DENTAL ABNORMALITIES IN PATIENTS WITH FAMILIAL HYPOPHOSPHATEMIC VITAMIN D–RESISTANT RICKETS: PREVENTION BY EARLY TREATMENT WITH 1-HYDROXYVITAMIN D C ATHERINE CHAUSSAIN-MILLER, MD, CHRISTIANE SINDING, MD, MARYSE WOLIKOW, MD, PHD, JEAN-JACQUES LASFARGUES, MD, PHD, GASTON GODEAU, PHD, AND MICHÈLE GARABÉDIAN, MD, PHD
Objective To evaluate the dental effects of 1-hydroxylated vitamin D3 treatment in patients with familial hypophosphatemic vitamin D–resistant rickets. Study design Forty-eight children and adult patients were included in the study; 16 had received no treatment or phosphate supplements with vitamin D/25-(OH) D3 before puberty. The 32 younger ones had received phosphate supplements with 1α-(OH)D3 from infancy. All patients were clinically examined, and panoramic and periapical radiographs were made. Evaluations of decayed, missing, or filled teeth and decayed or filled teeth indexes and of pulp ratios allowed comparison with healthy agematched control patients. Results Poor dental health and characteristic dental anomalies were found in the 16 older patients. In contrast, the 32 younger patients had a normal dental status as regards reference ranges in healthy age-matched populations, although they still showed prominent pulp horns on deciduous teeth and increased pulp area/tooth area ratios. Conclusions This investigation shows the beneficial effects of 1α-(OH)D3 treatment on the dental status of vitamin D–resistant rickets patients and emphasizes the necessity of early treatment. Remaining defects may result from early exposure of odontoblasts and surrounding osteoblasts to hypophosphatemia, before the commencement of treatment, and/or from intrinsic cell disturbances linked to the genetic alteration(s). (J Pediatr 2003;142:324-31)
ypophosphatemic rickets is in most cases transmitted as an X-linked dominant trait and results from mutation in the PHEX gene located in Xp22.2-22.1.1-3 The PHEX gene encodes a zinc metallopeptidase; its precise mode of action is uncertain. However, recent studies suggest that osteoblasts and odontoblasts, through the action of the PHEX gene, secrete a protein that enters the circulation and acts on distant target sites such as the kidney.4-6 Whatever their mode of action, alterations of the PHEX gene cause defective renal phosphate reabsorption with phosphaturia and hypophosphatemia, as well as impaired 1α-hydroxylation of 25-hydroxyvitamin D. These anomalies lead to discordance between the production and the rate of mineralization of bone matrix, hence the accumulation of unmineralized matrix and poorly mineralized bone. The main clinical features are severe bony deformities, especially bowing of the legs, impaired growth, and short stature.1,3,7 Craniosynostosis may be present. Dental features include unusually large pulp chambers and enlarged pulp horns associated with thin enamel and dentin defects.8-21 On histologic analysis, the dentin exhibits large tubular clefts or lacunae and the enlarged pulp horns may extend to or beyond the dentino-enamel junction.12,16,17,19-21 These changes may lead to rapid necrosis of the pulp with periapical complications both on deciduous and definitive dentition, the bacterial ingress to the pulp being facilitated. Spontaneous dental abscesses occur without any history of trauma or dental decay.
DFT DMFT VDRR
Decayed or filled teeth Decayed, missing, or filled teeth Familial hypophosphatemic vitamin D–resistant rickets
From the Conservative Dentistry and Endodontics Department, Dental School of University of Paris 5, and CNRS (UMR8104), St Vincent de Paul Hospital, Paris, and the Department of Odontology, Charles Foix Hospital, Ivry, Seine, France. Submitted for publication Feb 18, 2002; revisions received Aug 1, 2002, and Nov 4, 2002; accepted Dec 14, 2002. Reprint requests: Catherine ChaussainMiller, MD, Dental School of University of Paris 5, Department of Conservative Dentistry and Endodontics, 1 rue Maurice Arnoux, 92120 Montrouge, France. E-mail: [email protected]
Copyright © 2003, Mosby, Inc. All rights reserved. 0022-3476/2003/$30.00 + 0
Fig 1. Dental health of 48 patients with hypophosphatemic rickets as regards age at commencment and compliance with 1α-(OH)D3 treatment. To estimate the whole dentition status, the following indexes were used, depending on the age: DFT index for children up to 5 years of age; DMFT index for patients over 15 years of age; and DFT + DMFT index for children between 6 and 14 years. Grey bars represent mean ± 1 SD reference ranges for healthy age-matched adults (DMFT index) and children (DFT + DMFT indexes) in France.
