- Open Access
FGF23 and its role in X-linked hypophosphatemia-related morbidity
Orphanet Journal of Rare Diseasesvolume 14, Article number: 58 (2019)
X-linked hypophosphatemia (XLH) is an inherited disease of phosphate metabolism in which inactivating mutations of the Phosphate Regulating Endopeptidase Homolog, X-Linked (PHEX) gene lead to local and systemic effects including impaired growth, rickets, osteomalacia, bone abnormalities, bone pain, spontaneous dental abscesses, hearing difficulties, enthesopathy, osteoarthritis, and muscular dysfunction. Patients with XLH present with elevated levels of fibroblast growth factor 23 (FGF23), which is thought to mediate many of the aforementioned manifestations of the disease. Elevated FGF23 has also been observed in many other diseases of hypophosphatemia, and a range of animal models have been developed to study these diseases, yet the role of FGF23 in the pathophysiology of XLH is incompletely understood.
The role of FGF23 in the pathophysiology of XLH is here reviewed by describing what is known about phenotypes associated with various PHEX mutations, animal models of XLH, and non-nutritional diseases of hypophosphatemia, and by presenting molecular pathways that have been proposed to contribute to manifestations of XLH.
The pathophysiology of XLH is complex, involving a range of molecular pathways that variously contribute to different manifestations of the disease. Hypophosphatemia due to elevated FGF23 is the most obvious contributor, however localised fluctuations in tissue non-specific alkaline phosphatase (TNAP), pyrophosphate, calcitriol and direct effects of FGF23 have been observed to be associated with certain manifestations.
By describing what is known about these pathways, this review highlights key areas for future research that would contribute to the understanding and clinical treatment of non-nutritional diseases of hypophosphatemia, particularly XLH.
Background and Introduction
X-linked hypophosphatemia (also known as X-linked hypophosphatemic rickets, XLH; OMIM: #307800) is an inherited disease of phosphate metabolism, where inactivating mutations of the Phosphate Regulating Endopeptidase Homolog, X-Linked (PHEX, OMIM: #300550) gene lead to local and systemic effects. XLH affects approximately 1:20,000 individuals  who experience a diverse range of medical problems that are depicted in Fig. 1, and include impaired growth, rickets, osteomalacia, bone abnormalities, bone pain, spontaneous dental abscesses, hearing difficulties, enthesopathy, osteoarthritis, and muscular dysfunction [2, 3].
PHEX is predominantly expressed in osteoblasts and codes for an enzyme that degrades local small integrin-binding ligand, N-linked glycoproteins (SIBLING proteins), particularly osteopontin (OPN) , and suppresses serum levels of the phosphatonin, fibroblast growth factor 23 (FGF23). Despite being an enzyme, PHEX is thought to affect expression  rather than degradation of FGF23 [6, 7].
Downregulation of PHEX in XLH increases skeletal OPN deposition which contributes to local inhibition of mineralisation . Meanwhile, elevated levels of serum FGF23 increase urinary phosphate excretion by downregulating renal sodium-phosphate transporters, and limit intestinal phosphate absorption by restricting active vitamin D synthesis to levels that are abnormally low or normal despite hypophosphatemia  .
Since phosphate insufficiency and inappropriately low levels of calcitriol [also known as 1,25(OH)2D or active vitamin D] contribute to many symptoms of XLH, conventional therapy involves supplementation with oral phosphate and calcitriol or calcitriol analogues (commonly alfacalcidol). This can correct lower limb deformities, promote growth, and improve oral health , with earlier treatment leading to better results . However, conventional therapy insufficiently corrects the biochemistry and symptoms of XLH, and can further increase serum FGF23 levels [8, 11,12,13]. Conventional therapy has also been associated with adverse effects including secondary hyperparathyroidism, nephrocalcinosis, nephrolithiasis, and cardiovascular abnormalities .
This review describes the central role of FGF23 in XLH pathophysiology, outlining evidence that links upregulation of FGF23 to manifestations of XLH through various molecular pathways (outlined in Fig. 2). FGF23 is introduced along with its direct regulators and receptors, followed by a brief discussion of the dysregulation of serum FGF23 in various diseases of hypophosphatemia; animal models of these diseases are also described since they are essential for understanding molecular mechanisms involved in the pathology of XLH. Finally, the manifestations of XLH are grouped by molecular mechanism and discussed, with any potential involvement of FGF23 highlighted.
Regulation of serum FGF23
The FGF23 gene is located on chromosome 12 and codes for a 251-amino acid, 32 kDa pro-protein. Although FGF23 is predominantly expressed in and secreted by osteocytes and osteoblasts, lower levels of FGF23 expression have been detected in rodents in many non-bone tissues, including teeth and brain [16,17,18].
A 24-amino acid signalling peptide is cleaved from FGF23 post-translationally and directs active FGF23 protein (227 amino acids) to the Golgi apparatus for secretion. Some active FGF23 is further cleaved during secretion, and the resulting C- and N-terminal fragments are then released from the cell along with the remaining active FGF23; these FGF23 fragments are not thought to have any innate biological activity [19, 20] . FGF23 can either act locally or enter the bloodstream to interact with distant cell surface receptors. The molecular pathways involved in regulation of these processes are complex, and therefore are only briefly depicted in Fig. 2 and summarised below.
Factors that regulate FGF23 expression
Expression of FGF23 is predominantly regulated by serum phosphate and calcitriol . Phosphate-induced elevation of serum FGF23 mostly occurs in bone . The nature of this “phosphate sensing” mechanism is yet to be fully elucidated, but has been proposed to involve nicotinamide adenine dinucleotide phosphate (NADPH)-induced production of reactive oxygen species (ROS), and the mitogen-activated protein kinase kinase-extracellular signal-regulated kinases (MEK-ERK) pathway [23, 24]. Other molecular mechanisms that have been associated with FGF23 expression include FAM20C , ENPP1  and DMP1 , as well as the presence of SIBLING protein-derived acidic serine aspartate-rich-MEPE-associated protein (ASARM) peptides .
Recent additions to the long list of factors proposed to affect FGF23 expression include actin cytoskeleton reorganisation, NFκB signalling , aldosterone , ORAI1 , changes in calcium concentrations, activated renin angiotensin system, KLOTHO , and local osteoblastic conversion of 25(OH)D to calcitriol .
Factors that regulate FGF23 cleavage
Degradation of FGF23 has been proposed to be mediated by furin  and/or proprotein convertase, subtilisin/kexin-type 5/6 (PC5/6) , and to be inhibited by O-glycosylation at the site of proteolysis by polypeptide N-acteylgalatosaminyltransferase 3 (GalNAcT3), which is encoded by the GALNT3 gene [35, 36]. Homozygous inactivating mutations in GALNT3 result in low levels of intact FGF23 and familial tumoral calcinosis syndrome, a condition characterised by hyperphosphatemia and extraskeletal calcifications . There is also evidence that O-glycosylation can be blocked by FAM20C-mediated phosphorylation , and that FGF23 can be cleaved by proprotein convertases , although these findings have been challenged .
A recent study found that both expression and cleavage of FGF23 was promoted by iron deficiency and inflammation, so that secretion of C-terminal fragments was upregulated without significantly affecting serum concentrations of active FGF23 .
While it is important to appreciate the complexity of FGF23 regulation and to recognise that PHEX mutations disrupt a finely balanced system, many of the aforementioned pathways have already been well-reviewed [40, 41] and a more detailed description of them is beyond the scope of the current article.
FGF23 receptors and signalling
The poor in vitro affinity of FGF23 for its receptors made it seem like an unlikely candidate for the then putative phosphatonin . However, poor receptor-ligand affinity is overcome in vivo via utilisation of co-receptors, particularly α-KLOTHO (KLOTHO), which is schematically represented in Fig.3. Receptors for FGF23 include FGF receptor (FGFR)1, FGFR2, FGFR3, and FGFR4, and the expression of these receptors varies between cell types [43, 44]. In addition, FGF23 has unusually poor affinity for heparan sulfate (HS) that allows it to diffuse through the HS-rich extracellular matrix more readily than other FGFs, and to signal in an endocrine fashion .
KLOTHO greatly enhances the affinity of FGF23 for FGFR1 and FGFR3  and is required for many functions of FGF23. The close relationship between KLOTHO and FGF23 is highlighted in KLOTHO-deficient (Klotho-/-) mice, which display a very similar phenotype to Fgf23-/- mice, even when they are forced to overexpress FGF23 [43, 46, 47]. In addition, it was demonstrated that the shed extracellular domain of α-KLOTHO (α-KlOTHOecto) serves as a non-enzymatic molecular scaffold for FGF23 hormone signalling. α-KlOTHOecto is able to form a 1:1:1 ternary complex together with FGF23 and FGFR1 by implementing FGF23-FGFR1 proximity and conferring stability. As demonstrated for membrane bound α-KLOTHO, this is followed by heparan sulfate facilitated dimerisation of two ternary complexes promoting FGF23 signalling (Fig. 3).
KLOTHO expression was originally thought to limit FGF23 activity and to be restricted to the kidney, parathyroid gland and choroid plexus . However, recent reports of widespread KLOTHO expression , α-KlOTHOecto mediated FGFR activation, and KLOTHO-independent functions of FGF23  have expanded the proposed scope of FGF23 activity.
Post-cleavage C-terminal fragments of FGF23 have also been shown to block formation of FGF23-FGFR-KLOTHO complexes and to improve hypophosphatemia, which adds another regulatory level to FGF23 signalling .
Serum FGF23 and non-nutritional diseases of hypophosphatemia
Serum FGF23 is elevated in many non-nutritional diseases of hypophosphatemia, and the main characteristics that lead to differential diagnosis of these diseases are outlined in Table 1.
FGF23 was originally identified for its role in phosphate metabolism when mutated FGF23 was found in patients with autosomal dominant hypophosphatemic rickets (ADHR) , and FGF23 was identified as the causal agent in tumour-induced osteomalacia (TIO). Indeed, most inherited forms of hypophosphatemia are caused by mutations that directly increase serum concentrations of FGF23 and/or the activity of its receptors.
The three forms of autosomal recessive hypophosphatemic rickets (ARHR) result from mutations in DMP1 [ARHR1, ], ENPP1 [ARHR2, ], and FAM20C [ARHR3, ], while hypophosphatemic rickets and hyperparathyroidism (HRHPT) is caused by mutations that upregulate KLOTHO expression .
A key exception to the rule is hereditary hypophosphatemic rickets with hypercalciuria (HHRH) in which patients show suppressed or low-normal FGF23 levels. HHRH is caused by mutations in the renal phosphate transporter NPT2C [also known as NaPi-IIc or solute carrier family 34 member 3 (SLC34A3)]. Phosphate-independent effects of FGF23 can therefore be identified by comparing the pathophysiology of patients with HHRH to those with FGF23-high hypophosphatemias  (Table 1).
TIO is an interesting example of an FGF23-mediated hypophosphatemia, as this acquired disease is caused by FGF23-secreting tumours, whose total resection is completely curative . Symptoms of TIO can therefore be unambiguously attributed to over-expression of FGF23 and/or other tumour-secreted phosphatonins, without potential confounding contributions to the clinical phenotype from mutated genes.
Finally, XLH is the most common form of non-nutritional hypophosphatemia. The mechanisms by which PHEX mutations lead to elevated FGF23 levels remain poorly understood and have been attributed to increased expression  and reduced degradation [38, 40] of FGF23.
PHEX mutations and FGF23 regulation in XLH
Around 350 different PHEX mutations have been identified to date, including nonsense, missense, frameshift, splice site, deletion, and duplication mutations  – the mutations are represented in Fig. 4. Mutations have been observed to affect each of the 22 PHEX exons, as well as intronic splice sites [57,58,59] and the 5’ untranslated region .
Identifying consistent genotype-phenotype relationships in patients with mutations affecting similar genetic loci would indicate connections between those PHEX loci and specific phenotypes. The presence or absence of a correlation between such mutations and serum levels of FGF23 could further elucidate the role of PHEX in regulating FGF23, and/or the roles of PHEX and FGF23 in the pathophysiology of XLH. Indeed, specific mutations have been associated with specific manifestations of XLH , and attempts have been made to connect serum levels of FGF23 to severity of XLH .
PHEX mutations can lead to retention of PHEX protein in the endoplasmic reticulum  and/or expression of truncated PHEX proteins which may retain some functions of the full-length protein [61, 62]. Identifying direct functions of PHEX that may be retained in truncated proteins would therefore contribute to our understanding of the aetiology of XLH.
One mechanism by which the full-length PHEX protein has been proposed to regulate serum FGF23 is indirect cleavage by proprotein convertases [6, 40]. The proprotein convertase, subtilisin/kexin-type 2 (PC2) has been reported to be upregulated by PHEX, to cleave FGF23 directly , and to promote formation of PHEX-DMP1-integrin complexes that suppress FGF23 when activated by neuroendocrine protein 7B2 (7B2•PC2) . However, the potential for a direct interaction between 7B2•PC2 and FGF23 may be confounded by an apparent lack of potential for physical contact between the two proteins . Interactions between 7B2•PC2 and the FGF23-regulator FAM20C may  or may not  also affect interpretation of these studies.
However, studies searching for genotype-phenotype correlations in XLH patients have so far failed to identify significant correlations [64,65,66,67]. Reaching statistical significance in these studies is complicated by the rarity of the disease, the sheer diversity of mutations in XLH patients and the impact of conventional treatment on the natural course of the disease .
Although mutations can be grouped by locus  or by mutation type , larger data sets are ultimately required to establish specific genotype-phenotype correlations. The observation that disease severity may vary considerably in affected members of the same family indicates that there are other modifying factors and that a clear genotype-phenotype correlation may be difficult to identify .
Animal models of XLH
Despite the lack of obvious genotype-phenotype correlation in individuals with PHEX mutations, phenotypic differences have been observed between various animal models of XLH, which are easier to study but are not precisely representative of the patient population.
Mouse models possessing at least six different mutations of the Phex gene (Gy, Hyp, Hyp-Duk, Hyp-2J, Ska1 and Jrt) have been used to study XLH and are described in Table 2. The phenotypes of these mice vary depending on the specific Phex mutation and the mouse strain. Although these differences are rarely discussed in published works, they can shed light on FGF23-independent roles of PHEX in XLH pathology and resolve apparent contradictions in the literature.
