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Mineralization defects associated with X‐linked hypophosphatemia rickets (XLH) in primary teeth. (A‐I) Individual values, means, and SDs from μCT analyses of dental tissues of patients with XLH versus control individuals. Control 95% CIs are shaded in gray. Patients 1–6 are color coded to recognize patterns in data across measurements. Mt.D = Mantle dentin (outermost); Cp.D = circumpulpal dentin (middle); Pp.D = proximal pulpal dentin (inner and last formed). (J) Measured volumes of interglobular dentin. Values for mildly affected patients with XLH fall within the 95% CI, and values for severely affected patients are substantially elevated above the 95% CI.
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X‐linked hypophosphatemia rickets (XLH) is caused by inactivating mutations in the phosphate‐regulating endopeptidase homolog, X‐linked (PHEX) gene, leading to renal phosphate wasting and hypophosphatemia. Dental mineralized tissues are affected by XLH, though tissue‐specific dental mineralization defects have been variably described. We aimed to q...
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Purpose:
In X-linked hypophosphatemia (XLH), excess FGF23 causes hypophosphatemia and low calcitriol, leading to musculoskeletal disease with clinical consequences. XLH treatment options include conventional oral phosphate with active vitamin D, or monotherapy with burosumab, a monoclonal antibody approved to treat children and adults with XLH. We...
X‐linked hypophosphatemia (XLH) is a rare disexase in which patients present with severe bowing of the legs, joint pain, and mobility problems. XLH has major adverse repercussions on the quality of life. X‐linked hypophosphatemia (XLH) is a rare disease in which patients present with severe bowing of the legs, joint pain, and mobility problems. XLH...
Vitamin D-dependent rickets type II (VDDR2) is a rare inherited autosomal recessive disorder wherein the genetic mutation results in a defect in the vitamin D receptor (VDR), thus leading to target resistance to 1.25-dihydroxy vitamin D. This results in hypocalcemia, hypophosphatemia, secondary hyperparathyroidism, and rickets. We report a case of...
X-linked hypophosphatemia (XLH), the most common form of hereditary rickets, is due to inactivation of PHEX, resulting in increased circulating fibroblast growth factor 23. Consequent renal phosphate loss leads to hypophosphatemia, rickets, and progressive bow deformity. Inheritance is X-linked dominant, such that heterozygous females are affected,...
X-linked hypophosphatemia (XLH) is the most common monogenetic cause of chronic hypophosphatemia, characterized by rickets and osteomalacia. Disease manifestations and treatment of XLH patients in the Netherlands are currently unknown. Characteristics of XLH patients participating in the Dutch observational registry for genetic hypophosphatemia and...
Citations
... Typically, the thin dentin consists of large calcospherites and globules of abnormally calcified dentin that are surrounded by wide irregular zones of interglobular dentin [3]. In some cases, enamel hypoplasia can be found, though an effect on dentin is more common [2,32]. It is characterized by wide zones of irregular dentin, extensive interglobular unmineralized dentin, clefts, and tubular defects that extend to the enamel and allow bacterial invasion into the pulp [2,33]. ...
X-linked hypophosphatemia is a rare, hereditary disorder that significant influences teeth and alveolar bone. The first clinical sign leading to the diagnosis of X-linked hypophosphatemia is often dental impairment with dental abscesses and dentin mineralization defects. Genetic analysis helped find the responsible gene and therefore opened up new ways of therapeutically managing X-linked hypophosphatemia. The human monoclonal antibody Burosumab represents a milestone in the targeted therapy of this hereditary disease by directly addressing its pathophysiology. Targeted therapy has been shown to improve skeletal impairment, pain, and phosphate metabolism. However, the influence of this new therapy on dental impairment has only been addressed in a few recent studies with varying results. Therefore, in this review, we aim to summarize the dental phenotype and analyze the different treatment modalities with a focus on dental impairment.
