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Tumoral calcinosis (TC) is a rare entity causing abnormal periarticular calcifications in the affected joint observed in the first two decades of life. It is also known to affect the teeth. Few case reports on TC talk about the dental findings. This article presents the clinical, radiological and histological appearance of dental abnor...
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... Another potential phenotypic manifestation of the disease is tooth involvement, as evidenced by short, abnormal roots, pulp calcifications, and pulp cavity obliteration on a panoramic radiograph [18,41]. ...
Tumoral calcinosis is an extremely rare genetic disease caused by mutations in three genes, GALNT3, FGF23, and KL, which disrupt phosphorus metabolism. The hallmark of this condition is the formation of tumors in the soft tissues around the joints. Other phenotypic features of tumoral calcinosis are dental involvement and brain and vascular calcifications. The clinical case reported herein presents for the first time to the scientific community the c.202A>G (p.Thr68Ala) mutation of the FGF23 gene, associated with a hyperphosphatemic variant of tumoral calcinosis and multiple severe vascular aneurysms. A female patient underwent multiple surgeries for tumor formations in her soft tissues that first appeared at the age of 12 months. On this occurrence, the patient was found to have hyperphosphatemia, low phosphate clearance, increased tubular reabsorption with normal levels of total and ionized calcium, vitamin D3, and parathyroid hormone, and no effect of treatment with sevelamer hydrochloride and a low-phosphate diet. At the age of 39, the patient underwent imaging studies due to edema and a pulsating formation in the neck area, which revealed multiple vascular aneurysms with thrombosis, for which she received operative and interventional treatment. In this connection, and because of the established phosphorus metabolism disturbance, a genetic disease was suspected. The sequence analysis and deletion/duplication testing of the 358 genes performed on this occasion revealed that the woman was homozygous for a variant of the c.202A>G (p.Thr68Ala) mutation of the FGF23 gene. The established mutation is not present in population databases. The presented clinical case is the first and only one in the world to demonstrate the role of this type of FGF23 gene mutation in the development of a hyperphosphatemic variant of tumoral calcinosis characterized by aggressive formation of multiple vascular aneurysms.
... The pulp, normally an unmineralized oral tissue composed of vascular, nervous, and connective tissue, are often obstructed with pulp stones in HFTC (7,18). Complete obliteration of the pulp space is also observed in patients (46). The presence of abnormal calcification in the pulp space can hinder root canal therapies (47). ...
Hyperphosphatemic familial tumoral calcinosis (HFTC) is a rare and disabling disorder of fibroblast growth factor 23 (FGF23) deficiency or resistance. The disorder is manifest by hyperphosphatemia, inappropriately increased tubular reabsorption of phosphate and 1,25-dihydroxy-Vitamin D, and ectopic calcifications. HFTC has been associated with autosomal recessive pathogenic variants in: (1) the gene encoding FGF23; (2) GALNT3, which encodes a protein responsible for FGF23 glycosylation; and (3) KL, the gene encoding KLOTHO, a critical co-receptor for FGF23 signaling. An acquired autoimmune form of hyperphosphatemic tumoral calcinosis has also been reported. Periarticular tumoral calcinosis is the primary cause of disability in HFTC, leading to pain, reduced range-of-motion, and impaired physical function. Inflammatory disease is also prominent, including diaphysitis with cortical hyperostosis. Multiple treatment strategies have attempted to manage blood phosphate, reduce pain and inflammation, and address calcifications and their complications. Unfortunately, efficacy data are limited to case reports and small cohorts, and no clearly effective therapies have been identified. The purpose of this review is to provide a background on pathogenesis and clinical presentation in HFTC, discuss current approaches to clinical management, and outline critical areas of need for future research.
... In addition to these visible and palpable calcific masses, dental and ocular abnormalities may be observed [1,2,4,8]. Few reports have described the orofacial and dental findings in familial TC [7,[9][10][11][12][13][14][15][16][17]. ...
... Dental abnormalities in patients with TC have been described in a limited number of reports [7,[9][10][11][12][13][14][15]. Clinically, enamel hypoplasia [11][12][13]15] and morphological alterations of the crowns [14,15] or a normal coronal tooth structure [9] have been described. ...
... Dental abnormalities in patients with TC have been described in a limited number of reports [7,[9][10][11][12][13][14][15]. Clinically, enamel hypoplasia [11][12][13]15] and morphological alterations of the crowns [14,15] or a normal coronal tooth structure [9] have been described. In our case, the patient's dentition showed enamel hypoplasia but normal coronal color and morphology. ...
Tumoral calcinosis is a rare familial disorder characterized by masses of calcification in periarticular soft tissues. Few reports in the literature have described dental abnormalities in patients with tumoral calcinosis. These dental abnormalities include short bulbous roots, pulp stones, and obliteration of the pulp cavity. In this case report, we describe the dental radiographic findings in a patient with tumoral calcinosis; these findings were similar to dentin dysplasia. Periapical radiolucencies with noncarious teeth were observed in addition to the dental findings previously reported.
... The formation of an ectopic matrix was previously reported in the Klotho and Fgf23-deficient animals.14,15 Similarly, a dystrophic pulp calcification, root dilaceration, and a thistle shaped pulp have been reported in the tumoral calcinosis patients who are deficient in FGF23 and have increased phosphate levels.31,32 This ectopic ossification is linked to an increase in apoptosis of the odontoblasts.33 ...