Phex-non-specific animal models of XLH
The first two mouse models of XLH were named Hyp and Gy [69, 70]. Although both mice displayed hypophosphatemia and broadly similar phenotypes, Gy mice additionally displayed inner ear abnormalities and male sterility. The two models were originally thought to possess mutations in related X-linked genes, but Gy and Hyp have since been identified as mutations that both ablate the Phex gene (Table 2). While Hyp mice have mutations that affect exon 15 and 10 kb of downstream intergenic sequences, Gy mice contain large deletions of Phex exons 1-3 [71, 72]. The Gy deletion also extends upstream into the neighbouring spermine synthase (SmS) gene, which has been associated with hearing loss and infertility, thus confounding Gy mice as a model of XLH-related hearing loss .
Forced expression of human transgenic FGF23 has been shown to rescue the bone phenotype of Hyp mice, but not their hypophosphatemia . This result may be due to phosphate-independent effects of FGF23 on bone, or the Hyp mutation affecting expression of other genes or signal peptides involved in phosphate regulation and/or bone mineralisation.
Phex-specific models of XLH include Ska1 mice, which contain a chemically-induced point mutation in a splice donor site just after exon 8 , PhexK496X (Jrt) mice, which contain a stop codon at amino acid 496 , and Hyp-2J and Hyp-Duk mice , which contain larger frameshift deletions. Phenotypic differences between Hyp-2J and Hyp-Duk mice have been observed and are discussed below. The Hyp-Duk mutation can result in the production of truncated PHEX proteins, which may retain some functions of PHEX .
Despite the range of animal models available, major challenges remain for elucidating the pathogenesis of XLH including: the low disease prevalence, the complexity of FGF23-related molecular networks, the diversity of PHEX mutations, the potential for residual PHEX function, and the potential impact of random X-inactivation on the severity of the female phenotype. Considering these challenges, known and proposed role(s) of FGF23 in XLH sequelae are discussed below.
The role of FGF23 in XLH pathogenesis
When FGF23 was first described as the causative agent of ADHR, the authors commented on the similarities between ADHR and other diseases of inherited hypophosphatemia, including XLH . The relationship between FGF23 and the pathophysiology of diseases of inherited hypophosphatemia has since been well-studied by comparing phenotypes of patients with FGF23-high and FGF23-normal hypophosphatemias (Table 1) to animal models (Table 2), healthy controls, and cases where FGF23 levels have been lowered, including blocking and knock-out experiments.
Multiple pathways link elevated FGF23 to long bone abnormalities
Abnormal, disproportionate growth is a definitive feature of XLH and is primarily seen in reduced growth of endochondral long bones. Within the first few months of life, signs and symptoms of the disease become evident. Uncontrolled rickets and osteomalacia contribute to continuously diminished leg growth, which leads to short stature with elevated sitting height index (i.e. ratio between sitting height and stature), gait abnormalities due to deformities and muscle weakness, bone pain, deformity of weight-bearing limbs, with the development of Looser zones becoming evident in the mature skeleton (Fig. 1) [9, 78].
Briefly, endochondral bones develop from cartilaginous precursors that mineralise outwards from ossification sites. The cartilage remaining between ossification sites continues to grow, forming epiphyseal growth plates composed of germinal, proliferative and (upper and lower) hypertrophic zones. After completing active mitosis in the proliferative zone, epiphyseal chondrocytes of the upper hypertrophic zone enlarge and form columns that lengthen the developing bone, while chondrocytes of the lower hypertrophic zone mineralise the surrounding matrix and produce vascular endothelial growth factor that attracts invading vessel and bone cells . The terminal hypertrophic chondrocytes undergo apoptosis and are replaced by osteocytes and osteoid that is then overlaid with hydroxyapatite to form mineralised bone [80, 81].
In hypophosphatemia, apoptosis of hypertrophic chondrocytes is arrested and is, by an unknown mechanism, followed by decreased chondrocyte proliferation and loss of organisation of the proliferative columns . In addition, hypomineralisation of the newly formed bone leads to accumulation of osteoid and weakened bones. When pressure is applied to affected bones they bend under pressure, while loading appears to affect the function of hypomineralised growth plates, which collectively cause leg length to be more affected than arm span in XLH patients .
On the other hand, osteomalacia is caused by a generalised disruption of mineral deposition of newly-formed osteoid. Unlike rickets, which is a disease of the growth plates and thus only affects children, osteomalacia can affect both children and adults with XLH .
A role for FGF23 in the pathogenesis of rickets and osteomalacia in TIO was identified shortly after its discovery , and was supported by the consistent appearance of bone abnormalities in FGF23-high diseases and animal models (Tables 1 and 2). Furthermore, the skeletal phenotypes of Hyp mice in which Fgf23 was also ablated (Hyp-Fgf23-/-) were more similar to Fgf23-/- mice than to Hyp mice . The molecular pathways connecting FGF23 to abnormal bone development have since been further elucidated and include hypophosphatemia-mediated pathways and autocrine/paracrine pathways, which are respectively illustrated in parts A and B of Fig. 5 [84, 85].
Hypophosphatemia-mediated mechanisms of FGF23-induced bone abnormalities
Hypophosphatemia is the primary mechanism by which elevated serum FGF23 affects bone development. Excess FGF23 results in hypophosphatemia, whether induced by direct injection  or increased stability [87, 88] of FGF23 (Fgf23-TG), or by downregulation of FGF23-suppressors including PHEX [5, 25, 52].
Hypophosphatemia leads to rickets by inhibiting mineralisation and apoptosis of hypertrophic chondrocytes , yet the contributions of FGF23 to hypophosphatemia are mediated by a complex network of pathways that ultimately increase urinary wasting, due to downregulation of the renal sodium-phosphate co-transporters NPT2A and NPT2C [90, 91], and decrease intestinal absorption of phosphate (Fig. 5a) [80, 81].
NPT2A and NPT2C play different roles in mice and humans. While humans develop severe hypophosphatemia (HHRH) when NPT2C is lost, depletion of Npt2c-alone in mice has no apparent effect on phosphate metabolism . Depletion of Npt2a-alone results in upregulation of Npt2c and a mild hypophosphatemia and bone phenotype . Yet mice missing both Npt2a and Npt2c display severe hypophosphatemia and rickets, as well as hypercalciuria, indicating a functional redundancy that is not seen in humans . Such inter-species variation in gene function is a challenge for translating the study of these genes .
Nevertheless, the relationship between FGF23 and these phosphate channels is clear; direct administration of recombinant FGF23 has been seen to reduce renal expression of NPT2A in mice , and renal expression of NPT2A and/or NPT2C is downregulated in FGF23-high mice (Hyp or Fgf23-TG) and in patients with XLH [3, 90, 95].
Increased FGF23 affects calcitriol synthesis and degradation, thus hindering its ability to counterbalance hypophosphatemia. FGF23 downregulates renal 1α-hydroxylase (CYP27B1) and stimulates expression of 24-hydroxylase (CYP24A1), which limits production and increases degradation of calcitriol . FGF23 also suppresses the secretion of PTH, which would otherwise promote expression of calcitriol , reducing intestinal adsorption of phosphate . PTH is suppressed via MAPK/ERK signalling both in KLOTHO-dependent and -independent manners involving activation of the calcineurin-nuclear factor of activated T-cells (NFAT) pathway .
Disturbed regulation of the physiological responses of calcitriol to hypophosphatemia, in addition to the downregulation of the renal phosphate transporter channels, thus contribute to hypophosphatemia in diseases of excess FGF23 such as XLH (Fig. 5a). FGF23-mediated upregulation of prostaglandin E2 (PGE2) via inhibition of proximal tubule phosphate transport may also contribute to hypophosphatemia [98, 99], but the supporting evidence is less clear, since these animal studies were not supported by a subsequent under-powered crossover study in children .
FGF23-mediated autocrine/paracrine pathways linked to bone abnormalities
The discovery that achondroplasia (a well-known skeletal dysplasia in which serum phosphate is unaffected) is caused by activating mutations of an FGF23 receptor (FGFR3), indicated that FGF23-related pathways may affect skeletal development in phosphate-independent manners . This prospect was supported when abnormal mineralisation of Hyp osteocytes was observed in a phosphate-normal in vitro environment .
It has since become evident that hypophosphatemia-independent autocrine/paracrine effects of FGF23 can be mediated by calcitriol and tissue non-specific alkaline phosphatase (TNAP) (Fig. 5b).
A recent study linked autocrine/paracrine roles of locally-produced calcitriol to the FGF23-mediated regulation of chondrocyte differentiation and bone mineral deposition .
Despite displaying hypophosphatemia and low serum calcitriol, mice with elevated FGF23 (Hyp or Fgf23-TG) did not develop skeletal abnormalities when CYP24A1 levels were repressed, either in Cyp24a1-null mutants or following blocking with CTA102 . It was hypothesised that mineralisation in the control animals was disrupted by FGF23-mediated activation of CYP24A1 degrading locally-produced calcitriol, and CYP24A1-antagonists were proposed as novel therapeutic agents for XLH . Furthermore, regulation of local CYP27B1 has recently been shown to differ between bone and kidney and local regulation of calcitriol is generally poorly understood and may be affected in XLH .
Conversely, there is also evidence suggesting that vitamin D does not play a direct role in bone development. For example, an early study in which vitamin D-deficient rats were either given vitamin D and infused with saline, or infused with concentrations of calcium and phosphorus to maintain plasma concentrations equal to those in the vitamin D treated animals, indicated that vitamin D did not play a role in the density or calcium-phosphate ratio of bone .
Inhibition of bone-derived calcitriol may contribute to rickets by inhibiting chondrocyte differentiation through downregulation of p21Waf1/Cip1 pathways and upregulation of cyclin D1 . Calcitriol has also been shown to directly affect expression of OPN, a known inhibitor of hydroxyapatite crystal formation, however studies have indicated that calcitriol can either induce upregulation  or downregulation  of OPN, and whilst much of the literature suggests that calcitriol induces upregulation of OPN, no conclusive studies are currently available.
The SIBLING protein OPN contains an ASARM peptide motif [106, 107], cleavage of which releases phosphorylated ASARM (pASARM) peptides which are also potent inhibitors of mineralisation. Loose pASARM peptides are directly and exclusively cleaved by PHEX [4, 9, 40, 108]. Although reduced PHEX-mediated cleavage of pASARM also acts as an FGF23-independent mechanism for contributing to bone abnormalities in XLH [109,110,111,112], this process is exacerbated by FGF23-induced upregulation of OPN .
Furthermore, the recent observation of impaired urinary OPN excretion in Npt2a-/- mice could indicate another FGF23-mediated contribution to the pASARM-mediated demineralisation of bone . However, evidence that ablating Fgf23 can also lead to upregulation of OPN indicates that the relationship between FGF23 and OPN is poorly understood and is likely to be complex .
Recent evidence suggests that accumulation of pyrophosphate (PPi) may also play a role in impaired mineralisation in XLH.
Downregulation of TNAP (expressed by Alpl) suppresses hydrolysis of PPi and has been linked to post-natal mineralisation defects and hypophosphatasia, a normophosphataemic disease with rickets like bone abnormalities resembling those observed in XLH [115,116,117]. PPi is also a known mineralisation inhibitor, binding to and inhibiting formation of hydroxyapatite crystals [106, 107, 118].
A study comparing mice in which Fgf23, Klotho and/or vitamin D receptor (Vdr) genes were knocked out connected this TNAP-dependent pathway to FGF23, as accumulation of PPi was promoted in the osteoblastic cells of FGF23-/- mice  .
The proposed autocrine/paracrine role of FGF23 was observed to act through TNAP and PPi in Hyp mice, whose osteoblasts and osteocyte-like cells were cultured in vitro and ex vivo and were compared to sections of Hyp bone . Despite being separated from the in vivo hypophosphatemic environment, TNAP was inhibited and mineralisation defects arose in osteocyte-like cells, where PPi deposition was promoted and hydroxyapatite-formation was blocked .
That low levels of TNAP expression were observed in osteocyte-like cells but not in osteoblasts was further investigated and TNAP expression was found to correlate inversely with FGFR3 expression levels . Chondrocyte proliferation has also been suppressed by FGFR3 activation in vivo and in vitro, resulting in suppression of linear bone growth . Activation of FGFR3 can also lead to achondroplasia, which results in a more extreme disproportionate short stature than XLH. Experiments blocking FGF23 or FGFR3 demonstrated that FGF23 was suppressing TNAP transcription via KLOTHO-independent, FGFR3 signalling and ultimately leading to mineralisation defects . This KLOTHO-independent pathway may explain findings that the overexpression of FGF23 can suppress osteogenesis in osteoblastic cells, which do not express KLOTHO .
Another key FGF23 receptor, FGFR2, also plays an important role in skeletal development , and was upregulated in the bones of Hyp mice . There is a line of evidence connecting over-expression of FGFR2 in long bones to weakened long bones  via suppression of TNAP  and the production and accumulation of PPi [124, 125] (Fig. 5b).
Interestingly, the autocrine/paracrine effects of FGF23 appear to vary between mouse models of XLH. Although Jrt mice display growth retardation, skeletal abnormalities, hypophosphatemia and increased serum FGF23 and ALP levels similar to other murine models of XLH; unlike those models Jrt osteoblasts in vitro have been observed to resemble those from wild type males with respect to cellular differentiation and calcium deposition into bone matrix .
The osteoblast abnormality in Jrt mice may arise from a reduction in phosphate sensitivity mediated by Phex independently of FGF23 . While hemizygous Phex-/Y mice (100% of cells carry one mutant Phex) displayed comparable skeletal abnormalities to heterozygous Phex-/Phex+ mice (50% of cells carry one mutant Phex), homozygous female Phex-/Phex- mice (100% of cells carry two mutant Phex) displayed exaggerated abnormalities, despite having equivalent serum phosphate and FGF23 concentrations . Skeletal abnormalities in these animals therefore appeared to correlate with the dosage of Phex mutations, which may affect random X-chromosome inactivation or the sensitivity of osteocytes to serum phosphate and/or FGF23.
Jrt mice are an interesting model of XLH, and should be included in future studies investigating the roles of PHEX and FGF23 in the disease.
