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Agenesis of a large number of permanent teeth after treatment of neonatal leukemia
G Model JOMSMP-321; No. of Pages 4
ARTICLE IN PRESS Journal of Oral and Maxillofacial Surgery, Medicine, and Pathology xxx (2014) xxx–xxx
Contents lists available at ScienceDirect
Journal of Oral and Maxillofacial Surgery, Medicine, and Pathology journal homepage: www.elsevier.com/locate/jomsmp
Case Report
Agenesis of a large number of permanent teeth after treatment of neonatal leukemia Hirokazu Tanaka a,b,∗ , Hiroshi Kurita b , Hitoshi Aizawa b , Takahiro Kamata b a b
Department of Dentistry and Oral Surgery, Aizawa Hospital, Matsumoto, Japan Department of Dentistry and Oral Surgery, Shinshu University School of Medicine, Matsumoto, Japan
a r t i c l e
i n f o
Article history: Received 15 January 2014 Received in revised form 11 July 2014 Accepted 2 September 2014 Available online xxx Keywords: Dental development Stem cell transplantation Tooth agenesis Missing teeth Leukemia
a b s t r a c t The intensive treatment of hematological malignancy can cause dental abnormalities when applied during the period of dental and craniofacial development. Here, we report a case of absence of numerous teeth after treatment of neonatal leukemia. An 11-year-old boy was referred to our hospital complaining of delayed (no) eruption of many teeth. The patient had a history of neonatal acute monocytic leukemia. He had undergone systemic chemotherapy and allogeneic peripheral blood stem cell transplantation (PBSCT) during the period between 7 days and 9 months after his birth. Intraoral examination and a panoramic radiograph revealed absence of 25 of the permanent teeth (12, 13, 14, 15, 17, 18, 22, 23, 24, 25, 27, 28, 31, 32, 33, 34, 35, 37, 38, 41, 42, 44, 45, 47, and 48). Microdontia of the bilateral maxillary central incisors and right mandibular canine and taurodontism of the bilateral maxillary first molars were also observed. The developmental period of these affected teeth agreed with the period of chemotherapy and PBSCT. © 2014 Asian AOMS, ASOMP, JSOP, JSOMS, JSOM, and JAMI. Published by Elsevier Ltd. All rights reserved.夽
1. Introduction In recent years, advances in treatments of childhood leukemia have been remarkable. The number of long-term survivors has increased as a result of improvement of treatment outcomes, and increasing interest has been focused on the long-term survivors of childhood cancer and their quality of life. With regard to dental and maxillofacial development, antioncologic treatments including combination chemotherapy, total body irradiation (TBI), and hematopoietic stem cell transplantation (HSCT) have significant potential for adverse impacts [1]. The severity of long-term disturbances in dental and craniofacial development is dependent on the age when the patient underwent diagnosis and treatment [2]. Survivors of childhood leukemia often have dental abnormalities that may affect their quality of life. Dental abnormalities including root stunting, microdontia, hypodontia,
夽 Asian AOMS: Asian Association of Oral and Maxillofacial Surgeons; ASOMP: Asian Society of Oral and Maxillofacial Pathology; JSOP: Japanese Society of Oral Pathology; JSOMS: Japanese Society of Oral and Maxillofacial Surgeons; JSOM: Japanese Society of Oral Medicine; JAMI: Japanese Academy of Maxillofacial Implants. ∗ Corresponding author at: Department of Oral and Maxillofacial Surgery, Aizawa Hospital, 2-5-1 Honjo, Matsumoto, Nagano 390-8510, Japan. Tel.: +81 263 33 8600; fax: +81 263 32 6763. E-mail address: [email protected] (H. Tanaka).
