Autosomal Dominant Hypophosphatemic Rickets Research Articles

Iron and fibroblast growth factor 23 in X-linked hypophosphatemia

BackgroundExcess fibroblast growth factor 23 (FGF23) causes hypophosphatemia in autosomal dominant hypophosphatemic rickets (ADHR) and X-linked hypophosphatemia (XLH). Iron status influences C-terminal FGF23 (incorporating fragments plus intact FGF23) in ADHR and healthy subjects, and intact FGF23 in ADHR. We hypothesized that in XLH serum iron would inversely correlate to C-terminal FGF23, but not to intact FGF23, mirroring the relationships in normal controls. MethodsSubjects included 25 untreated outpatients with XLH at a tertiary medical center and 158 healthy adult controls. Serum iron and plasma intact FGF23 and C-terminal FGF23 were measured in stored samples. ResultsIntact FGF23 was greater than the control mean in 100% of XLH patients, and >2SD above the control mean in 88%, compared to 71% and 21% respectively for C-terminal FGF23. In XLH, iron correlated negatively to log-C-terminal FGF23 (r=−0.523, p<0.01), with a steeper slope than in controls (p<0.001). Iron was not related to log-intact FGF23 in either group. The log-ratio of intact FGF23 to C-terminal FGF23 was higher in XLH (0.00±0.44) than controls (−0.28±0.21, p<0.01), and correlated positively to serum iron (controls r=0.276, p<0.001; XLH r=0.428, p<0.05), with a steeper slope in XLH (p<0.01). ConclusionLike controls, serum iron in XLH is inversely related to C-terminal FGF23 but not intact FGF23. XLH patients are more likely to have elevated intact FGF23 than C-terminal FGF23. The relationships of iron to FGF23 in XLH suggest that altered regulation of FGF23 cleaving may contribute to maintaining hypophosphatemia around an abnormal set-point.

Neonatal Iron Deficiency Causes Abnormal Phosphate Metabolism by Elevating FGF23 in Normal and ADHR Mice

Fibroblast growth factor 23 (FGF23) gain of function mutations can lead to autosomal dominant hypophosphatemic rickets (ADHR) disease onset at birth, or delayed onset following puberty or pregnancy. We previously demonstrated that the combination of iron deficiency and a knock-in R176Q FGF23 mutation in mature mice induced FGF23 expression and hypophosphatemia that paralleled the late-onset ADHR phenotype. Because anemia in pregnancy and in premature infants is common, the goal of this study was to test whether iron deficiency alters phosphate handling in neonatal life. Wild-type (WT) and ADHR female breeder mice were provided control or iron-deficient diets during pregnancy and nursing. Iron-deficient breeders were also made iron replete. Iron-deficient WT and ADHR pups were hypophosphatemic, with ADHR pups having significantly lower serum phosphate (p < 0.01) and widened growth plates. Both genotypes increased bone FGF23 mRNA (>50 fold; p < 0.01). WT and ADHR pups receiving low iron had elevated intact serum FGF23; ADHR mice were affected to a greater degree (p < 0.01). Iron-deficient mice also showed increased Cyp24a1 and reduced Cyp27b1, and low serum 1,25-dihydroxyvitamin D (1,25D). Iron repletion normalized most abnormalities. Because iron deficiency can induce tissue hypoxia, oxygen deprivation was tested as a regulator of FGF23, and was shown to stimulate FGF23 mRNA in vitro and serum C-terminal FGF23 in normal rats in vivo. These studies demonstrate that FGF23 is modulated by iron status in young WT and ADHR mice and that hypoxia independently controls FGF23 expression in situations of normal iron. Therefore, disturbed iron and oxygen metabolism in neonatal life may have important effects on skeletal function and structure through FGF23 activity on phosphate regulation.

Interaction between FGF23 R176W mutation and C716T nonsynonymous change (T239M, rs7955866) in FGF23 on the clinical phenotype in a family with autosomal dominant hypophosphatemic rickets

Interaction between FGF23 R176W mutation and C716T nonsynonymous change (T239M, rs7955866) in FGF23 on the clinical phenotype in a family with autosomal dominant hypophosphatemic rickets

Late onset autosomal dominant hypophosphatemic rickets; confirmation of the diagnosis with genomic analysis

Searchable abstracts of presentations at key conferences on calcified tissues ISSN 2052-1219 (online)