Treatment of rickets with vitamin D and phosphate supplements has been shown to prevent or cure the dental anomalies in some8,9 but not all patients.13-15 Local prophylactic measures have therefore been proposed to prevent the occurrence of multiple dental abscesses.22-25 Beginning in the 1970s, 1-hydroxylated forms of vitamin D have progressively superseded vitamin D itself for the treatment of hypophosphatemic rickets. 1α-Hydroxycholecalciferol is a synthetic 1-hydroxylated vitamin D3 compound that is rapidly converted to 1,25-(OH)2D3 in the liver and has a pharmacologic profile similar to that of 1,25-(OH)2D3, the current standard therapy for familial hypophosphatemic vitamin D–resistant rickets (VDRR) in the United States.26 This later strategy clearly improved the prevention and correction of bone deformities in children with hypophosphatemic rickets, as well as their skeletal growth.7 However, its influence on teeth abnormalities has not been specifically addressed. We evaluated the effects of 1-hydroxylated vitamin D treatment on the dental status of patients with familial VDRR.
METHODS We examined 48 children and adults with VDRR regularly followed as outpatients in the Saint Vincent de Paul HosDental Abnormalities in Patients With Familial Hypophosphatemic Vitamin D–Resistant Rickets: Prevention by Early Treatment With 1-Hydroxyvitamin D
pital, Paris, and analyzed the results as regards the vitamin D form administrated during childhood and their compliance to treatment. Patients were recruited over a period of 18 months on the occasion of a systematic outpatient follow-up; 39 had been followed since early childhood in our department (age, 335 years). They had received vitamin D or 1α-hydroxy vitamin D3 (Unalfa, Leo Laboratories, St Quentin on Yvelines, France) during infancy and/or childhood, depending on their year of birth. The 9 others were adults when first seen in our department (age, 29-52 years) and had received vitamin D or no treatment during childhood. Familial transmission of the disease was observed in 32 patients (15 families). Eleven had established mutations in the PHEX gene (5 families), as previously reported for 3 of the families.3 The 16 other patients had no known familial history of hypophosphatemic rickets. Informed consent was obtained from all patients and/or their parents before the dental examination. All patients had a thorough dental examination for malposition, dysplasia, carious lesions, pulp disease, and gingival disease. For each patient the decayed, missing, or filled teeth (DMFT) index for permanent teeth and decayed or filled teeth (DFT) index for primary teeth was evaluated. Eighteen patients had radiologic examination (orthopantomogram, periapical, and bite-wing radiographs) to analyze the volume of the pulp cham325
tween 9 and 14 years of age (n = 3), or after the end of puberty (n = 6). Male and female adult patients in this group had a short stature (156 ± 1.7 and 150 ± 6.0 cm, respectively; mean ± 1 SD). Their mean height was 2.4 ± 0.9 SD less the mean height of French reference adult populations. Group 2 includes the 32 patients born after 1972 (20 female and 12 male patients; mean age, 11 years; range, 3-25 years). All received phosphate supplements and Unalfa from a mean age of 18 months (range, 1 to 6 years) and were still treated on the day of dental examination. Seven of these patients were siblings (3 families), 4 patients had an affected father belonging to group 1 (2 families), and 11 had an affected mother belonging to group 1 (9 families). Only 4 patients had reached adulthood, but 3 were taller than group 1 patients (163, 167, and 172 cm). The mean statural growth defect in this group was –1.2 ± 1.3 SD.
2.4 ± 2.4
Table I. Dental status of 48 patients with hypophosphatemic rickets Group 1 Age (y) Mean (range) 37 (28-52) Missing teeth (permanent dentition)* No. of patients with ≥2 9/16 missing teeth Percentage of missing teeth 22 (0-100) per patient† M/DMFT 101/329 = 0.3 Necrosed or endodontically treated teeth No. of patients with necrosed 16/16 or endodontically treated teeth Percentage of altered teeth 58 (25-100) per patient† DMFT (mean ± SD) 20.4 ± 6.4
Group 2 11 (3-25) 2/27 0.5 (0-14) 5/49 = 0.1 10/32
*Only patients with permanent teeth were considered for evaluation of missing teeth. †Values are presented as mean and range.
