debutant deafness. He received many regular blood transfusions. In 19S8, the medical council suggested a bone marrow transplant. Splenectomy was performed in February 1989 to relieve severe thromboeytopenia and anemia. It was effective, but not for long; the platelet count decreased again after one month dropping to 70 000/1. A BMT was decided on. Physical examination H. looked like a poorly developed boy: he was but 96 cm tall and weighed only I4kgsat age 6. He presented osseous delormaties: genu valgum, bilateral flexum and forearms valgus. Radiographs showed osseous condensation, loss of distinction between the cortex and medullary cortex, clubbing of the long bones with transverse bands at their ends (Fig. 1). His long bones were extremely dense, as were Case report the carpals and phalanges. His heart was Pretransplantation evaluation normal and his chest was clear to ausculFast medical history Osteopetrosis was tation. Vision wasab.sent and hearing rediagnosed when H. was 2 yr of age. He duced. He became very introverted and had a slow development, loss of hearing was extremely shy and withdrawn. and sight. His parents were first cousins. Dentat course All risk of infection There was no history of osteopetrosis in had to be removed before a bone marhis family and none of his three siblings row transplant (BMT), so H. wasexatni(2 brothers and I sister) has osteope- ned by the detital service for a lull astrosis. He walked at age 3. At four, he sessment before a bone marrow transhad bicytopenia (thrombopenia and plant. Dental examination revealed
Osteopetrosis and dental findings 423 extracted. An orifice which looked like a gubernaculum dentale above the pritnary tnandibular left second molar level was observed. A panoratnic radiograph (Fig. 2) revealed one lesion on the tooth bud which evoked a carious lesion and serious bone density renders reading of panoramic radiograph difficult, particularly at the tnaxillary level. Tooth eruption is significantly reduced. It was difficult to recognize and to count the tooth buds: there were some odontomas. The first pertnanent molars, permanent incisors are underdeveloped and cannot erupt. The pritnary second tnolars are under the gingival level. After discussion with the medical service, germeetomy of the mandibular second left primary molar was decided on, as well as a histologic examination. Fig. L Radiograph of pelvis before bone marrow transplantation (BMT) at 6 yr. There is marked sclerosis of hone, obliteration of marrow spaees of long bones, clubbing with transverse bands at the ends of long bones.
poor tooth development: he had only primary incisors, canines and first molars. The prirnary maxillary canines and primary maxillary left eentral incisor were missing. All the maxillary and mandibular ineisors and canines were deeayed, as were the primary mandibular first tnolars. The decay in the mandibular incisors was symptomatic of a particular dental fragility. At the time of general anesthesia, amalgam restorations were placed on the primary mandibular first tnoUtrs and the pritnaiy mandibular central incisors and canines as the primary maxillary incisors were
Bone marrow transplant (BMT)
Bone Marrow was transplanted from the HLA, AB, DR of his 11-yr-old twin brother. On April 17, 1989 H. received 3.9 X 10 cells/kg of his brother's T-cell non-depleted marrow after cytoreduetion with busulfan (16 mg per kg of body weight), etidoxan (200 mg per kg), araeytine (9 grams per m-) and ATG (antithymocyte globulins. Laboratoire Mcrieux. France) (1 vial per 10 kg) for 5 days before BMT. He also received methotrexate and cyciosporin A for prophylaxis of graft-versus-host disease (G-VHD) (14), Post BMT clinical course
extensive chronic graft-versus-host disease diagnosed on day 108 after BMT and treated by methylprednisolone (2,5 mg/kg/day). On day 149 post BMT, cholestasis and cytolysis remained unchanged and a course of intravenous desferal was then continued on a subcutaneous traet with a pump. On day 169, phospho-calcium metabolism was stabilized by three injections of diphosphate type ADP atid it was noticed that H. had grown 5 cm. On day 190, 7 months after bone marrow transplant, graft versus host disease (GVHD) was stabilized by corticotherapy but this therapy had stopped his growth. There was evidence of a stable red blood-cell chimera (80% donor and 20% host) and of normalizing bone: radiographs revealed medullary cavities in the long bones (Fig. 3), Bone marrow transplant (BMT) has permitted bone resorption and active hematopoiesis, but fragility of individual bones remains: H. was admitted twice: in April 1990 and in January 1991, because of a fractured femoral and humoral. Hearing is better: auditory threshold was at 80 dB before BMT and at 40 dB afterwards. He has not recovered his sight but has, however, some luminar perception. KAPLAN (3) said that improvement of neurologic status probably depends on the degree of neural itijury and compression before transplant. H. recovered hearing, but his condition was too advanced before BMT for him to recover anything other than very slight vision.