taurodontia, over-retention of primary dentition, etc. [3,4] have been reported. However, few studies have reported deficiency of a large number of permanent teeth. In this paper, we report a case of absence of 25 permanent teeth. The patient had a history of allogeneic peripheral blood stem cell transplantation and chemotherapy for acute monocytic leukemia (AML) in infancy. 2. Case report An 11-year 4-month-old boy came to our department for further evaluation of missing (delayed eruption) of a large number of permanent teeth. His medical history revealed that he was a survivor of hematological malignancy. He had been diagnosed as acute monocytic leukemia (AML-M5b) right after birth. He subsequently underwent high-dose multiagent induction chemotherapy [5] (ANLL91 protocol, Table 1) during the period between 7 days and 8 months of age. At 9 months after birth, he received peripheral blood stem cell transplantation (PBSCT) from his sister after pretreatment with the alkylating agents busulfan (BUS) and melphalan (L-PAM). Total body irradiation (TBI) was not applied in the preparative regimen. The clinical course after PBSCT was not eventful and he had been followed-up by his pediatrician. Dental history revealed that he visited his dentist at the ages of 7 years 5 months and 9 years 7 months complaining of tooth
http://dx.doi.org/10.1016/j.ajoms.2014.09.001 2212-5558/© 2014 Asian AOMS, ASOMP, JSOP, JSOMS, JSOM, and JAMI. Published by Elsevier Ltd. All rights reserved.夽
Please cite this article in press as: Tanaka H, et al. Agenesis of a large number of permanent teeth after treatment of neonatal leukemia. J Oral Maxillofac Surg Med Pathol (2014), http://dx.doi.org/10.1016/j.ajoms.2014.09.001
G Model
ARTICLE IN PRESS
JOMSMP-321; No. of Pages 4
H. Tanaka et al. / Journal of Oral and Maxillofacial Surgery, Medicine, and Pathology xxx (2014) xxx–xxx
2
Table 1 Treatment scheme of the ANLL91 regimen for infant AML. Induction
d
1
2
3
4
5
Etoposide AraC Mitoxantrone
150 mg/m2 200 mg/m2 5 mg/m2
↓
↓
↓
↓
↓
6
7
8
9
10
11
12
|
|
|
|
|
Intensification
d
1
2
3
4
5
Courses 1 and 2 HD-AraC Etoposide Mitoxantrone
3 g/m2 × 2 100 mg/m2 10 mg/m2
↓ |
↓
↓
↓
↓
Courses 3 and 4 AraC Etoposide THP-ADR
200 mg/m2 100 mg/m2 45 mg/m2
. . . ↓
. . . ↓
. . . ↓
. . . ↓
. . . ↓
Courses 5 and 6 HD-AraC Etoposide Aclarubicin
3 g/m2 100 mg/m2 30 mg/m2
↓
↓
↓
↓
↓
Courses 7 and 8 HD-AraC Etoposide VCR
3 g/m2 200 mg/m2 1.5 mg/m2
↓ ↑
↓
↓
↓
↓
The use of each drug was as follows. Induction: etoposide, 2 h drip i.v. (intravenous) for 5 days; cytarabine (AraC), 2 h drip i.v. for 7 days; mitoxantrone, i.v. for 5 days. Courses 1 and 2: HD-AraC, 3 h drip i.v. twice a day for 3 days; etoposide, 2 h drip i.v. for 5 days; mitoxantrone, i.v. Courses 3 and 4: AraC, 20 h drip i.v. for 5 days; etoposide, 2 h drip i.v. for 5 days; THP-ADR, 2 h drip i.v. Courses 5 and 6: HD-AraC, 3 h drip i.v. for 5 days; etoposide, 2 h drip i.v. for 5 days; aclarubicin, i.v. for 3 days. Courses 7 and 8: HD-AraC, 3 h drip i.v. for 5 days; etoposide, 2 h drip i.v. for 5 days; VCR, i.v. As a CNS prophylaxis, intrathecal methotrexate, Ara-C, and hydrocortisone were used in induction and each course of intensification therapy.
Fig. 1. Dental radiographs at patient’s family dental clinic. (A) Maxillary central incisors at the age of 7 years 5 months. (B) Maxillary central incisors at the age of 9 years 7 months. (C) Lower right canine at the age of 10 years 6 months.