ber and to detect periodontal, dental and periapical alterations, or dental and root maturation delay. Moreover, the periapical radiographs were analyzed to estimate the pulp ratio (pulp chamber area/tooth area) in 13 patients (8 children 8 to 11 years of age and 5 patients 15 to 21 years of age), as reported.14 A specific paralleling technique was used to minimize the radiographic distortions (Rinn XCP apparatus, Dentsply, Montigny le Bretonneux, France), and the distance between teeth and the X-ray unit was maximized. A similar analysis was performed on the periapical radiographs of 15 age-matched control patients, 10 healthy children seen as outpatients for orthodontic treatment and 5 adult volunteers. Computerized images of tooth and correspondent pulp chamber were observed under a Zeiss standard 14 microscope equipped with a Sophretec CFR 126 video camera (Levallois-Perrot, France). The black-and-white images generated by the video camera were converted to images of 256 Gray levels by using a Sophretec MVM 600 image memory, transferred to a BFM 186 microcomputer. The tooth and pulp chamber areas per contour (mm2) were calculated with the use of mathematic morphology software. All teeth with necrotic pulp, large restorations, or cavities; teeth with gross malalignment; permanent maxillary molars with trifurcated root structure; and mandibular third molars were excluded.14 Patients were divided into 2 groups according to their year of birth and therefore to the type of vitamin D treatment they had received from infancy for the analysis of the clinical and dental data. Group 1 included the 16 patients born before 1970 (12 female and 4 male patients; mean age, 37 years; range, 28-52 years). The 7 older patients (38-52 years of age) received no therapy or only phosphate and vitamin D until adulthood. The 9 younger patients had received vitamin D and phosphate from infancy and then, when available, 1α-hydroxy vitamin D3 (Unalfa) and phosphate. This treatment was started be326 Chaussain-Miller et al
Patients Treated With 1α-(OH)D3 From Infancy Had a Normal Dental History The 16 hypophosphatemic patients born before 1970 had poor dental health (Table I). One patient had lost all his teeth and 8 others had 2 missing teeth or more, with a mean percentage of missing teeth per patient of 22%. All patients with some teeth had necrosed or endodontically treated teeth, and the mean percentage of pulpally diseased or treated teeth in this group was high (58%; range, 25-100%). By contrast, only 2 of the patients born after 1970 had permanent missing teeth (1 tooth in a 7-year-old girl and 4 teeth in a 19-year-old girl), all resulting from trauma. Moreover, only one third of the 32 patients had endodontically treated teeth (6 boys and 4 girls), trauma being the cause of the anomaly for 3 patients, and the mean percentage of endodontically treated teeth per patient was low (4%; range, 0-24%). As a result of these differences, DMFT index, which reflects the dental history of the patients, was high in group 1 and low in group 2 (Table I). It was not significantly influenced by sex in any of the groups. The mean DMFT and range were 24 (18-28) for male patients and 19 (10-28) for female patients in group 1; they were 2.7 (0-6) for male patients and 1.9 (0-9) for female patients in group 2. Comparison of the DMFT indexes found in group 1 to published age-matched reference values in France27,28 showed abnormally high values for the 7 older patients (Fig 1). The 9 younger patients, born between 1962 and 1970, had better dental health, although DMFT values were still in the high normal range for 5 of the 6 patients treated with vitamin D during childhood and puberty. By contrast, DMFT values were at the mean of reference curves for the 3 patients who could benefit from the Unalfa treatment before 14 years of age. In group 2, all patients had DMFT and DFT values in the reference range of age-matched populations (Fig 1). Patients with poor compliance with treatment were also in the normal range but tended to have higher DMFT indexes. Separate analysis of deciduous and permanent teeth in the 23 children with either a deciduous dentition (n = 5) or a mixed The Journal of Pediatrics • March 2003
Fig 2. Dental health of the 23 hypophosphatemic children according to mother’s health status. All children under 15 years of age had either deciduous or mixed dentition. All had been given 1α-(OH)D3 treatment from infancy. Deciduous teeth (DFT index) and permanent teeth (DMFT index) were evaluated separately. Open circles represent patients with unaffected mother; closed circles, patients with mother with VDRR. Reference ranges (mean ± 1 SD) for deciduous and permanent teeth in healthy age-matched populations in France are noted.
