Improved Oral Health in Adults with X-Linked Hypophosphatemia Treated with Burosumab.

CONTEXT: X-linked hypophosphatemia (XLH) is a rare genetic bone disease affecting both children and adults, with oral manifestations such as spontaneous dental infections. The main treatments for XLH are conventional treatment (CT) with oral phosphate salts and active vitamin D supplementation, and burosumab, an antibody targeting Fibroblast Growth Factor 23 (FGF23). While the beneficial effect of CT on oral manifestations is established, the effect of burosumab on oral health is unknown, especially in adults. OBJECTIVE: We aimed to compare the oral health (number of missing or endodontically treated teeth and presence of periodontal disease) and incidence of endodontic infections of adult patients with XLH according to their treatment's modalities (no treatment, CT, or burosumab). METHODS: This was achieved through a single-center, retrospective analysis of oral health data from 44 patients who had undergone dental monitoring for at least 6 months. RESULTS: Oral health varied according to the proportion of their adult life spent under treatment for XLH and the incidence of dental infections during follow-up was influenced by the type of treatment received. There was a 55.9% reduction of infections during CT and an 86.4% reduction during burosumab treatment compared to periods with no treatment (P < 0.0001). Comparing treatment and non-treatment periods within the same patient showed a strong association between burosumab treatment and decreased infection incidence (0.006 vs 0.09 infection per month, P<0.01). CONCLUSIONS: We observed that adults with XLH treated with burosumab developed fewer endodontic infections during dental follow-up than patients who were untreated or received CT.

Dental impact of anti-fibroblast growth factor 23 therapy in X-linked hypophosphatemia.

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.

Burosumab and Dental Abscesses in Children With X-Linked Hypophosphatemia.

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. Hypomineralized 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 fibroblast growth factor 23 (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. A total of 71 children were included in the study, with a mean ± standard deviation (SD) age at the start of dental follow-up of 7.86 ± 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 versus 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. © 2022 The Authors. JBMR Plus published by Wiley Periodicals LLC on behalf of American Society for Bone and Mineral Research.

Oral health-related quality of life in patients with X-linked hypophosphatemia: a qualitative exploration.

Introduction: X-linked hypophosphatemia (XLH) is a rare, hereditary, and lifelong phosphate-wasting disorder characterized by rickets in childhood and impaired teeth mineralization. In the oral cavity, spontaneous abscesses can often occur without any clinical signs of alteration of the causal tooth. The objective of our study was to evaluate the oral care pathway and the oral health-related quality of life (OHRQoL) of patients following in an expert oral medicine department located within a Parisian hospital and working in close collaboration with an endocrinology department expert in this pathology. Methods: This study employed a qualitative descriptive design including semi-structured interviews using guiding themes. Results: Twenty-one patients were included in the study. The topics brought up exceeded the initial objectives as the patients mostly addressed the alteration of their oral health-related and general quality of life; a very chaotic oral health care pathway with oral health professionals not aware of their pathology; consequences on their social, professional, and school integration. Patients declared the importance of having a multidisciplinary team around them, including medical and dental professionals. Conclusions: The variety of manifestations in patients with XLH necessitates high coordination of multidisciplinary patient care to optimize quality of life and reduce disease burden. Oral health care pathways are very chaotic for patients who have difficulty in finding professionals with sufficient knowledge of the disease. OHRQoL is therefore diminished. This situation improves when patients enter a coordinated care network.

Chronic neutropenia: how best to assess severity and approach management?

INTRODUCTION: Neutropenia is a relatively common finding in medical practice and the medical approach requires a gradual and pertinent diagnostic procedure as well as adapted management. AREAS COVERED: The area of chronic neutropenia remains fragmented between diverse diseases or situations. Here physicians involved in different aspects of chronic neutropenia gather both the data from medical literature till the end of May 2021 and their experience to offer a global approach for the diagnosis of chronic neutropenia as well as their medical care. EXPERT OPINION: In most cases, the neutropenia is transient, frequently related to a viral infection, and not harmful. However, neutropenia can be chronic (i.e. >3 months) and related to a number of etiologies, some clinically benign, such as so-called 'ethnic' neutropenia. Autoimmune neutropenia is the common form in young children, whereas idiopathic/immune neutropenia is a frequent etiology in young females. Inherited neutropenia (or congenital neutropenia) is exceptional, with approximately 30 new cases per 106 births and 30 known subtypes. Such patients have a high risk of invasive bacterial infections, and oral infections. Supportive therapy, which is primarily based on daily administration of an antibiotic prophylaxis and/or treatment with granulocyte-colony stimulating factor (G-CSF), contributes to avoiding recurrent infections.