Deletion or mutation of dentin matrix protein 1 (DMP1) leads to hypophosphatemic rickets and defects within the dentin. However, it is largely unknown if this pathological change is a direct role of DMP1 or an indirect role of phosphate (Pi) or both. It has also been previously shown that Klotho-deficient mice, which displayed a high Pi level due to a failure of Pi excretion, causes mild defects in the dentinal structure. This study was to address the distinct roles of DMP1 and Pi homeostasis in cell differentiation, apoptosis and mineralization of dentin and enamel. Our working hypothesis was that a stable Pi homeostasis is critical for postnatal tooth formation, and that DMP1 has an antiapoptotic role in both amelogenesis and dentinogenesis. To test this hypothesis, Dmp1-null (Dmp1−/−), Klotho-deficient (kl/kl), Dmp1/Klotho-double-deficient (Dmp1−/−/kl/kl) and wild-type (WT) mice were killed at the age of 6 weeks. Combinations of X-ray, microcomputed tomography (μCT), scanning electron microscopy (SEM), histology, apoptosis and immunohistochemical methods were used for characterization of dentin, enamel and pulp structures in these mutant mice. Our results showed that Dmp1−/− (a low Pi level) or kl/kl (a high Pi level) mice displayed mild dentin defects such as thin dentin and a reduction of dentin tubules. Neither deficient mouse line exhibited any apparent changes in enamel or pulp structure. However, the double-deficient mice (a high Pi level) displayed severe defects in dentin and enamel structures, including loss of dentinal tubules and enamel prisms, as well as unexpected ectopic ossification within the pulp root canal. TUNEL assay showed a sharp increase in apoptotic cells in ameloblasts and odontoblasts. Based on the above findings, we conclude that DMP1 has a protective role for odontoblasts and ameloblasts in a pro-apoptotic environment (a high Pi level).
... In contrast, the teeth of hyperphosphatemic TC patients or mouse models (Fgf23 −/− , Klotho −/− , and GALNT3 mutant mice) have not been studied extensively. Limited case reports of TC skeletal and tooth abnormalities noted calcification around major joints, hyperostosis, and ectopic calcification of the pulp chambers (Naikmasur et al., 2008; Witcher et al., 1989). Further, examination of incisors from Klotho −/− revealed dentin abnormalities (Suzuki et al., 2008). ...
... The alterations noted in the dentoalveolar complex of Fgf23 −/− are consistent with case studies of TC patients and other hyperphosphatemic animal models. Reports of tumoral calcinosis patients, who have deficient FGF23 and elevated phosphate levels, include dystrophic pulp calcification, root dilacerations, and thistle shaped pulps (Dumitrescu et al., 2009; Naikmasur et al., 2008; Witcher et al., 1989). Further, Klotho −/− mice exhibit a nearly identical physical and biochemical phenotype to Fgf23 −/− mice (e.g. ...
Fibroblast growth factor-23 (FGF23) is a hormone that modulates circulating phosphate (P(i)) levels by controlling P(i) reabsorption from the kidneys. When FGF23 levels are deficient, as in tumoral calcinosis patients, hyperphosphatemia ensues. We show here in a murine model that Fgf23 ablation disrupted morphology and protein expression within the dentoalveolar complex. Ectopic matrix formation in pulp chambers, odontoblast layer disruption, narrowing of periodontal ligament space, and alteration of cementum structure were observed in histological and electron microscopy sections. Because serum P(i) levels are dramatically elevated in Fgf23(-/-), we assayed for apoptosis and expression of members from the small integrin-binding ligand, N-linked glycoprotein (SIBLING) family, both of which are sensitive to elevated P(i) in vitro. Unlike X-linked hypophosphatemic (Hyp) and wild-type (WT) specimens, numerous apoptotic osteocytes and osteoblasts were detected in Fgf23(-/-) specimens. Further, in comparison to Hyp and WT samples, decreased bone sialoprotein and elevated dentin matrix protein-1 protein levels were observed in cementum of Fgf23(-/-) mice. Additional dentin-associated proteins, such as dentin sialoprotein and dentin phosphoprotein, exhibited altered localization in both Fgf23(-/-) and Hyp samples. Based on these results, we propose that FGF23 and (P(i)) homeostasis play a significant role in maintenance of the dentoalveolar complex.
Teeth are mineralized organs comprised of three unique hard tissues, enamel, dentin, and cementum, and supported by the surrounding alveolar bone. While odontogenesis differs from osteogenesis in several respects, tooth mineralization is susceptible to similar developmental failures as bone. Here we discuss conditions fitting under the umbrella of "rickets," which traditionally referred to skeletal disease associated with vitamin D deficiency, but has been more recently expanded to include newly identified factors involved in endocrine regulation of vitamin D, phosphate, and calcium, including phosphate regulating endopeptidase homolog, X-linked (PHEX), fibroblast growth factor 23 (FGF23), and dentin matrix protein 1 (DMP1). Systemic mineral metabolism intersects with local regulation of mineralization, and factors including tissue nonspecific alkaline phosphatase (TNAP) are necessary for proper mineralization, where rickets can result from loss of activity of TNAP. Individuals suffering from rickets often bear the additional burden of a defective dentition, and transgenic mouse models have aided in understanding the nature and mechanisms involved in tooth defects, which may or may not parallel rachitic bone defects. This report reviews dental effects of the range of rachitic disorders, including discussion of etiologies of hereditary forms of rickets, a survey of resulting bone and tooth mineralization disorders, and a discussion of mechanisms, known and hypothesized, involved in the observed dental pathologies. Descriptions of human pathology are augmented by analysis of transgenic mouse models, and new interpretations are brought to bear on questions of how teeth are affected under conditions of rickets. In short, the "rachitic tooth" will be revealed.
