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www.nature.com/bdjopen ARTICLE OPEN Dental manifestations and treatment of hypophosphatemic rickets: A case report and review of literature 1 2 2 2 2 2 2 2 Xinyang Jin , Yuedan Xu , Wei Liu , Zhiwei Shi , Yi Sun , Xinni Pan , Ling Zhang and Baiping Fu © The Author(s) 2023 BACKGROUND: The treatment and management of patients suffering from hypophosphatemic rickets (HR) remain a major challenge for dental practitioners and affected patients. OBJECTIVES: To report a case of HR presenting with speciﬁc dental ﬁndings and to review the dental manifestations and treatment of HR patients. METHODS: Case: A 32-year-old male presented with multiple dental abscesses and short stature. A thorough history was taken followed by clinical oral examination, and relevant radiological investigation was done. Literature research: In 2020, electronic literature searches were carried out in PubMed and complemented by a careful assessment of the reference lists of the identiﬁed relevant papers. Articles and reports fulﬁlled the inclusion criteria: indexed reviews, case series and case reports in English and restricted to human studies were considered. RESULTS: The intraoral examination revealed multiple dental abscesses and general periodontal disease; the radiographic examination showed poorly deﬁned lamina dura, large pulp chambers and periapical lesions. Based on the contents of the 43 articles identiﬁed in the search, the current knowledge of dental manifestations, treatment and management of HR was summarized. CONCLUSIONS: As HR is a multisystem disease, multidisciplinary care is needed. By summarizing current evidences, we proposed an evidence-based dental management and provided recommendations on diagnosis and treatment of the disease.It is of profound clinical signiﬁcance to acquire knowledge of the dental manifestations and provide optimal treatment options for patients. BDJ Open (2023) 9:2 ; https://doi.org/10.1038/s41405-023-00129-9 INTRODUCTION PHEX, mainly expressed in osteocytes and odontoblasts, is located Hypophosphatemic rickets (HR) is a group of hereditary metabolic on chromosome Xp22.1 and encodes for an endopeptidase . bone diseases caused by renal phosphate wasting, which has no Inactivating PHEX mutations contribute to the increasing secretion response of high doses of vitamin D . HR is characterized of FGF23 . As a key circulating factor that directs sodium- by short stature, delayed walking, bow legs, bone/joint pain, dependent phosphate transporters in the kidney and intestine, spontaneous dental abscess, hypophosphatemia, and inappropri- the high level FGF23 results in impaired proximal renal phosphate ately normal serum 1,25(OH) D level . Genetic defects in factors reabsorption, causing hypophosphatemia and systemic regulation necessary for phosphate handling is the main cause of phosphate of mineralization . Meanwhile, the PHEX mutations contribute wasting . HR can be mainly divided into three types, including to the local accumulation of mineralization inhibitors such as OPN X-linked hypophosphatemic rickets (XLHR) due to a loss function (osteopontin) and ASARM (the acidic serine- and aspartate-rich of phosphate regulating gene with homologies to endopeptidases motif) peptides at the level of the extracellular matrix . on the X chromosome (PHEX) , autosomal dominant hypopho- Likewise, the certain genetic mutation emphasizes the importance sphatemic rickets (ADHR) caused by mutation in the ﬁbroblast of FGF23 and DMP1 in the pathogenesis of ADHR and ARHR, growth factor 23 (FGF23) gene  and autosomal recessive respectively [5, 6]. As the same result of phosphate wasting, it is hypophosphatemic rickets (ARHR) as a result of mutation in dentin found that different types of HR cause similar, though not matrix protein 1 (DMP1) gene, ecto-nucleotide pyrophos- phatase/ identical, clinical and radiographical parameters, which mostly phosphodiesterase 1 (ENNP1) gene, or family with sequence depend on the duration of hypophosphatemia . similarity 20, member C (FAM20C) [6–8]. Early diagnosis of HR is of great signiﬁcance, since early XLHR, also named as vitamin D resistant rickets, familial treatment promotes growth, reduces bone pain and improves hypophosphatemic rickets, or phosphate diabetes, is the most dental health [13, 14]. The diagnosis of HR is on the basis of common form of HR, with an incidence of around 1:20000 . combination of clinical, radiological and biochemical ﬁndings. 