INTRODUCTION

X-linked hypophosphatemia (XLH) is a skeletal genetic disease in which increased loss of phosphate in the kidney leads to hypophosphatemia and prevents normal mineralization of bones and tooth hard tissues. It is a rare disease caused by mutations in the PHEX (phosphate regulating endopeptidase analog, X-linked) gene. The gene encodes an endopeptidase that is expressed primarily on the surface of osteoblasts, osteocytes, odontoblasts, and cementoblasts. The disease follows an X-linked mode of transmission with dominant expression and represents the first cause of hypophosphatemic rickets (1,2,3,4).

The problem derived from this congenital pathology is that, typically, patients show low levels of serum phosphate secondary to an increase in phosphaturia, elevated alkaline phosphatase, normal levels of parathyroid hormone (PTH), and low urinary calcium. X-rays show the typical features of rickets without significant bone resorption, unlike rickets secondary to vitamin D deficiency. The growth plates of long bones have a hollow appearance, with greater thickness and irregularities (1).

Phosphate loss has been linked to two causes. First, the loss of phosphate may be secondary to increased signaling of fibroblast growth factor 23 (FGF23), which is a circulating factor secreted by osteoblasts, odontoblasts, and osteocytes. In the renal proximal tubule, FGF23 inhibits the transport of sodium phosphate through the NPT2a and NPT2c ion channels, and prevents the production of 1,25-diOH-vitamin D. As a consequence, it decreases the renal and digestive absorption of phosphate. Phosphate loss secondary to elevated FGF23 primarily results in X-linked hypophosphatemic rickets (XLHR), due to loss-of-function mutations in PHEX. Hypophosphatemia due to excess FGF23 and a direct effect of the absence of functional PHEX on the mineralization of the extracellular matrix (ECM) of the bone or tooth, generates mineralization defects that involve bones and teeth (5,6). Second, phosphate loss may be due to a primary renal tubular defect, that is, hereditary hypophosphatemic rickets with hypercalciuria (HHRH) due to molecular defects of the NPT2c sodium phosphate channel. All of these conditions share a decreased ability to transport phosphate from the glomerular filtration to the bloodstream (5,7).

The reduction in phosphate circulating levels disturbs the mineralization of bones and teeth, resulting in various clinical signs and symptoms. Those manifestations include bone tissue pain, bone deformities and fractures, growth failure, spontaneous pulpitis, abscesses, and hearing loss in both children and adults. Infection of the dental pulp tissue could be considered a secondary effect as a result of microcracks in the enamel and poor mineralization of the dentin, which facilitates microbial invasion (2).

Since this is a rare disease, there is not much bibliography currently available, so it was pertinent to take a preliminary look at the existing evidence. For this reason, the purpose was to analyze this genetic pathology and its impact on the oral hard dental and periodontal tissues such as enamel, dentin, cementum, and alveolar bone. This, in the future, will allow increasing the number of observational and experimental clinical studies to clarify the impact on the oral cavity of this disease as well as its possible treatment alternatives. Therefore, the research question was: What impact does XLH have on the dental and periodontal hard tissues of the oral cavity?

MATERIALS AND METHODS

An integrative literature review (8) was conducted, summarizing theoretical or empirical literature to provide a comprehensive understanding of XLH, particularly its impact on oral cavity hard tissues. In this integrative review, a search was carried out in the PubMed and SciELO databases. The search terms were X-linked hypophosphatemia, dental tissue, periodontium, dentin, enamel, cementum, and alveolar bone using AND, OR and NOT Boolean connectors. The search was limited to literature in Spanish and English published between 2000 and 2020.

RESULTS

13 articles were selected and included in the present review, which are presented in Table 1.

Hypophosphatemia and its Relationship with Dental Tissues

Hypophosphatemia has been associated with hypomineralization of dental tissues. Ali Rabbani et al. (9) in 2012 carried out a study with 19 patients with an average age of 10 (± 4.23) years. All cases of suspected hypophosphatemic rickets were enrolled in this study. The diagnosis of hypophosphatemic rickets was made on the basis of clinical and radiological findings of rickets in patients with low serum phosphate, normal or low serum calcium (<8.2 mg/dL), normal levels of 25 (OH) 2.-vit D (<15 pg/mL), and normal or slightly elevated PTH with high level of serum alkaline phosphatase (> 55 pg/mL). The most frequent dental problems were dental caries and delayed tooth eruption in 9 (47.7 %) patients. Enamel hypoplasia was found in 8 (42.1 %) patients, and 3 (15.8 %) patients had taurodontism; all in the latter groups were male. Both dental abscesses and gingivitis were found in 2 (10.5 %) patients. Six (54.5 %) female patients and 3 (37.5 %) male patients had dental caries. The prevalence of dental caries was significantly higher in the case group (p = 0.04) than it was in the healthy control group (10.5 %). They conclude that hypophosphatemic rickets is a disease that can present different clinical characteristics, such as alteration in the hard tissues of the tooth, and in which dental caries is one of the most prevalent (9).