abnormal contour (microdontia) of 21 and 11, respectively. On each occasion he underwent tooth restorations with resin filling (Fig. 1 A and B). At the age of 10 years 6 months, he again consulted the dentist complaining of delayed tooth eruption after the loss of a deciduous tooth (83). The dental radiograph revealed abnormal shape of the successor (Fig. 1C). The absence of multiple permanent teeth was suspected and the patient was referred to us for further examination. At the first clinical examination, his height was 134 cm and his weight was 26 kg, which was below average size. An X-ray of his carpal bone at the age of 7 years and 8 months had suggested that his skeletal age was the same as a 6 year-old. (The Japanese standard bone age TW2 method was investigated using the Honetaro Ver5.0 software package.) Intra-oral examination showed that oral hygiene was fair and the gingivae were healthy (Fig. 2). There were 23 teeth (6 permanent teeth and 17 deciduous teeth), as listed below: 16 55 54 53 52 11 21 62 63 64 65 26 46 85 84 82 81 71 72 73 74 75 36 (FDI two-digit system)
Fig. 2. Intra-oral views at the first medical examination.
Please cite this article in press as: Tanaka H, et al. Agenesis of a large number of permanent teeth after treatment of neonatal leukemia. J Oral Maxillofac Surg Med Pathol (2014), http://dx.doi.org/10.1016/j.ajoms.2014.09.001
G Model JOMSMP-321; No. of Pages 4
ARTICLE IN PRESS H. Tanaka et al. / Journal of Oral and Maxillofacial Surgery, Medicine, and Pathology xxx (2014) xxx–xxx
Fig. 3. Panoramic radiograph at the first visit (age 11 years) shows multiple missing dental germs of permanent teeth.
The bilateral upper central incisors (11 and 21) were microdontic and had been restored with composite resin fillings. Occlusion was open-bite and all the erupted deciduous teeth had slight mobility. A panoramic radiograph taken at his first visit is shown in Fig. 3. This revealed absence of 25 permanent teeth (12, 13, 14, 15, 17, 18, 22, 23, 24, 25, 27, 28, 31, 32, 33, 34, 35, 37, 38, 41, 42, 44, 45, 47, and 48). Tooth germs were not observed for all second and third molars. Taurodontism of the bilateral first molars (16 and 26) and enamel hypoplasia of erupted incisors and a canine (11, 21, and 43) were evident. The roots of the deciduous teeth were relatively short. After the examination, the patient underwent intensive preventive measures and a regular 6 monthly follow-up examinations. Dental rehabilitation will be performed after his body matures. 3. Discussion Stem cell transplantation (SCT) has an established role in the treatment of leukemia in children. High-dose chemotherapy (HDC) and total body irradiation (TBI) used in the preparative regimens for SCT give rise to multiple, acute, and long-term adverse effects, which also involve the teeth. Morphogenesis and calcification of teeth form a sequence of events that begins in utero and continues for 14–15 years [6]. Therefore, HDC administered in childhood
3
causes permanent dental disturbance, including tooth agenesis, microdontia, and disturbed root development [1,7,8]. The scale of tooth abnormalities runs from mild mineralization of the enamel to arrested root development, microdontia and aplasia of the permanent teeth, depending on the patient’s age at cancer therapy and the kinds and doses of cytotoxic agents. The same treatment may lead to dental agenesis or microdontia at an early stage of tooth development but, later on, disturb root development. Agenesis is the most severe developmental dental disturbance. Agenesis of teeth is also observed in the healthy population, and its prevalence reportedly ranges from 2.8% [9] to 10% [10]. Multiagent chemotherapy and radiotherapy are known to cause tooth agenesis when used in pediatric cancer patients. The percentage of cancer patients with missing teeth is reported to range from 5 to 28% after conventional chemotherapy [1,4]. There have been few studies on SCT recipients. It was reported that the preparative regimens for SCT caused tooth agenesis at frequencies ranging from 31 to 80% [1,4,8]. HDC tends to cause more frequent and more severe dental abnormalities compared with conventional chemotherapy. The number of missing teeth in SCT patients reportedly ranged from 1 to 12 teeth [4]. In our case, a total of 21 permanent teeth, excluding four third molars, were missing. To the best of our knowledge, this is the highest reported number of affected teeth. Recipient age at the time of SCT was reported to have a negative correlation with the number of missing teeth [4]. If this is correct, the neonatal HDC in our patient may be a reason for the agenesis of such a large number of permanent teeth. Some researchers found, from animal studies, that antineoplastic drugs have harmful and irreversible effects on odontogenesis. Chemotherapy agents have no selective toxicity to tumor cells and, thus also affect normal cells at proliferation stages [11]. The mechanisms of defects in dental developmental are not fully understood. It is speculated that pediatric anticancer therapy may affect tooth development either by a direct toxicity toward the developing cells, or by interfering with the delicate signaling network between ectoderm and mesenchyme or within one tissue layer. If HDC results in dental agenesis, it must either destroy the cells programmed to form a tooth, or affect the complicated signaling systems between the tissues in a tooth bud and prevent calcification. Young age at the time of SCT predisposes a tooth germ to permanent destruction prior to its mineralization due to the chemotherapy or chemoradiation therapy. It was reported that a high prevalence of patients with tooth agenesis and high numbers
Table 2 Relationship between treatment schedule for leukemia and developmental stage of the dental germ of permanent teeth in this patient.
