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Familial hypophosphatemic vitamin D-resistant rickets: Dental findings and histologic study of teeth
Familial hypophosphatemic vitamin D-resistant rickets: Dental findings and histologic study of teeth Takafumi Murayama, DDS, PhD,a Reiko Iwatsubo, DDS, PhD,b Shigehisa Akiyama, DDS,c Atsuo Amano, DDS, PhD,d and Ichijiro Morisaki, DDS, PhD,e Osaka, Japan KYOTO FIRST RED CROSS HOSPITAL AND OSAKA UNIVERSITY
A case of familial hypophosphatemic vitamin D-resistant rickets or X-linked hypophosphatemia (XLH) accompanied by specific systemic and dental findings is reported. A 15-year-old boy with XLH visited our facility complaining of a toothache in the left lower canine region. Two other family members of the patient, his younger sister and their mother, also had XLH, whereas the other 2 members, his younger brother and father, are healthy. Those with XLH show systemic signs of the disease, such as growth retardation, limb deformity, and spinal curvature disorders; however, these symptoms are more severe in the patient than in the others. The patient had multiple periodontal abscesses, but no evidence of dental caries, trauma, or periodontal disease on the corresponding teeth at the time of his oral examination. A radiographic examination showed root dysplasia and enlarged pulp chambers. A histologic examination of an extracted third molar showed marked globular dentin and an increased predentin width. The abscess was thought to be caused by pulpal infection, which came from bacterial invasion through enamel cracks and dentinal microcleavage of the teeth. The treatments provided in this case are discussed. (Oral Surg Oral Med Oral
Pathol Oral Radiol Endod 2000;90:310-6)
Hypophosphatemic vitamin D-resistant rickets or Xlinked hypophosphatemia (XLH) is a hereditary disease manifesting marked hypophosphatemia caused by renal tubular loss of phosphate into urine and an associated decrease in the calcium and potassium ion product (Ca × P).1 The pathophysiology of the disease is thought to be impaired phosphate transport, especially decreased phosphate resorption in the renal proximal tubule, as well as in the intestine. In most patients, XLH appears in a familial line of X-linked, dominant inheritance with the same prevalence in both sexes; however, it may also occur sporadically. In general, more severe symptoms are noted in males.2-4 Sporadic cases are often initially detected by limb deformity or gait abnormality. The systemic findings of XLH include bowed legs because of a body load showing immature skeletal bone calcification, spinal curvature deformities, short stature, and beading of the ribs called rachitic rosary. Oral findings of XLH have aChief, Division of Oral and Maxillofacial Surgery, Kyoto First Red Cross Hospital. bHonorary chief, Division of Oral and Maxillofacial Surgery, Kyoto First Red Cross Hospital. cSenior Instructor, Division of Special Care Dentistry, Osaka University Faculty of Dentistry. dAssistant Professor, Division of Special Care Dentistry, Osaka University Faculty of Dentistry. eAssociate Professor and Chief, Division of Special Care Dentistry, Osaka University, Faculty of Dentistry. Received for publication Dec 22, 1999; returned for revision Feb 8, 2000; accepted for publication Mar 17, 2000. Copyright © 2000 by Mosby, Inc. 1079-2104/2000/$12.00 + 0 7/13/107522 doi:10.1067/moe.2000.107522
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Fig 1. Family line. Open box, male; open circle, female; solid box or circle, person with XLH. Arrow indicates patient.
been characterized by poorly mineralized dentin dysplasia in both primary and permanent teeth.5-7 Spontaneous periapical abscess formation is also often observed in patients with XLH without dental caries or traumatic injury.8,9 Because the teeth of patients with XLH are often associated with high pulp horns, large pulp chambers, and dentinal clefts, it is believed that the abscesses are caused by pulpal infection that was caused by bacterial invasion through enamel cracks and dentinal microcleavage of the teeth. We report the dental findings of familial XLH in a 15-year-old Japanese boy, as well as the histologic findings of his extracted mandibular right third molar. CASE REPORT A Japanese boy who was 15 years, 2 months old with XLH was referred to the Department of Oral and Maxillofacial
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Fig 2. Photo of patient’s younger sister (at 12 years).
Surgery at Kyoto First Red Cross Hospital with a complaint of spontaneous pain in the left mandibular canine. Family history His mother and younger sister also had XLH; however, neither paternal nor maternal relatives showed any signs of XLH (Fig 1). The mother had also experienced toothaches without any macroscopic decay or associated periodontal lesions. A 12-year-old sister also had bowed legs, the characteristic sign of rickets (Fig 2). Past history The patient was the first offspring of the parents after a full term gestation and measured 3990 g in weight and 50.5 cm in length at birth. Because he had not yet walked by the age of 1 year, 6 months, he was referred to the pediatric clinic of a medical school, where a diagnosis of skeletal hypoplasia was made. At the age of 2 years, 8 months, skeletal abnormalities and bowed legs were noted at the public health examination for infants. The patient was admitted to the same pediatric clinic as before for a thorough examination. Rachitic changes at epiphyses of the radius, ulna, tibia, and fibula were showed by radiographic examination (Fig 3). Laboratory examinations showed an elevated alkaline phosphate level at 367 mU/mL (normal range, 30 - 85 mU/mL) and hypophosphatemia at 2.7 to 2.9 mg/dL (normal range in children, 4.5 - 6.5 mg/dL). Measurement of urinary phosphate excretion also showed an abnormal phosphate reabsorption
Fig 3. Radiograph of patient’s lower limbs (at 2 years and 9 months). Definite bowlegs can be observed.