The patietit"s hospital course was complicated by severe hypercalcemia and by
Fig. 2. Panoramic radiograph reveals of lesion which resembles a carious lesion on primary niandibiiUir left second molar bud.
Eig. .1 Radiograph of forearms utter B.M.T. shows evidence of normalizing bone with medullary cavity.
424
DROZ-DESPREZ et al.
washing in the same cacodylate buffer, sample was ethanol-dehydrated in progressive alcohol solutions. It was kept in pure acetone and sliced for scanning electronmicroscopy. Fragments were critical point dried and metallized with gold and were observed under a JEOL JSM 35 scanning electron microscope.
Results
Eig. 4. A. B. Radiographs shows poor osseous healing at extraction site, no more root development for permanent first molar and odontoma on site of mandibular left second premolar.
He will be transferred to an institution for blind and partially-sighted children. Dental examination did not show any improvement; none of the permanent incisors or permanent molars had erupted. Radiographs showed poor healing at the extraction levels, with no more root development of buds. The buds are malformed. Some odontoma appeared on a retroalveolar radiograph on the site of the second mandibular left premolar (Fig. 4A, B). HIttologic procedure
After extraction, the tooth was fixed in a cacodylate buffered 3% glutaraldehyde solution (0.1 M pH 7.2). After
Eig. 5. Extracted tooth. TEM, x 20
The crown has a primary molar globular shape. The roots are underdeveloped, short and squat (Fig. 5). The enamel observation of proximal surfaces shows normal perikymatia with alternating strips. On the occlusal face enamel is normal or decayed. At the dentin-enamel junction, it is difficult to differentiate dentin from enamel: dentin and enamel are strongly intricated and present a foliated aspect (Fig, 6), But in the deep dentin, the tubular dentin is recognizable. A carious lesion is characterized by lack of odontoblastic process, an altered intertubular dentin and a dentinar selerosis (Fig. 7). Bacteria can be seen in dentin tubuli and surfaces. A magnificant of root shows a particular aspect with numerous apical foramina. A study of one detail allows us to observe cementum with classieal organization, but the cellular and accellular parts are irregular. Around a seeondary apical foramina, resorption pictures are demonstrated. A majority of the root surface is covered by bone. The cementum-enamel junction is normally scalloped, but the cementum is covered by bone (Fig. 8). To sum up, the tooth has normal constituants, but their repartition is anarchic. Each element is strongly intricated with its neighbors. The alveolar ligament is absent. Collagen extrinsic fibers were not observed.
Eig. 6. Occlusal enamel surface with carious lesions. TF-M, x40()
Eig. 7. Carious dentin. I hM, x 2000
Discussion
In osteopetro,sis dentition is greatly affected by the disease process. At 6 yr of age, the intraoral examination of our patient revealed a constricted, underdeveloped maxillary arch and H. showed the absence of some temporary teeth as well as many decayed teeth. On a panoramic radiograph, dental structures were difficult to identify because of the increased density of the bone: we could see unerupted and tnalformed teeth and the permanent first molars and the permanent incisors showed no propensity for eruption, as in other studies (2, 5). For FRIHDI: (5), the poor development of dental structures, resulting from increased bone density, is probably cau.sed by progressive inadequacy of the supply of nutrients to the developing tooth germs, DotJRov & PuiLii'i'ARi (II) have studied tooth eruption in osteopetrotic rats: they have described a gubernaculum dentale opening, but without eruption or root formation. For them, fai-
Eig. fl. Under bone alveolar, cementum. TEM, < 1000.