... Our study also showed that the first molar of the Hyp mice is a robust model to study tooth mineralization rather than the continuously growing incisor, as it exhibits most of the dental features previously reported in patients with XLH. 6,32 A recent study analyzed the impact of XLH treatments on dentoalveolar tissues in Hyp mice, including a therapy targeting FGF23. 23 In contrast with the positive outcomes reported here, this therapy showed a limited impact on alveolar bone and dental features, failing to demonstrate additional benefits compared to 1,25-(OH) 2 -vitamin D3 treatment. ...
Elevated fibroblast growth factor 23 (FGF23) in X-linked hypophosphatemia (XLH) results in rickets and phosphate wasting, manifesting by severe bone and dental abnormalities. Burosumab, a FGF23-neutralizing antibody, an alternative to conventional treatment (phosphorus and active vitamin D analogs), showed significant improvement in the long bone phenotype. Here, we examined whether FGF23 antibody (FGF23-mAb) also improved the dentoalveolar features associated with XLH. Four-week-old male Hyp mice were injected weekly with 4 or 16 mg·kg⁻¹ of FGF23-mAb for 2 months and compared to wild-type (WT) and vehicle (PBS) treated Hyp mice (n = 3–7 mice). Micro-CT analyses showed that both doses of FGF23-mAb restored dentin/cementum volume and corrected the enlarged pulp volume in Hyp mice, the higher concentration resulting in a rescue similar to WT levels. FGF23-mAb treatment also improved alveolar bone volume fraction and mineral density compared to vehicle-treated ones. Histology revealed improved mineralization of the dentoalveolar tissues, with a decreased amount of osteoid, predentin and cementoid. Better periodontal ligament attachment was also observed, evidenced by restoration of the acellular cementum. These preclinical data were consistent with the retrospective analysis of two patients with XLH showing that burosumab treatment improved oral features. Taken together, our data show that the dentoalveolar tissues are greatly improved by FGF23-mAb treatment, heralding its benefit in clinics for dental abnormalities.
... Severe 25-OHD deficiency during early life can result in rickets and dental defects including enamel hypoplasia. [38][39][40][41] However, the consequences of lesser degrees of deficiency perinatally and in early childhood are less well understood. The lack of additional evidence has led to considerable debate and lack of clarity around the importance of maintaining normal 25-OHD levels during pregnancy, lactation, and early childhood. ...
Postnatally, severe vitamin D deficiency commonly results in rickets as well as potentially defects in tooth mineralisation. The effects of milder deficiency on oral health outcomes later in life are still unclear. This study used Micro‐Computed Tomography (Micro‐CT), Energy Dispersive X‐ray analysis (EDX) and Raman spectroscopy to investigate mineral density, total density, and elemental composition of enamel and dentine in 63 exfoliated primary incisors from participants with known 25‐hydroxyvitamin D levels (25‐OHD) at birth. No differences in mineralisation and chemical composition using Micro‐CT and EDX analysis were observed irrespective of 25‐OHD status. Subtle structural differences were observed via Raman Spectroscopy, with more crystalline enamel observed in those with sufficient 25‐OHD at birth. While subtle, the differences seen suggest further attention should be given to children with known milder levels of vitamin D deficiency in early life.
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... Previously published clinical studies on dental complications in patients with XLH were mainly case reports and case series (24)(25)(26)(27)(28)(29). Some studies with larger cohorts focused on the severity of periodontitis or apical periodontitis, the histology and morphology of the teeth, or the associations between enthesopathy and the severity of dental complications (6,9,12,(30)(31)(32). Accordingly, to date, comprehensive information about dental complications associated with rickets (eg, periodontitis, apical periodontitis, and cavities) in adult patients with XLH is missing. ...
Context:
Conventional treatment of XLH was reported to prevent dental complications, but whether the preventive effect was different among different types of teeth, including anterior teeth and molar teeth, is uncertain. Evidence of the preventive effect of conventional treatment on ectopic ossifications is also limited.
Objective:
To compare dental complications and ectopic ossifications among XLH adults with early (< 5 years old) or late (≥5 years old) conventional treatment.