dentition (n = 18) showed similar mean indexes for deciduous teeth (DFT index) and permanent teeth (DFT index) (1.0 ± 2.6 and 1.4 ± 2.4, respectively). Both indexes were in the normal range for the age (Fig 2). Comparison of DFT and DMFT indexes in the 18 children with mixed dentition (5-13 years) showed that these indexes were not related. Moreover, they appeared to be distinctly influenced by the health status of the mothers (Fig 2). The DFT index for deciduous teeth was low in children born to healthy mothers (mean DFT: 0.7, with 70% of the children having a null index) and higher in children born to hypophosphatemic mothers (mean DFT: 2.1, with 40% of the children having a null index). Inversely, DMFT for permanent teeth was lower in children born to affected mothers (mean DMFT: 0.1; 85% with a null DMFT index) compared with those born to unaffected mothers (mean DMFT: 1; 45% with a null DMFT).
Patients Treated With 1α-(OH)D3 From Infancy Had Normal Enamel Mineralization In group 1, contrasting with their high DMFT index, only 1 female patient had active caries (10% of her teeth). However, all patients showed poorly mineralized enamel (Fig 3). The enamel was brown or gray, and its surface was porous with striae. Group 2 was not prone to caries (1.7%), and only limited white or brown enamel spots were found. These enamel defects were more frequently observed on permanent teeth than Dental Abnormalities in Patients With Familial Hypophosphatemic Vitamin D–Resistant Rickets: Prevention by Early Treatment With 1-Hydroxyvitamin D
on primary teeth (35% versus 8%). They were not affected by sex or prenatal history (affected or unaffected mothers).
Only Few Patients Treated With 1α-(OH)D3 From Infancy Had Dental Abscesses Clinical examination of the soft tissues surrounding the teeth did not reveal any abscess for patients born before 1972 (group 1), although histories in this group revealed frequent past dental troubles. Only 4 of the 32 patients born after 1972, all boys, had dental abscesses. One had trauma to his maxillary central incisor. The other 3 boys, 7, 10, and 11 years of age, had abscesses on primary molars not related to trauma or caries. Their compliance with treatment had been good or (in a single case) moderate. The gingival abscesses were observed on primary molars, and periapical radiographs revealed severe bone loss surrounding teeth in resorption (Fig 4).
1α-(OH)D3–Treated Patients Showed Persistency of Prominent Primary Molar Pulp Horns Four patients in group 1 had a radiographic evaluation of their dental status (Table II). Three had a thin and radiolucent dentin layer. All had unusually wide pulp chambers for their maxillary and mandibular molars as well as prominent pulp horns extending up to the dentino-enamel junction. The secondary dentin apposition at the furcation level was weak, resulting in a pulp aspect evocative of taurodontism. 327
Fig 3. Percentage of patients with generalized (dark bars), localized (hatched bars), or no (open bars) enamel defects in the two groups of patients. For the younger group of patients, primary and permanent teeth are presented separately.
Table II. Radiographic analysis of dental status of 18 hypophosphatemic patients Group 1 Group 2 Group 2 Permanent Permanent Primary teeth teeth teeth (n = 4) (n = 10)* (n = 8)† Percentage of patients with Dentin aspect Normal 25 Thin and radiolucent 75 Pulp chamber aspect Normal 0 Large 100 Pulp horn aspect Normal 0 Prominent 100
*This group includes 4 children with mixed dentitions (age, 8-10 years) and 6 older patients with only permanent teeth (age, 12-22 years). †This group includes the 4 children above with mixed dentition and 4 younger children with deciduous teeth only.
All the 14 patients examined in group 2 had a normal dentin aspect of the primary and permanent teeth and all had normal radiodensity of the alveolar bone (Table II and Fig 4). Most patients (11 of 14) had a normal root maturation of their permanent teeth. The wideness of the pulp chambers and the root canals were also normal for most permanent and deciduous teeth examined (Table II). However, a thorough radiographic examination of the primary molars revealed an abnormal persistence of prominent pulp horns extending up to or beyond the dentino-enamel junction in 6 of the 8 children. This feature was observed even in the most compliant and early-treated patients and was found in children born to hypophosphatemic mothers as well as in sporadic cases. The pulp horn enlargement was less frequently observed in permanent teeth (Table II). It was found in 2 boys and 1 girl 15 to 21 years of age. All had been treated with Unalfa from early childhood, but their compliance was 328 Chaussain-Miller et al
Fig 4. Radiographs of two 10-year-old boys treated with Unalfa since infancy. A, Right maxillary periapical radiograph of hypophosphatemic boy with insufficient treatment. B, Left mandibular periapical radiograph of the same boy. Bone resorption is observed surrounding the roots of the deciduous molar (75). Both radiographs show prominent pulp horns extending up to dentinoenamel junction. C, Left mandibular periapical radiograph of 10year-old compliant patient. Both the dentinal aspect of the deciduous and permanent teeth and the radiodensity of the alveolar bone are normal. Wideness of pulp chambers and root canals are normal but prominent pulp horns can be seen on the deciduous molars.