Hypophosphatemic rickets

Description of the recent advances on the regulation of phosphate metabolism, gene mutations, and new approaches to treatment in patients with hypophosphatemic rickets. Fibroblast growth factor 23 (FGF23) overproduction may be a primary cause of hypophosphatemic rickets. Inactivating mutations of phosphate-regulating gene with homologies to endopeptidases on the X chromosome, dentin matrix acidic phosphoprotein 1, and ectonucleotide pyrophosphatase/phosphodiesterase 1 are associated with X-linked hypophosphatemic rickets, autosomal recessive hypophosphatemic rickets 1, and autosomal recessive hypophosphatemic rickets 2, respectively. Activating mutations of FGF23 gene is the cause of autosomal dominant hypophosphatemic rickets. Iron deficiency may affect autosomal dominant hypophosphatemic rickets phenotype by regulating FGF23 production.Current treatment with activated vitamin D metabolites and oral inorganic phosphate salts may partially correct skeletal lesions and linear growth in patients with hypophosphatemic rickets. However, some patients have poor improvement by the current treatment. Identification of the causative mutation in patients with hypophosphatemic rickets may be useful to confirm the diagnosis and probably for prognosis. Inhibition of FGF23 overproduction by anti-FGF23 neutralizing antibodies could be a future approach for treatment of patients with FGF23-dependent hypophosphatemic rickets.

Autosomal dominant hypophosphatemic rickets in an 85 year old woman: Characterization of her disease from infancy through adulthood

BackgroundAutosomal dominant hypophosphatemic rickets (ADHR) is a rare genetic disorder of phosphate homeostasis characterized, when severely expressed, by osteomalacia, suppressed levels of calcitriol, and renal phosphate wasting due to elevated levels of fibroblast growth factor 23 (FGF23). The disease is caused by heterozygous FGF23 mutations at the RXXR site that prevent cleavage of the intact hormone. ObjectivesAn FGF23 mutation was identified in the proband an 85-year-old woman with elevated FGF23 levels, and her clinical course was characterized. Medical records revealed she was treated for rickets as an infant. She was then asymptomatic until soon after her 4th pregnancy, when she suffered incapacitating bone pain and weakness, age 37. Symptoms remitted with brief treatment. ResultsThe proband and one son, but not other family members, were found to be heterozygous for the R176Q mutation in FGF23. Expression of this germ line mutation was strikingly different in both individuals in terms of skeletal health, FGF23 levels and disease activity. ConclusionsThe identified FGF23 mutation in two members of this family raises questions about molecular mechanisms that have led to intermittent increases in FGF23 synthesis and secretion, and disease expression.

Diabètes phosphatés

Phosphated diabetes are rare diseases, characterized by renal phosphate wasting, which results in hypophosphatemia, bone demineralization and osteomalacia. We review the pathophysiology of phosphate metabolism, revolutionized by the discovery of phosphatonines, particularly the FGF23, which sheds a new light on the various etiologies which are detailed: tumor-induced osteomalacia, genetic phosphate diabetes (X-linked hypophosphatemia, autosomal-dominant hypophosphatemic rickets, autosomal-recessive hypophosphatemic rickets, hypophosphatemic rickets with hypercalciuria, hypophosphatemia with nephrolithiasis by mutation of NPT2A and NHERF1), hyperparathyroidism, Fanconi syndrome and drug-induced phosphated diabetes. Diagnostic tools, improved by FGF23 dosage and treatment are also discussed.

The chicken or the egg: PHEX, FGF23 and SIBLINGs unscrambled.

The eggshell is an ancient innovation that helped the vertebrates' transition from the oceans and gain dominion over the land. Coincident with this conquest, several new eggshell and noncollagenous bone-matrix proteins (NCPs) emerged. The protein ovocleidin-116 is one of these proteins with an ancestry stretching back to the Triassic. Ovocleidin-116 is an avian homolog of Matrix Extracellular Phosphoglycoprotein (MEPE) and belongs to a group of proteins called Small Integrin-Binding Ligand Interacting Glycoproteins (SIBLINGs). The genes for these NCPs are all clustered on chromosome 5q in mice and chromosome 4q in humans. A unifying feature of the SIBLING proteins is an Acidic Serine Aspartate-Rich MEPE (ASARM)-associated motif. The ASARM motif and the released ASARM peptide play roles in mineralization, bone turnover, mechanotransduction, phosphate regulation and energy metabolism. ASARM peptides and motifs are physiological substrates for phosphate-regulating gene with homologies to endopeptidases on the X chromosome (PHEX), a Zn metalloendopeptidase. Defects in PHEX are responsible for X-linked hypophosphatemic rickets. PHEX interacts with another ASARM motif containing SIBLING protein, Dentin Matrix Protein-1 (DMP1). DMP1 mutations cause bone-renal defects that are identical with the defects caused by loss of PHEX function. This results in autosomal recessive hypophosphatemic rickets (ARHR). In both X-linked hypophosphatemic rickets and ARHR, increased fibroblast growth factor 23 (FGF23) expression occurs, and activating mutations in FGF23 cause autosomal dominant hypophosphatemic rickets (ADHR). ASARM peptide administration in vitro and in vivo also induces increased FGF23 expression. This review will discuss the evidence for a new integrative pathway involved in bone formation, bone-renal mineralization, renal phosphate homeostasis and energy metabolism in disease and health.