Term of the chemotherapy
Please cite this article in press as: Tanaka H, et al. Agenesis of a large number of permanent teeth after treatment of neonatal leukemia. J Oral Maxillofac Surg Med Pathol (2014), http://dx.doi.org/10.1016/j.ajoms.2014.09.001
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ARTICLE IN PRESS H. Tanaka et al. / Journal of Oral and Maxillofacial Surgery, Medicine, and Pathology xxx (2014) xxx–xxx
of missing teeth per patient was observed among younger patients [4]. The permanent teeth start to form between the 20th week of prenatal and the 10th month of postnatal development. Formation of the permanent tooth germs completes during the period from birth to approximately 3 years of age. Depending on the dental age and the duration of anticancer chemotherapy, the adverse effects may be directed differentially on different teeth. Table 2 illustrates the periods of formation of tooth germ and calcification as compared with the periods of chemotherapy and PBSCT in this patient. Chemotherapy was started shortly after birth (7 days) and continued to 8 months after birth before PBSCT. Twenty-five permanent teeth except all first molars, two upper first incisors, and a lower canine were missing. The bilateral upper first molars showed taurodontism, and enamel hypoplasia of the erupted incisors and the extant canine (11, 21, and 43) were observed. The roots of the deciduous teeth were relatively short. These findings suggested that tooth developments that started after birth were affected by the HDC, i.e., the anticancer agents caused toxic death of odontogenic cells, resulting in agenesis of numerous teeth that were programmed to form after birth. In recent years, remarkable advances have been made in treatments for childhood leukemia. The number of long-term survivors has increased due to improved treatment outcomes. HDC and SCT have resulted in improved long-term survival rates of these patients, who later experience various adverse-events of the treatment including disturbed tooth development. Proper dental care and rehabilitation, from the beginning of the treatment until adulthood, play important roles in achieving a good quality of life for this increasingly larger group of children. Intense and lifelong dental care is necessary for pediatric SCT survivors.
Conflicts of interest No conflicts of interest declared. References [1] Näsman M, Forsberg C-M, Dahllöf G. Long-term dental development in children after treatment for malignant disease. Eur J Orthod 1997;19:151–9. [2] Vesterbacka M, Ringdén O, Remberger M, Huggare J, Dahllöf G. Disturbances in dental development and craniofacial growth in children treated with hematopoietic stem cell transplantation. Orthod Craniofac Res 2012;15: 21–9. [3] Hölttä P, Hovi L, Saarinen-Pihkala UM, Peltola J, Alaluusua S. Disturbed root development of permanent teeth after pediatric stem cell transplantation. Dental root development after SCT. Cancer 2005;103:1484–93. [4] Hölttä P, Alaluusua S, Saarinen-Pihkala UM, Peltola J, Hovi L. Agenesis and microdontia of permanent teeth as late adverse effects after stem cell transplantation in young children. Cancer 2005;103(January (1)):181–90. [5] Kawasaki H, Isoyama K, Eguchi M, Hibi S, Kinukawa N, Kosaka Y, et al. Superior outcome of infant acute myeloid leukemia with intensive chemotherapy: results of the Japan Infant Leukemia Study Group. Blood 2001;98:3589–94. [6] Schour I, Massler M. Studies in tooth development: the growth pattern of human teeth. Parts I and II. J Am Dent Assoc 1940;27:1778–93, 1918–1931. [7] Dahllöf G, Barr M, Bolme P, Modéer T, Lönnqvist B, Ringdén O, et al. Disturbances in dental development after total body irradiation in bone marrow transplant recipients. Oral Surg Oral Med Oral Pathol 1988;65:41–4. [8] Hölttä P, Alaluusua S, Saarinen-Pihkala UM, Wolf J, Nyström M, Hovi L. Long-term adverse effects on dentition in children with poor-risk neuroblastoma treated with high-dose chemotherapy and autologous stem cell transplantation with or without total body irradiation. Bone Marrow Transplant 2002;29:121–7. [9] Byrd ED. Incidence of supernumerary and congenitally missing teeth. J Dent Child 1943;10:84–6. [10] Hunstadbraten K. Hypodonti i det permanente tannsett. Nor Tannlaegeforen Tid 1964;74:64–9. [11] Maguire A, Welbury RR. Long-term effects of antineoplastic chemotherapy and radiotherapy on dental development. Dent Update 1996;23:188–94.