Methods:
This retrospective observational study included a total of 30 adults with XLH using orthopantomograms, spinal computed tomography scans and X-rays of hip/knee joints. Dental complications, including decayed, missing filled (DMF) index and devitalized tooth, apical periodontitis, and periodontitis, were evaluated. The index of ossification of the anterior/posterior longitudinal ligament and yellow ligament (OA/OP/OY index) and the sum of the OA/OP/OY index (OS index) were utilized to evaluate the severity of spinal ligament ossification. The severity of the hip/knee osteophytes was evaluated by the Kellgren-Lawrence (KL) classification.
Results:
The number of sound teeth was significantly lower, and the DMF index was significantly higher in patients with late treatment. The severity of dental complications in the anterior tooth and molar tooth, OA/OP/OY/OS index, and KL grade were not significantly different among patients with early treatment and those with late treatment.
Conclusion:
Early treatment could prevent dental complications but did not prevent ectopic ossification in adult patients with XLH. The difference in the preventive effect was not observed among different types of teeth.
... Inorganic phosphate and calcium are essential for the mineralization of teeth and bone. Abnormal mineralization of dentin is the main cause of dental problems in XLH patients [23][24][25][26][27][28]. ...
X-linked hypophosphatemia (XLH) is the most common genetic form of rickets and osteomalacia and is characterized by growth retardation, deformities of the lower limbs, and bone and muscular pain. Spontaneous dental abscesses caused by endodontic infections due to dentin dysplasia are well-known dental manifestations. When dentin affected by microcracks or attrition of the enamel is exposed to oral fluids, oral bacteria are able to invade the hypomineralized dentin and pulp space, leading to pulp necrosis, followed by the formation of a periapical gingival abscess. Without appropriate dental management, this dental manifestation results in early loss of teeth and deterioration in the patient’s quality of life. Early specific dental intervention and oral management in collaboration with medical personnel are strongly recommended for XLH patients. Importantly, dental manifestations sometimes appear before the diagnosis of XLH. Dentists should be alert for this first sign of XLH and refer affected children to a pediatrician for early diagnosis. A humanized monoclonal antibody for FGF23 (burosumab) is a promising new treatment for XLH; however, the effects on the dental manifestations remain to be elucidated. The establishment of fundamental dental therapy to solve dental problems is still underway and is eagerly anticipated.
... (5,6) These infections are very frequent, (7)(8)(9)(10) increase the risk of tooth loss, and alter the quality of life of XLH patients. (11,12) The origin of these infections is the combination of hypomineralized and hypoplastic dentin, (13,14) enlarged pulp chambers with prominent pulp horns, and microcracks in the enamel, which favor the infection of the pulp chamber by oral bacteria. In children, these infections lead to dental abscesses, which translate clinically into painful swelling of the gum. ...
X‐linked hypophosphatemia (XLH) is a rare genetic disorder that disrupts skeletal and dental mineralization. In addition to rickets in children, XLH patients also have frequent spontaneous dental abscesses that increase the risk of tooth loss and may lead to facial cellulitis. Hypo‐mineralized and hypoplastic dentin is the main driver of these infections. Conventional treatment (CT) of XLH improves this tissue defect and reduces the occurrence of dental abscesses. Burosumab is a recent treatment for XLH that targets excess circulating FGF23, and its benefits on rickets have been demonstrated. It is not yet known whether burosumab improves dental manifestations of XLH. The main objective of our study was to compare the incidence of dental abscesses with XLH treated with either CT or burosumab. In this monocentric retrospective study, we measured and compared the incidence of dental abscess in children with XLH treated with either CT or burosumab, followed at our dental center for at least 1 year. The primary endpoint was the number of dental abscesses per month of dental follow‐up. Seventy‐one children were included in the study, with a mean age at the start of dental follow‐up of 7.86 (SD 3.76). Thirty‐eight children were treated with CT (53.5%) and 33 with burosumab (46.5%). All children treated with burosumab had previously been treated with CT. The mean number of dental abscesses per month of dental follow‐up was significantly reduced in the burosumab group compared with the CT group (0.01 vs. 0.04; P= 0.04). Burosumab treatment appears to be associated with a reduction in the number of dental abscesses in XLH children, compared with CT. This article is protected by copyright. All rights reserved.