FGF23-blocking ameliorates bone abnormalities
Finally, the relevance of FGF23 to bone abnormalities in XLH and other diseases of hypophosphatemia has been indicated by various animal experiments and clinical trials. For example, complete resection of FGF23-producing tumours has resolved hypophosphatemia, osteomalacia, bone pain and improved other skeletal manifestations in TIO [128, 129] and administration of FGF23-blocking antibodies has improved growth retardation of juvenile Hyp mice, accelerating weight gain, increasing tail length, decreasing osteoid volume and thus improving bone mineralisation while improving elongation of femoral and tibial bones [130,131,132]. FGF23 antibodies have also improved levels of serum phosphate, serum calcitriol, and alkaline phosphatase, as well as rickets severity (RSS), radiographic global impression of change (RGI-C), and Western Ontario and the McMaster Universities Osteoarthritis Index (WOMAC) scores in clinical trials involving paediatric or adult patients with XLH (Paediatric trial: NCT02163577; Adult trial NCT02526160) [133,134,135].
Ectopic calcification and ossification in XLH
Ectopic calcification in XLH can affect the kidneys (nephrocalcinosis), joints, and bone attachments of tendons (enthesopathies) (Fig. 6). While nephrocalcinosis has long been considered a side effect of conventional treatment , enthesopathies have also been observed in untreated patients .
Nephrocalcinosis has been observed in as few as 22% and as many as 100% of XLH patients [66, 138, 139]. This variation can be partially attributed to small study sizes and high patient and treatment variability.
Nephrocalcinosis is often composed of calcium phosphate precipitation and is thought to be due to one or a combination of hypercalciuria, hyperphosphaturia, hyperoxaluria, and secondary hyperparathyroidism [140,141,142]. Nephrocalcinosis has not been reported in untreated XLH patients and is widely considered to be a result of conventional therapy  associated with active vitamin D dosage . In addition, other soft-tissue calcifications such as ocular, myocardial, and aortic valve calcification have been reported in XLH patients with persistent secondary or tertiary hyperparathyroidism and/or high dose calcitriol and phosphate treatment .
The hypercalciuric properties of NPT2A/C downregulation, alongside the effects of FGF23 on NPT2A/C expression, have been briefly discussed above, and the impact of NPT2A/C impairments in patients are further explored in the paper by Bergwitz and Jüppner . Dysfunctions in NPT2A alone have been associated with severe renal calcification , whilst mutations in NPT2A and NPT2C have also been reported in patients with renal stone disease and nephrocalcinosis [148, 149].
A recent study has also shown that upregulation of OPN via FGF23/PHEX can contribute to nephrocalcinosis and nephrolithiasis observed in mice on a high-phosphate diet .
A potential role for FGF23 in enhancing renal calcium reabsorption has also been observed in XLH , which may be mediated through the transient receptor potential cation channel subfamily V member 5 (TRPV5) channel, which promotes cellular uptake of calcium and therefore calcification [151, 152].
Excessive mineralisation also occurs in the heart and kidney of mice in which Fgf23 has been ablated, regardless of whether or not the mice possessed the Hyp mutation . This further illustrates the suppressive effect FGF23 has on mineralisation.
Nephrocalcinosis has not been observed during FGF23-blocking trials, probably because the treatment does not include active vitamin D ; however, long-term data are lacking.
Cardiovascular calcification and hypertension
Reports of cardiovascular abnormalities and hypertension in patients with XLH are rare, inconsistent, and considered to be side effects of conventional therapy and/or FGF23-driven increased renal sodium reabsorption [14, 66, 139, 152, 153]. Studies have reported hypertension  and left ventricular hypertrophy in only a minority of subjects , or found no evidence of cardiovascular myocardial dysfunction symptoms in any of 11 XLH patients .
A recent study of XLH patients found hypertension correlating with reduced estimated glomerular filtration rate (eGFR) in 6/22 patients, most of whom also had secondary hyperparathyroidism . The authors were unable to determine whether hypertension was a primary consequence of XLH or a secondary consequence of conventional therapy and concluded that “multiple factors” presumably played a role .
The over-expression of FGF23 has also been associated with various aspects of cardiovascular disease in chronic kidney disease (CKD) including cardiomyocyte hypertrophy, vascular calcification, stroke, and endothelial dysfunction [155,156,157,158,159,160]. Atherosclerosis has been proposed as a mechanism by which FGF23 may promote cardiovascular events and stroke in these patients . However, the pathogenic mechanism is unlikely to be mediated by KLOTHO, which is excreted by the CKD-affected kidney . FGF23 may instead contribute to cardiovascular disease in CKD by directly interacting with FGFR4 on cardiomyocytes to induce cardiomyocyte hypertrophy [162, 163] or with hepatocyte FGFRs to induce hypertension  which can lead to blood vessel calcification [165, 166].
In addition, FGF23 was shown to directly regulate the membrane abundance of the Na(+):Cl(-) co-transporter NCC in distal renal tubules by a signalling mechanism involving the FGF receptor/αKlotho complex . This suggests that FGF23 is a key regulator of renal sodium reabsorption and plasma volume and may explain the association of FGF23 with cardiovascular risk in CKD patients. In addition, FGF23 is also generally associated with the progression of CKD . Nevertheless, FGF23 levels in CKD are elevated well above those observed in hereditary hypophosphatemia and at those concentrations FGF23 may reach toxic levels that are not relevant to XLH .
In patients with hereditary hypophosphatemia, inappropriate mineralisation of fibrocartilage can develop where tendons insert into bone (entheses). The developing spurs (enthesophytes) can then cause joint stiffness and pain (enthesopathy), which often affects patients with XLH . Mineralising enthesopathies of fibrocartilaginous insertion sites affect a majority of ankles in patients with XLH, and appear to be strongly correlated with increasing age [2, 169, 170]. Enthesopathies are also commonly observed in other phosphate-wasting disorders of excessive FGF23 (ARHR1, AHRH2), and in murine models of XLH (Hyp, Fgf23-TG) [171,172,173].
The initiation of mineralising enthesophytes at the bony insertion site is poorly understood, but is thought to occur following degeneration of mineralised cartilage during insertion site development . Expression of Fgfr3 and Klotho in murine fibrocartilage cells indicates that they are likely to be directly affected by FGF23 .
Fibrocartilage is composed of an uncalcified zone containing alkaline phosphatase-negative chondrocytes, and a calcified zone where chondrocytes express alkaline phosphatase and are surrounded by a mineralised matrix that covers the bone surface. Significantly greater numbers of alkaline phosphatase-positive fibrocartilage cells have been observed in joints of Hyp mice than in control mice, yet the typically narrow mineralised zone was also completely lost . The observed fibrochondrocyte hyperplasia was proposed to pre-date loss of the mineralised zone and to cause enthesopathy .
Enthesopathies have been observed in untreated XLH patients [137, 175] and they have been reported to be unaffected by conventional therapy in XLH patients . In Hyp mice conventional therapy has not only failed to ameliorate fibrochondrocyte hyperplasia, but also exacerbated mineralisation of enthesopathies .
Development of enthesopathies may be mediated by matrix metalloproteinase 13 (MMP13), a gene that prepares cartilage matrix for calcification  and a critical target gene during the progression of osteoarthritis.
Expression of MMP13, FGF23 and OPN are all downregulated in enthesopathic Hyp cartilage, but not in the osteoblasts of those same mice. This indicates that the downregulation of these genes is chondrocyte-specific and may indicate that the hyperplastic chondrocytes observed in enthesopathies are immature . This observation also highlights the importance of assessing gene expression levels of specific cell types where possible, rather than relying on serum levels to develop mechanistic models.
Enthesopathic sites in Hyp and Fgf23-TG mice also displayed increases in sulphated proteoglycans . The cushioning effect of the sulphated proteoglycans combined with the greater surface area of XLH bones are thought to stabilise and protect joints from the abnormally high compressive forces exerted through weakened and misshapen long bones . Mineralising enthesopathies may therefore be a secondary effect of long bone hypomineralisation causing weaker and more bendable bones, with potentially more strain on the entheses and their attachment. Therefore, correcting gross skeletal abnormalities and restoring normal biomechanics may theoretically contribute to correction of enthesopathy.
Although the effects of FGF23 blocking on enthesopathies have not specifically been assessed, significant improvements have been observed in treated XLH patients scored on the Western Ontario and McMaster Universities Osteoarthritis Index (WOMAC), which focuses on patient perception of joint pain .
Skeletal muscle defects in XLH
Muscle pain or weakness has been reported by a majority of adult hereditary hypophosphatemic rickets patients in one study , and Hyp mice display reduced grip strength and spontaneous movement compared to controls .
Despite having normal muscle size, and in the absence of leg deformities, subjects with hereditary hypophosphatemic rickets had lower muscle density and lower peak muscle force and power compared to age- and gender-matched controls [179, 180]. Since muscle force is strongly correlated with bone strength, and osteocytes have been connected to muscle mass and function via mechanical loading, PGE2 and Wnt3a , the abnormal skeletal phenotype in XLH patients may contribute to skeletal muscle defects.
It is also interesting to note that some studies have found strong correlations between extremes in phosphate levels and impaired muscle force, whilst others have found that hypophosphatemia appears to be associated with muscle weakness. These findings suggest that the development of the skeletal muscle defects observed in patients with XLH may be multifaceted [182, 183].
Skeletal muscle wasting, weakness and pain have also been observed in patients with TIO [128, 129, 184]. The lack of either skeletal abnormality or genetic mutation in these patients indicates that FGF23 may contribute to the development of these manifestations either directly or via hypophosphatemia.
The phosphaturic actions of FGF23 may contribute to the muscular phenotype by decreasing muscle ATP synthesis and causing muscle weakness, which has been observed in both HHRH patients and Npt2a-/- mice . This correlation is supported by evidence that phosphate supplementation has reversed skeletal muscle abnormalities in a case of chronic fatigue  and reversed muscle weakness in a patient suffering FGF23-induced hypophosphatemic osteomalacia . Phosphate supplementation has also ameliorated post-operative weakness and muscle tremors in a dog  and vitamin D-deficiency-induced muscle weakness in rats .
Collectively, these results indicate that FGF23-induced hypophosphatemia is associated with muscle weakness in XLH. However, the expression of PHEX in myocytes indicates the potential for a more direct role for FGF23 in muscular weakness in XLH , and FGF23 has been shown to induce senescence in mesenchymal stem cells derived from skeletal muscle .
On the other hand, there may be a role for exercise-stimulated FGF23 in controlling production of ROS production and enhancing mitochondrial function . Although FGF23 levels are likely to be consistently higher in XLH than during exercise, the study by Li et al identifies a novel effect of FGF23 on skeletal muscle, which may be induced by the high FGF23 levels in XLH. Plasma levels of FGF23 are also positively associated with muscle mass in haemodialysis patients, which could indicate a role for FGF23 in improving muscle strength .
Nevertheless, resection of an FGF23-producing tumour has resolved muscle pain in a patient with TIO  and therapeutic application of an FGF23-blocking antibody has increased grip strength and spontaneous movement in Hyp mice  and led to full recovery of bone and muscle pain when treating patients with iron-induced FGF23-mediated hypophosphatemic osteomalacia .
Craniosynostosis in XLH
Craniosynostosis is a cranial malformation that results from premature fusing of the cranial sutures during development (illustrated in Fig. 7). Beyond abnormal skull shape, craniosynostosis and defective mineralisation in XLH patients can be associated with Arnold-Chiari malformations, which may cause central nervous system problems  . Hypophosphatemic rickets has long been linked to craniosynostosis , but the relationship is poorly understood .
Cranial malformations arise in a range of diseases that involve activation of FGF23 receptors, including osteoglophonic dysplasia (OGD) (FGFR1, ), Crouzon and Apert syndromes (FGFR2, ) and achondroplasia (FGFR3, ). Achondroplasia affects the size and shape of the cranial base, as well as reducing length of the nasal bone , which has also been observed in patients with hereditary hypophosphatemia  and Hyp mice .
Overexpression of FGFR2 and FGFR3 have been shown to affect both intramembranous and endochondral ossification in the skull [123, 197]. Beyond downregulation of TNAP, proposed mechanisms for these changes include TGF-β/BMP signalling (ERK1/2) and Wnt signalling [125, 201, 202], while cross-binding of FGF23 with FGFR2 and FGFR3 at the cranial sutures has also been proposed to contribute to craniosynostosis . However, it remains difficult to isolate these pathways as specific mechanistic links to craniosynostosis because they have also been linked to bone mineralisation.
Dental defects in XLH
Despite an outwardly normal dental appearance, severe dental disease including dental abscesses, periodontal problems and malocclusion  has been observed in as many as 75% of untreated XLH patients .
Teeth are primarily composed of three layers, the internal pulp is surrounded by dentin, which is itself coated on the crown by enamel and on the root by cementum. Although the dental manifestations of XLH have been well-reviewed, the responsible molecular mechanisms are poorly understood . Proposed mechanisms are illustrated in Fig. 8.
Normal development of dental tissues
During normal dental development, collagenous predentin is deposited by odontoblasts and matures into dentin through two phases. The first phase involves formation of calcium hydroxyapatite crystals as globules (or calcospherules) in the predentin collagen fibres. The second phase involves deposition of new areas of mineralisation that are layered onto the original crystals, expanding them almost to the point of fusion.
Enamel formation (amelogenesis) commences after the first layer of dentin has been deposited and continues in repeated stages of secretion and maturation. The development of enamel and dentin is thereafter mutually induced, while deposition of cementum by cementoblasts occurs later in tooth development.
Although some incompletely-crystallised interglobular dentin usually remains in the spaces between fully-formed hydroxyapatite crystals, excess interglobular dentin is a marker of certain dental abnormalities.
Severe under-mineralisation of circumpulpal dentin is a hallmark of untreated children with XLH, whose teeth contain large interglobular spaces, enlarged pulp chambers, and prominent pulp horns that extend to the dentino-enamel junction [207, 208]. The porous nature of dentin in children with XLH makes their teeth prone to bacterial invasion, abscesses, and necrosis , which often occur “spontaneously” in the absence of previous damage .
The presence of FGF23 mRNA in ameloblasts and odontoblasts, along with observations of significant reductions in mineral density, dental volume, and reparative dentin area in Fgf23-TG mice indicates that FGF23 may be directly involved in dentinogenesis and mineralisation , as do observations of excess interglobular dentin in Hyp and Fgf23-TG model mice from an early age [209, 210].
Contrasting the high frequency of dental abscesses in Hyp mice  with their relative absence in Phex- and Fgf23-normal hypophosphatemic mouse models  or in HHRH patients [213, 214] indicates that a phosphate-independent mechanism is likely to contribute to formation of dental abscesses in XLH.