rate of 66.7% (normal range, 84.7% - 97.9%). From these clinical, radiographic, and laboratory findings, the patient was diagnosed with hypophosphatemic rickets and was administered neutral phosphate. The patient received orthopedic treatment to correct his bowed legs for 55 months, from the age of 3 years, 2 months to 7 years, 9 months. The rachitic symptoms were markedly improved by initiation of active vitamin D and neutral phosphate administration at the age of 5 years, 0 months. Although the patient refused to take these drugs for a short time in his adolescence, his systemic condition had been generally well controlled. General findinqs At age 15, the patient’s height and weight were 159 cm and 43.4 kg, which were –1.45 SD and –1.52 SD from the height and weight averages, respectively, for 15-year-old Japanese boys, as reported in the 1989 School Health Survey by the Ministry of Welfare. Except for a shortening of the lower limbs, no other apparent abnormalities were noted in his body habitus (Fig 4). Oral findings An abscess was found at the labial periapical region of the
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Fig 5. Dental radiograph of left mandibular canine. Pulp cavity was large, but showed no dental caries. Root dysplasia and absence of lamina dura were observed in left mandibular central incisor and left mandibular first premolar.
Fig 4. Photo of patient (at 19 years).
left mandibular canine, along with a negative response to pulp vitality testing; however, no clinically detectable changes such as caries, tooth fractures, or periodontal pockets that could induce pulp necrosis were found. Radiographic findings Short roots and large pulp chambers were observed radiographically in all premolars, second molars, and mandibular central incisors (Figs 5 and 6); however, the root apices appeared to be closed, even in the hypoplastic teeth (Fig 5). The right mandibular first molar had been treated endodontically before taking the panoramic radiograph. Periapical radiolucencies were found on the mandibular first molars and canines. Treatment An incision and drainage was performed to relieve pain and pus retention from the periodontal abscess of the left mandibular canine. Initially, symptomatic treatment only was provided for the patient because the exact cause of the abscess was not evident. One month later, a fistula developed on the buccal gingiva of the right mandibular first molar. Four months later, a gingival abscess was found in the buccal periapical region of the left mandibular first molar. Neither dental nor periodontal abnormalities were found clinically with these teeth. The molars were treated endodontically (Fig 7). A large periapical radiolucency was found at the left mandibular canine, and both endodontic treatment and apicoectomy were performed. Pulp necrosis developed subse-
quently in the right mandibular and the left maxillary canine 1 year later and in the right mandibular central incisor another 2 years later. All these teeth were treated endodontically and restored with composite resin or cast metal (Fig 7). Histologic examination Because the right mandibular third molar had manifested suppurative pericoronitis and there was no available space for its eruption, the tooth was extracted at age 18. The tooth was bisected and examined histologically. One half was decalcified and stained with hematoxylin and eosin. The other half was ground into thin sections for microradiographic examination. Marked globular dentin and a wide layer of predentin were observed on both the decalcified and ground sections (Figs 8 and 9). An extracted deciduous mandibular canine from the patient’s younger sister was also processed for histologic examination. Findings similar to those found of her brother’s permanent molar were observed in the canine (Fig 10).
DISCUSSION Vitamin D-deficient rickets has become less prevalent throughout most of the world because of marked improvements in living environments and nutrition. However, endogenous rickets caused by abnormalities in the vitamin D receptive system or in phosphate and calcium metabolism, such as XLH, have been reported.1 XLH, first reported by Albright et al,l0 is a syndrome showing marked hypophosphatemia, short stature, and rickets. In general, the main abnormality is considered to be a congenital impairment of phosphate transport and hypophosphatemia, resulting from decreased phos-
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Fig 6. Panoramic radiograph (after endodontic therapy of right mandibular first molar at 15 years). Root dysplasia (short root tooth) was observed bilaterally in maxillary and mandibular first premolars, second premolars, second molars, and bilateral mandibular central incisors, but degree was slight in right mandibular first premolar. Trabecular structure was abnormal.