Please cite this article in press as: Tanaka H, et al. Agenesis of a large number of permanent teeth after treatment of neonatal leukemia. J Oral Maxillofac Surg Med Pathol (2014), http://dx.doi.org/10.1016/j.ajoms.2014.09.001
ARTICLE IN PRESS Journal of Oral and Maxillofacial Surgery, Medicine, and Pathology xxx (2014) xxx–xxx
Contents lists available at ScienceDirect
Journal of Oral and Maxillofacial Surgery, Medicine, and Pathology journal homepage: www.elsevier.com/locate/jomsmp
Case Report
Agenesis of a large number of permanent teeth after treatment of neonatal leukemia Hirokazu Tanaka a,b,∗ , Hiroshi Kurita b , Hitoshi Aizawa b , Takahiro Kamata b a b
Department of Dentistry and Oral Surgery, Aizawa Hospital, Matsumoto, Japan Department of Dentistry and Oral Surgery, Shinshu University School of Medicine, Matsumoto, Japan
a r t i c l e
i n f o
Article history: Received 15 January 2014 Received in revised form 11 July 2014 Accepted 2 September 2014 Available online xxx Keywords: Dental development Stem cell transplantation Tooth agenesis Missing teeth Leukemia
a b s t r a c t The intensive treatment of hematological malignancy can cause dental abnormalities when applied during the period of dental and craniofacial development. Here, we report a case of absence of numerous teeth after treatment of neonatal leukemia. An 11-year-old boy was referred to our hospital complaining of delayed (no) eruption of many teeth. The patient had a history of neonatal acute monocytic leukemia. He had undergone systemic chemotherapy and allogeneic peripheral blood stem cell transplantation (PBSCT) during the period between 7 days and 9 months after his birth. Intraoral examination and a panoramic radiograph revealed absence of 25 of the permanent teeth (12, 13, 14, 15, 17, 18, 22, 23, 24, 25, 27, 28, 31, 32, 33, 34, 35, 37, 38, 41, 42, 44, 45, 47, and 48). Microdontia of the bilateral maxillary central incisors and right mandibular canine and taurodontism of the bilateral maxillary first molars were also observed. The developmental period of these affected teeth agreed with the period of chemotherapy and PBSCT. © 2014 Asian AOMS, ASOMP, JSOP, JSOMS, JSOM, and JAMI. Published by Elsevier Ltd. All rights reserved.夽
1. Introduction In recent years, advances in treatments of childhood leukemia have been remarkable. The number of long-term survivors has increased as a result of improvement of treatment outcomes, and increasing interest has been focused on the long-term survivors of childhood cancer and their quality of life. With regard to dental and maxillofacial development, antioncologic treatments including combination chemotherapy, total body irradiation (TBI), and hematopoietic stem cell transplantation (HSCT) have significant potential for adverse impacts [1]. The severity of long-term disturbances in dental and craniofacial development is dependent on the age when the patient underwent diagnosis and treatment [2]. Survivors of childhood leukemia often have dental abnormalities that may affect their quality of life. Dental abnormalities including root stunting, microdontia, hypodontia,
夽 Asian AOMS: Asian Association of Oral and Maxillofacial Surgeons; ASOMP: Asian Society of Oral and Maxillofacial Pathology; JSOP: Japanese Society of Oral Pathology; JSOMS: Japanese Society of Oral and Maxillofacial Surgeons; JSOM: Japanese Society of Oral Medicine; JAMI: Japanese Academy of Maxillofacial Implants. ∗ Corresponding author at: Department of Oral and Maxillofacial Surgery, Aizawa Hospital, 2-5-1 Honjo, Matsumoto, Nagano 390-8510, Japan. Tel.: +81 263 33 8600; fax: +81 263 32 6763. E-mail address: [email protected] (H. Tanaka).