Furthermore, spontaneous dental abscesses have not been reported as clinical features of TIO and iron-induced osteomalacia, which are FGF23-high diseases of hypophosphatemia that develop later in life. This may indicate that hereditary hypophosphatemia and/or other effects of FGF23 affects formation of dentin and enamel structures during early dental development. Accordingly, treatment with calcitriol and phosphate supplementation during the early time window of dental development correlates with improved dental health later in life [208, 215, 216].
Enamel defects observed in XLH patients include microclefts and irregular surface structure, through which bacteria could invade the tooth and form abscesses .
Evidence from rodent models indicates that enamel phenotypes in XLH may be phosphate-independent and mediated by calcitriol via osteocalcin [218,219,220]. However, reports of dental osteocalcin levels vary between Hyp and Fgf23-TG mouse models of XLH, which have been reported to respectively up- and down-regulate osteocalcin compared to wild type mice . If these results are accurate, there may be an FGF23- and calcitriol-independent role of PHEX in mediating osteocalcin deposition.
Loss of dental attachment is common in XLH, and can result from defects in cementum, periodontal ligament and/or alveolar bone .
Studies of Hyp and FGF23-/- mice have identified a role for FGF23 in the development and maintenance of the dentoalveolar complex [112, 221], and cementum has been observed to be thinner in Hyp mice than in wild type controls, with discontinuous mineralisation and a globular appearance .
A variety of molecular mechanisms have been proposed to contribute to cementum defects in XLH, including sensitivity to local levels of phosphate  and to altered regulation of TNAP . Bone-targeted TNAP has also rescued defects in cementum and alveolar bone in patients with hypophosphatasia .
Calcitriol has also been reported to affect murine cementogenesis in a DMP1- and FGF23-mediated manner . A role for FGF23 in regulation of cementum is also indicated by the levels of bone sialoprotein (BSP) (decreased) and DMP1 (elevated) in the cementum of Fgf23−/− mice . Furthermore, in human studies it has been shown that early childhood initiation and long-term persistence of conventional XLH therapy into adulthood improves the periodontal deformities typical of XLH, likely as a result of cementum and dentin defect correction .
Despite the differences between tooth and bone development, mineralisation of both tissues involves similar molecular processes and is often affected by similar molecular mechanisms . However, the effects of blocking FGF23 on dental development – of particular interest for treatment of patients with XLH – have not been reported at this stage [130, 131, 204].
Patients with XLH have been observed to experience hearing loss affecting low and high frequencies, which can be associated with tinnitus and vertigo, and has been compared to symptoms of endolymphatic hydrops (ELH) [226,227,228].
Molecular mechanisms that have been reported to contribute to hearing loss in XLH are depicted in Fig. 9, yet the aetiology of endocrinological and metabolic hearing loss is complex [229, 230], and the literature can be even more difficult to interpret than for other manifestations. As such, more work is needed to fully elucidate the molecular links between FGF23, XLH and hearing loss.
Hearing Loss and XLH
Reports of hearing loss in XLH patients are variable depending on the age and selection criteria of the cohort and range from 16% of subjects with hypophosphatemic bone disease experiencing sensorineural hearing loss , to 76% of subjects with X-linked hypophosphatemic osteomalacia experiencing hearing loss as detected by pure tone audiometry . In the latter study, subjective hearing loss was reported by 48% of subjects.
Other studies have assessed conductive hearing loss , sensorineural hearing loss , cochlear dysfunction  and electrical activity in the auditory centres of the brain  with widely varying results. A more standardised approach for assessing hearing loss is clearly required for future studies.
A low prevalence of hearing loss has been reported in many studies of XLH patients, and the cause of hearing loss is often confounded by age, other genetic or environmental factors. Hearing loss in XLH patients and in general has been observed to occur in certain families , or in older patients who had experienced excessive noise exposure . The prevalence of hearing loss has also been observed to vary between mouse models of XLH with different Phex mutations, genetic backgrounds or sex [77, 233]. These confounding factors make it difficult to identify mechanisms that contribute to hearing loss in XLH.
Hearing loss was first associated with specific Phex mutations when Hyp mice (in which ear-related phenotypes had not been observed) were compared to Gy mice (who were commonly deaf) . Potential contributions of PHEX and FGF23 to hearing loss were confounded because both mutations extended beyond the Phex coding region (Table 2), and Gy mutations affected the nearby SmS gene, which has been associated with hearing loss . The role of FGF23 in XLH-related hearing loss should instead be studied using animal models with Phex-specific mutations like Hyp-Duk, Hyp-2J, and Ska1 mice.
Of the Phex-specific models, male Hyp-Duk mice commonly displayed hearing loss, but Hyp-2J mice did not . Furthermore, the prevalence of hearing loss in Hyp-Duk mutants decreased when the mice were cross-bred onto different strains . These confounding effects of specific mutation and genetic background on XLH-related hearing loss would be further compounded when studying genetically diverse patients with XLH that have various PHEX mutations. Nevertheless, these findings have led the BALB/cUrd strain of Hyp-Duk mice being used as a model for studying the natural history of ELH [230, 233, 235].
ELH has been associated with damage to the organ of Corti and spiral ganglion neurons (SGNs) and is the most well-studied mechanism of hearing loss in XLH [226, 236]. The severity of ELH has also correlated with the severity of hearing loss in Hyp-Duk mice .
ELH is caused by an inappropriate volume or composition of endolymph within the inner ear, and hearing loss followed by neuronal loss and then hair cell loss is commonly observed in models of ELH [238, 239]. In the Hyp-Duk model, ELH developed by P21 (21 days after birth), SGN in the organ of Corti were lost by around P90, and morphologically abnormal hair cells arose much later (>P300) . SGN loss in ELH progresses from the apical to the basal cochlear turn and is at least partially caused by apoptosis [77, 233, 239]. It is unclear whether the relationship between ELH and SGN is causative or correlative, although it has been suggested that cell stress caused by elevated pressure associated with hydrops may contribute to the observed apoptosis . The cause of ELH in XLH is also unclear .
With regards to the volume of endolymph, hearing loss in the Hyp-Duk model of XLH does not consistently correlate with increased endolymph space [77, 233], with morphological abnormalities of the surrounding temporal bone [77, 233], or with obstruction of the endolymphatic duct . Disruption of periductal channels embedded in the temporal bone is therefore a candidate for contributing to ELH [230, 241], but has not yet been studied in XLH.
Furthermore, although conventional therapy has been observed to improve the bony structure surrounding the ear and prevent osteoid deposition, the treatment did not prevent ELH or hearing loss . Unfortunately, in this study mice were under-dosed with phosphate and other symptoms were also unaffected, so a follow up study would be required to test these findings .
The chemical composition of endolymph in XLH could be altered by varied aural expression of ion channels  or through metabolic interactions with the surrounding phosphate-deprived bone . A disrupted chemical composition could also be linked to aural precipitates that have been observed in various animal models of XLH [77, 242]. Characterising the endolymphatic fluid and any precipitate in XLH patients would shed light on this matter.
Inflammation and hearing loss
The reported formation of perilymphatic precipitate and of inappropriate bone formation in the membranous labyrinth (a potential mechanistic parallel to nephrocalcinosis or enthesopathy in XLH)  may also contribute to inflammation (otitis media and serous labyrinthitis), which has in turn been linked to ELH  and to hearing loss in XLH [62, 233, 243].
However, these results have all come from animal studies, and otitis media has not been observed in XLH patients . To determine if these animal models are suitable, XLH patients that experience hearing loss should therefore be assessed for inflammation and have their DNA sequenced for mutations that resemble Gy or Hyp-Duk.
Other XLH manifestations
Patients with XLH rarely report symptoms related to a weakened immune system, however FGF23 has been connected to the innate immune system in CKD, impairing neutrophil recruitment [44, 245] and the antimicrobial molecule LL37 synthesis in peripheral blood mononuclear cell monocytes . FGF23 has also been connected to increased deaths by infectious diseases . As these sequelae have not been connected to XLH, they are beyond the scope of this article, and we refer to a recent review of the subject .
Since FGF23 was identified as the causative agent of ADHR and TIO, it has been shown to play a key role in the pathology of XLH and most other inherited hypophosphatemic diseases. This review has described literature exploring the mechanisms by which excess FGF23 contributes to the clinical manifestations and morbidity of XLH.
There has been considerable advancement in the understanding of XLH pathogenesis over the last two decades. Indeed, most manifestations of XLH are now known to be caused by FGF23-induced hypophosphatemia resulting from downregulation of sodium-phosphate transporters in the renal distal tubule, and repression of serum calcitriol. In addition, local repression of calcitriol and TNAP may also inhibit mineralisation via FGF23-mediated upregulation and loss of PHEX-mediated degradation of OPN and pASARM, alongside accumulation of PPi.
These roles of FGF23 in XLH pathology have been further demonstrated by anti-FGF23 antibody treatment, which can normalise phosphate and vitamin D metabolism and improve rachitic changes in XLH patients  and Hyp mice [130,131,132].
To further elucidate the role of FGF23 in manifestations of XLH, it is important to clearly define and compare the causes and manifestations of other diseases of hypophosphatemia and their representative animal models. Studies assessing individual manifestations of XLH are often under-powered and generate vastly different estimates of frequency, intensity, and correlation with specific genotypes.
Larger patient registries and multicentre studies that include greater numbers of XLH patients are needed to further clarify the prevalence, phenotypic spectrum, genotype-phenotype correlation, and response to treatment of patients with XLH.
Neuroendocrine protein 7B2
Autosomal dominant hypophosphatemic rickets
Alkaline phosphatase gene
Autosomal recessive hypophosphatemic rickets
Acidic serine aspartate-rich-MEPE-associated protein
1,25(OH)2D, active vitamin D
Chronic kidney disease
Cytochrome P450 family 24 subfamily A member 1, CYP24A1
Dentin matrix acidic phosphoprotein 1
Ectonucleotide pyrophosphatase/phosphodiesterase family member 1
Family with sequence similarity 20, member C
Fibroblast growth factor
Murine antibody against FGF23
Fibroblast growth factor receptor
Generalised arterial calcification of infancy
Gene encoding Polypeptide N-acetylgalactosaminyltransferase 3
Hereditary hypophosphatemic rickets with hypercalciuria
Hypophosphatemic rickets and hyperparathyroidism
Mitogen-activated protein kinase kinase-extracellular signal-regulated kinases
Matrix extracellular phosphoglycoprotein
Mendelian Inheritance in Man
Matrix metalloproteinase 13
Messenger ribonucleic acid
Nicotinamide adenine dinucleotide phosphate
Nuclear factor of activated T-cells
Nuclear factor kappa-light-chain-enhancer of activated B cells
Online Mendelian Inheritance in Man
Gene encoding calcium release-activated calcium channel protein 1
Phosphorylated acidic serine aspartate-rich-MEPE-associated protein
Proprotein convertase, subtilisin/kexin-type 2
Proprotein convertase, subtilisin/kexin-type 5/6
Phosphate Regulating Endopeptidase Homolog, X-Linked
- ppGalNAc-T3 :
Polypeptide N-acetylgalactosaminyltransferase 3
Radiographic global impression of change
Reactive oxygen species
Rickets severity score
Spiral ganglion neurons
Small integrin-binding ligand, N-linked glycoprotein
Solute carrier family 34 member 3
Transforming growth factor beta/bone morphogenetic protein
Tissue non-specific alkaline phosphatase
Transient receptor potential cation channel subfamily V member 5
Vitamin D dependent rickets type 1A
Vitamin D receptor
The Western Ontario and McMaster Universities Osteoarthritis Index
X-linked hypophosphatemic rickets
Hypoxia inducible factor-1 alpha
Beck-Nielsen SS, Brock-Jacobsen B, Gram J, Brixen K, Jensen TK. Incidence and prevalence of nutritional and hereditary rickets in southern Denmark. Eur J Endocrinol. 2009;160:491–7.
Reid IR, Hardy DC, Murphy WA, Teitelbaum SL, Bergfeld MA, Whyte MP. X-Linked Hypophosphatemia: A Clinical, Biochemical, and Histopathologic Assessment of Morbidity in Adults. Medicine (Baltimore). 1989;68:336.
Carpenter TO, Imel EA, Holm IA, Jan de Beur SM, Insogna KL. A clinician’s guide to X-linked hypophosphatemia. J Bone Miner Res. 2011;26:1381–8.
Barros NM, Hoac B, Neves RL, Addison WN, Assis DM, Murshed M, et al. Proteolytic processing of osteopontin by PHEX and accumulation of osteopontin fragments in Hyp mouse bone, the murine model of X-linked hypophosphatemia. J Bone Min Res. 2013;28:688–99.
Liu S, Guo R, Simpson LG, Xiao Z-S, Burnham CE, Quarles LD. Regulation of fibroblastic growth factor 23 expression but not degradation by PHEX. J Biol Chem. 2003;278:37419–26.
Benet-Pages A, Lorenz-Depiereux B, Zischka H, White KE, Econs MJ, Strom TM. FGF23 is processed by proprotein convertases but not by PHEX. Bone. 2004;35:455–62.
Murali SK, Andrukhova O, Clinkenbeard EL, White KE, Erben RG. Excessive Osteocytic Fgf23 Secretion Contributes to Pyrophosphate Accumulation and Mineralization Defect in Hyp Mice. PLoS Biol. 2016;14:e1002427.
Imel EA, DiMeglio LA, Hui SL, Carpenter TO, Econs MJ. Treatment of X-linked hypophosphatemia with calcitriol and phosphate increases circulating fibroblast growth factor 23 concentrations. J Clin Endocrinol Metab. 2010;95:1846–50.
Linglart A, Biosse-Duplan M, Briot K, Chaussain C, Esterle L, Guillaume-Czitrom S, et al. Therapeutic management of hypophosphatemic rickets from infancy to adulthood. Endocr Connect. 2014;3:R13–30.
Makitie O, Doria A, Kooh SW, Cole WG, Daneman A, Sochett E. Early treatment improves growth and biochemical and radiographic outcome in X-linked hypophosphatemic rickets. J Clin Endocrinol Metab. 2003;88:3591–7.
Antoniucci DM, Yamashita T, Portale AA. Dietary phosphorus regulates serum fibroblast growth factor-23 concentrations in healthy men. J Clin Endocrinol Metab. 2006;91:3144–9.
Burnett SM, Gunawardene SC, Bringhurst FR, Juppner H, Lee H, Finkelstein JS. Regulation of C-terminal and intact FGF-23 by dietary phosphate in men and women. J Bone Min Res. 2006;21:1187–96.