Fig 7. Panoramic radiograph (at 23 years).
phate reabsorption in the brush border membrane on the luminal side of the proximal renal tubule and impaired phosphate reabsorption in the intestine. Recently, 2 theories on impaired phosphate transport have been proposed. One is an impairment of the sodium-dependent phosphate transporter,11 and the other is a phosphatic factor that increases phosphate excretion.12,13 However, impaired lα(OH)2D metabolism has also been suggested.14,15 XLH is identified by clinical symptoms, such as deformities in the limbs, gait disturbance, dwarfism, familial occurrence, bowlegs, and knock-knees, as well
as by laboratory findings. Since the early case reports of XLH, a specific dental finding of abscess formation in clinically normal teeth has been described in most cases.8,9 Furthermore, a case of XLH was detected based on gingival abscess formation in clinically normal teeth.16 Histologic findings of teeth in XLH include enlarged pulp chambers, wide predentin, marked globular dentin, and tubular dentinal defects extending from the pulp to the enamel. In this patient, clinical findings (such as dental caries or tooth fractures) were not detected, and we speculated that the gingival abscess had been caused by bacterial invasion
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Fig 8. Histopathology of right mandibular third molar (decalcified section, hematoxylin-eosin stain). Wide globular dentin was characteristic. Predentin was also wide (D, dentin; PD, predentin; P, pulp).
Fig 9. Histopathology of right mandibular third molar. Contact microradiograph of polished section. Marked globular dentin was observed (E, enamel, D, dentin).
into the pulp tissue by means of a microscopic cleavage of the enamel and dentin. In all previous known reports with a histologic examination, dentinal hypoplasia showing marked globular dentin is a common finding in XLH.5,6,9 As to the cause of the globular dentin in XLH, some authors have suggested an impaired dentinogenesis of odontoblasts.17-19 On the other hand, Abe et al,6 noting restorative dentin formation in XLH, suggested that the odontoblast function was not aberrant, but that the calcification process of the dentin was impaired because of hypophosphatemia. In bone, an impaired osteoblast function has been suggested.20-22 With regard to tooth enamel in XLH, one study showed an absence of enamel hypoplasia in most patients,6 whereas another showed enamel defects including hypoplasia in one third of the patients.7,23 In this study, we did not observe specific enamel defects or hypoplasia in the patient or in his affected sister.
XLH is transmitted as a sex-linked dominant trait, and the causative gene is reported to be positioned at Xp22.1.24 Our case confirmed this. It was also confirmed because the patient’s brother did not manifest any signs of XLH. In general, the incidence of XLH is higher and symptoms are more severe in males than in females, and no male-to-male transmission has been observed. In Japan, most reported cases have occurred sporadically,25 as shown in this case. Our patient began to receive neutral phosphate at the age of 2 years, 11 months but refused to take the medication during a period in his adolescence, resulting in an irregular drug administration. From the radiographic examination, the root dysplasia was considered to have occurred when the patient was between 8 and 14 years of age. This period is consistent with the time of the patient’s refusal to take medications and is assumed to be a hypophosphatemic condition. Taken together, it appears that the severe hypophosphatemia induced globular dentin and short roots in the permanent dentition.
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In patients with XLH, the dentition is highly susceptible to dental caries or attrition, and bacteria can invade easily from the oral cavity to dental pulp by menas of structural defects in enamel and dentin, resulting in pulpitis. Therefore, to prevent multiple gingival abscesses as observed in our patient, both early treatment and preventive care for caries and attrition are necessary. Application of prefabricated metal or polycarbonate crowns for deciduous teeth without caries has been reported to be effective for prevention of attrition and enamel microfracture.26 However, this aggressive preventive method cannot be adopted in all patients with XLH, because not all the pulp tissue is infected and iatrogenic pulp infection may occur during the tooth crown preparation. In patients with either definite or suspected XLH, professional dental care consisting of periodical examinations, topical fluoride application, and the maintenance of good oral hygiene should be performed. Moreover, dentists are advised to provide information about the dental characteristics of XLH to the pediatrician who might first diagnose such patients and who might request referrals to dentists as early as possible to prevent potential, subsequent serious dental infections. REFERENCES 1. Francis HG. Hypophosphatemic vitamin D resistant rickets. In: Murray JF, editor. Primer on the metabolic bone dieases and disorder of the mineral metabolism. 2nd ed. New York: The American Society for Bone and Mineral Research; 1993. p. 279. 2. Walton J. Familial hypophosphatemic rickets. A delineation of its subdivisions and pathogenesis. Clin Ped 1976;15:1007-12. 3. Winters RW, McFalls VW, Graham JB. “Sporadic” hypophosphatemia and vitamin D-resistant rickets. Pediatr 1960;25:959-66. 4. Burnett CH, Dent CE, Harper C, Warland BJ. Vitamin D-resistant rickets: analysis of 24 pedigrees with hereditary and sporadic cases. Am J Med 1964;36:222-32. 5. Witkop CJ Jr. Hereditary defects of dentin. Dent Clin North Am 1975;19:25-45. 6. Abe K, Ooshima T, Tong SML, Yasufuku Y, Sobue S. Structural deformities of deciduous teeth in patients with hypophosphatemic vitamin D-resistant rickets. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1988;65:191-8. 7. Berndt M, Ehrich JH, Lazovic D, Zimmermann J, Hillmann G, Kayser C, et al. Clinical course of hypophosphatemic rickets in 23 adults. Clin Nephrol 1996;45:33-41. 8. Gallo LG, Merle SG. Spontaneous dental abscess in vitamin-Dresistant rickets: report of case. J Dent Child 1979;46:327-29. 9. Yamamoto T. Diagnosis of X-linked hypophosphatemic vitamin D resistant rickets. Acta Paediatr Japan 1997;39:499-502. 10. Albright F, Butler A, Bloomberg E. Rickets resistant to vitamin D therapy. Am J Dis Child 1937;54:529-47. 11. Tenenhouse HS, Klugerman AH, Neal JL. Effect of phosphonoformic acid, dietary phosphate and the Hyp mutation on kinetically distinct phosphate transport processes in mouse kidney. Biochim Biophys Acta 1989;984:207-13. 12. Meyer RA Jr, Tenenhouse HS, Meyer MH, Klugerman AH. The renal phosphate transport defect in normal mice parabiosed to X-linked hypophosphatemic mice persists after parathyroidectomy. J Bone Miner Res 1989;4:523-32. 13. Nesbitt T, Coffman TM, Griffiths R, Drezner MK. Crosstransplantation of kidneys in normal and Hyp mice: evidence that the
Fig 10. Histopathology of left mandibular deciduous canine of patient’s younger sister (decalcified section, hematoxylineosin stain). Degree of dentin hypoplasia was less marked than in her brother.