... Children with XLH are born without rickets and signs of rickets develop over several months, presenting with bowing of lower limbs, and short stature (33). Patients with XLH also have frequent dental abscesses, wide dental canals and open apices, which may require root canal treatments or tooth extractions (33)(34)(35). Sensorineural hearing loss is common in adults and some children with XLH, and may include cochlear malformation (36). ...
Hypophosphatemic rickets typically presents in infancy or early childhood with skeletal deformities and growth plate abnormalities. The most common causes are genetic (such as X-linked hypophosphatemia), and these typically will result in lifelong hypophosphatemia and osteomalacia. Knowledge of phosphate metabolism, including the effects of fibroblast growth factor 23 (FGF23) (an osteocyte produced hormone that downregulates renal phosphate reabsorption and 1,25-dihydroxyvitamin-D (1,25(OH)2D) production), is critical to determining the underlying genetic or acquired causes of hypophosphatemia, and to facilitate appropriate treatment. Serum phosphorus should be measured in any child or adult with musculoskeletal complaints suggesting rickets or osteomalacia. Clinical evaluation incudes thorough history, physical exam, laboratory investigations, genetic analysis (especially in the absence of a guiding family history) and imaging to establish etiology and to monitor severity and treatment course. The treatment depends on the underlying cause, but often includes active forms of vitamin D combined with phosphate salts, or anti-FGF23 antibody treatment (burosumab) for X-linked hypophosphatemia. The purpose of this article is to explore the approach to evaluating hypophosphatemic rickets and its treatment options.
... Interglobular dentin results from disrupted mineralization due to TNAP inactivation, resulting in unmerged calcospherites, discrete mineralization foci that normally would grow and merge into a unified mineralization front. Interglobular dentin is more commonly reported in rachitic conditions including X-linked hypophosphatemia (XLH), (47) and to date only a very few case reports to our knowledge have described interglobular dentin in teeth from HPP patients. (44,48) HPP mouse models have, to date, not been useful for modeling mantle dentin defects or interglobular dentin, (19) in part due to the extremely small size of mouse dentition, as well as rapid crown and root development with different sequences of mineralization events than in human odontogenesis. ...
Hypophosphatasia (HPP) is the inherited error‐of‐metabolism caused by mutations in ALPL, reducing the function of tissue‐nonspecific alkaline phosphatase (TNAP/TNALP/TNSALP). HPP is characterized by defective skeletal and dental mineralization and is categorized into several clinical subtypes based on age of onset and severity of manifestations, though premature tooth loss from acellular cementum defects is common across most HPP subtypes. Genotype‐phenotype associations and mechanisms underlying musculoskeletal, dental, and other defects remain poorly characterized. Murine models that have provided significant insights into HPP pathophysiology also carry limitations including monophyodont dentition, lack of osteonal remodeling of cortical bone, and differing patterns of skeletal growth. To address this, we generated the first gene edited large animal model of HPP in sheep via CRISPR/Cas9‐mediated knock‐in of a missense mutation (c.1077C>G; p.I359M) associated with skeletal and dental manifestations in humans. We hypothesized that this HPP sheep model would recapitulate the human dentoalveolar manifestations of HPP. Compared to wild‐type (WT), compound heterozygous (cHet) sheep with one null allele and the other with the targeted mutant allele exhibited the most severe alveolar bone, acellular cementum, and dentin hypomineralization defects. Sheep homozygous for the mutant allele (Hom) showed alveolar bone and hypomineralization effects and trends in dentin and cementum, while sheep heterozygous (Het) for the mutation did not exhibit significant effects. Important insights gained include existence of early alveolar bone defects that may contribute to tooth loss in HPP, observation of severe mantle dentin hypomineralization in an HPP animal model, association of cementum hypoplasia with genotype, and correlation of dentoalveolar defects with ALP levels. The sheep model of HPP faithfully recapitulated dentoalveolar defects reported in individuals with HPP, providing a new translational model for studies into etiopathology and novel therapies of this disorder, as well as proof‐of‐principle that genetically engineered large sheep models can replicate human dentoalveolar disorders.