Alon US, Levy-Olomucki R, Moore WV, Stubbs J, Liu S, Quarles LD. Calcimimetics as an adjuvant treatment for familial hypophosphatemic rickets. Clin J Am Soc Nephrol. 2008;3:658–64.
Raeder H, Shaw N, Netelenbos C, Bjerknes R. A case of X-linked hypophosphatemic rickets: complications and the therapeutic use of cinacalcet. Eur J Endocrinol. 2008;159(Suppl 1):S101–5.
Bai X, Miao D, Xiao S, Qiu D, St-Arnaud R, Petkovich M, et al. CYP24 inhibition as a therapeutic target in FGF23-mediated renal phosphate wasting disorders. J Clin Invest. 2016;126:667–80.
Yamashita T, Yoshioka M, Itoh N. Identification of a novel fibroblast growth factor, FGF-23, preferentially expressed in the ventrolateral thalamic nucleus of the brain. Biochem Biophys Res Commun. 2000;277:494–8.
Yoshiko Y, Wang H, Minamizaki T, Ijuin C, Yamamoto R, Suemune S, et al. Mineralized tissue cells are a principal source of FGF23. Bone. 2007;40:1565–73.
Jiang B, Cao Z, Lu Y, Janik C, Lauziere S, Xie Y, et al. DMP1 C-terminal mutant mice recapture the human ARHR tooth phenotype. J Bone Min Res. 2010;25:2155–64.
Tagliabracci VS, Engel JL, Wiley SE, Xiao J, Gonzalez DJ, Nidumanda Appaiah H, et al. Dynamic regulation of FGF23 by Fam20C phosphorylation, GalNAc-T3 glycosylation, and furin proteolysis. Proc Natl Acad Sci U A. 2014;111:5520–5.
Shimada T, Muto T, Urakawa I, Yoneya T, Yamazaki Y, Okawa K, et al. Mutant FGF-23 Responsible for Autosomal Dominant Hypophosphatemic Rickets Is Resistant to Proteolytic Cleavage and Causes Hypophosphatemia in Vivo. Endocrinology. 2002;143:3179–82.
Saito H, Maeda A, Ohtomo S, Hirata M, Kusano K, Kato S, et al. Circulating FGF-23 is regulated by 1alpha,25-dihydroxyvitamin D3 and phosphorus in vivo. J Biol Chem. 2005;280:2543–9.
Clinkenbeard EL, Cass TA, Ni P, Hum JM, Bellido T, Allen MR, et al. Conditional Deletion of Murine Fgf23: Interruption of the Normal Skeletal Responses to Phosphate Challenge and Rescue of Genetic Hypophosphatemia. J Bone Min Res. 2016;31:1247–57.
Scanni R, vonRotz M, Jehle S, Hulter HN, Krapf R. The human response to acute enteral and parenteral phosphate loads. J Am Soc Nephrol. 2014;25:2730–9.
Hori M, Kinoshita Y, Taguchi M, Fukumoto S. Phosphate enhances Fgf23 expression through reactive oxygen species in UMR-106 cells. J Bone Min Metab. 2016;34:132–9.
Wang X, Wang S, Li C, Gao T, Liu Y, Rangiani A, et al. Inactivation of a Novel FGF23 Regulator, FAM20C, Leads to Hypophosphatemic Rickets in Mice. PLOS Genet. 2012;8:e1002708.
Lorenz-Depiereux B, Schnabel D, Tiosano D, Hausler G, Strom TM. Loss-of-function ENPP1 mutations cause both generalized arterial calcification of infancy and autosomal-recessive hypophosphatemic rickets. Am J Hum Genet. 2010;86:267–72.
Samadfam R, Richard C, Nguyen-Yamamoto L, Bolivar I, Goltzman D. Bone formation regulates circulating concentrations of fibroblast growth factor 23. Endocrinology. 2009;150:4835–45.
Liu S, Rowe PS, Vierthaler L, Zhou J, Quarles LD. Phosphorylated acidic serine-aspartate-rich MEPE-associated motif peptide from matrix extracellular phosphoglycoprotein inhibits phosphate regulating gene with homologies to endopeptidases on the X-chromosome enzyme activity. J Endocrinol. 2007;192:261–7.
Fajol A, Honisch S, Zhang B, Schmidt S, Alkahtani S, Alarifi S, et al. Fibroblast growth factor (Fgf) 23 gene transcription depends on actin cytoskeleton reorganization. FEBS Lett. 2016;590:705–15.
Zhang B, Umbach AT, Chen H, Yan J, Fakhri H, Fajol A, et al. Up-regulation of FGF23 release by aldosterone. Biochem Biophys Res Commun. 2016;470:384–90.
Zhang B, Yan J, Umbach AT, Fakhri H, Fajol A, Schmidt S, et al. NFkappaB-sensitive Orai1 expression in the regulation of FGF23 release. J Mol Med Berl. 2016;94:557–66.
Leifheit-Nestler M, Kucka J, Yoshizawa E, Behets G, D’Haese P, Bergen C, et al. Comparison of calcimimetic R568 and calcitriol in mineral homeostasis in the Hyp mouse, a murine homolog of X-linked hypophosphatemia. Bone. 2017;103:224–32.
Nguyen-Yamamoto L, Karaplis AC, St-Arnaud R, Goltzman D. Fibroblast Growth Factor 23 Regulation by Systemic and Local Osteoblast-Synthesized 1,25-Dihydroxyvitamin D. J Am Soc Nephrol. 2017;28:586–97.
Yamamoto H, Ramos-Molina B, Lick AN, Prideaux M, Albornoz V, Bonewald L, et al. Posttranslational processing of FGF23 in osteocytes during the osteoblast to osteocyte transition. Bone. 2016;84:120–30.
Frishberg Y, Ito N, Rinat C, Yamazaki Y, Feinstein S, Urakawa I, et al. Hyperostosis-hyperphosphatemia syndrome: a congenital disorder of O-glycosylation associated with augmented processing of fibroblast growth factor 23. J Bone Min Res. 2007;22:235–42.
Kato K, Jeanneau C, Tarp MA, Benet-Pages A, Lorenz-Depiereux B, Bennett EP, et al. Polypeptide GalNAc-transferase T3 and familial tumoral calcinosis. Secretion of fibroblast growth factor 23 requires O-glycosylation. J Biol Chem. 2006;281:18370–7.
Ichikawa S, Imel EA, Sorenson AH, Severe R, Knudson P, Harris GJ, et al. Tumoral Calcinosis Presenting with Eyelid Calcifications due to Novel Missense Mutations in the Glycosyl Transferase Domain of the GALNT3 Gene. J Clin Endocrinol Metab. 2006;91:4472–5.
Yuan B, Feng JQ, Bowman S, Liu Y, Blank RD, Lindberg I, et al. Hexa-D-arginine treatment increases 7B2*PC2 activity in hyp-mouse osteoblasts and rescues the HYP phenotype. J Bone Min Res. 2013;28:56–72.
David V, Martin A, Isakova T, Spaulding C, Qi L, Ramirez V, et al. Inflammation and functional iron deficiency regulate fibroblast growth factor 23 production. Kidney Int. 2016;89:135–46.
Rowe PS. Regulation of bone-renal mineral and energy metabolism: the PHEX, FGF23, DMP1, MEPE ASARM pathway. Crit Rev Eukaryot Gene Expr. 2012;22:61–86.
Kawai M. The FGF23/Klotho axis in the regulation of mineral and metabolic homeostasis. Horm Mol Biol Clin Investig. 2016;28:55–67.
Erben RG. Update on FGF23 and Klotho signaling. Mol Cell Endocrinol. 2016;432:56–65.
Kurosu H, Ogawa Y, Miyoshi M, Yamamoto M, Nandi A, Rosenblatt KP, et al. Regulation of fibroblast growth factor-23 signaling by klotho. J Biol Chem. 2006;281:6120–3.
Rossaint J, Oehmichen J, Van Aken H, Reuter S, Pavenstadt HJ, Meersch M, et al. FGF23 signaling impairs neutrophil recruitment and host defense during CKD. J Clin Invest. 2016;126:962–74.
Beenken A, Mohammadi M. THE STRUCTURAL BIOLOGY OF THE FGF19 SUBFAMILY. Adv Exp Med Biol. 2012;728:1–24.
Kuro-o M, Matsumura Y, Aizawa H, Kawaguchi H, Suga T, Utsugi T, et al. Mutation of the mouse klotho gene leads to a syndrome resembling ageing. Nature. 1997;390:45–51.
Bai X, Dinghong Q, Miao D, Goltzman D, Karaplis AC. Klotho ablation converts the biochemical and skeletal alterations in FGF23 (R176Q) transgenic mice to a Klotho-deficient phenotype. Am J Physiol Endocrinol Metab. 2009;296:E79–88.
Olauson H, Mencke R, Hillebrands JL, Larsson TE. Tissue expression and source of circulating alphaKlotho. Bone. 2017;100:19–35.
Murali SK, Roschger P, Zeitz U, Klaushofer K, Andrukhova O, Erben RG. FGF23 Regulates Bone Mineralization in a 1,25(OH)2 D3 and Klotho-Independent Manner. J Bone Min Res. 2016;31:129–42.
Goetz R, Nakada Y, Hu MC, Kurosu H, Wang L, Nakatani T, et al. Isolated C-terminal tail of FGF23 alleviates hypophosphatemia by inhibiting FGF23-FGFR-Klotho complex formation. Proc Natl Acad Sci U A. 2010;107:407–12.
ADHR Consortium. Autosomal dominant hypophosphataemic rickets is associated with mutations in FGF23. Nat Genet. 2000;26:345–8.
Feng JQ, Ward LM, Liu S, Lu Y, Xie Y, Yuan B, et al. Loss of DMP1 causes rickets and osteomalacia and identifies a role for osteocytes in mineral metabolism. Nat Genet. 2006;38:1310–5.
Brownstein CA, Adler F, Nelson-Williams C, Iijima J, Li P, Imura A, et al. A translocation causing increased alpha-klotho level results in hypophosphatemic rickets and hyperparathyroidism. Proc Natl Acad Sci U A. 2008;105:3455–60.
Lorenz-Depiereux B, Benet-Pages A, Eckstein G, Tenenbaum-Rakover Y, Wagenstaller J, Tiosano D, et al. Hereditary hypophosphatemic rickets with hypercalciuria is caused by mutations in the sodium-phosphate cotransporter gene SLC34A3. Am J Hum Genet. 2006;78:193–201.
Khosravi A, Cutler CM, Kelly MH, Chang R, Royal RE, Sherry RM, et al. Determination of the elimination half-life of fibroblast growth factor-23. J Clin Endocrinol Metab. 2007;92:2374–7.
McGill University. The PHEX database. https://web.archive.org/web/20180127031217/http://www.phexdb.mcgill.ca/. Accessed 27 Jan 2018.
Beck-Nielsen SS, Brusgaard K, Rasmussen LM, Brixen K, Brock-Jacobsen B, Poulsen MR, et al. Phenotype presentation of hypophosphatemic rickets in adults. Calcif Tissue Int. 2010;87:108–19.
Gaucher C, Walrant-Debray O, Nguyen T-M, Esterle L, Garabédian M, Jehan F. PHEX analysis in 118 pedigrees reveals new genetic clues in hypophosphatemic rickets. Hum Genet. 2009;125:401–11.
Popowska E, Pronicka E, Sulek A, Jurkiewicz D, Rowe P, Rowinska E, et al. X-linked hypophosphatemia in Polish patients. 1. Mutations in the PHEX gene. J Appl Genet. 2000;41:293–302.
Sabbagh Y, Boileau G, DesGroseillers L, Tenenhouse HS. Disease-causing missense mutations in the PHEX gene interfere with membrane targeting of the recombinant protein. Hum Mol Genet. 2001;10:1539–46.
Beck-Nielsen SS, Brixen K, Gram J, Brusgaard K. Mutational analysis of PHEX, FGF23, DMP1, SLC34A3 and CLCN5 in patients with hypophosphatemic rickets. J Hum Genet. 2012;57:453–8.
Han F, Yu H, Li P, Zhang J, Tian C, Li H, et al. Mutation in Phex gene predisposes BALB/c-Phex(Hyp-Duk)/Y mice to otitis media. PLoS One. 2012;7:e43010.
Yang X, Yan W, Tian Y, Ma P, Opperman LA, Wang X. Family with sequence similarity member 20C is the primary but not the only kinase for the small-integrin-binding ligand N-linked glycoproteins in bone. Faseb J. 2016;30:121–8.
Song H-R, Park J-W, Cho D-Y, Yang JH, Yoon H-R, Jung S-C. PHEX Gene Mutations and Genotype-Phenotype Analysis of Korean Patients with Hypophosphatemic Rickets. J Korean Med Sci. 2007;22:981–6.
Morey M, Castro-Feijoo L, Barreiro J, Cabanas P, Pombo M, Gil M, et al. Genetic diagnosis of X-linked dominant Hypophosphatemic Rickets in a cohort study: tubular reabsorption of phosphate and 1,25(OH)2D serum levels are associated with PHEX mutation type. BMC Med Genet. 2011;12:116.
Nakamura Y, Takagi M, Takeda R, Miyai K, Hasegawa Y. Hypertension is a characteristic complication of X-linked hypophosphatemia. Endocr J. 2017;64:283–9.
Chesher D, Oddy M, Darbar U, Sayal P, Casey A, Ryan A, et al. Outcome of adult patients with X-linked hypophosphatemia caused by PHEX gene mutations. J Inherit Metab Dis. 2018;41:865–76.
Beck-Nielsen SS. Rickets in Denmark. Dan Med J. 2012;59:B4384.
Eicher EM, Southard JL, Scriver CR, Glorieux FH. Hypophosphatemia: mouse model for human familial hypophosphatemic (vitamin D-resistant) rickets. Proc Natl Acad Sci U A. 1976;73:4667–71.
Lyon MF, Scriver CR, Baker LR, Tenenhouse HS, Kronick J, Mandla S. The Gy mutation: another cause of X-linked hypophosphatemia in mouse. Proc Natl Acad Sci U A. 1986;83:4899–903.
Sabbagh Y, Gauthier C, Tenenhouse HS. The X chromosome deletion in HYP mice extends into the intergenic region but does not include the SAT gene downstream from Phex. Cytogenet Genome Res. 2002;99:344–9.