taurodontia, over-retention of primary dentition, etc. [3,4] have been reported. However, few studies have reported deficiency of a large number of permanent teeth. In this paper, we report a case of absence of 25 permanent teeth. The patient had a history of allogeneic peripheral blood stem cell transplantation and chemotherapy for acute monocytic leukemia (AML) in infancy. 2. Case report An 11-year 4-month-old boy came to our department for further evaluation of missing (delayed eruption) of a large number of permanent teeth. His medical history revealed that he was a survivor of hematological malignancy. He had been diagnosed as acute monocytic leukemia (AML-M5b) right after birth. He subsequently underwent high-dose multiagent induction chemotherapy [5] (ANLL91 protocol, Table 1) during the period between 7 days and 8 months of age. At 9 months after birth, he received peripheral blood stem cell transplantation (PBSCT) from his sister after pretreatment with the alkylating agents busulfan (BUS) and melphalan (L-PAM). Total body irradiation (TBI) was not applied in the preparative regimen. The clinical course after PBSCT was not eventful and he had been followed-up by his pediatrician. Dental history revealed that he visited his dentist at the ages of 7 years 5 months and 9 years 7 months complaining of tooth
http://dx.doi.org/10.1016/j.ajoms.2014.09.001 2212-5558/© 2014 Asian AOMS, ASOMP, JSOP, JSOMS, JSOM, and JAMI. Published by Elsevier Ltd. All rights reserved.夽
Please cite this article in press as: Tanaka H, et al. Agenesis of a large number of permanent teeth after treatment of neonatal leukemia. J Oral Maxillofac Surg Med Pathol (2014), http://dx.doi.org/10.1016/j.ajoms.2014.09.001
G Model
ARTICLE IN PRESS
JOMSMP-321; No. of Pages 4
H. Tanaka et al. / Journal of Oral and Maxillofacial Surgery, Medicine, and Pathology xxx (2014) xxx–xxx
2
Table 1 Treatment scheme of the ANLL91 regimen for infant AML. Induction
d
1
2
3
4
5
Etoposide AraC Mitoxantrone
150 mg/m2 200 mg/m2 5 mg/m2
↓
↓
↓
↓
↓
6
7
8
9
10
11
12
|
|
|
|
|
Intensification
d
1
2
3
4
5
Courses 1 and 2 HD-AraC Etoposide Mitoxantrone
3 g/m2 × 2 100 mg/m2 10 mg/m2
↓ |
↓
↓
↓
↓
Courses 3 and 4 AraC Etoposide THP-ADR
200 mg/m2 100 mg/m2 45 mg/m2
. . . ↓
. . . ↓
. . . ↓
. . . ↓
. . . ↓
Courses 5 and 6 HD-AraC Etoposide Aclarubicin
3 g/m2 100 mg/m2 30 mg/m2
↓
↓
↓
↓
↓
Courses 7 and 8 HD-AraC Etoposide VCR
3 g/m2 200 mg/m2 1.5 mg/m2
↓ ↑
↓
↓
↓
↓
The use of each drug was as follows. Induction: etoposide, 2 h drip i.v. (intravenous) for 5 days; cytarabine (AraC), 2 h drip i.v. for 7 days; mitoxantrone, i.v. for 5 days. Courses 1 and 2: HD-AraC, 3 h drip i.v. twice a day for 3 days; etoposide, 2 h drip i.v. for 5 days; mitoxantrone, i.v. Courses 3 and 4: AraC, 20 h drip i.v. for 5 days; etoposide, 2 h drip i.v. for 5 days; THP-ADR, 2 h drip i.v. Courses 5 and 6: HD-AraC, 3 h drip i.v. for 5 days; etoposide, 2 h drip i.v. for 5 days; aclarubicin, i.v. for 3 days. Courses 7 and 8: HD-AraC, 3 h drip i.v. for 5 days; etoposide, 2 h drip i.v. for 5 days; VCR, i.v. As a CNS prophylaxis, intrathecal methotrexate, Ara-C, and hydrocortisone were used in induction and each course of intensification therapy.