14. 15. 16. 17. 18. 19. 20.
21. 22.
Hyp mouse phenotype is unrelated to an intrinsic renal defect. J Clin Invest 1992;89:1453-9. Seino Y, Yamaoka K, Ishida M. Plasma clearance for high doses of exogenous 1,25-dihydroxy[23,24(n)-3H] cholecalciferol in X-linked hypophosphatemic mice. Biomed Res 1982;3:683-7. Tenenhouse HS, Jones G. Abnormal regulation of renal vitamin D catabolism by dietary phosphate in murine X-linked hypophosphatemic rickets. J Clin Invest 1990;85:1450-5. Yamazaki H, Otake Y, Tomizawa M, Noda T, Suzuki M. A case of hypophosphatemic rickets in which spontaneous dental abscesses were the first evidence. Jpn J Pediatr Dent 1985;23:204-14. Marks SC, Lindahl RL, Bawden JW. Dental and cephalometric findings in vitamin D resistant rickets. J Dent Child 1965;32:25965. Via WF. Spontaneous degeneration of the dental pulp associated with phosphate diabetes. Oral Surg Oral Med Oral Pathol 1967;24:623-8. Soni NN, Marks SC. Microradiographic and polarized-light study of dental tissues. Oral Surg Oral Med Oral Pathol 1967;23:755-62. Ecarot-Charrier B, Glorieux FH, Traverse R, Desbarats M, Bouchard F, Hinek A. Defective bone formation by transplanted Hyp mouse bone cells into normal mice. Endocrinol 1988;123:768-73. Yamamoto T, Ecarot B, Glorieux FH. Abnormal response of osteoblasts from Hyp mice to 1,25-dihydroxyvitamin D3. Bone 1992;13:209-15. Yamamoto T, Ecarot-Charrier B, Seino Y, Glorieux FH. Familial
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hypophosphatemia: altered regulation of osteocalcin synthesis in bone cells. Calcium Regul Bone Metab 1990;10:239-42. 23. Goodmann JR, Gelbier MJ, Bennett JH, Winter GB. Dental problems associated with hypophosphaemic vitamin D resistant rickets. Int J Paediatr Dent 1998;8:1928. 24. The HYP Consortium: A gene (PEX) with homologies to endopeptidases is mutated in patients with X-linked hypophosphatemic rickets. Nat Genet 1995;11:130-6. 25. Seino Y, Shimotsuji T, Matsuura N, Nakajima H, Tsuchiya H, Kitagawa T. The survey of children with calcium metabolism disorders in Japan: familial hypophosphatemia and vitamin Dresistant rickets. Acta Pediatr Japan 1984;88:165-8. Japanese.
26. Yasufuku Y, Kohno N, Tsutsumi N, Ooshima T, Sobue S, Murakami Y, et al. Dental management of familial hypophosphatemic vitamin D-resistant rickets. J Dent Child 1983;50:3004. Reprint requests: Ichijiro Morisaki, DDS, PhD Associate Professor and Chief Division of Special Care Dentistry Osaka University Faculty of Dentistry, 1-8 Yamadaoka, Suita-Osaka 565-0871, Japan [email protected]
CALL FOR REVIEW ARTICLES The January 1993 issue of Oral Surgery, Oral Medicine, Oral Pathology, Oral Radiology, and Endodontics contained an Editorial by the Journal’s Editor in Chief, Larry J. Peterson, that called for a Review Article to appear in each issue. These Review Articles should be designed to review the current status of matters that are important to the practitioner. These articles should contain current developments, changing trends, as well as reaffirmation of current techniques and policies. Please consider submitting your article to appear as a Review Article. Information for authors appears in each issue of Oral Surgery, Oral Medicine, Oral Pathology, Oral Radiology, and Endodontics. We look forward to hearing from you.