irregular. Figure 5 shows the dental status of the 15-year-old boy. This boy had dental abscesses in deciduous teeth but had a normal dental clinical status at the time of the study. Orthopantomogram radiography showed a normal radioopacity of the mineralized tissues and the absence of The Journal of Pediatrics • March 2003
Table III. Pulp ratio (pulp area/tooth area) in 13 patients with VDRR and 15 age-matched control patients Tooth analyzed
Fig 5. Orthopantomogram radiograph of 15-year-old hypophosphatemic boy with irregular compliance to treatment. Normal radiodensity of mineralized tissues and absence of necrosed or treated teeth is evident. Large pulp chambers evocative of taurodontism, short dental crowns, and long roots are shown.
necrosed or treated teeth. However, large pulp chambers evocative of taurodontism, short dental crowns, and long roots were observed. Evaluation of the pulp ratio (pulp chamber area/tooth area) could be performed on the primary teeth (maxillary and mandibular second molars) of 8 patients 8 to 11 years of age and 10 healthy age-matched children and on the permanent teeth (maxillary bicuspids and mandibular molars and bicuspids) of 5 patients 15 to 21 years of age and 5 aged-matched control patients (Table III). Primary molars from hypophosphatemic children showed a 2- fold significantly higher pulp ratio, and permanent teeth from hypophosphatemic adolescents and adults showed a 1.6-fold significantly higher pulp ratio than their respective age-matched control patients.
DISCUSSION Familial hypophosphatemic vitamin D– resistant rickets is classically associated with several dental anomalies.8-16 These alterations lead to spontaneous dental abscesses and loss of primary and permanent teeth. Yet, the causal mechanism(s) remain unclear. Part of the mineralization defects may result from the abnormal environment of the dental and peridental cells, as patients with an altered PHEX gene have low concentration of phosphates in the extracellular fluids and low serum concentrations of 1,25-dihydroxyvitamin D. However, the localization of a PHEX mRNA expression in osteoblasts and odontoblasts5 suggests a local effect of the deficient production of the PHEX-derived protein. The current investigation of the dental status of 48 patients with VDRR show clear differences between patients born before 1970 and those born after. Patients born before 1970 had the poor dental status classically described for hypophosphatemic patients.8-13,15,18,20,21 In sharp contrast, all the 32 patients born after 1970 had a normal dental history, with DFT, DMFT, and/or DFT + DMFT indexes in the normal range for the age. Moreover, the higher incidence observed in boys (33%) resembles that described in healthy populations,29 whether or not resulting from the poor dental hygiene more often observed in boys. Dental Abnormalities in Patients With Familial Hypophosphatemic Vitamin D–Resistant Rickets: Prevention by Early Treatment With 1-Hydroxyvitamin D
Primary second molars 55 179 ± 32 (8)* 65 174 ± 29 (7)* 75 207 ± 60 (8)* 85 195 ± 54 (7)† Maxillary bicuspids Mandibular molars and bicuspids 15-25 212 ± 43 (4)* 35-45 258 ± 47 (6)* 36-46 225 ± 20 (7)* 37-47 227 ± 8 (5)*
Control patients 86 ± 23 (9) 89 ± 18 (9) 103 ± 20 (10) 118 ± 60 (10)
131 ± 17 (9) 148 ± 16 (7) 152 ± 34 (9) 152 ± 12 (6)
Pulp ratio (pulp area/tooth area 1000) was evaluated on semiautomatic analysis of dental radiographs. Total of 68 primary second molars (8 patients with VDRR 8 to 11 years of age and 8 age-matched control patients) and 53 maxillary bicuspids and mandibular molars and bicuspids (5 patients with VDRR aged 15-21 years and 5 control patients 19-21 years) was analyzed. Results are mean ± SD of pulp ratio for each type of teeth analyzed (number of teeth measured for each type is shown in brackets). Data in patients and control patients were compared by means of MannWhitney U test. *P < .001; †P = .002.