Recurrent bacterial infections, but not fungal infections, characterise patients with ELANE-related neutropenia: a French Severe Chronic Neutropenia Registry study.

Among 143 patients with elastase, neutrophil-expressed (ELANE)-related neutropenia enrolled in the French Severe Chronic Neutropenia Registry, 94 were classified as having severe chronic neutropenia (SCN) and 49 with cyclic neutropenia (CyN). Their infectious episodes were classified as severe, mild or oral, and analysed according to their natural occurrence without granulocyte-colony stimulating factor (G-CSF), on G-CSF, after myelodysplasia/acute leukaemia or after haematopoietic stem-cell transplantation. During the disease's natural history period (without G-CSF; 1913 person-years), 302, 957 and 754 severe, mild and oral infectious events, respectively, occurred. Among severe infections, cellulitis (48%) and pneumonia (38%) were the most common. Only 38% of episodes were microbiologically documented. The most frequent pathogens were Staphylococcus aureus (37·4%), Escherichia coli (20%) and Pseudomonas aeruginosa (16%), while fungal infections accounted for 1%. Profound neutropenia (<200/mm3 ), high lymphocyte count (>3000/mm3 ) and neutropenia subtype were associated with high risk of infection. Only the p.Gly214Arg variant (5% of the patients) was associated with infections but not the overall genotype. The first year of life was associated with the highest infection risk throughout life. G-CSF therapy achieved lower ratios of serious or oral infectious event numbers per period but was less protective for patients requiring >10 µg/kg/day. Infections had permanent consequences in 33% of patients, most frequently edentulism.

Phosphatase inhibition by LB-100 enhances BMN-111 stimulation of bone growth.

Activating mutations in fibroblast growth factor receptor 3 (FGFR3) and inactivating mutations in the natriuretic peptide receptor 2 (NPR2) guanylyl cyclase both result in decreased production of cyclic GMP in chondrocytes and severe short stature, causing achondroplasia (ACH) and acromesomelic dysplasia, type Maroteaux, respectively. Previously, we showed that an NPR2 agonist BMN-111 (vosoritide) increases bone growth in mice mimicking ACH (Fgfr3Y367C/+). Here, because FGFR3 signaling decreases NPR2 activity by dephosphorylating the NPR2 protein, we tested whether a phosphatase inhibitor (LB-100) could enhance BMN-111-stimulated bone growth in ACH. Measurements of cGMP production in chondrocytes of living tibias, and of NPR2 phosphorylation in primary chondrocytes, showed that LB-100 counteracted FGF-induced dephosphorylation and inactivation of NPR2. In ex vivo experiments with Fgfr3Y367C/+ mice, the combination of BMN-111 and LB-100 increased bone length and cartilage area, restored chondrocyte terminal differentiation, and increased the proliferative growth plate area, more than BMN-111 alone. The combination treatment also reduced the abnormal elevation of MAP kinase activity in the growth plate of Fgfr3Y367C/+ mice and improved the skull base anomalies. Our results provide a proof of concept that a phosphatase inhibitor could be used together with an NPR2 agonist to enhance cGMP production as a therapy for ACH.

An Fgfr3-activating mutation in immature murine osteoblasts affects the appendicular and craniofacial skeleton.