... Our µCT analyses of mouse molars revealed that odontoblast-specific deletion of Trps1 leads to decreased crown dentin volume, while no significant differences were detected in dentin mineral density. However, histological analyses revealed a wider predentin and globular dentin pattern in Trps1 Col1a1 cKO mice, which are indicative of disturbed dentin mineralization (68). Interestingly, the functional ex vivo assays assessing dental tissues hardness and their susceptibility to acidinduced demineralization revealed that not only dentin, but also enamel hardness was decreased in Trps1 Col1a1 cKO mice, with some sex-specific differences. ...
Dental caries is the most common chronic disease in children and adults worldwide. The complex etiology of dental caries includes environmental factors as well as host genetics, which together contribute to inter-individual variation in susceptibility. The goal of this study was to provide insights into the molecular pathology underlying increased predisposition to dental caries in trichorhinophalangeal syndrome (TRPS). This rare inherited skeletal dysplasia is caused by mutations in the TRPS1 gene coding for the TRPS1 transcription factor. Considering Trps1 expression in odontoblasts, where Trps1 supports expression of multiple mineralization-related genes, we focused on determining the consequences of odontoblast-specific Trps1 deficiency on the quality of dental tissues. We generated a conditional Trps1Col1a1 knockout mouse, in which Trps1 is deleted in differentiated odontoblasts using 2.3kbCol1a1-CreERT2 driver. Mandibular first molars of 4wk old male and female mice were analyzed by micro-computed tomography (μCT) and histology. Mechanical properties of dentin and enamel were analyzed by Vickers microhardness test. The susceptibility to acid demineralization was compared between WT and Trps1Col1a1cKO molars using an ex vivo artificial caries procedure. μCT analyses demonstrated that odontoblast-specific deletion of Trps1 results in decreased dentin volume in male and female mice, while no significant differences were detected in dentin mineral density. However, histology revealed a wider predentin layer and the presence of globular dentin, which are indicative of disturbed mineralization. The secondary effect on enamel was also detected, with both dentin and enamel of Trps1Col1a1cKO mice being more susceptible to demineralization than WT tissues. The quality of dental tissues was particularly impaired in molar pits, which are sites highly susceptible to dental caries in human teeth. Interestingly, Trps1Col1a1cKO males demonstrated a stronger phenotype than females, which calls for attention to genetically-driven sex differences in predisposition to dental caries. In conclusion, the analyses of Trps1Col1a1cKO mice suggest that compromised quality of dental tissues contributes to the high prevalence of dental caries in TRPS patients. Furthermore, our results suggest that TRPS patients will benefit particularly from improved dental caries prevention strategies tailored for individuals genetically predisposed due to developmental defects in tooth mineralization.
... These defects contribute to pulpal necrosis and abscesses, which may necessitate endodontic therapy and extractions (Baroncelli et al., 2021;Chesher et al., 2018;Foster, Nociti Jr., & Somerman, 2014;Opsahl Vital et al., 2012). Clayton et al., 2021;Figure 2c,d), and cellular cementum is hypomineralized . The Hyp mutant mouse model of XLH carries Phex mutations and phenocopies aspects of XLH (Eicher et al., 1976), including enamel and dentin mineralization defects (Coyac et al., 2018;Zhang et al., 2020). ...
The periodontium supports and attaches teeth via mineralized and nonmineralized tissues. It consists of two, unique mineralized tissues, cementum and alveolar bone. In between these tissues, lies an unmineralized, fibrous periodontal ligament (PDL), which distributes occlusal forces, nourishes and invests teeth, and harbors progenitor cells for dentoalveolar repair. Many unanswered questions remain regarding periodontal biology. This review will focus on recent research providing insights into one enduring mystery: the precise regulation of the hard‐soft tissue borders in the periodontium which define the interfaces of the cementum–PDL–alveolar bone structure. We will focus on advances in understanding the molecular mechanisms that maintain the unmineralized PDL “between a rock and a hard place” by regulating the mineralization of cementum and alveolar bone.