A case of familial hypophosphatemic vitamin D-resistant rickets or X-linked hypophosphatemia (XLH) accompanied by specific systemic and dental findings is reported. A 15-year-old boy with XLH visited our facility complaining of a toothache in the left lower canine region. Two other family members of the patient, his younger sister and their mother, also had XLH, whereas the other 2 members, his younger brother and father, are healthy. Those with XLH show systemic signs of the disease, such as growth retardation, limb deformity, and spinal curvature disorders; however, these symptoms are more severe in the patient than in the others. The patient had multiple periodontal abscesses, but no evidence of dental caries, trauma, or periodontal disease on the corresponding teeth at the time of his oral examination. A radiographic examination showed root dysplasia and enlarged pulp chambers. A histologic examination of an extracted third molar showed marked globular dentin and an increased predentin width. The abscess was thought to be caused by pulpal infection, which came from bacterial invasion through enamel cracks and dentinal microcleavage of the teeth. The treatments provided in this case are discussed. (Oral Surg Oral Med Oral
Pathol Oral Radiol Endod 2000;90:310-6)
Hypophosphatemic vitamin D-resistant rickets or Xlinked hypophosphatemia (XLH) is a hereditary disease manifesting marked hypophosphatemia caused by renal tubular loss of phosphate into urine and an associated decrease in the calcium and potassium ion product (Ca × P).1 The pathophysiology of the disease is thought to be impaired phosphate transport, especially decreased phosphate resorption in the renal proximal tubule, as well as in the intestine. In most patients, XLH appears in a familial line of X-linked, dominant inheritance with the same prevalence in both sexes; however, it may also occur sporadically. In general, more severe symptoms are noted in males.2-4 Sporadic cases are often initially detected by limb deformity or gait abnormality. The systemic findings of XLH include bowed legs because of a body load showing immature skeletal bone calcification, spinal curvature deformities, short stature, and beading of the ribs called rachitic rosary. Oral findings of XLH have aChief, Division of Oral and Maxillofacial Surgery, Kyoto First Red Cross Hospital. bHonorary chief, Division of Oral and Maxillofacial Surgery, Kyoto First Red Cross Hospital. cSenior Instructor, Division of Special Care Dentistry, Osaka University Faculty of Dentistry. dAssistant Professor, Division of Special Care Dentistry, Osaka University Faculty of Dentistry. eAssociate Professor and Chief, Division of Special Care Dentistry, Osaka University, Faculty of Dentistry. Received for publication Dec 22, 1999; returned for revision Feb 8, 2000; accepted for publication Mar 17, 2000. Copyright © 2000 by Mosby, Inc. 1079-2104/2000/$12.00 + 0 7/13/107522 doi:10.1067/moe.2000.107522
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Fig 1. Family line. Open box, male; open circle, female; solid box or circle, person with XLH. Arrow indicates patient.
been characterized by poorly mineralized dentin dysplasia in both primary and permanent teeth.5-7 Spontaneous periapical abscess formation is also often observed in patients with XLH without dental caries or traumatic injury.8,9 Because the teeth of patients with XLH are often associated with high pulp horns, large pulp chambers, and dentinal clefts, it is believed that the abscesses are caused by pulpal infection that was caused by bacterial invasion through enamel cracks and dentinal microcleavage of the teeth. We report the dental findings of familial XLH in a 15-year-old Japanese boy, as well as the histologic findings of his extracted mandibular right third molar. CASE REPORT A Japanese boy who was 15 years, 2 months old with XLH was referred to the Department of Oral and Maxillofacial
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Fig 2. Photo of patient’s younger sister (at 12 years).
Surgery at Kyoto First Red Cross Hospital with a complaint of spontaneous pain in the left mandibular canine. Family history His mother and younger sister also had XLH; however, neither paternal nor maternal relatives showed any signs of XLH (Fig 1). The mother had also experienced toothaches without any macroscopic decay or associated periodontal lesions. A 12-year-old sister also had bowed legs, the characteristic sign of rickets (Fig 2). Past history The patient was the first offspring of the parents after a full term gestation and measured 3990 g in weight and 50.5 cm in length at birth. Because he had not yet walked by the age of 1 year, 6 months, he was referred to the pediatric clinic of a medical school, where a diagnosis of skeletal hypoplasia was made. At the age of 2 years, 8 months, skeletal abnormalities and bowed legs were noted at the public health examination for infants. The patient was admitted to the same pediatric clinic as before for a thorough examination. Rachitic changes at epiphyses of the radius, ulna, tibia, and fibula were showed by radiographic examination (Fig 3). Laboratory examinations showed an elevated alkaline phosphate level at 367 mU/mL (normal range, 30 - 85 mU/mL) and hypophosphatemia at 2.7 to 2.9 mg/dL (normal range in children, 4.5 - 6.5 mg/dL). Measurement of urinary phosphate excretion also showed an abnormal phosphate reabsorption
Fig 3. Radiograph of patient’s lower limbs (at 2 years and 9 months). Definite bowlegs can be observed.