Fig. 1. Dental radiographs at patient’s family dental clinic. (A) Maxillary central incisors at the age of 7 years 5 months. (B) Maxillary central incisors at the age of 9 years 7 months. (C) Lower right canine at the age of 10 years 6 months.
abnormal contour (microdontia) of 21 and 11, respectively. On each occasion he underwent tooth restorations with resin filling (Fig. 1 A and B). At the age of 10 years 6 months, he again consulted the dentist complaining of delayed tooth eruption after the loss of a deciduous tooth (83). The dental radiograph revealed abnormal shape of the successor (Fig. 1C). The absence of multiple permanent teeth was suspected and the patient was referred to us for further examination. At the first clinical examination, his height was 134 cm and his weight was 26 kg, which was below average size. An X-ray of his carpal bone at the age of 7 years and 8 months had suggested that his skeletal age was the same as a 6 year-old. (The Japanese standard bone age TW2 method was investigated using the Honetaro Ver5.0 software package.) Intra-oral examination showed that oral hygiene was fair and the gingivae were healthy (Fig. 2). There were 23 teeth (6 permanent teeth and 17 deciduous teeth), as listed below: 16 55 54 53 52 11 21 62 63 64 65 26 46 85 84 82 81 71 72 73 74 75 36 (FDI two-digit system)
Fig. 2. Intra-oral views at the first medical examination.
Please cite this article in press as: Tanaka H, et al. Agenesis of a large number of permanent teeth after treatment of neonatal leukemia. J Oral Maxillofac Surg Med Pathol (2014), http://dx.doi.org/10.1016/j.ajoms.2014.09.001
G Model JOMSMP-321; No. of Pages 4
ARTICLE IN PRESS H. Tanaka et al. / Journal of Oral and Maxillofacial Surgery, Medicine, and Pathology xxx (2014) xxx–xxx
Fig. 3. Panoramic radiograph at the first visit (age 11 years) shows multiple missing dental germs of permanent teeth.
The bilateral upper central incisors (11 and 21) were microdontic and had been restored with composite resin fillings. Occlusion was open-bite and all the erupted deciduous teeth had slight mobility. A panoramic radiograph taken at his first visit is shown in Fig. 3. This revealed absence of 25 permanent teeth (12, 13, 14, 15, 17, 18, 22, 23, 24, 25, 27, 28, 31, 32, 33, 34, 35, 37, 38, 41, 42, 44, 45, 47, and 48). Tooth germs were not observed for all second and third molars. Taurodontism of the bilateral first molars (16 and 26) and enamel hypoplasia of erupted incisors and a canine (11, 21, and 43) were evident. The roots of the deciduous teeth were relatively short. After the examination, the patient underwent intensive preventive measures and a regular 6 monthly follow-up examinations. Dental rehabilitation will be performed after his body matures. 3. Discussion Stem cell transplantation (SCT) has an established role in the treatment of leukemia in children. High-dose chemotherapy (HDC) and total body irradiation (TBI) used in the preparative regimens for SCT give rise to multiple, acute, and long-term adverse effects, which also involve the teeth. Morphogenesis and calcification of teeth form a sequence of events that begins in utero and continues for 14–15 years [6]. Therefore, HDC administered in childhood
3
causes permanent dental disturbance, including tooth agenesis, microdontia, and disturbed root development [1,7,8]. The scale of tooth abnormalities runs from mild mineralization of the enamel to arrested root development, microdontia and aplasia of the permanent teeth, depending on the patient’s age at cancer therapy and the kinds and doses of cytotoxic agents. The same treatment may lead to dental agenesis or microdontia at an early stage of tooth development but, later on, disturb root development. Agenesis is the most severe developmental dental disturbance. Agenesis of teeth is also observed in the healthy population, and its prevalence reportedly ranges from 2.8% [9] to 10% [10]. Multiagent chemotherapy and radiotherapy are known to cause tooth agenesis when used in pediatric cancer patients. The percentage of cancer patients with missing teeth is reported to range from 5 to 28% after conventional chemotherapy [1,4]. There have been few studies on SCT recipients. It was reported that the preparative regimens for SCT caused tooth agenesis at frequencies ranging from 31 to 80% [1,4,8]. HDC tends to cause