A mathematical model of calcium and phosphate homeostasis and early chronic kidney disease

A complex network of hormones, buffers, and signaling mechanisms must work together to maintain proper calcium and phosphate levels in the human body. Quantification of this network is necessary to gain understanding about how various pathophysiologies develop, and how they can be treated. In particular, calcium and phosphate homeostasis are intertwined through the interactions of parathyroid hormone (PTH), fibroblast growth factor 23 (FGF23), and 1α,25(OH)2D3 (Calcitriol). In vitro and in vivo studies were used to parameterize a model of hormone production and secretion for PTH, FGF23, and calcitriol including anabolic and catabolic pathways. In addition, it contains a three‐stage kinetic model of Vitamin D with the metabolic shunt path of 24 hydroxylation. The homeostatic mechanism includes various buffering mechanisms within the extracellular fluid compartment, hormonal influence on renal clearance mechanisms, and servo‐control of the calcium‐phosphorus product by a solubility model proposed by Talmage, Bronner, and Stein. The model responds properly to disturbances in the clearance of FGF23 characteristic in autosomal dominant hypophosphatemic rickets, and simulates low calcium or high phosphate diets properly. As an application of the model, we demonstrate the mechanism believed to describe the onset of metabolic bone disease as a complication of chronic kidney disease. In particular, renal damage reduces the ability of the kidney to create calcitriol resulting in increased PTH leading to increased FGF. When renal damage is minimal, compensation is possible, but as kidney damage becomes more intense, compensation is lost and FGF23 rises, the first general clinical indicator of skeletal involvement of CKD. This model does not include a specific bone cell axis, and is thus unable to demonstrate the effects of subsequent decompensation. This project is supported by NIH 1T32HL105324‐01 and EPSCoR 0903787.

Mechanism of FGF23 processing in fibrous dysplasia.

Fibroblast growth factor-23 (FGF23) is a phosphate- and vitamin D-regulating hormone derived from osteoblasts/osteocytes that circulates in both active (intact, iFGF23) and inactive (C-terminal, cFGF23) forms. O-glycosylation by O-glycosyl transferase N-acetylgalactosaminyltransferase 3 (ppGalNAcT3) and differential cleavage by furin have been shown to be involved in regulating the ratio of active to inactive FGF23. Elevated iFGF23 levels are observed in a number of hypophosphatemic disorders, such as X-linked, autosomal recessive, and autosomal dominant hypophosphatemic rickets, whereas low iFGF23 levels are found in the hyperphosphatemic disorder familial tumoral calcinosis/hyperphosphatemic hyperostosis syndrome. Fibrous dysplasia of bone (FD) is associated with increased total FGF23 levels (cFGF23 + iFGF23); however, classic hypophosphatemic rickets is uncommon. Our results suggest that it can be explained by increased FGF23 cleavage leading to an increase in inactive cFGF23 relative to active iFGF23. Given the fact that FD is caused by activating mutations in the small G-protein G(s) α that results in increased cyclic adenosine monophosphate (cAMP) levels, we postulated that there may be altered FGF23 cleavage in FD and that the mechanism may involve alterations in cAMP levels and ppGalNacT3 and furin activities. Analysis of blood specimens from patients with FD confirmed that the elevated total FGF23 levels are the result of proportionally increased cFGF23 levels, consistent with less glycosylation and enhanced cleavage by furin. Analysis of primary cell lines of normal and mutation-harboring bone marrow stromal cells (BMSCs) from patients with FD demonstrated that BMSCs harboring the causative G(s) α mutation had higher cAMP levels, lower ppGalNAcT3, and higher furin activity. These data support the model wherein glycosylation by ppGalNAcT3 inhibits FGF23 cleavage by furin and suggest that FGF23 processing is a regulated process that controls overall FGF23 activity in FD patients.

Hypophosphatemic rickets.