rate of 66.7% (normal range, 84.7% - 97.9%). From these clinical, radiographic, and laboratory findings, the patient was diagnosed with hypophosphatemic rickets and was administered neutral phosphate. The patient received orthopedic treatment to correct his bowed legs for 55 months, from the age of 3 years, 2 months to 7 years, 9 months. The rachitic symptoms were markedly improved by initiation of active vitamin D and neutral phosphate administration at the age of 5 years, 0 months. Although the patient refused to take these drugs for a short time in his adolescence, his systemic condition had been generally well controlled. General findinqs At age 15, the patient’s height and weight were 159 cm and 43.4 kg, which were –1.45 SD and –1.52 SD from the height and weight averages, respectively, for 15-year-old Japanese boys, as reported in the 1989 School Health Survey by the Ministry of Welfare. Except for a shortening of the lower limbs, no other apparent abnormalities were noted in his body habitus (Fig 4). Oral findings An abscess was found at the labial periapical region of the
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Fig 5. Dental radiograph of left mandibular canine. Pulp cavity was large, but showed no dental caries. Root dysplasia and absence of lamina dura were observed in left mandibular central incisor and left mandibular first premolar.
Fig 4. Photo of patient (at 19 years).
left mandibular canine, along with a negative response to pulp vitality testing; however, no clinically detectable changes such as caries, tooth fractures, or periodontal pockets that could induce pulp necrosis were found. Radiographic findings Short roots and large pulp chambers were observed radiographically in all premolars, second molars, and mandibular central incisors (Figs 5 and 6); however, the root apices appeared to be closed, even in the hypoplastic teeth (Fig 5). The right mandibular first molar had been treated endodontically before taking the panoramic radiograph. Periapical radiolucencies were found on the mandibular first molars and canines. Treatment An incision and drainage was performed to relieve pain and pus retention from the periodontal abscess of the left mandibular canine. Initially, symptomatic treatment only was provided for the patient because the exact cause of the abscess was not evident. One month later, a fistula developed on the buccal gingiva of the right mandibular first molar. Four months later, a gingival abscess was found in the buccal periapical region of the left mandibular first molar. Neither dental nor periodontal abnormalities were found clinically with these teeth. The molars were treated endodontically (Fig 7). A large periapical radiolucency was found at the left mandibular canine, and both endodontic treatment and apicoectomy were performed. Pulp necrosis developed subse-
quently in the right mandibular and the left maxillary canine 1 year later and in the right mandibular central incisor another 2 years later. All these teeth were treated endodontically and restored with composite resin or cast metal (Fig 7). Histologic examination Because the right mandibular third molar had manifested suppurative pericoronitis and there was no available space for its eruption, the tooth was extracted at age 18. The tooth was bisected and examined histologically. One half was decalcified and stained with hematoxylin and eosin. The other half was ground into thin sections for microradiographic examination. Marked globular dentin and a wide layer of predentin were observed on both the decalcified and ground sections (Figs 8 and 9). An extracted deciduous mandibular canine from the patient’s younger sister was also processed for histologic examination. Findings similar to those found of her brother’s permanent molar were observed in the canine (Fig 10).
DISCUSSION Vitamin D-deficient rickets has become less prevalent throughout most of the world because of marked improvements in living environments and nutrition. However, endogenous rickets caused by abnormalities in the vitamin D receptive system or in phosphate and calcium metabolism, such as XLH, have been reported.1 XLH, first reported by Albright et al,l0 is a syndrome showing marked hypophosphatemia, short stature, and rickets. In general, the main abnormality is considered to be a congenital impairment of phosphate transport and hypophosphatemia, resulting from decreased phos-
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Fig 6. Panoramic radiograph (after endodontic therapy of right mandibular first molar at 15 years). Root dysplasia (short root tooth) was observed bilaterally in maxillary and mandibular first premolars, second premolars, second molars, and bilateral mandibular central incisors, but degree was slight in right mandibular first premolar. Trabecular structure was abnormal.