1 2 Department of Stomatology, The Fourth Afﬁliated Hospital, Zhejiang University School of Medicine, Yiwu, China. Department of Prosthodontics, Stomatology Hospital, School of Stomatology, Zhejiang University School of Medicine, Zhejiang Provincial Clinical Research Center for Oral Diseases, Key Laboratory of Oral Biomedical Research of Zhejiang Province, Cancer Center of Zhejiang University, Engineering Research Center of Oral Biomaterials and Devices of Zhejiang Province, Hangzhou, China. email: email@example.com Received: 31 October 2022 Revised: 29 December 2022 Accepted: 2 January 2023 1234567890();,: X. Jin et al. Fig. 1 Intraoral views and panoramic radiograph of a 32-year-old male patient with HR. Intraoral views (a–e) showed multiple ﬁstulas and abscesses, malocclusion, and dental attrition in the left lower incisors; Panoramic radiograph (f) revealed enlarged pulp chambers, the radiolucencies at periapical regions of teeth # 12, 13, 17, 22, 23, 32, 36, 37, 41, 42, 43 and 48, and the presence of endodontically treated teeth # 12, 13, 23 and 32. Clinically, patients of HR feature leg bowing, delayed walking, provide timely treatment options, which does help to improve the waddling gait, bone/joint pain, short stature and dental abscesses quality of HR patients’ life . This article aimed at reporting a . Especially, any form of leg bowing and widening of the case of male with HR, reviewing the dental manifestations and metaphysis acquire a further radiological and biomedical exam- treatment of HR patients and providing suggestions of dental ination . Radiographic manifestations show the long bone management. deformities and abnormal growth plates with widened and frayed metaphyses . Biomedical criteria for the diagnosis of HR includes serum phosphate below the normal threshold for age, CASE REPORT elevated alkaline phosphatase, normal or upper normal parathyr- A 32-year-old male was referred to the Department of Prosthodon- oid hormone levels, normal serum calcium, and low urinary tics with the complaint of “several abscesses that appeared in the calcium excretion . In addition, a family history of the disease is mouth”. The patient was diagnosed with HR at the age of 2, but his beneﬁt for diagnosis due to an X-linked dominant inheritance parents didn’t have metabolic disorder. Since been diagnosed, he pattern of PHEX mutation. Genetic analysis, which identiﬁes was treated with oral phosphate supplementation, calcitriol and mutations in the PHEX gene in about 70% of patients with HR, is vitamin D2. In addition, he was undergoing pharmaceutical therapy the ﬁnal conﬁrmation . If genetic analysis is not available, with burosumab at a dose of 60 mg/month by hypodermic injection elevated plasma levels of intact FGF23 supports the diagnosis . at the age of 31. Treatment initiation is recommended as soon as diagnosis is On physical examination, the patient showed short stature, bow established . Conventional treatment with oral phosphate legs, achilles tendinitis and mild hearing loss. The intraoral supplements and active vitamin D (calcitriol or alfacalcidol), has examination revealed multiple ﬁstulas and abscesses at the been proposed for decades [3, 18, 19]. This kind of therapy has periapical regions of maxillary right lateral incisor, mandibular left been shown to result in the positive outcomes of decrease in bone lateral incisor and ﬁrst molar, and mandibular right central incisor pain, normalization of alkaline phosphatase level, increase in (Fig. 1a–e). The pulpal vitality test was negative at maxillary right growth velocity, straightening of legs and improving dental lateral incisor, maxillary right canine and second molar, mandibular mineralization [3, 13, 20, 21]. However, due to the limitations, such left canine, mandibular left lateral incisor and ﬁrst molar, and as increasing risk of nephrocalcinosis, urolithiasis or hyperpar- mandibular right central incisor and third molar. Periodontal athyroidism, the dose of phosphate supplements and vitamin D examination revealed the absence of many teeth, and general analogues should be strictly controlled according to individual periodontal disease resulting in some teeth increased probing situation [22, 23]. Recently, a novel therapy with burosumab, a pocket depth of 10 mm or more. Radiographic examination in Fig. 1f kind of humanized monoclonal anti-FGF23 antibody, has been showed poorly deﬁned lamina dura and enlarged pulp chambers approved