Achondroplasia (ACH), the most common form of dwarfism, is caused by a missense mutation in the gene coding for fibroblast growth factor receptor 3 (FGFR3). The resulting increase in FGFR3 signaling perturbs the proliferation and differentiation of chondrocytes (CCs), alters the process of endochondral ossification and thus reduces bone elongation. Increased FGFR3 signaling in osteoblasts (OBs) might also contribute to bone anomalies in ACH. In the present study of a mouse model of ACH, we sought to determine whether FGFR3 overactivation in OBs leads to bone modifications. The model carries an Fgfr3-activating mutation (Fgfr3Y367C/+) that accurately mimics ACH; we targeted the mutation to either immature OBs and hypertrophic CCs or to mature OBs by using the Osx-cre and collagen 1α1 (2.3 kb Col1a1)-cre mouse strains, respectively. We observed that Fgfr3 activation in immature OBs and hypertrophic CCs (Osx-Fgfr3) not only perturbed the hypertrophic cells of the growth plate (thus affecting long bone growth) but also led to osteopenia and low cortical thickness in long bones in adult (3-month-old) mice but not growing (3-week-old) mice. Importantly, craniofacial membranous bone defects were present in the adult mice. In contrast, activation of Fgfr3 in mature OBs (Col1-Fgfr3) had very limited effects on skeletal shape, size and micro-architecture. In vitro, we observed that Fgfr3 activation in immature OBs was associated with low mineralization activity. In conclusion, immature OBs appear to be affected by Fgfr3 overactivation, which might contribute to the bone modifications observed in ACH independently of CCs.

Prevalence and risk indicators of first-wave COVID-19 among oral health-care workers: A French epidemiological survey.

BACKGROUND: Previous studies have highlighted the increased risk of contracting the COVID-19 for health-care workers and suggest that oral health-care workers may carry the greatest risk. Considering the transmission route of the SARS-CoV-2 infection, a similar increased risk can be hypothesized for other respiratory infections. However, no study has specifically assessed the risk of contracting COVID-19 within the dental profession. METHODS: An online survey was conducted within a population of French dental professionals between April 1 and April 29, 2020. Univariable and multivariable logistic regression analyses were performed to explore risk indicators associated with laboratory-confirmed COVID-19 and COVID-19-related clinical phenotypes (i.e. phenotypes present in 15% or more of SARS-CoV-2-positive cases). RESULTS: 4172 dentists and 1868 dental assistants responded to the survey, representing approximately 10% of French oral health-care workers. The prevalence of laboratory-confirmed COVID-19 was 1.9% for dentists and 0.8% for dental assistants. Higher prevalence was found for COVID-19-related clinical phenotypes both in dentists (15.0%) and dental assistants (11.8%). Chronic kidney disease and obesity were associated with increased odds of laboratory-confirmed COVID-19, whereas working in a practice limited to endodontics was associated with decreased odds. Chronic obstructive pulmonary disease, use of public transportation and having a practice limited to periodontology were associated with increased odds of presenting a COVID-19-related clinical phenotype. Moreover, changes in work rhythm or clinical practice were associated with decreased odds of both outcomes. CONCLUSIONS: Although oral health-care professionals were surprisingly not at higher risk of COVID-19 than the general population, specific risk indicators could exist, notably among high aerosol-generating dental subspecialties such as periodontology. Considering the similarities between COVID-19-related clinical phenotypes other viral respiratory infections, lessons can be learned from the COVID-19 pandemic regarding the usefulness of equipping and protecting oral health-care workers, notably during seasonal viral outbreaks, to limit infection spread. IMPACT: Results from this study may provide important insights for relevant health authorities regarding the overall infection status of oral health-care workers in the current pandemic and draw attention to particular at-risk groups, as illustrated in the present study. Protecting oral health-care workers could be an interesting public health strategy to prevent the resurgence of COVID-19 and/or the emergence of new pandemics.

Dental and periodontal manifestations of glycogen storage diseases: a case series of 60 patients.

Glycogen storage diseases (GSDs) are rare genetic disorders of glycogen metabolism where the liver, kidneys, respiratory and cardiac muscles, as well as the immune and skeletal systems can be affected. Oral manifestations can also be present, but the specificity and frequency of these manifestations in the different forms of GSD are unknown. Analysis of a case series of 60 patients presenting four types of GSD (Ia, Ib, III, and IX) showed that the different types of GSDs have common and specific oral manifestations. In none of the GSD types studied, the prevalence of caries was higher than in the general population, especially in patients benefiting from current nutritional therapy, while in all GSD types the prevalence of delayed tooth eruption, agenesis, and tooth shape abnormalities was increased compared to the general population. Severe periodontitis prevalence was increased in patients with GSD Ib and neutropenia. Our results show that GSDs have oral manifestations and suggest some specificity depending on the type of GSDs.

Coordination of early cellular reactions during activation of bone resorption in the rat mandible periosteum: An immunohistochemical study.