Fig 7. Panoramic radiograph (at 23 years).
phate reabsorption in the brush border membrane on the luminal side of the proximal renal tubule and impaired phosphate reabsorption in the intestine. Recently, 2 theories on impaired phosphate transport have been proposed. One is an impairment of the sodium-dependent phosphate transporter,11 and the other is a phosphatic factor that increases phosphate excretion.12,13 However, impaired lα(OH)2D metabolism has also been suggested.14,15 XLH is identified by clinical symptoms, such as deformities in the limbs, gait disturbance, dwarfism, familial occurrence, bowlegs, and knock-knees, as well
as by laboratory findings. Since the early case reports of XLH, a specific dental finding of abscess formation in clinically normal teeth has been described in most cases.8,9 Furthermore, a case of XLH was detected based on gingival abscess formation in clinically normal teeth.16 Histologic findings of teeth in XLH include enlarged pulp chambers, wide predentin, marked globular dentin, and tubular dentinal defects extending from the pulp to the enamel. In this patient, clinical findings (such as dental caries or tooth fractures) were not detected, and we speculated that the gingival abscess had been caused by bacterial invasion
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Fig 8. Histopathology of right mandibular third molar (decalcified section, hematoxylin-eosin stain). Wide globular dentin was characteristic. Predentin was also wide (D, dentin; PD, predentin; P, pulp).
Fig 9. Histopathology of right mandibular third molar. Contact microradiograph of polished section. Marked globular dentin was observed (E, enamel, D, dentin).
into the pulp tissue by means of a microscopic cleavage of the enamel and dentin. In all previous known reports with a histologic examination, dentinal hypoplasia showing marked globular dentin is a common finding in XLH.5,6,9 As to the cause of the globular dentin in XLH, some authors have suggested an impaired dentinogenesis of odontoblasts.17-19 On the other hand, Abe et al,6 noting restorative dentin formation in XLH, suggested that the odontoblast function was not aberrant, but that the calcification process of the dentin was impaired because of hypophosphatemia. In bone, an impaired osteoblast function has been suggested.20-22 With regard to tooth enamel in XLH, one study showed an absence of enamel hypoplasia in most patients,6 whereas another showed enamel defects including hypoplasia in one third of the patients.7,23 In this study, we did not observe specific enamel defects or hypoplasia in the patient or in his affected sister.
XLH is transmitted as a sex-linked dominant trait, and the causative gene is reported to be positioned at Xp22.1.24 Our case confirmed this. It was also confirmed because the patient’s brother did not manifest any signs of XLH. In general, the incidence of XLH is higher and symptoms are more severe in males than in females, and no male-to-male transmission has been observed. In Japan, most reported cases have occurred sporadically,25 as shown in this case. Our patient began to receive neutral phosphate at the age of 2 years, 11 months but refused to take the medication during a period in his adolescence, resulting in an irregular drug administration. From the radiographic examination, the root dysplasia was considered to have occurred when the patient was between 8 and 14 years of age. This period is consistent with the time of the patient’s refusal to take medications and is assumed to be a hypophosphatemic condition. Taken together, it appears that the severe hypophosphatemia induced globular dentin and short roots in the permanent dentition.
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In patients with XLH, the dentition is highly susceptible to dental caries or attrition, and bacteria can invade easily from the oral cavity to dental pulp by menas of structural defects in enamel and dentin, resulting in pulpitis. Therefore, to prevent multiple gingival abscesses as observed in our patient, both early treatment and preventive care for caries and attrition are necessary. Application of prefabricated metal or polycarbonate crowns for deciduous teeth without caries has been reported to be effective for prevention of attrition and enamel microfracture.26 However, this aggressive preventive method cannot be adopted in all patients with XLH, because not all the pulp tissue is infected and iatrogenic pulp infection may occur during the tooth crown preparation. In patients with either definite or suspected XLH, professional dental care consisting of periodical examinations, topical fluoride application, and the maintenance of good oral hygiene should be performed. Moreover, dentists are advised to provide information about the dental characteristics of XLH to the pediatrician who might first diagnose such patients and who might request referrals to dentists as early as possible to prevent potential, subsequent serious dental infections. REFERENCES 1. Francis HG. Hypophosphatemic vitamin D resistant rickets. In: Murray JF, editor. Primer on the metabolic bone dieases and disorder of the mineral metabolism. 2nd ed. New York: The American Society for Bone and Mineral Research; 1993. p. 279. 2. Walton J. Familial hypophosphatemic rickets. A delineation of its subdivisions and pathogenesis. Clin Ped 1976;15:1007-12. 3. Winters RW, McFalls VW, Graham JB. “Sporadic” hypophosphatemia and vitamin D-resistant rickets. Pediatr 1960;25:959-66. 4. Burnett CH, Dent CE, Harper C, Warland BJ. Vitamin D-resistant rickets: analysis of 24 pedigrees with hereditary and sporadic cases. Am J Med 1964;36:222-32. 5. Witkop CJ Jr. Hereditary defects of dentin. Dent Clin North Am 1975;19:25-45. 6. Abe K, Ooshima T, Tong SML, Yasufuku Y, Sobue S. Structural deformities of deciduous teeth in patients with hypophosphatemic vitamin D-resistant rickets. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 1988;65:191-8. 7. Berndt M, Ehrich JH, Lazovic D, Zimmermann J, Hillmann G, Kayser C, et al. Clinical course of hypophosphatemic rickets in 23 adults. Clin Nephrol 1996;45:33-41. 8. Gallo LG, Merle SG. Spontaneous dental abscess in vitamin-Dresistant rickets: report of case. J Dent Child 1979;46:327-29. 9. Yamamoto T. Diagnosis of X-linked hypophosphatemic vitamin D resistant rickets. Acta Paediatr Japan 1997;39:499-502. 10. Albright F, Butler A, Bloomberg E. Rickets resistant to vitamin D therapy. Am J Dis Child 1937;54:529-47. 11. Tenenhouse HS, Klugerman AH, Neal JL. Effect of phosphonoformic acid, dietary phosphate and the Hyp mutation on kinetically distinct phosphate transport processes in mouse kidney. Biochim Biophys Acta 1989;984:207-13. 12. Meyer RA Jr, Tenenhouse HS, Meyer MH, Klugerman AH. The renal phosphate transport defect in normal mice parabiosed to X-linked hypophosphatemic mice persists after parathyroidectomy. J Bone Miner Res 1989;4:523-32. 13. Nesbitt T, Coffman TM, Griffiths R, Drezner MK. Crosstransplantation of kidneys in normal and Hyp mice: evidence that the
Fig 10. Histopathology of left mandibular deciduous canine of patient’s younger sister (decalcified section, hematoxylineosin stain). Degree of dentin hypoplasia was less marked than in her brother.