Du L, Desbarats M, Cornibert S, Malo D, Ecarot B. Fine genetic mapping of the Hyp mutation on mouse chromosome X. Genomics. 1996;32:177–83.
Lorenz B, Francis F, Gempel K, Boddrich A, Josten M, Schmahl W, et al. Spermine deficiency in Gy mice caused by deletion of the spermine synthase gene. Hum Mol Genet. 1998;7:541–7.
Erben RG, Mayer D, Weber K, Jonsson K, Juppner H, Lanske B. Overexpression of human PHEX under the human beta-actin promoter does not fully rescue the Hyp mouse phenotype. J Bone Min Res. 2005;20:1149–60.
Carpinelli MR, Wicks IP, Sims NA, O’Donnell K, Hanzinikolas K, Burt R, et al. An ethyl-nitrosourea-induced point mutation in phex causes exon skipping, x-linked hypophosphatemia, and rickets. Am J Pathol. 2002;161:1925–33.
Owen C, Chen F, Flenniken AM, Osborne LR, Ichikawa S, Adamson SL, et al. A novel Phex mutation in a new mouse model of hypophosphatemic rickets. J Cell Biochem. 2012;113:2432–41.
Lorenz-Depiereux B, Guido VE, Johnson KR, Zheng QY, Gagnon LH, Bauschatz JD, et al. New intragenic deletions in the Phex gene clarify X-linked hypophosphatemia-related abnormalities in mice. Mamm Genome. 2004;15:151–61.
Zivicnjak M, Schnabel D, Staude H, Even G, Marx M, Beetz R, et al. Three-year growth hormone treatment in short children with X-linked hypophosphatemic rickets: effects on linear growth and body disproportion. J Clin Endocrinol Metab. 2011;96:E2097–105.
Gerber HP, Vu TH, Ryan AM, Kowalski J, Werb Z, Ferrara N. VEGF couples hypertrophic cartilage remodeling, ossification and angiogenesis during endochondral bone formation. Nat Med. 1999;5:623–8.
Tiosano D, Hochberg Z. Hypophosphatemia: the common denominator of all rickets. J Bone Min Metab. 2009;27:392–401.
Penido M, Alon US. Phosphate homeostasis and its role in bone health. Pediatr Nephrol. 2012;27:2039–48.
Shimada T, Mizutani S, Muto T, Yoneya T, Hino R, Takeda S, et al. Cloning and characterization of FGF23 as a causative factor of tumor-induced osteomalacia. Proc Natl Acad Sci U A. 2001;98:6500–5.
Sitara D, Razzaque MS, Hesse M, Yoganathan S, Taguchi T, Erben RG, et al. Homozygous ablation of fibroblast growth factor-23 results in hyperphosphatemia and impaired skeletogenesis, and reverses hypophosphatemia in Phex-deficient mice. Matrix Biol. 2004;23:421–32.
Wang H, Yoshiko Y, Yamamoto R, Minamizaki T, Kozai K, Tanne K, et al. Overexpression of fibroblast growth factor 23 suppresses osteoblast differentiation and matrix mineralization in vitro. J Bone Min Res. 2008;23:939–48.
Sitara D, Kim S, Razzaque MS, Bergwitz C, Taguchi T, Schuler C, et al. Genetic evidence of serum phosphate-independent functions of FGF-23 on bone. PLoS Genet. 2008;4:e1000154.
Saito H, Kusano K, Kinosaki M, Ito H, Hirata M, Segawa H, et al. Human fibroblast growth factor-23 mutants suppress Na+-dependent phosphate co-transport activity and 1alpha,25-dihydroxyvitamin D3 production. J Biol Chem. 2003;278:2206–11.
Segawa H, Kawakami E, Kaneko I, Kuwahata M, Ito M, Kusano K, et al. Effect of hydrolysis-resistant FGF23-R179Q on dietary phosphate regulation of the renal type-II Na/Pi transporter. Pflugers Arch. 2003;446:585–92.
Bai X, Miao D, Li J, Goltzman D, Karaplis AC. Transgenic mice overexpressing human fibroblast growth factor 23 (R176Q) delineate a putative role for parathyroid hormone in renal phosphate wasting disorders. Endocrinology. 2004;145:5269–79.
Sabbagh Y, Carpenter TO, Demay MB. Hypophosphatemia leads to rickets by impairing caspase-mediated apoptosis of hypertrophic chondrocytes. Proc Natl Acad Sci U A. 2005;102:9637–42.
Larsson T, Marsell R, Schipani E, Ohlsson C, Ljunggren O, Tenenhouse HS, et al. Transgenic mice expressing fibroblast growth factor 23 under the control of the alpha1(I) collagen promoter exhibit growth retardation, osteomalacia, and disturbed phosphate homeostasis. Endocrinology. 2004;145:3087–94.
Andrukhova O, Zeitz U, Goetz R, Mohammadi M, Lanske B, Erben RG. FGF23 acts directly on renal proximal tubules to induce phosphaturia through activation of the ERK1/2-SGK1 signaling pathway. Bone. 2012;51:621–8.
Segawa H, Onitsuka A, Furutani J, Kaneko I, Aranami F, Matsumoto N, et al. Npt2a and Npt2c in mice play distinct and synergistic roles in inorganic phosphate metabolism and skeletal development. Am J Physiol Ren Physiol. 2009;297:F671–8.
Myakala K, Motta S, Murer H, Wagner CA, Koesters R, Biber J, et al. Renal-specific and inducible depletion of NaPi-IIc/Slc34a3, the cotransporter mutated in HHRH, does not affect phosphate or calcium homeostasis in mice. Am J Physiol Ren Physiol. 2014;306:F833–43.
Shimada T, Yamazaki Y, Takahashi M, Hasegawa H, Urakawa I, Oshima T, et al. Vitamin D receptor-independent FGF23 actions in regulating phosphate and vitamin D metabolism. Am J Physiol Ren Physiol. 2005;289:F1088–95.
Tenenhouse HS, Beck L. Renal Na(+)-phosphate cotransporter gene expression in X-linked Hyp and Gy mice. Kidney Int. 1996;49:1027–32.
Olauson H, Lindberg K, Amin R, Sato T, Jia T, Goetz R, et al. Parathyroid-specific deletion of Klotho unravels a novel calcineurin-dependent FGF23 signaling pathway that regulates PTH secretion. PLoS Genet. 2013;9:e1003975.
Rizzoli R, Fleisch H, Bonjour JP. Role of 1,25-dihydroxyvitamin D3 on intestinal phosphate absorption in rats with a normal vitamin D supply. J Clin Invest. 1977;60:639–47.
Syal A, Schiavi S, Chakravarty S, Dwarakanath V, Quigley R, Baum M. Fibroblast growth factor-23 increases mouse PGE2 production in vivo and in vitro. Am J Physiol Ren Physiol. 2006;290:F450–5.
Baum M, Loleh S, Saini N, Seikaly M, Dwarakanath V, Quigley R. Correction of proximal tubule phosphate transport defect in Hyp mice in vivo and in vitro with indomethacin. Proc Natl Acad Sci U A. 2003;100:11098–103.
Seikaly MG, Waber PG, Baum M. Urinary prostaglandins and the effect of indomethacin on phosphate excretion in children with hypophosphatemic rickets. Pediatr Res. 2008;64:210–2.
Shiang R, Thompson LM, Zhu YZ, Church DM, Fielder TJ, Bocian M, et al. Mutations in the transmembrane domain of FGFR3 cause the most common genetic form of dwarfism, achondroplasia. Cell. 1994;78:335–42.
Xiao ZS, Crenshaw M, Guo R, Nesbitt T, Drezner MK, Quarles LD. Intrinsic mineralization defect in Hyp mouse osteoblasts. Am J Physiol. 1998;275(4 Pt 1):E700–8.
van der Meijden K, van Essen HW, Bloemers FW, Schulten EA, Lips P, Bravenboer N. Regulation of CYP27B1 mRNA Expression in Primary Human Osteoblasts. Calcif Tissue Int. 2016;99:164–73.
Underwood JL, DeLuca HF. Vitamin D is not directly necessary for bone growth and mineralization. Am J Physiol. 1984;246(6 Pt 1):E493–8.
Chang PL, Ridall AL, Prince CW. Calcitriol regulation of osteopontin expression in mouse epidermal cells. Endocrinology. 1994;135:863–9.
Addison WN, Azari F, Sorensen ES, Kaartinen MT, McKee MD. Pyrophosphate inhibits mineralization of osteoblast cultures by binding to mineral, up-regulating osteopontin, and inhibiting alkaline phosphatase activity. J Biol Chem. 2007;282:15872–83.
Lieben L, Masuyama R, Torrekens S, Van Looveren R, Schrooten J, Baatsen P, et al. Normocalcemia is maintained in mice under conditions of calcium malabsorption by vitamin D-induced inhibition of bone mineralization. J Clin Invest. 2012;122:1803–15.
Addison WN, Masica DL, Gray JJ, McKee MD. Phosphorylation-dependent inhibition of mineralization by osteopontin ASARM peptides is regulated by PHEX cleavage. J Bone Min Res. 2010;25:695–705.
Martin A, David V, Laurence JS, Schwarz PM, Lafer EM, Hedge A-M, et al. Degradation of MEPE, DMP1, and Release of SIBLING ASARM-Peptides (Minhibins): ASARM-Peptide(s) Are Directly Responsible for Defective Mineralization in HYP. Endocrinology. 2008;149:1757–72.
Staines KA, MacRae VE, Farquharson C. The importance of the SIBLING family of proteins on skeletal mineralisation and bone remodelling. J Endocrinol. 2012;214:241–55.
Neves RL, Chiarantin GM, Nascimento FD, Pesquero JB, Nader HB, Tersariol IL, et al. Expression and inactivation of osteopontin-degrading PHEX enzyme in squamous cell carcinoma. Int J Biochem Cell Biol. 2016;77(Pt A):155–64.
Salmon B, Bardet C, Khaddam M, Naji J, Coyac BR, Baroukh B, et al. MEPE-derived ASARM peptide inhibits odontogenic differentiation of dental pulp stem cells and impairs mineralization in tooth models of X-linked hypophosphatemia. PLoS One. 2013;8:e56749.
Caballero D, Li Y, Ponsetto J, Zhu C, Bergwitz C. Impaired urinary osteopontin excretion in Npt2a-/- mice. Am J Physiol Ren Physiol. 2017;312:F77–f83.
Yuan Q, Jiang Y, Zhao X, Sato T, Densmore M, Schüler C, et al. Increased osteopontin contributes to inhibition of bone mineralization in FGF23-deficient mice. J Bone Miner Res Off J Am Soc Bone Miner Res. 2014;29:693–704.
Narisawa S, Frohlander N, Millan JL. Inactivation of two mouse alkaline phosphatase genes and establishment of a model of infantile hypophosphatasia. Dev Dyn. 1997;208:432–46.
Mumm S, Jones J, Finnegan P, Whyte MP. Hypophosphatasia: molecular diagnosis of Rathbun’s original case. J Bone Min Res. 2001;16:1724–7.
Murshed M, Harmey D, Millan JL, McKee MD, Karsenty G. Unique coexpression in osteoblasts of broadly expressed genes accounts for the spatial restriction of ECM mineralization to bone. Genes Dev. 2005;19:1093–104.
Russell RG, Bisaz S, Donath A, Morgan DB, Fleisch H. Inorganic pyrophosphate in plasma in normal persons and in patients with hypophosphatasia, osteogenesis imperfecta, and other disorders of bone. J Clin Invest. 1971;50:961–9.
Kawai M, Kinoshita S, Kimoto A, Hasegawa Y, Miyagawa K, Yamazaki M, et al. FGF23 suppresses chondrocyte proliferation in the presence of soluble alpha-Klotho both in vitro and in vivo. J Biol Chem. 2013;288:2414–27.
Kinoshita S, Kawai M. The FGF23/KLOTHO Regulatory Network and Its Roles in Human Disorders. Vitam Horm. 2016;101:151–74.
Su CC, Kao CT, Hung CJ, Chen YJ, Huang TH, Shie MY. Regulation of physicochemical properties, osteogenesis activity, and fibroblast growth factor-2 release ability of beta-tricalcium phosphate for bone cement by calcium silicate. Mater Sci Eng C Mater Biol Appl. 2014;37:156–63.
Xiao Z, Huang J, Cao L, Liang Y, Han X, Quarles LD. Osteocyte-specific deletion of Fgfr1 suppresses FGF23. PLoS One. 2014;9:e104154.
Liu J, Kwon TG, Nam HK, Hatch NE. Craniosynostosis-Associated Fgfr2(C342Y) Mutant Bone Marrow Stromal Cells Exhibit Cell Autonomous Abnormalities in Osteoblast Differentiation and Bone Formation. BioMed Res Int. 2013;2013:292506.
Hatch NE, Li Y, Franceschi RT. FGF2 stimulation of the pyrophosphate-generating enzyme, PC-1, in pre-osteoblast cells is mediated by RUNX2. J Bone Min Res. 2009;24:652–62.
Wang E, Nam HK, Liu J, Hatch NE. The Effects of Tissue-Nonspecific Alkaline Phosphatase Gene Therapy on Craniosynostosis and Craniofacial Morphology in the FGFR2(C342Y/+) Mouse Model of Crouzon Craniosynostosis. Orthod Craniofac Res. 2015;18(0 1):196–206.
Ichikawa S, Austin AM, Gray AK, Econs MJ. A Phex mutation in a murine model of X-linked hypophosphatemia alters phosphate responsiveness of bone cells. J Bone Miner Res. 2012;27:453–60.
Ichikawa S, Gray AK, Bikorimana E, Econs MJ. Dosage effect of a Phex mutation in a murine model of X-linked hypophosphatemia. Calcif Tissue Int. 2013;93:155–62.
Hana T, Tanaka S, Nakatomi H, Shojima M, Fukumoto S, Ikemura M, et al. Definitive surgical treatment of osteomalacia induced by skull base tumor and determination of the half-life of serum fibroblast growth factor 23. Endocr J. 2017;64(10):1033–9.
Yavropoulou MP, Gerothanasi N, Frydas A, Triantafyllou E, Poulios C, Hytiroglou P, et al. Tumor-induced osteomalacia due to a recurrent mesenchymal tumor overexpressing several growth factor receptors. Endocrinol Diabetes Metab Case Rep. 2015;2015:150025.
Aono Y, Yamazaki Y, Yasutake J, Kawata T, Hasegawa H, Urakawa I, et al. Therapeutic Effects of Anti-FGF23 Antibodies in Hypophosphatemic Rickets/Osteomalacia. J Bone Miner Res. 2009;24:1879–88.