Osteopetrosis and dental findings 425 lure of eruption results frotn fragmenting atid dispersion of the tooth germ in the osteopetrotic bone (15). For CAHILL & MARKS (16), root formation does not have a direct influence, but is pertnitted by tooth eruption. YouNAi et at. (2) suggest that failure of teeth to erupt is not due to mechanical obstruction alone but to bone ankylosis as well. These authors also describe a defective periodontal ligament. The histologic finditigs illustrate this opinion: examination of the cetnentutn interface of the root of the unerupted extracted tooth showed areas of ankylosis and the absence of alveolar ligament. Bands of resorption were observed around a secondary apical forameti. Dental findings concerning osteopetrosis include enatnel hypoplasia, abnormal pulp chambers, a tendency to early decay, and early tooth loss due to caries ( 1 2 , 6), In the present case no enamel hypoplasia was demonstrated but there was one particularity: tissues fitted into each other: dentin into enamel, enamel into cetnentutn and dentin into cementum. We had no alteration in dentin mineralization, as des-
(11) have described different treatments by op/op rats. In osteopetrotic op/op rats, the incisors and the molars do not erupt. In op/op rats who reeeived at day 3, intraperitoneally medullary cells, aetive hetiiatopoiesis and nortnal osteous resorption were observed. The tnolars erupt in the oral cavity but the incisors never erupt. Resumption of osteoclasis began too late to allow eruption of incisors. This failure of incisor ertiption in op/op treated rats could be explained by the early interruption of the periodontal membrane and by the mechanical lock caused by the growing odontomas. The proliferation of the apical odontogenic tissue of the incisors led to the fortnation of odontonias composed of disorganized pulp, dentin and enamel. In most cases, the shape of the root of the maxillary first tnolar was atypical (13), PHILIPPART
In the present case, a bone marrow transplant (BMT) was given too late to allow tooth eruption. Perhaps corticotherapy, as treatment for graft versus host disease (GVHD), could explain the occurtencc of delayed teeth. The verdict is not yet final, but it could be that osteopetrosis will leave its mark in the cribed by SYMONS (9) and no abnormal pulp chatnber as described by CR(K- failure of tooth eruption. KI:TT (6). Many authors have described Acknowledgements The authors thank early tooh loss due to caries in osteope- PKTtR Rt:Ai). BILL COURTNHV and MICHEL trosis (6, 10) but we have found no refe- BLIQUK for their helpful review of the manurences reporting that an unerupted script and Dr. BoRDKiONi for hi,s permission tooth can be decayed. Some articles to refer to medical records of the patient. have described unerupted decayed References teeth, but there was always hypoplasia 1. GoMKZ LSA, TAYLOR R , COHKN M , S H or resorption whieh looked like earies KLAR G. The jaws in osteopetrosis (Al(17-19). In the present case, real decay bers-Schonberg disease): report of case. was present. Scanning electrontiiicroJ Orat Surg 1966; 24: 67 74. graphs showed decayed enamel and al2. YOUNAI F, ElSENBUD L, SCIUBBA JJ. Ostered dentin, as well as sclerosis in tuteopetrosis: a case report including gross buli, disorganized interglobular dentin and microscopic fmdings in the mandible and bacteria iti dentin tubuli. As in the at autopsy. Orat Surg Orat Med Orat Pattiot 1988; 65: 214 21. case described by DotiROV & PUILIP3. KAPLAN FS, Auciusr CS, FALLON MD, PAR r (11), gubernaculum dentale was DAtiNKA M, AxKL L, HAODAO JG. Sucopened, but there was no eruption and cessful treatment of infantile malignant bacteria may have found a way through osteopetrosis by bone marrow transplangubernaculum dentale to reach the untation. J Bone Joint Surg 1988; 70: erupied tooth. Perhaps this could ex617 2^. plain the osteomyelitis, related to the 4. SiEFF CA, LEVINSKV RJ, RcKitRS DW, et eruption of the dentition. at. Allogenic bone-marrow transplantation in infantile malignant osteopetrosis. After BMT, H. had no teeth eruption, Lancet 1983; 26: 437-41. but there are some odontomas, other leeth are ankylosed. MARKS (20) has de-
5. FRiEt>t H, MANALIGOD JR, ROSENTHAL
scribed the dependence of tooth eruption on bone resorption by direct application of some of Walker's original observation to the ia mutation.