14. 15. 16. 17. 18. 19. 20.
21. 22.
Hyp mouse phenotype is unrelated to an intrinsic renal defect. J Clin Invest 1992;89:1453-9. Seino Y, Yamaoka K, Ishida M. Plasma clearance for high doses of exogenous 1,25-dihydroxy[23,24(n)-3H] cholecalciferol in X-linked hypophosphatemic mice. Biomed Res 1982;3:683-7. Tenenhouse HS, Jones G. Abnormal regulation of renal vitamin D catabolism by dietary phosphate in murine X-linked hypophosphatemic rickets. J Clin Invest 1990;85:1450-5. Yamazaki H, Otake Y, Tomizawa M, Noda T, Suzuki M. A case of hypophosphatemic rickets in which spontaneous dental abscesses were the first evidence. Jpn J Pediatr Dent 1985;23:204-14. Marks SC, Lindahl RL, Bawden JW. Dental and cephalometric findings in vitamin D resistant rickets. J Dent Child 1965;32:25965. Via WF. Spontaneous degeneration of the dental pulp associated with phosphate diabetes. Oral Surg Oral Med Oral Pathol 1967;24:623-8. Soni NN, Marks SC. Microradiographic and polarized-light study of dental tissues. Oral Surg Oral Med Oral Pathol 1967;23:755-62. Ecarot-Charrier B, Glorieux FH, Traverse R, Desbarats M, Bouchard F, Hinek A. Defective bone formation by transplanted Hyp mouse bone cells into normal mice. Endocrinol 1988;123:768-73. Yamamoto T, Ecarot B, Glorieux FH. Abnormal response of osteoblasts from Hyp mice to 1,25-dihydroxyvitamin D3. Bone 1992;13:209-15. Yamamoto T, Ecarot-Charrier B, Seino Y, Glorieux FH. Familial
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hypophosphatemia: altered regulation of osteocalcin synthesis in bone cells. Calcium Regul Bone Metab 1990;10:239-42. 23. Goodmann JR, Gelbier MJ, Bennett JH, Winter GB. Dental problems associated with hypophosphaemic vitamin D resistant rickets. Int J Paediatr Dent 1998;8:1928. 24. The HYP Consortium: A gene (PEX) with homologies to endopeptidases is mutated in patients with X-linked hypophosphatemic rickets. Nat Genet 1995;11:130-6. 25. Seino Y, Shimotsuji T, Matsuura N, Nakajima H, Tsuchiya H, Kitagawa T. The survey of children with calcium metabolism disorders in Japan: familial hypophosphatemia and vitamin Dresistant rickets. Acta Pediatr Japan 1984;88:165-8. Japanese.
26. Yasufuku Y, Kohno N, Tsutsumi N, Ooshima T, Sobue S, Murakami Y, et al. Dental management of familial hypophosphatemic vitamin D-resistant rickets. J Dent Child 1983;50:3004. Reprint requests: Ichijiro Morisaki, DDS, PhD Associate Professor and Chief Division of Special Care Dentistry Osaka University Faculty of Dentistry, 1-8 Yamadaoka, Suita-Osaka 565-0871, Japan [email protected]
CALL FOR REVIEW ARTICLES The January 1993 issue of Oral Surgery, Oral Medicine, Oral Pathology, Oral Radiology, and Endodontics contained an Editorial by the Journal’s Editor in Chief, Larry J. Peterson, that called for a Review Article to appear in each issue. These Review Articles should be designed to review the current status of matters that are important to the practitioner. These articles should contain current developments, changing trends, as well as reaffirmation of current techniques and policies. Please consider submitting your article to appear as a Review Article. Information for authors appears in each issue of Oral Surgery, Oral Medicine, Oral Pathology, Oral Radiology, and Endodontics. We look forward to hearing from you.