The activation step of bone remodeling remains poorly characterized. Activation comprises determination of the site to be remodeled, osteoclast precursor recruitment, their migration to the site of remodeling, and differentiation. These actions involve different compartments and cell types. The aim of this study was to investigate events and cell types involved during activation. We used a bone remodeling model in rats where extractions of the upper jaw molars initiate remodeling of the antagonist lower jaw (mandible) cortex along the periosteum. In this model osteoclastic resorption peaks 4 days after extractions. We previously reported that mast cell activation in the periosteum fibrous compartment is an early event of activation, associated with recruitment of circulating monocyte osteoclast precursors. By using immunohistochemistry, we observed 9 hours after induction a spatially oriented expression of InterCellular Adhesion Molecule-1 in the vessels that was inhibited by antagonists of histamine receptors 1 and 2. It was followed at 12 hours by the recruitment of ED1+ monocytes. In parallel, at 9 hours, Vascular Cellular Adhesion Molecule-1+ fibroblast-like cells scattered in the fibrous compartment of the periosteum between the vessels and the osteogenic compartment increased; these cells may be implicated in osteoclast precursor migration. Receptor Activator of NF KappaB Ligand+ cells increased at 12 hours in the osteogenic compartment and reached a peak at 18 hours. At 24 hours the numbers of osteogenic cells and subjacent osteocytes expressing semaphorin 3a, a repulsive for osteoclast precursors, decreased before returning to baseline at 48 hours. These data show that during activation the two periosteum compartments and several cell types are coordinated to recruit and guide osteoclast precursors towards the bone surface.

Tissue-specific mineralization defects in the periodontium of the Hyp mouse model of X-linked hypophosphatemia.

X-linked hypophosphatemia (XLH) is a dento-osseous disorder caused by inactivating mutations in the PHEX gene, leading to renal phosphate wasting and hypophosphatemia, and impaired mineralization of bones and teeth. In the oral cavity, recent reports suggest a higher susceptibility of XLH patients to periodontitis, where patients present with impaired tooth cementum - a bone-like tissue involved in tooth attachment to the jaw bones and post-eruption tooth positioning - and a higher frequency of intrabony defects. In the present study, the pathobiology of alveolar bone and tooth cementum was investigated in the Hyp mouse, the murine analog of XLH. PHEX deficiency in XLH/Hyp dramatically alters the periodontal phenotype, with hypoplasia of tooth root cementum associated with a lack of periodontal ligament attachment and the presence of an immature apatitic mineral phase of all periodontal mineralized tissues. Challenging the Hyp periodontium in two surgical experimental models - ligature-induced periodontal breakdown and repair, and a model of tooth movement adaptation inducing cementum formation - we show that bone and cementum formation, and their healing, are altered. Bone and cementum mineralization appear similarly disturbed, where hypomineralized pericellular matrix surrounds cells, and where the protein osteopontin (OPN, a mineralization inhibitor) accumulates in a tissue-specific manner, most notably in the perilacunar matrix surrounding osteocytes. Although the pathobiology is different between XLH/Hyp bone and cementum, our results show a major XLH phenotype in oral mineralized tissues consistent with variations in patient susceptibility to periodontal disorders.

Meckel's and condylar cartilages anomalies in achondroplasia result in defective development and growth of the mandible.

Activating FGFR3 mutations in human result in achondroplasia (ACH), the most frequent form of dwarfism, where cartilages are severely disturbed causing long bones, cranial base and vertebrae defects. Because mandibular development and growth rely on cartilages that guide or directly participate to the ossification process, we investigated the impact of FGFR3 mutations on mandibular shape, size and position. By using CT scan imaging of ACH children and by analyzing Fgfr3Y367C/+ mice, a model of ACH, we show that FGFR3 gain-of-function mutations lead to structural anomalies of primary (Meckel's) and secondary (condylar) cartilages of the mandible, resulting in mandibular hypoplasia and dysmorphogenesis. These defects are likely related to a defective chondrocyte proliferation and differentiation and pan-FGFR tyrosine kinase inhibitor NVP-BGJ398 corrects Meckel's and condylar cartilages defects ex vivo. Moreover, we show that low dose of NVP-BGJ398 improves in vivo condyle growth and corrects dysmorphologies in Fgfr3Y367C/+ mice, suggesting that postnatal treatment with NVP-BGJ398 mice might offer a new therapeutic strategy to improve mandible anomalies in ACH and others FGFR3-related disorders.