IM. Craniofacial abnormalities in osteopetrosis with precocious manifestations: report of a case with .serial cephalometric roentgenograms. J Craniofac Genet Dev Biot 198,S; 5: 247 57.
LAMKNDIN et at. (12) and DOUROV &
6. CROtKETT DM, STANLEY RB, LUBKA R .
Osteomyelitis of the maxilla in a patient with osteopetrosis (Albers Schonberg disease). Ototarvngot Head Neet< Surg 1986; 95: 117 2i. 7. WALKER DG. Spleen cells transmit osteopetrois in mice. Science \915: 190: 785-7. 8. BAt LET J J , GRISCELLt C , COUTRIS C , et
at. Bone marrow transplant in osteopetrosis. Lancet 1977; 2: 1137 (only). 9. SYMONS AL, POWELL R N , SEYMOUR GY,
HARBROW DJ. Disturbances of tooth form and eruption in the microphtalmic (mi) mouse: a light and electron microscopic study. Areh Orat Biot 1989; 34: 71-6. 10. Dt( K HM, SIMPSON WJ. Dental changes in osteopetrosis. Orat Surg Orat Med Orat Pathot 1972: 34: 408-16. 11. DotiROv N, PHit.ippART C. Acquisitions nouvelles sur Teruption dentaire en relation avec Ies interactions osteodontaires chez le rat osteopetrotique op/op. Effet curatif des greffes precoces de la moelle osseuse. Butt Mem Aead R .Med Betg 1987; 142: 297 303. 12. L A M E N D I N H , MOUTIER R, TOYAMA K ,
BERENHOLC S. A propos de la guerison de l'osteopetrose par injection de cellules de moelle osseuse allogenique chez le rat double mutant osteopetrotique athymique: observation des signes bucco-dentaires. Chir Dent E 1980; 65: 49 50. 13. PHU.tppART C, ARYS A , DOUROV N . Ef-
fects of bone marrow transplantation on impacted dental germs in osteopetrotic op/op rats. J Oral Pathol .Med 1989; 18: 163 6. 14. STORB R , DEEG HJ, PEPE M , et at.
Methotrexate and cyclosporine versus cyclosporine alone for prophylaxis of graft-versus-host disease in patients given HLA-identical marrow grafts for leukemia: long-term tbllow-up of a controlled trial. Blood 1989; 73: 1729 34. 15. PHiLiPPARr C, ARYS ,\. DOUROV N . His-
topathology of the interactions between alveolar bone and impacted dental germs in osteopetrotic op/op rats. J Orat Pathol Med \989. 18: 157 62. 16. CAHILL D , MARKS JR. Tooth eruption:
evidence for the central role of the dental follicle. J Orat Pathot 1980; 9: 189 200. 17. Wcx)DEN KuETiNEC. Decay of unerupted premolar. Orat Surg Orat Med Oral Pattiot 1974; 38: 491 2. 18. MtlELLER BH, LirHTY GC, TALLERICO ME, BuGG JL. Caries like resorption of unerupted permanent teeth. J Pedod 1980; 4: 266 72. 19. RANKOW H , CROLL T P , MILLER AS. Pre-
eruptive idiopathic coronal resorption of permanent teeth in children. J Endo 1986; 12: ,16 9. 20. MARKS SC. Tooth eruption depends on bone resorption: experimental evidence from osteopetrotic rats (ia). Metahot Bone Dis Ret Res 1981; 3: 107-15,