Aono Y, Hasegawa H, Yamazaki Y, Shimada T, Fujita T, Yamashita T, et al. Anti-FGF-23 neutralizing antibodies ameliorate muscle weakness and decreased spontaneous movement of Hyp mice. J Bone Miner Res. 2011;26:803–10.
Wohrle S, Henninger C, Bonny O, Thuery A, Beluch N, Hynes NE, et al. Pharmacological inhibition of fibroblast growth factor (FGF) receptor signaling ameliorates FGF23-mediated hypophosphatemic rickets. J Bone Min Res. 2013;28:899–911.
Kinoshita Y, Fukumoto S. X-linked hypophosphatemia and FGF23-related hypophosphatemic diseases -Prospect for new treatment. Endocr Rev. 2018. https://doi.org/10.1210/er.2017-00220.
Insogna KL, Briot K, Imel EA, Kamenický P, Ruppe MD, Portale AA, et al. A Randomized, Double-Blind, Placebo-Controlled, Phase 3 Trial Evaluating the Efficacy of Burosumab, an Anti-FGF23 Antibody, in Adults With X-Linked Hypophosphatemia: Week 24 Primary Analysis. J Bone Miner Res. 2018;33:1383–93.
Carpenter TO, Whyte MP, Imel EA, Boot AM, Högler W, Linglart A, et al. Burosumab Therapy in Children with X-Linked Hypophosphatemia. N Engl J Med. 2018;378:1987–98.
Harrell RM, Lyles KW, Harrelson JM, Friedman NE, Drezner MK. Healing of bone disease in X-linked hypophosphatemic rickets/osteomalacia. Induction and maintenance with phosphorus and calcitriol. J Clin Invest. 1985;75:1858–68.
Polisson RP, Martinez S, Khoury M, Harrell RM, Lyles KW, Friedman N, et al. Calcification of entheses associated with X-linked hypophosphatemic osteomalacia. N Engl J Med. 1985;313:1–6.
Skrinar A, Marshall A, Martin JS, Dvorak-Ewell M. X-Linked hypophosphatemia (XLH) impairs skeletal health outcomes and physical function in affected adults. Endocrine Reviews. 2015;36(2).
Nehgme R, Fahey JT, Smith C, Carpenter TO. Cardiovascular abnormalities in patients with X-linked hypophosphatemia. J Clin Endocrinol Metab. 1997;82:2450–4.
Reusz GS, Brodehl J, Krohn HP, Ehrich JH. Hypophosphataemic rickets. Lancet. 1990;335:178.
Patzer L, van’t Hoff W, Shah V, Hallson P, Kasidas GP, Samuell C, et al. Urinary supersaturation of calcium oxalate and phosphate in patients with X-linked hypophosphatemic rickets and in healthy schoolchildren. J Pediatr. 1999;135:611–7.
Alon U, Donaldson DL, Hellerstein S, Warady BA, Harris DJ. Metabolic and histologic investigation of the nature of nephrocalcinosis in children with hypophosphatemic rickets and in the Hyp mouse. J Pediatr. 1992;120:899–905.
Taylor A, Sherman NH, Norman ME. Nephrocalcinosis in X-linked hypophosphatemia: effect of treatment versus disease. Pediatr Nephrol. 1995;9:173–5.
Savage M. Complications with reformulated One-Alpha vitamin D. BMJ. 2001;322:799.
Sun GE, Suer O, Carpenter TO, Tan CD, Li-Ng M. Heart failure in hypophosphatemic rickets: complications from high-dose phosphate therapy. Endocr Pr. 2013;19:e8–11.
Bergwitz C, Jüppner H. FGF23 AND SYNDROMES OF ABNORMAL RENAL PHOSPHATE HANDLING. Adv Exp Med Biol. 2012;728:41–64.
Dinour D, Davidovits M, Ganon L, Ruminska J, Forster IC, Hernando N, et al. Loss of function of NaPiIIa causes nephrocalcinosis and possibly kidney insufficiency. Pediatr Nephrol. 2016;31:2289–97.
Rajagopal A, Braslavsky D, Lu JT, Kleppe S, Clement F, Cassinelli H, et al. Exome sequencing identifies a novel homozygous mutation in the phosphate transporter SLC34A1 in hypophosphatemia and nephrocalcinosis. J Clin Endocrinol Metab. 2014;99:E2451–6.
Li Y, Caballero D, Ponsetto J, Chen A, Zhu C, Guo J, et al. Response of Npt2a knockout mice to dietary calcium and phosphorus. PLoS One. 2017;12:e0176232.
Mitchell DM, Juppner H, Burnett-Bowie SM. FGF23 Is Not Associated With Age-Related Changes in Phosphate, but Enhances Renal Calcium Reabsorption in Girls. J Clin Endocrinol Metab. 2017;102:1151–60.
Andrukhova O, Smorodchenko A, Egerbacher M, Streicher C, Zeitz U, Goetz R, et al. FGF23 promotes renal calcium reabsorption through the TRPV5 channel. EMBO J. 2014;33:229–46.
Andrukhova O, Slavic S, Smorodchenko A, Zeitz U, Shalhoub V, Lanske B, et al. FGF23 regulates renal sodium handling and blood pressure. EMBO Mol Med. 2014;6:744–59.
Alon US, Monzavi R, Lilien M, Rasoulpour M, Geffner ME, Yadin O. Hypertension in hypophosphatemic rickets--role of secondary hyperparathyroidism. Pediatr Nephrol. 2003;18:155–8.
Vered I, Vered Z, Perez JE, Jaffe AS, Whyte MP. Normal left ventricular performance in children with X-linked hypophosphatemic rickets: a Doppler echocardiography study. J Bone Min Res. 1990;5:469–74.
Kuczera P, Adamczak M, Wiecek A. Fibroblast Growth Factor-23-A Potential Uremic Toxin. Toxins Basel. 2016;8. https://doi.org/10.3390/toxins8120369.
Panwar B, Jenny NS, Howard VJ, Wadley VG, Muntner P, Kissela BM, et al. Fibroblast growth factor 23 and risk of incident stroke in community-living adults. Stroke. 2015;46:322–8.
Shah NH, Dong C, Elkind MS, Sacco RL, Mendez AJ, Hudson BI, et al. Fibroblast Growth Factor 23 Is Associated With Carotid Plaque Presence and Area: The Northern Manhattan Study. Arter Thromb Vasc Biol. 2015;35:2048–53.
Leifheit-Nestler M, Grosse Siemer R, Flasbart K, Richter B, Kirchhoff F, Ziegler WH, et al. Induction of cardiac FGF23/FGFR4 expression is associated with left ventricular hypertrophy in patients with chronic kidney disease. Nephrol Dial Transpl. 2016;31:1088–99.
Wright CB, Shah NH, Mendez AJ, DeRosa JT, Yoshita M, Elkind MS, et al. Fibroblast Growth Factor 23 Is Associated With Subclinical Cerebrovascular Damage: The Northern Manhattan Study. Stroke. 2016;47:923–8.
Hao H, Li X, Li Q, Lin H, Chen Z, Xie J, et al. FGF23 promotes myocardial fibrosis in mice through activation of beta-catenin. Oncotarget. 2016;7:64649–64.
Rotondi S, Pasquali M, Tartaglione L, Muci ML, Mandanici G, Leonangeli C, et al. Soluble α-Klotho Serum Levels in Chronic Kidney Disease. Int J Endocrinol. 2015;2015:872193.
Faul C, Amaral AP, Oskouei B, Hu MC, Sloan A, Isakova T, et al. FGF23 induces left ventricular hypertrophy. J Clin Invest. 2011;121:4393–408.
Grabner A, Amaral AP, Schramm K, Singh S, Sloan A, Yanucil C, et al. Activation of Cardiac Fibroblast Growth Factor Receptor 4 Causes Left Ventricular Hypertrophy. Cell Metab. 2015;22:1020–32.
Singh S, Grabner A, Yanucil C, Schramm K, Czaya B, Krick S, et al. Fibroblast growth factor 23 directly targets hepatocytes to promote inflammation in chronic kidney disease. Kidney Int. 2016;90:985–96.
Andrukhova O, Slavic S, Zeitz U, Riesen SC, Heppelmann MS, Ambrisko TD, et al. Vitamin D is a regulator of endothelial nitric oxide synthase and arterial stiffness in mice. Mol Endocrinol. 2014;28:53–64.
Cianciolo G, Galassi A, Capelli I, Schillaci R, La Manna G, Cozzolino M. Klotho-FGF23, cardiovascular disease, and vascular calcification: black or white. Curr Vasc Pharmacol. 2018;16:143-56.
Portale AA, Wolf MS, Messinger S, Perwad F, Juppner H, Warady BA, et al. Fibroblast Growth Factor 23 and Risk of CKD Progression in Children. Clin J Am Soc Nephrol. 2016;11:1989–98.
Schnedl C, Fahrleitner-Pammer A, Pietschmann P, Amrein K. FGF23 in Acute and Chronic Illness. Markers. 2015;2015:358086.
Liang G, Katz LD, Insogna KL, Carpenter TO, Macica CM. Survey of the Enthesopathy of X-Linked Hypophosphatemia and Its Characterization in Hyp Mice. Calcif Tissue Int. 2009;85:235–46.
Che H, Roux C, Etcheto A, Rothenbuhler A, Kamenicky P, Linglart A, et al. Impaired quality of life in adults with X-linked hypophosphatemia and skeletal symptoms. Eur J Endocrinol. 2016;174:325–33.
Karaplis AC, Bai X, Falet JP, Macica CM. Mineralizing enthesopathy is a common feature of renal phosphate-wasting disorders attributed to FGF23 and is exacerbated by standard therapy in hyp mice. Endocrinology. 2012;153:5906–17.
Saito T, Shimizu Y, Hori M, Taguchi M, Igarashi T, Fukumoto S, et al. A patient with hypophosphatemic rickets and ossification of posterior longitudinal ligament caused by a novel homozygous mutation in ENPP1 gene. Bone. 2011;49:913–6.
Makitie O, Pereira RC, Kaitila I, Turan S, Bastepe M, Laine T, et al. Long-term clinical outcome and carrier phenotype in autosomal recessive hypophosphatemia caused by a novel DMP1 mutation. J Bone Min Res. 2010;25:2165–74.
Liang G, Vanhouten J, Macica CM. An atypical degenerative osteoarthropathy in Hyp mice is characterized by a loss in the mineralized zone of articular cartilage. Calcif Tissue Int. 2011;89:151–62.
Hardy DC, Murphy WA, Siegel BA, Reid IR, Whyte MP. X-linked hypophosphatemia in adults: prevalence of skeletal radiographic and scintigraphic features. Radiology. 1989;171:403–14.
Econs MJ. Conventional Therapy in Adults With XLH Improves Dental Manifestations, But Not Enthesopathy. J Clin Endocrinol Metab. 2015;100:3622–4.
D’Angelo M, Yan Z, Nooreyazdan M, Pacifici M, Sarment DS, Billings PC, et al. MMP-13 is induced during chondrocyte hypertrophy. J Cell Biochem. 2000;77:678–93.
Ruppe MD, Zhang X, Imel EA, Weber TJ, Klausner MA, Ito T, et al. Effect of four monthly doses of a human monoclonal anti-FGF23 antibody (KRN23) on quality of life in X-linked hypophosphatemia. Bone Rep. 2016;5:158–62.
Veilleux LN, Cheung M, Ben Amor M, Rauch F. Abnormalities in muscle density and muscle function in hypophosphatemic rickets. J Clin Endocrinol Metab. 2012;97:E1492–8.
Veilleux LN, Cheung MS, Glorieux FH, Rauch F. The muscle-bone relationship in X-linked hypophosphatemic rickets. J Clin Endocrinol Metab. 2013;98:E990–5.
Bonewald LF. The Role of the Osteocyte in Bone and Nonbone Disease. Endocrinol Metab Clin North Am. 2017;46:1–18.
Schubert L, DeLuca HF. Hypophosphatemia is responsible for skeletal muscle weakness of vitamin D deficiency. Arch Biochem Biophys. 2010;500:157–61.
Chen Y-Y, Kao T-W, Chou C-W, Wu C-J, Yang H-F, Lai C-H, et al. Exploring the Link between Serum Phosphate Levels and Low Muscle Strength, Dynapenia, and Sarcopenia. Sci Rep. 2018;8:3573.
Minisola S, Peacock M, Fukumoto S, Cipriani C, Pepe J, Tella SH, et al. Tumour-induced osteomalacia. Nat Rev Primer. 2017;3:17044.
Pesta DH, Tsirigotis DN, Befroy DE, Caballero D, Jurczak MJ, Rahimi Y, et al. Hypophosphatemia promotes lower rates of muscle ATP synthesis. Faseb J. 2016;30:3378–87.
Larner AJ. Oral phosphate supplements reverse skeletal muscle abnormalities in a case of chronic fatigue with idiopathic renal hypophosphataemia. Neuromuscul Disord. 1994;4:155.
Hoshino C, Satoh N, Sugawara S, Kuriyama C, Kikuchi A, Ohta M. Sporadic adult-onset hypophosphatemic osteomalacia caused by excessive action of fibroblast growth factor 23. Intern Med. 2008;47:453–7.
Claus KN, Day TK, Wolf C. Neuromuscular signs associated with acute hypophosphatemia in a dog. J Am Anim Hosp Assoc. 2015;51:161–6.
Sato C, Iso Y, Mizukami T, Otabe K, Sasai M, Kurata M, et al. Fibroblast growth factor-23 induces cellular senescence in human mesenchymal stem cells from skeletal muscle. Biochem Biophys Res Commun. 2016;470:657–62.
Li DJ, Fu H, Zhao T, Ni M, Shen FM. Exercise-stimulated FGF23 promotes exercise performance via controlling the excess reactive oxygen species production and enhancing mitochondrial function in skeletal muscle. Metabolism. 2016;65:747–56.
Fukasawa H, Ishigaki S, Kinoshita-Katahashi N, Niwa H, Yasuda H, Kumagai H, et al. Plasma levels of fibroblast growth factor-23 are associated with muscle mass in haemodialysis patients. Nephrol Carlton. 2014;19:784–90.
Zoller H, Schaefer B, Glodny B. Iron-induced hypophosphatemia: an emerging complication. Curr Opin Nephrol Hypertens. 2017;26:266–75.