for the treatment of XLHR patients over 1 year of age in and radicular canals. Radiolucencies were detected at periapical Europe and US, with the function of increasing renal phosphate regions of maxillary right lateral incisor, maxillary right canine and reabsorption and normalizing serum phosphate [15, 24]. Never- second molar, mandibular left lateral incisor and canine, mandibular theless, all of those therapies focus on regulation of systemic left lateral incisor, mandibular left second and third molar, serum phosphate, the defects in mineral quality and quantity mandibular right central and lateral incisor, and mandibular right during formation of mineralized tissues such as tooth and bone canine and third molar. Several teeth (i.e., maxillary right lateral due to the local dysfunction of PHEX intend to be treated . incisor and canine, maxillary left canine, and mandibular left lateral Given that, the disease follow-up and treatment management are incisor) had received endodontic treatment before. essential. For some patients, dental manifestations might be the ﬁrst symptom diagnosed . Furthermore, early prophylaxis and LITERATURE SEARCH treatment can improve dental status . Hence, broadening A literature search was carried out to identify all cases of HR knowledge of various dental manifestations of HR is required to associated dental manifestations. The PubMed database was BDJ Open (2023) 9:2 X. Jin et al. Table 1. Number of reported cases of hypophosphatemic rickets with dental manifestations. Author Year No. of cases Author Year No. of cases Gigliotti et al.  1971 3 Baroncelli et al.  2006 9 Sauk et al.  1973 1 Chaussain-Miller et al.  2007 7 Cohen et al.  1976 1 Douyere et al.  2009 1 Ainley et al.  1978 1 Souza et al.  2010 14 Nikiforuk et al.  1979 26 Al-Jundi et al.  2010 21 Rakocz et al.  1982 1 Sh AJ et al.  2010 21 Lyles et al.  1985 1 Al-Jundi et al.  2011 1 Bender et al.  1985 50 Ye et al.  2011 10 Abe et al.  1988 3 Beltes et al.  2012 1 Schwartz et al.  1988 18 Rabbani et al.  2012 19 Daley et al.  1990 3 Andersen et al.  2012 52 Hintze et al.  1990 1 Soares et al.  2013 3 Shields et al.  1990 17 Rathore et al.  2013 1 Chadwick et al.  1992 1 Friberg et al.  2013 3 Hillmann et al.  1996 2 Souza et al.  2013 1 Goodman et al.  1998 17 McKee et al.  2013 1 Resnick et al.  1998 1 Cremonesi et al.  2014 10 Murayama et al.  2000 1 Yuan et al.  2015 4 Alexander et al.  2001 1 Ayesha et al.  2016 1 Chaussain-Miller et al.  2003 48 Biosse et al.  2016 34 Pereira et al.  2004 3 Paredes et al.  2017 1 Batra et al.  2006 1 Total cases reported 416 searched until 10 March 2020 with the following MESH term: characteristics of HR [25, 27, 32, 41, 44, 46–48, 53, 54]. “Rickets, Hypophosphatemic” and a keyword: “dental”.Itwas Other common manifestations are thinner enamel and dentin supplemented by manual searches in the reference lists of [21, 30, 40, 53], primary tooth resorption [44, 56] and short root relevant articles. The search retrieved 198 results. Articles and [43, 57]. reports including indexed reviews, case series and case reports Histopathologically, hypomineralized dentin, featured by a published in English and in peer-reviewed journals were widened predentin with fewer well-deﬁned dentinal tubules and considered, and restricted to human studies. After screening numerous unmerged calcospherites creating interglobular spaces, is the title and abstract, 43 relevant full-length articles were commonly seen in teeth of HR patients, while the mantle dentin is included. This search identiﬁed about 416 reported cases unaffected [12, 14, 21, 30–32, 37, 40, 52, 53, 55–60]. The organization [12, 14, 21, 25, 27–65], as presented in Table 1. and polarization of odontoblasts are also impaired . Enamel alternation, such as numerous crater-shaped depressions and deep microcleavages penetrating into the enamel thickness, can be seen DENTAL MANIFESTATION in some patients [21, 32, 35, 37, 39, 49, 58, 61, 62]. Due to the dentin Clinically, recurrent spontaneous dental abscesses both in primary and enamel alternation, bacteria can invade easily from the oral and permanent dentition without carries, periodontal problems, cavity to the dental pulp, causing pulp necrosis in caries-free tooth traumatic injuries or restorations are common ﬁndings in HR . Cementum is thinner, with roughly granular with hypominer- patients [12, 14, 21, 25, 27–44]. Meanwhile, with the increasing alized interglobular patterns [48, 67]. age, the