Dentin is one of the dental tissues most affected by this pathology. Human dentin mineralization is a continuous process that occurs by growth and fusion of calcospherites. This process appears to be controlled by non-collagenous proteins, particularly by a family of phosphorylated proteins called as small integrin-binding ligand N-linked glycoproteins (SIBLINGs). Some non-phosphorylated proteins such as osteocalcin, osteonectin, and proteoglycans are also involved in this process (10,11).

Patients with hypophosphatemia have been reported to show large interglobular spaces in circumpulpal dentin. With regard to XLH-related dentin alterations, a peptide, ASARM, derived from matrix extracellular phosphoglycoprotein (MEPE) has been observed to inhibit ECM mineralization and odontoblast differentiation, while increasing matrix expression extracellular phosphoglycoprotein and tissue nonspecific alkaline phosphatase (TNAP) (10,11).

Salmon et al. (10), in an analysis of dental germs, indicated that alkaline phosphatase activation, MEPE localization and osteopontin (OPN) in odontoblasts and in dentin of patients with XLH is abnormal and shows an accumulation of MEPE in non-mineralized interglobular spaces. Interestingly, the pulp-dentin complex in teeth of patients with XLH is poorly organized and shows impaired odontoblast polarization and arrangement. This observation is consistent with an inhibition of odontoblast differentiation, possibly resulting from increased expression of MEPE in patients with XLH. Mutations in the PHEX gene lead to an accumulation of protein fragments that contribute to mineralization defects observed in pathological bone and dentin. OPN accumulates in the dental dentin of patients with XLH, especially in abnormal calcospherites.

Dental abnormalities that occur due to XLH affect both primary and permanent dentitions and are caused by impaired dentin mineralization. This results in a dental pulp with a large chamber, presence of globular dentin and large tubules, which connect the dental pulp to the dentin-enamel junction, providing a direct channel for bacteria and pulp irritants, which could be the route through which spontaneous dental abscesses occur. Front teeth can be affected more quickly and severely than molars. Other dental abnormalities include delayed tooth eruption, possible enamel hypoplasia, and short roots (12,13).

Boukpessi et al. (14) analyzed seven young patients with XLH and reported they accumulated OPN, which was also localized in the pericanalicular matrix that extends beyond the osteocyte lacunae, as well as in the hypomineralized dentin matrix. OPN, a potent mineralization inhibitor, is a member of an acidic, phosphorylated ECM protein family that binds to calcium and are known to regulate dental and skeletal mineralization.

Coyac et al. (15) evaluated the local role of the PHEX gene in a 3D MEC mineralization model. Collagen-dense hydrogels were seeded with human dental pulp cells from patients with characterized PHEX gene mutations or with healthy controls, and cultured for up to 24 days using osteogenic medium with standard phosphate concentration. Calcium quantification, tomography, and histology with von Kossa stain for minerals showed significantly less mineralization in seeded cultures of cells from patients with XLH. Although atypical mineralization was observed along the collagen fibrils by electron microscopy in both groups, Raman microspectrometry indicated that cells from XLH patients harboring the PHEX mutation produced less mineralized tissues. These tissues had a deteriorated mineral quality, with less carbonate substitution and lower crystallinity. In cultures of patients with XLH, immunoblot revealed higher amounts of OPN, dentin matrix protein 1 (DMP1) and MEPE than controls. Fragments of these proteins that were not found in the controls were also present, suggesting a role for the mutation of the PHEX gene in the degradation of the SIBLING protein.

Likewise, Coyac et al. (16) examined changes in dentin composition and structure using Raman spectroscopy in human teeth with XLH and transmission electron microscopy in the dentin of Hyp mice (XLH mouse model). The dentin of patients with XLH showed changes in the quality of the apatite mineral, with higher carbonate substitution and lower crystallinity compared to the dentin of control teeth of the same age. Furthermore, ultrastructural analysis by transmission electron microscopy revealed a significant disorganization of dentin peri and intertubular structure, with odontoblast processes residing within a non-mineralized matrix sheath in the Hyp mouse. Taken together, these results indicate that, as for cementum and bone, there are mineral quality alterations and matrix changes in the dentin of subjects with XLH that reflect a high sensitivity to serum phosphate levels and possibly other local changes in the dentin matrix.