Finally, the radiographs performed in 14 patients showed a normal dentin aspect of the primary and permanent teeth as well as normal mineralization of the periodontal tissue. The satisfactory dental health in the younger hypophosphatemic patients may result in part from the general improvement of dental care resulting from the systematic use of fluoride-enriched toothpaste, better dental hygiene, and better follow-up of the children teething.27,30 It may also result from the change in the late 1970s of the therapeutic strategy proposed to correct the mineralization defects of hypophosphatemic patients. All patients born after 1972 had received phosphate supplements and Unalfa, from a mean age of 18 months (range, 1-6 years), whereas most older patients had received vitamin D or its reserve form (25-(OH)D3) but no Unalfa before the end of growth. Currently, most reports have shown no13-15 or little ef8,9 fect of treatment with vitamin D and phosphate supplements on dental anomalies. Local prophylactic measures have therefore been proposed to prevent the occurrence of multiple dental abscesses.22-25 The results obtained in group 1 patients are in agreement with these observations. Yet, the observations of low 1,25-dihydroxyvitamin D levels in patients with VDRR and the results in group 2 patients suggest that part of the failure of the vitamin D treatment to prevent dental mineralization defects may have resulted from an insufficient conversion of the administered vitamin D to its active form during the development and mineralization of primary and permanent dentitions. 329
Age at the commencement of the 1α-(OH)D3 treatment and compliance appear to be important contributors to dental health, the best results being observed in compliant patients treated from infancy, even though the clinical investigation of young adults (25-35 years of age) suggests that Unalfa treatment before 14 years of age may still have some beneficial effects on permanent teeth. Another noticeable observation concerns the dental status of the young patients with mixed dentition. Indeed, although all patients had normal DFT and DMFT indexes, patients born to affected mothers tended to have a poorer dental status for deciduous teeth (higher DFT index) than patients born to healthy mothers, possibly as a result of the low phosphate and vitamin D status of the mother during fetal odontogenesis. In contrast, these patients tended to have a better dental status for permanent teeth (lower DMFT index) than sporadic cases, possibly as a result of an earlier diagnosis and treatment. The beneficial dental effect of Unalfa and phosphate supplements after birth and the possible influence of maternal phosphate homeostasis suggest that most of the abnormal dental features presented by hypophosphatemic patients are linked to hypophosphatemia and/or to the deficient renal production of 1,25-(OH)2D. Part of the 1,25-(OH)2D dental actions may be indirect, through an increased intestinal absorption of calcium and phosphates. 1,25-(OH)2D may also exert some direct effect on the dental cells, as odontoblasts and ameloblasts express the vitamin D receptor and respond in vitro to this vitamin.31,32 Although the therapeutic improvement of phosphate and vitamin D metabolism normalizes the clinical dental status of patients, some alterations remain even in earlytreated, compliant patients, especially an abnormally high pulp area/tooth ratio of primary and permanent teeth, prominent pulp horns on deciduous molars, and, less frequently, prominent pulp horns and enlarged pulp chambers on permanent teeth. Findings of prominent pulp horns that extend up to the dentino-enamel junction, even in children with optimal treatment, are consistent with the earlier proposition that this sign should be considered pathognomonic for the disease.12 Previous reports have shown higher pulp area/tooth area ratios, 14 more frequent dental abscesses,15 taurodontism, and ectopic permanent canines18 in boys, suggesting a gene dosage effect. The current data as well as the results of an extensive review of the literature12 do not support such a sex-related effect. The prevalence of pulp chamber and pulp horn alterations was also not influenced by the phosphate status of the mother, normal or hypophosphatemic, suggesting that they do not closely depend on exposure to hypophosphatemia during fetal life. However, the prevalence of these alterations was higher in primary teeth. This may result from the early exposure of the primary teeth to decreased serum levels of phosphates and 1,25(OH)2D before beginning treatment. Alternatively, a greater sensitivity of the primary teeth to hypophosphatemia cannot be excluded, nor can be excluded the existence of an unknown factor, the PHEX gene product or another protein 330 Chaussain-Miller et al
controlled by this product, which would specifically control the maturation and mineralization of the primary teeth. These hypothetical mechanisms remain to be explored precisely. We thank Professor Mel Grumbach, PhD (San Francisco,CA), and Pr Michel Goldberg, PhD (Paris, France), for reading the manuscript and for helpful discussion. We also thank Pr Denis Bourgeois, PhD (Lyon, France), for his advice on national data and indexes.
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