Tyrosine kinase inhibitor NVP-BGJ398 functionally improves FGFR3-related dwarfism in mouse model.

Achondroplasia (ACH) is the most frequent form of dwarfism and is caused by gain-of-function mutations in the fibroblast growth factor receptor 3-encoding (FGFR3-encoding) gene. Although potential therapeutic strategies for ACH, which aim to reduce excessive FGFR3 activation, have emerged over many years, the use of tyrosine kinase inhibitor (TKI) to counteract FGFR3 hyperactivity has yet to be evaluated. Here, we have reported that the pan-FGFR TKI, NVP-BGJ398, reduces FGFR3 phosphorylation and corrects the abnormal femoral growth plate and calvaria in organ cultures from embryos of the Fgfr3Y367C/+ mouse model of ACH. Moreover, we demonstrated that a low dose of NVP-BGJ398, injected subcutaneously, was able to penetrate into the growth plate of Fgfr3Y367C/+ mice and modify its organization. Improvements to the axial and appendicular skeletons were noticeable after 10 days of treatment and were more extensive after 15 days of treatment that started from postnatal day 1. Low-dose NVP-BGJ398 treatment reduced intervertebral disc defects of lumbar vertebrae, loss of synchondroses, and foramen-magnum shape anomalies. NVP-BGJ398 inhibited FGFR3 downstream signaling pathways, including MAPK, SOX9, STAT1, and PLCγ, in the growth plates of Fgfr3Y367C/+ mice and in cultured chondrocyte models of ACH. Together, our data demonstrate that NVP-BGJ398 corrects pathological hallmarks of ACH and support TKIs as a potential therapeutic approach for ACH.

Hypophosphatasia.

Hypophosphatasia is a rare disorder due to a mutation in the ALPL gene encoding the alkaline phosphatase (ALP) leading to a diminished activity of the enzyme in bone, liver, and kidney. Hypophosphatasia is a heterogeneous disease, ranging from extreme life-threatening forms revealed at birth in young infants presenting with severely impaired bone mineralization, seizures, and hypercalcemia, to young adults with premature exfoliation of their teeth without any other symptom. We will review the challenges of the clinical, biochemical, radiological, and genetic diagnosis. Schematically, the diagnosis relies on low ALP levels and, in most cases, on the genetic defect in the ALPL gene. An enzyme replacement therapy is now developed for hypophosphatasia; early results in the severe form of the disease are extremely encouraging. However, multidisciplinary care remains the core of treatment of hypophosphatasia encompassing nutritional support, adjustment of calcium and phosphate intake, monitoring of vitamin D levels, careful and personalized physical therapy, and regular dental monitoring and care.

Periosteum Metabolism and Nerve Fiber Positioning Depend on Interactions between Osteoblasts and Peripheral Innervation in Rat Mandible.

The sympathetic nervous system controls bone remodeling by regulating bone formation and resorption. How nerves and bone cells influence each other remains elusive. Here we modulated the content or activity of the neuropeptide Vasoactive Intestinal Peptide to investigate nerve-bone cell interplays in the mandible periosteum by assessing factors involved in nerve and bone behaviors. Young adult rats were chemically sympathectomized or treated with Vasoactive Intestinal Peptide or Vasoactive Intestinal Peptide10-28, a receptor antagonist. Sympathectomy depleted the osteogenic layer of the periosteum in neurotrophic proNerve Growth Factor and neurorepulsive semaphorin3a; sensory Calcitonin-Gene Related Peptide-positive fibers invaded this layer physiologically devoid of sensory fibers. In the periosteum non-osteogenic layer, sympathectomy activated mast cells to release mature Nerve Growth Factor while Calcitonin-Gene Related Peptide-positive fibers increased. Vasoactive Intestinal Peptide treatment reversed sympathectomy effects. Treating intact animals with Vasoactive Intestinal Peptide increased proNerve Growth Factor expression and stabilized mast cells. Vasoactive Intestinal Peptide10-28 treatment mimicked sympathectomy effects. Our data suggest that sympathetic Vasoactive Intestinal Peptide modulate the interactions between nervous fibers and bone cells by tuning expressions by osteogenic cells of factors responsible for mandible periosteum maintenance while osteogenic cells keep nervous fibers at a distance from the bone surface.