number of endodontically affected teeth signiﬁcantly rises, and the incisors and canines usually get affected prior to molars and premolars . HR patients are more prone to suffer DENTAL TREATMENT periodontal bone loss than the general population, while the Prophylaxis percentage of BOP seems to be similar without commensurate Preventing bacteria invading dentin and pulp is important to increase [33, 39, 41, 46–48]. Another main dental ﬁnding is the reduce dental abscesses . Stainless steel crown was used to smaller dental arches which always accompany with crowded cover the crown of primary molar in the past [30, 55]. However, dentition and class III occlusion [29, 46, 49, 50]. Other infrequent the limitations of large pulp chamber, high pulp horn, thin enamel dental ﬁndings are ectopic permanent canines , delayed and hypomineralized dentin should be taken into strict considera- eruption of both primary and permanent teeth , delayed tion. Sealing occlusal surfaces of primary and permanent teeth dental development [41, 51] and dental hypersensitivity . with composite resin is suggested, the properties of which have Radiologically, both primary and permanent teeth exhibit greatly improved over the last decade [26, 68]. It is worth noting enlarged pulp chambers with high pulp horns which sometimes that self-etch adhesive system is recommended to minimize risk of extend up to or beyond the dentino-enamel junction pulp irritation, and the sealing must be repeated every year due to [12, 21, 27, 29, 30, 32–34, 37, 39–45, 49, 52–56]. Zones of gradual wear of the resin . The early monitored use of topical hypomineralized early forming coronal dentin appear as a “halo” applications of ﬂuoride is critical for preventing subsequent at the dentino-enamel junction around the circumpulpal dentin serious dental infections [33, 36–39, 42]. Tooth attrition is easier to [52, 55]. Hypoplastic alveolar ridge, reduced radiopacity of lamina be seen in HR patients for the enamel alternation, so a nightguard dura and varying degree of alveolar bone loss are also radiological acrylic splint is also suggested [53, 55]. BDJ Open (2023) 9:2 X. Jin et al. Endodontic treatment enlarged pulp chambers, periapical bone loss and pulp necrosis For the endodontically affected teeth, root canal treatment is . (5) In adults, it is suggested to perform conventional the conventional choice, while extraction is necessary for those supportive periodontal therapy, including periodontal risk assess- of abscesses spread quickly in jaw bone especially in primary ment as well as supragingival and subgingival debridement twice teeth . The procedures of endodontic treatment should try to a year if necessary . (6) If orthodontic and implant treatment be sterile. Using sodium hypochlorite to irrigate canals and are required, it must be based on the premise that conventional Ca(OH) as intracanal medicament for a 10-day interval is therapy is correctly treated [26, 63, 64]. recommended, and the determination of working length is preferred to combine electronic apex locators and radiograph . Avoiding any voids and achieving the best possible density DISCUSSION of the root canal ﬁlling are the goal of the obturation of the root HR is genetic disorders, whose main symptoms are hypominer- canal system . Meanwhile, the ﬁlling of root canal might be alized skeleton and dentition . Dental abscesses without caries suggested using thermoplasticized obturation techniques with a are observed most frequently in HR, even in some cases as the ﬁrst virtually insoluble sealer . Apical curettage procedure and symptom diagnosed . In the present report (Fig. 1), the apical barriers with mineral trioxide aggregate might be symptoms were enlarged pulp chambers and multiple dental performed in sever abscessesand open apical foramens, abscesses. The cause of dental abscesses is the enamel alternation respectively [28, 33]. and hypomineralized dentin . However, the relationship between HR and hypomineralized dentin remains unclear. In the Prosthodontic treatment past, hypophosphatemia was thought to be responsible for For some mild or moderate damages, adhesive procedures can be dysplastic and poorly mineralized circumpulpal dentin with wide used, but in sever situation, such as dominant enamel fracturing areas of interglobular dentin, which limited growth and fusion of and rapid dental wear, full coverage restoration should be chosen calcospherites . Recent researches have shown that the . Regarding to the coronal restoration of endodontic treatment mineralization induced by human cells is disturbed independently teeth, occlusal coverage with ﬁtted stainless steel crowns is of hypophosphatemia and supported a local role for PHEX, DMP1 suggested to protect teeth from recurrent infections, however, or FAM20C in matrix mineralization [11, 70, 71]. This ﬁnding might posts cannot be supported due to the thin dentin [40, 55]. As for illustrate that conventional therapy improve dental complications the ceramic crown, it is not recommended for teeth with but not prevent . Due to different mechanisms of three forms prominent pulp horns, since the preparation costs a greater loss of HR, the article mainly focused on XLHR. Several studies have of dentin than metal crown . Therefore, all-ceramic occlusal conﬁrmed that PHEX regulates the mineralization of the veneer might be another choice not only as a minimal invasive extracellular matrix at the local level in mineralized bone and approach but for aesthetic reason . dentin and maintains mineralized matrix homeostasis by cleaving of acidic, non-collagenous SIBLING proteins and peptides of the Periodontal treatment extracellular matrix such as OPN, MEPE (matrix extracellular Conventional supportive periodontal therapy is of great beneﬁt phosphoglycoprotein) and ARARM [66, 72, 73]. Furthermore, it is for HR patients . Hence, twice-yearly visits to perform suggested that OPN and MEPE inhibit tooth mineralization conventional supportive periodontal therapy aimed to decrease through different ways, with OPN acting at the mineralized gingival inﬂammation and suppress periodontal pockets for adults calcospherites and MEPE at the region of the unmineralized is suggested . interglobular dentin . From the literature review (Table 1), we can ﬁnd that the Orthodontic treatment majority of reported patients are females, which seems to indicate Although it is conﬁrmed that the periodontium of HR patients is a higher HR prevalence in female. However, male patients are less prone to orthodontic treatment , orthodontic treatment is usually shown severer dental complications, such as taurodontism not contraindicated especially for those treated with conventional . Since most cases are determined by PHEX, an X-linked systemic treatment, and could trigger extensive remodeling of the dominant mutant gene, it might be a gene dose effect . The alveolar bone . severity of complications might depend on three factors, including family history, medical history and age. Patients born to affected Implant treatment mother are inclined to bear poorer dental status for primary Implants are acceptable for HR patients and several successful dentition than those born to healthy mother, due to the lower cases have been reported [63, 64]. However, the successful rate is phosphate and vitamin D obtained from the affected mother declined in those who are not under conventional treatment, during fetal odontogenesis . Nevertheless, a family history hence, implant surgery is recommended to be performed after 3-6 contributes to an earlier diagnosis of HR, which might take an months of conventional treatment, which should be continued for earlier treatment for patients, resulting a better outcome for 6 months following implant surgery . It might be better permanent dentition . Although conventional treatment is not to prolong the healing time up to 6 months to obtain a good able to prevent oral complications, its beneﬁcial effects on dental stability . and periodontal tissues cannot be underestimated . It has already been conﬁrmed that conventional treatment for HR patients improves mineralization of dentin and decreases the DENTAL MANAGEMENT incidence of endodontic infection in children [14, 21]. Meanwhile, In summary, the lifetime dental management for a particular the beneﬁt of continuing treatment for adults has been proved in patient is as followed. (1) Once the diagnosis is established, the permanent teeth and periodontal health recent years . conventional treatment should be initiated and last a lifetime if However, the dose of medicine should depend on the age and possible . (2) The dental examination should be performed stage of development, for excessive phosphate might result in twice a year regularly for adults and children, including dental hyperparathyroidism . The number of endodontically affected orthopantomogram, of which the ﬁrst time is suggested at age 5 teeth raises signiﬁcantly with