Hypophosphatemia and its Relationship with the Periodontium: Cementum and Alveolar Bone

The tooth attachment apparatus is the fundamental element of the periodontium, which is based mainly on two mineralized tissues, alveolar bone and root cement, which are attached by the periodontal ligament. Cement is part of the tooth but, from a functional point of view, it is considered part of the attachment apparatus or periodontium. Structural defects in these tissues caused by genetic diseases have been shown to result in loss of periodontal attachment and eventually loose and lost teeth. This is the case in patients with hypophosphatemia (2).

Attachment loss in hypophosphatemia arises from cementum aplasia or hypoplasia that prevents normal attachment of periodontal ligament fibers. XLH could also cause periodontal attachment loss. Evidence indicates that adults with XLH present increased prevalence and severity of periodontitis, bone loss, deep periodontal pockets, and advanced periodontal attachment loss. Preliminary data suggest that patients with hypophosphatemic rickets are more prone to periodontal bone loss than the general population and may require more careful examination by specialists (2,17).

Ye et al. (18) analyzed whether cementum and defective alveolar bone can explain periodontal degradation and increased susceptibility to bacterial infection in Dmp1-deficient mice. In different murine models with hypophosphatemic rickets they found reduced thickness of acellular cementum, reduced cellular cementum, and defective alveolar bone matrix. The authors note that, unlike humans, mice do not naturally develop periodontal disease until extreme old age, usually over one year and mainly in the maxilla. Despite the above, it was observed that Dmp1-deficient mice develop an early-onset periodontal defect.

Zhang et al. (19) analyzed Hyp mice (Phex mutants) in which the XLH phenotype is mimicked. They studied dentoalveolar defects of the Hyp mouse at 42 and 90 days after birth to comparatively define the effects of XLH on tooth formation and function. Phex mRNA was expressed by odontoblasts (dentin), osteocytes (bone), and cementocytes (cementum) in normal mice (WT). The study showed that, compared to WT, 42-day-old Hyp mice had shorter, arched long bones, small skulls, and radiolucent jaws, whose molars showed thin dentin and expanded pulp space. Enamel density was normal, although enamel volume was significantly reduced in Hyp mice. Compared to normal mice, Hyp molars showed greatly reduced dentin/cementum volumes and densities at both ages (30 % to 40 %, p < 0.001). Cellular cementum in Hyp mice at 42 and 90 days of birth appeared to have large ECM regions of hypomineralized cementum, or cementoid, and showed a lack of periodontal ligament attachment. Pulp and PDL volumes increased, and densities decreased in molars of Hyp mice when compared to WT mice (19).

Mechanical periodontal properties were found dramatically altered in Hyp mice when compared to WT. Hyp mice presented an expanded alveolar bone with osteoid accumulation, and microtomography showed a decrease in the volume fraction and alveolar bone density. The cellular cementum area increased significantly more in Hyp than in the molars of WT mice due to the accumulation of cementoid. Hypomineralized “halos” surrounding the cementum and osteocyte lacunae of Hyp mice were shown on scanning electron microscopy and nanoindentation. Computed microtomography confirmed larger cement/osteocyte lacunae as well as a reduction in perilacunar mineral density. Long bone and alveolar bone osteocytes in Hyp mice overexpressed fibroblast growth factor 23. That study reported for the first time a quantitative analysis of Hyp mouse dentoalveolar phenotype that included all mineralized tissues (19).

Hypophosphatemia Treatment on Dental and Periodontal Hard Tissues

Treatment effect of hypophosphatemia on oral cavity hard tissues is also being studied. In this regard, Biosse Duplan et al. (2) examined the periodontal status of 34 adults with XLH and grouped them according to treatment they received for hypophosphatemia. They reported the frequency of periodontitis and the severity of this pathology increased in adults with XLH, and the severity varied according to the treatment for hypophosphatemia. Patients who received early and continuous vitamin D and phosphate supplementation during childhood had less periodontal attachment loss than patients with late or incomplete supplementation. Continued treatment of hypophosphatemia throughout adulthood further improved periodontal health. When analyzing the extracted teeth in patients with late or incomplete supplements, greater acellular cementum hypoplasia was found than in healthy controls of the same age. These results show that XLH not only alters bone and dentin formation, but also alters cementum, which has been associated with periodontal attachment loss.