more frequent and more severe dental abnormalities compared with conventional chemotherapy. The number of missing teeth in SCT patients reportedly ranged from 1 to 12 teeth [4]. In our case, a total of 21 permanent teeth, excluding four third molars, were missing. To the best of our knowledge, this is the highest reported number of affected teeth. Recipient age at the time of SCT was reported to have a negative correlation with the number of missing teeth [4]. If this is correct, the neonatal HDC in our patient may be a reason for the agenesis of such a large number of permanent teeth. Some researchers found, from animal studies, that antineoplastic drugs have harmful and irreversible effects on odontogenesis. Chemotherapy agents have no selective toxicity to tumor cells and, thus also affect normal cells at proliferation stages [11]. The mechanisms of defects in dental developmental are not fully understood. It is speculated that pediatric anticancer therapy may affect tooth development either by a direct toxicity toward the developing cells, or by interfering with the delicate signaling network between ectoderm and mesenchyme or within one tissue layer. If HDC results in dental agenesis, it must either destroy the cells programmed to form a tooth, or affect the complicated signaling systems between the tissues in a tooth bud and prevent calcification. Young age at the time of SCT predisposes a tooth germ to permanent destruction prior to its mineralization due to the chemotherapy or chemoradiation therapy. It was reported that a high prevalence of patients with tooth agenesis and high numbers
Table 2 Relationship between treatment schedule for leukemia and developmental stage of the dental germ of permanent teeth in this patient.
Term of the chemotherapy
Please cite this article in press as: Tanaka H, et al. Agenesis of a large number of permanent teeth after treatment of neonatal leukemia. J Oral Maxillofac Surg Med Pathol (2014), http://dx.doi.org/10.1016/j.ajoms.2014.09.001
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ARTICLE IN PRESS H. Tanaka et al. / Journal of Oral and Maxillofacial Surgery, Medicine, and Pathology xxx (2014) xxx–xxx
of missing teeth per patient was observed among younger patients [4]. The permanent teeth start to form between the 20th week of prenatal and the 10th month of postnatal development. Formation of the permanent tooth germs completes during the period from birth to approximately 3 years of age. Depending on the dental age and the duration of anticancer chemotherapy, the adverse effects may be directed differentially on different teeth. Table 2 illustrates the periods of formation of tooth germ and calcification as compared with the periods of chemotherapy and PBSCT in this patient. Chemotherapy was started shortly after birth (7 days) and continued to 8 months after birth before PBSCT. Twenty-five permanent teeth except all first molars, two upper first incisors, and a lower canine were missing. The bilateral upper first molars showed taurodontism, and enamel hypoplasia of the erupted incisors and the extant canine (11, 21, and 43) were observed. The roots of the deciduous teeth were relatively short. These findings suggested that tooth developments that started after birth were affected by the HDC, i.e., the anticancer agents caused toxic death of odontogenic cells, resulting in agenesis of numerous teeth that were programmed to form after birth. In recent years, remarkable advances have been made in treatments for childhood leukemia. The number of long-term survivors has increased due to improved treatment outcomes. HDC and SCT have resulted in improved long-term survival rates of these patients, who later experience various adverse-events of the treatment including disturbed tooth development. Proper dental care and rehabilitation, from the beginning of the treatment until adulthood, play important roles in achieving a good quality of life for this increasingly larger group of children. Intense and lifelong dental care is necessary for pediatric SCT survivors.
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Please cite this article in press as: Tanaka H, et al. Agenesis of a large number of permanent teeth after treatment of neonatal leukemia. J Oral Maxillofac Surg Med Pathol (2014), http://dx.doi.org/10.1016/j.ajoms.2014.09.001