age, due to the exposure of [17, 68]. (3) Typical ﬂuoride application and pit and ﬁssure sealing defective dentin . Thus, only incisors or canines are affected both in primary and permanent teeth should be carried out as in younger patients and affected posterior teeth are more soon as acquired [40, 42]. (4) We recommend a thorough dental commonly seen in older patients . Similar situation is present examination clinically and radiologically searching for all of the in the case report (Fig. 1). BDJ Open (2023) 9:2 X. Jin et al. In order to decrease the risk of dental abscess, preventive CONCLUSION approaches, such as topical ﬂuoride application, pit and ﬁssure HR is associated with marked dental manifestations and patients sealing, stainless steel crown and nightguard acrylic splint are with them exhibit a tendency of poorer quality of life. Early proposed for decades [30, 33, 55]. As the using of conventional diagnosis, treatment and management are the keys to successful steel crown requires tooth preparation which might cause the outcomes. It is of great essence to carry out frequent and regular irritation of pulp, a crown conservative technique that using dental care for HR patients. Since HR is a multisystem disease, separating elastic and non-removal tooth structure has been multidisciplinary care is needed. Hence, it is important for dentists recommended . Resulting from the progress in bonding to master the knowledge of various dental manifestations and dentistry and the principle of sealing the wells and grooves of provide optimal treatment options along with other specialists in permanent teeth, pit and ﬁssure sealing using ﬂuid composite pediatric and adult ﬁelds. resin with self-etching bonding system might be a better choice . And it is suggested that all occlusal surfaces, including REFERENCES principal and secondary grooves should be covered . However, 1. Bitzan M, Goodyer PR. Hypophosphatemic Rickets. Pediatr Clin North Am. this preventive approach needs to be reperformed annually 2019;66:179–207. because of the loss or attrition of resin . The self-etching 2. Durmaz E, Zou M, Al-Rijjal RA, Baitei EY, Hammami S, Bircan I, et al. Novel and de bonding system is recommended because of its simple imple- novo PHEX mutations in patients with hypophosphatemic rickets. 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Periodontal breakdown in the Dmp1 (No. 2020-16). null mouse model of hypophosphatemic rickets. J Dent Res. 2008;87:624–9. 77. Zhang H, Chavez MB, Kolli TN, Tan MH, Fong H, Chu EY, et al. Dentoalveolar defects in the Hyp Mouse Model of X-linked Hypophosphatemia. Physiol Rep. ADDITIONAL INFORMATION 2020;99:419–28. Correspondence and requests for materials should be addressed to Baiping Fu. 78. Al-Jundi SH, Dabous IM, Al-Jamal GA. Craniofacial morphology in patients with hypophosphataemic vitamin-D-resistant rickets: A cephalometric study. J Oral Reprints and permission information is available at http://www.nature.com/ Rehabil. 2009;36:483–90. reprints Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims ACKNOWLEDGEMENTS in published maps and institutional afﬁliations. This work was supported by National Natural Science Foundation of China (81970982). XJ and YX contributed equally to this work and should be considered as co-ﬁrst authors. BF and LZ contributed equally to this work and should be considered as co-corresponding authors. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative AUTHOR CONTRIBUTIONS Commons license, and indicate if changes were made. The images or other third party BF and LZ coordinated the project. XJ and YX performed the basic literature research material in this article are included in the article’s Creative Commons license, unless and drafted the ﬁrst version of the manuscript. WL, ZS, YS, and XP added further indicated otherwise in a credit line to the material. If material is not included in the literature identiﬁed by manual search. BF, LZ, XJ, YX, WL, ZS, YS, and XP discussed the article’s Creative Commons license and your intended use is not permitted by statutory successive versions. regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http:// creativecommons.org/licenses/by/4.0/. COMPETING INTERESTS The authors declare that they have no conﬂict of interest. The patient involved in the study have signed a written informed consent that the health-related data © The Author(s) 2023 BDJ Open (2023) 9:2
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