Caldemeyer KS, Boaz JC, Wappner RS, Moran CC, Smith RR, Quets JP. Chiari I malformation: association with hypophosphatemic rickets and MR imaging appearance. Radiology. 1995;195:733–8.
Imerslund O. Craniostenosis and vitamin D resistant rickets. Acta Paediatr. 1951;40:449–56.
Vega RA, Opalak C, Harshbarger RJ, Fearon JA, Ritter AM, Collins JJ, et al. Hypophosphatemic rickets and craniosynostosis: a multicenter case series. J Neurosurg Pediatr. 2016;17:694–700.
White KE, Cabral JM, Davis SI, Fishburn T, Evans WE, Ichikawa S, et al. Mutations that Cause Osteoglophonic Dysplasia Define Novel Roles for FGFR1 in Bone Elongation. Am J Hum Genet. 2005;76:361–7.
Di Rocco F, Biosse Duplan M, Heuze Y, Kaci N, Komla-Ebri D, Munnich A, et al. FGFR3 mutation causes abnormal membranous ossification in achondroplasia. Hum Mol Genet. 2014;23:2914–25.
Cohen MM Jr, Walker GF, Phillips C. A morphometric analysis of the craniofacial configuration in achondroplasia. J Craniofac Genet Dev Biol Suppl. 1985;1:139–65.
Gjorup H, Kjaer I, Sonnesen L, Beck-Nielsen SS, Haubek D. Morphological characteristics of frontal sinus and nasal bone focusing on bone resorption and apposition in hypophosphatemic rickets. Orthod Craniofac Res. 2013;16:246–55.
Iorio RJ, Murray G, Meyer RA Jr. Craniometric measurements of craniofacial malformations in mice with X-linked, dominant hypophosphatemia (vitamin D-resistant rickets). Teratology. 1980;22:291–8.
Katsianou MA, Adamopoulos C, Vastardis H, Basdra EK. Signaling mechanisms implicated in cranial sutures pathophysiology: Craniosynostosis. BBA Clin. 2016;6:165–76.
Morriss-Kay GM, Wilkie AO. Growth of the normal skull vault and its alteration in craniosynostosis: insights from human genetics and experimental studies. J Anat. 2005;207:637–53.
Murthy AS. X-linked hypophosphatemic rickets and craniosynostosis. J Craniofac Surg. 2009;20:439–42.
Carpenter TO, Imel EA, Ruppe MD, Weber TJ, Klausner MA, Wooddell MM, et al. Randomized trial of the anti-FGF23 antibody KRN23 in X-linked hypophosphatemia. J Clin Invest. 2014;124:1587–97.
Foster BL, Nociti FH, Somerman MJ. The Rachitic Tooth. Endocr Rev. 2014;35:1–34.
Connor J, Olear EA, Insogna KL, Katz L, Baker S, Kaur R, et al. Conventional Therapy in Adults With X-Linked Hypophosphatemia: Effects on Enthesopathy and Dental Disease. J Clin Endocrinol Metab. 2015;100:3625–32.
Baroncelli GI, Angiolini M, Ninni E, Galli V, Saggese R, Giuca MR. Prevalence and pathogenesis of dental and periodontal lesions in children with X-linked hypophosphatemic rickets. Eur J Paediatr Dent. 2006;7:61–6.
Chaussain-Miller C, Sinding C, Septier D, Wolikow M, Goldberg M, Garabedian M. Dentin structure in familial hypophosphatemic rickets: benefits of vitamin D and phosphate treatment. Oral Dis. 2007;13:482–9.
Chen L, Liu H, Sun W, Bai X, Karaplis AC, Goltzman D, et al. Fibroblast growth factor 23 overexpression impacts negatively on dentin mineralization and dentinogenesis in mice. Clin Exp Pharmacol Physiol. 2011;38:395–402.
Fong H, Chu EY, Tompkins KA, Foster BL, Sitara D, Lanske B, et al. Aberrant cementum phenotype associated with the hypophosphatemic hyp mouse. J Periodontol. 2009;80:1348–54.
Abe K, Masatomi Y, Nakajima Y, Shintani S, Moriwaki Y, Sobue S, et al. The occurrence of interglobular dentin in incisors of hypophosphatemic mice fed a high-calcium and high-phosphate diet. J Dent Res. 1992;71:478–83.
Ogawa T, Onishi T, Hayashibara T, Sakashita S, Okawa R, Ooshima T. Dentinal defects in Hyp mice not caused by hypophosphatemia alone. Arch Oral Biol. 2006;51:58–63.
Jones A, Tzenova J, Frappier D, Crumley M, Roslin N, Kos C, et al. Hereditary hypophosphatemic rickets with hypercalciuria is not caused by mutations in the Na/Pi cotransporter NPT2 gene. J Am Soc Nephrol. 2001;12:507–14.
Tenenhouse HS, Martel J, Gauthier C, Zhang MY, Portale AA. Renal expression of the sodium/phosphate cotransporter gene, Npt2, is not required for regulation of renal 1 alpha-hydroxylase by phosphate. Endocrinology. 2001;142:1124–9.
Chaussain-Miller C, Sinding C, Wolikow M, Lasfargues JJ, Godeau G, Garabedian M. Dental abnormalities in patients with familial hypophosphatemic vitamin D-resistant rickets: prevention by early treatment with 1-hydroxyvitamin D. J Pediatr. 2003;142:324–31.
Biosse Duplan M, Coyac BR, Bardet C, Zadikian C, Rothenbuhler A, Kamenicky P, et al. Phosphate and Vitamin D Prevent Periodontitis in X-Linked Hypophosphatemia. J Dent Res. 2017;96:388–95.
Cremonesi I, Nucci C, D’Alessandro G, Alkhamis N, Marchionni S, Piana G. X-linked hypophosphatemic rickets: enamel abnormalities and oral clinical findings. Scanning. 2014;36:456–61.
Carpenter TO, Gundberg CM. Osteocalcin abnormalities in Hyp mice reflect altered genetic expression and are not due to altered clearance, affinity for mineral, or ambient phosphorus levels. Endocrinology. 1996;137:5213–9.
Onishi T, Ogawa T, Hayashibara T, Hoshino T, Okawa R, Ooshima T. Hyper-expression of osteocalcin mRNA in odontoblasts of Hyp mice. J Dent Res. 2005;84:84–8.
Bronckers AL, Price PA, Schrijvers A, Bervoets TJ, Karsenty G. Studies of osteocalcin function in dentin formation in rodent teeth. Eur J Oral Sci. 1998;106:795–807.
Wang X, Wang J, Liu Y, Yuan B, Ruest LB, Feng JQ, et al. The specific role of FAM20C in dentinogenesis. J Dent Res. 2015;94:330–6.
Nociti FH Jr, Berry JE, Foster BL, Gurley KA, Kingsley DM, Takata T, et al. Cementum: a phosphate-sensitive tissue. J Dent Res. 2002;81:817–21.
Beertsen W, VandenBos T, Everts V. Root development in mice lacking functional tissue non-specific alkaline phosphatase gene: inhibition of acellular cementum formation. J Dent Res. 1999;78:1221–9.
Nociti FH Jr, Foster BL, Tran AB, Dunn D, Presland RB, Wang L, et al. Vitamin D represses dentin matrix protein 1 in cementoblasts and osteocytes. J Dent Res. 2014;93:148–54.
Chu EY, Fong H, Blethen FA, Tompkins KA, Foster BL, Yeh KD, et al. Ablation of systemic phosphate-regulating gene fibroblast growth factor 23 (Fgf23) compromises the dentoalveolar complex. Anat Rec Hoboken. 2010;293:1214–26.
Davies M, Kane R, Valentine J. Impaired hearing in X-linked hypophosphataemic (vitamin-D-resistant) osteomalacia. Ann Intern Med. 1984;100:230–2.
Fishman G, Miller-Hansen D, Jacobsen C, Singhal VK, Alon US. Hearing impairment in familial X-linked hypophosphatemic rickets. Eur J Pediatr. 2004;163:622–3.
Pantel G, Probst R, Podvinec M, Gurtler N. Hearing loss and fluctuating hearing levels in X-linked hypophosphataemic osteomalacia. J Laryngol Otol. 2009;123:136–40.
Cherian KE, Kapoor N, Mathews SS, Paul TV. Endocrine Glands and Hearing: Auditory Manifestations of Various Endocrine and Metabolic Conditions. Indian J Endocrinol Metab. 2017;21:464–9.
Wick CC, Lin SJ, Yu H, Megerian CA, Zheng QY. Treatment of ear and bone disease in the Phex mouse mutant with dietary supplementation. Am J Otolaryngol. 2017;38:44–51.
Meister M, Johnson A, Popelka GR, Kim GS, Whyte MP. Audiologic findings in young patients with hypophosphatemic bone disease. Ann Otol Rhinol Laryngol. 1986;95(4 Pt 1):415–20.
Boneh A, Reade TM, Scriver CR, Rishikof E. Audiometric evidence for two forms of X-linked hypophosphatemia in humans, apparent counterparts of Hyp and Gy mutations in mouse. Am J Med Genet. 1987;27:997–1003.
Megerian CA, Semaan MT, Aftab S, Kisley LB, Zheng QY, Pawlowski KS, et al. A mouse model with postnatal endolymphatic hydrops and hearing loss. Hear Res. 2008;237:90–105.
Wang X, Levic S, Gratton MA, Doyle KJ, Yamoah EN, Pegg AE. Spermine synthase deficiency leads to deafness and a profound sensitivity to alpha-difluoromethylornithine. J Biol Chem. 2009;284:930–7.
Wick CC, Semaan MT, Zheng QY, Megerian CA. A Genetic Murine Model of Endolymphatic Hydrops: The Phex Mouse. Curr Otorhinolaryngol Rep. 2014;2:144–51.
O’Malley S, Ramsden RT, Latif A, Kane R, Davies M. Electrocochleographic changes in the hearing loss associated with X-linked hypophosphataemic osteomalacia. Acta Otolaryngol. 1985;100:13–8.
Melki SJ, Li Y, Semaan MT, Zheng QY, Megerian CA, Alagramam KN. A mouse model validates the utility of electrocochleography in verifying endolymphatic hydrops. J Assoc Res Otolaryngol. 2014;15:413–21.
Momin SR, Melki SJ, Alagramam KN, Megerian CA. Spiral ganglion loss outpaces inner hair cell loss in endolymphatic hydrops. Laryngoscope. 2010;120:159–65.
Semaan MT, Zheng QY, Han F, Zheng Y, Yu H, Heaphy JC, et al. Characterization of neuronal cell death in the spiral ganglia of a mouse model of endolymphatic hydrops. Otol Neurotol. 2013;34:559–69.
Semaan MT, Megerian CA. Contemporary perspectives on the pathophysiology of Meniere’s disease: implications for treatment. Curr Opin Otolaryngol Head Neck Surg. 2010;18:392–8.
Linthicum FH Jr, Doherty J, Webster P, Makarem A. The periductal channels of the endolymphatic duct, hydrodynamic implications. Otolaryngol Head Neck Surg. 2014;150:441–7.
Gurkov R, Speierer G, Wittwer L, Kalla R. Effect of Elevated Intracranial Pressure on Amplitudes and Frequency Tuning of Ocular Vestibular Evoked Myogenic Potentials Elicited by Bone-Conducted Vibration. Ear Hear. 2016;37:e409–13.
Kaya S, Tsuprun V, Hizli O, Schachern PA, Paparella MM, Cureoglu S. Cochlear changes in serous labyrinthitis associated with silent otitis media: A human temporal bone study. Am J Otolaryngol. 2016;37:83–8.
Melki SJ, Heddon CM, Frankel JK, Levitt AH, Momin SR, Alagramam KN, et al. Pharmacological protection of hearing loss in the mouse model of endolymphatic hydrops. Laryngoscope. 2010;120:1637–45.
Abdullah Z, Kurts C. More trouble with FGF23: a novel role in systemic immunosuppression. Kidney Int. 2016;89:1176–7.
Bacchetta J, Salusky IB, Hewison M. Beyond mineral metabolism, is there an interplay between FGF23 and vitamin D in innate immunity? Pediatr Nephrol. 2013;28:577–82.
Chonchol M, Greene T, Zhang Y, Hoofnagle AN, Cheung AK. Low Vitamin D and High Fibroblast Growth Factor 23 Serum Levels Associate with Infectious and Cardiac Deaths in the HEMO Study. J Am Soc Nephrol. 2016;27:227–37.
Ferreira C, Ziegler S, Gahl W. Generalized Arterial Calcification of Infancy. In: Adam MP, Ardinger HH, Pagon RA, Wallace SE, LJH B, Stephens K, et al., editors. GeneReviews((R)). Seattle (WA): University of Washington, Seattle; 1993.
Chong WH, Molinolo AA, Chen CC, Collins MT. Tumor-induced osteomalacia. Endocr Relat Cancer. 2011;18:R53–77.
Florenzano P, Gafni RI, Collins MT. Tumor-induced osteomalacia. Bone Rep. 2017;7:90–7.
Areses-Trapote R, Lopez-Garcia JA, Ubetagoyena-Arrieta M, Eizaguirre A, Saez-Villaverde R. Hereditary hypophosphatemic rickets with hypercalciuria: case report. Nefrologia. 2012;32:529–34.
Jack Lambshead and Alexander Hardy of Medialis Ltd provided medical writing support for this manuscript.
Kyowa Kirin Services Ltd provided financial support for the writing of this manuscript. Medialis Ltd provided medical writing support and were also funded by Kyowa Kirin Services Ltd.
Availability of data and materials
Data sharing is not applicable to this article as no datasets were generated or analysed during the current study. Any data referred to in the text is available from the attached references.
Ethics approval and consent to participate
Consent for publication
SBN, ZM, DH, ON, EL, GA, CDL, DS and OM have received honoraria and/or consultancy fees from Kyowa Kirin Services Ltd. DH and GA have received research support from Kyowa Kirin Services Ltd. SBN, DH and GA have received travel support from Kyowa Kirin Services Ltd. RJ is acting in a consultancy/advisory role for Kyowa Kirin Services Ltd.
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
About this article
- X-linked hypophosphatemia (XLH)
- fibroblast growth factor 23 (FGF23)
- phosphate regulating endopeptidase homolog, X-linked (PHEX)
- vitamin D deficiency
- bone dysplasia
- ectopic calcification
- muscle weakness
- dental abscess
- hearing impairment