Mutations in the endothelin receptor type A cause mandibulofacial dysostosis with alopecia.

The endothelin receptor type A (EDNRA) signaling pathway is essential for the establishment of mandibular identity during development of the first pharyngeal arch. We report four unrelated individuals with the syndrome mandibulofacial dysostosis with alopecia (MFDA) who have de novo missense variants in EDNRA. Three of the four individuals have the same substitution, p.Tyr129Phe. Tyr129 is known to determine the selective affinity of EDNRA for endothelin 1 (EDN1), its major physiological ligand, and the p.Tyr129Phe variant increases the affinity of the receptor for EDN3, its non-preferred ligand, by two orders of magnitude. The fourth individual has a somatic mosaic substitution, p.Glu303Lys, and was previously described as having Johnson-McMillin syndrome. The zygomatic arch of individuals with MFDA resembles that of mice in which EDNRA is ectopically activated in the maxillary prominence, resulting in a maxillary to mandibular transformation, suggesting that the p.Tyr129Phe variant causes an EDNRA gain of function in the developing upper jaw. Our in vitro and in vivo assays suggested complex, context-dependent effects of the EDNRA variants on downstream signaling. Our findings highlight the importance of finely tuned regulation of EDNRA signaling during human craniofacial development and suggest that modification of endothelin receptor-ligand specificity was a key step in the evolution of vertebrate jaws.

Therapeutic management of hypophosphatemic rickets from infancy to adulthood.

In children, hypophosphatemic rickets (HR) is revealed by delayed walking, waddling gait, leg bowing, enlarged cartilages, bone pain, craniostenosis, spontaneous dental abscesses, and growth failure. If undiagnosed during childhood, patients with hypophosphatemia present with bone and/or joint pain, fractures, mineralization defects such as osteomalacia, entesopathy, severe dental anomalies, hearing loss, and fatigue. Healing rickets is the initial endpoint of treatment in children. Therapy aims at counteracting consequences of FGF23 excess, i.e. oral phosphorus supplementation with multiple daily intakes to compensate for renal phosphate wasting and active vitamin D analogs (alfacalcidol or calcitriol) to counter the 1,25-diOH-vitamin D deficiency. Corrective surgeries for residual leg bowing at the end of growth are occasionally performed. In absence of consensus regarding indications of the treatment in adults, it is generally accepted that medical treatment should be reinitiated (or maintained) in symptomatic patients to reduce pain, which may be due to bone microfractures and/or osteomalacia. In addition to the conventional treatment, optimal care of symptomatic patients requires pharmacological and non-pharmacological management of pain and joint stiffness, through appropriated rehabilitation. Much attention should be given to the dental and periodontal manifestations of HR. Besides vitamin D analogs and phosphate supplements that improve tooth mineralization, rigorous oral hygiene, active endodontic treatment of root abscesses and preventive protection of teeth surfaces are recommended. Current outcomes of this therapy are still not optimal, and therapies targeting the pathophysiology of the disease, i.e. FGF23 excess, are desirable. In this review, medical, dental, surgical, and contributions of various expertises to the treatment of HR are described, with an effort to highlight the importance of coordinated care.

FGFR3 mutation causes abnormal membranous ossification in achondroplasia.

FGFR3 gain-of-function mutations lead to both chondrodysplasias and craniosynostoses. Achondroplasia (ACH), the most frequent dwarfism, is due to an FGFR3-activating mutation which results in impaired endochondral ossification. The effects of the mutation on membranous ossification are unknown. Fgfr3(Y367C/+) mice mimicking ACH and craniofacial analysis of patients with ACH and FGFR3-related craniosynostoses provide an opportunity to address this issue. Studying the calvaria and skull base, we observed abnormal cartilage and premature fusion of the synchondroses leading to modifications of foramen magnum shape and size in Fgfr3(Y367C/+) mice, ACH and FGFR3-related craniosynostoses patients. Partial premature fusion of the coronal sutures and non-ossified gaps in frontal bones were also present in Fgfr3(Y367C/+) mice and ACH patients. Our data provide strong support that not only endochondral ossification but also membranous ossification is severely affected in ACH. Demonstration of the impact of FGFR3 mutations on craniofacial development should initiate novel pharmacological and surgical therapeutic approaches.