Connor et al. (20) analyzed conventional therapy (calcitriol or high doses of vitamin D and phosphate) and its effects on dental disease in adults with XLH. When analyzing the relationship between the proportion of adult life with treatment, as well as other predictors, and the number of enthesopathy sites, after adjusting for age, the proportion of adult life with treatment was not a significant predictor of the number of enthesopathy sites (global p adjusted for age = 0.96). This finding remained after adjusting for confounding factors (multivariate adjusted global p = 0.90). The researchers reported that age, BMI, and sex were important predictors of the number of enthesopathy sites (pain at tendon insertion). Age and BMI were positively associated with the number of enthesopathy sites (p <0.0010 for each covariate). Female sex was negatively associated with the number of enthesopathy sites (p = 0.0080). Those who did not receive treatment during adult life were more likely to experience severe dental disease than those who were treated. They also found that age was a significant predictor of the severity of dental disease, since with a 1-year increase in age, the odds of having severe dental disease increased by 10 % (OR 1.1 [CI 95 % 1.0-1.2]). People treated for less than 80 % of childhood were more likely to experience severe dental disease compared to people treated for 80 % or more of childhood (OR 7.2 [95 % CI 0.71-73] ). The severity of the mutation was positively associated with the severity of dental disease, as those with severe mutations were more likely to experience severe dental disease compared to those who did not have such severe mutations (OR 3.9 [95 % CI 0 , 63-25]). However, these relationships did not show statistical significance.

DISCUSSION

In light of what has been found in the scientific literature collected and analyzed, it is evident that there is little research that accounts for the impact of XLH on dental and periodontal tissues. The evidence reported is low-level and focuses mainly on descriptive studies, case reports, and case series.

From the point of view of biological plausibility, there is literature explaining how hypophosphatemia can impact and alter the structure of dental hard tissues (10,11,12,13,14,15,16). An emerging explanation is that structural change produced by hypophosphatemia, mainly in the dentin, could secondarily prompt dental caries because it allows the entry of cryogenic bacteria.

When analyzing the impact of hypophosphatemia on periodontal hard tissues, attachment loss in hypophosphatemia seems to be mainly related to aplasia or hypoplasia of the cementum, which could prevent normal attachment of ligament fibers and favor faster progression of periodontal disease. The biomechanical capacity of the periodontal support is also altered, which is an interesting point for future analysis, given the relevant role of the periodontium in the distribution and damping of occlusal loads (17,18,19).

The treatment of hypophosphatemia seems to have a positive impact on the hard tissues of the oral cavity, noting that those patients who receive early and continuous treatment of their systemic condition (hypophosphatemia) with Vitamin D and phosphate could present better dental and periodontal conditions. It is worth mentioning that the level of evidence is also low, and no well-conducted randomized controlled clinical trials were found that conclusively show the effect of hypophosphatemia treatment on dental and periodontal tissues.

CONCLUSIONS AND RECOMMENDATIONS

Patients with XLH have structural changes in enamel and dentin. Studies show that the genetic mutation does not cause cavities, but the structural changes it generates could favor its appearance.

Likewise, structural changes in the cementum and alveolar bone could favor the progression of periodontal disease.

The findings presented in this literature review show the need to continue investigating the effect that XLH has on hard tissues of the oral cavity. Similarly, future studies should focus on the behavior of this pathology as a risk factor for the presence of dental and periodontal disease.

This literature review provides a preliminary basis for the analysis of the relationship of hypophosphatemia with the hard tissues of the oral cavity. Within the limits of the integrative review research design it is possible to envision the need for studies with a higher level of evidence.

It is recommended to conduct analytical observational clinical studies focused on early diagnosis and control of risk factors, as well as rigorous and well-designed controlled clinical trials reporting on treatment effectiveness in patients with XLH, in such a way that it can contribute to the improvement of oral tissues and their quality of life.

REFERENCES

Notes

* Original research.

Author notes

Author’s note:^a Correspondence:escobar.f@javeriana.edu.co. francinaescobar@yahoo.es

Additional information

How to cite: Escobar Arregocés FM. X-linked Hypophosphatemia and its Impact on Hard Tissues of the Oral Cavity. An Integrative Review. Univ Odontol. 2021; 40. https://doi.org/10.11144/Javeriana.uo40.xhih

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