Hypophosphatemic rickets is a disorder of bone mineralization caused due to defects (inherited/acquired) in the renal handling of phosphorus. This group includes varied conditions, X-linked hypophosphatemic rickets being the most common inheritable form of rickets. The other common forms are autosomal dominant hypophosphatemic rickets and tumor-induced osteomalacia. Although these conditions exhibit different etiologies, increased phosphatonins form a common link among them. Fibroblast growth factor 23 (FGF23) is the most widely studied phosphatonin. Genetic studies tend to show that the phosphorus homeostasis depends on a complex osteo-renal axis, whose mechanisms have been poorly understood so far. Newer disorders are being added as the mechanisms in this axis get discovered. This review focuses on the clinical, biochemical, genetic features and management of hypophosphatemic disorders leading to defective mineralization.

Regulation of bone-renal mineral and energy metabolism: the PHEX, FGF23, DMP1, MEPE ASARM pathway.

More than 300 million years ago, vertebrates emerged from the vast oceans to conquer gravity and the dry land. With this transition, new adaptations occurred that included ingenious changes in reproduction, waste secretion, and bone physiology. One new innovation, the egg shell, contained an ancestral protein (ovocleidin-116) that likely first appeared with the dinosaurs and was preserved through the theropod lineage in modern birds and reptiles. Ovocleidin-116 is an avian homolog of matrix extracellular phosphoglycoprotein (MEPE) and belongs to a group of proteins called short integrin-binding ligand-interacting glycoproteins (SIBLINGs). These proteins are all localized to a defined region on chromosome 5q in mice and chromosome 4q in humans. A unifying feature of SIBLING proteins is an acidic serine aspartate-rich MEPE-associated motif (ASARM). Recent research has shown that the ASARM motif and the released ASARM peptide have regulatory roles in mineralization (bone and teeth), phosphate regulation, vascularization, soft-tissue calcification, osteoclastogenesis, mechanotransduction, and fat energy metabolism. The MEPE ASARM motif and peptide are physiological substrates for PHEX, a zinc metalloendopeptidase. Defects in PHEX are responsible for X-linked hypophosphatemic rickets (HYP). There is evidence that PHEX interacts with another ASARM motif containing SIBLING protein, dentin matrix protein-1 (DMP1). DMP1 mutations cause bone and renal defects that are identical with the defects caused by a loss of PHEX function. This results in autosomal recessive hypophosphatemic rickets (ARHR). In both HYP and ARHR, increased FGF23 expression plays a major role in the disease and in autosomal dominant hypophosphatemic rickets (ADHR), FGF23 half-life is increased by activating mutations. ASARM peptide administration in vitro and in vivo also induces increased FGF23 expression. FGF23 is a member of the fibroblast growth factor (FGF) family of cytokines, which surfaced 500 million years ago with the boney fish (i.e., teleosts) that do not contain SIBLING proteins. In terrestrial vertebrates, FGF23, like SIBLING proteins, is expressed in the osteocyte. The boney fish, however, are an-osteocytic, so a physiological bone-renal link with FGF23 and the SIBLINGs was cemented when life ventured from the oceans to the land during the Triassic period, approximately 300 million years ago. This link has been revealed by recent research that indicates a competitive displacement of a PHEX-DMP1 interaction by an ASARM peptide that leads to increased FGF23 expression. This review discusses the new discoveries that reveal a novel PHEX, DMP1, MEPE, ASARM peptide, and FGF23 bone-renal pathway. This pathway impacts not only bone formation, bone-renal mineralization, and renal phosphate homeostasis but also energy metabolism. The study of this new pathway is relevant for developing therapies for several diseases: bone-teeth mineral loss disorders, renal osteodystrophy, chronic kidney disease and bone mineralization disorders (CKD-MBD), end-stage renal diseases, ectopic arterial-calcification, cardiovascular disease renal calcification, diabetes, and obesity.

Iron deficiency drives an autosomal dominant hypophosphatemic rickets (ADHR) phenotype in fibroblast growth factor-23 (Fgf23) knock-in mice

Autosomal dominant hypophosphatemic rickets (ADHR) is unique among the disorders involving Fibroblast growth factor 23 (FGF23) because individuals with R176Q/W and R179Q/W mutations in the FGF23 (176)RXXR(179)/S(180) proteolytic cleavage motif can cycle from unaffected status to delayed onset of disease. This onset may occur in physiological states associated with iron deficiency, including puberty and pregnancy. To test the role of iron status in development of the ADHR phenotype, WT and R176Q-Fgf23 knock-in (ADHR) mice were placed on control or low-iron diets. Both the WT and ADHR mice receiving low-iron diet had significantly elevated bone Fgf23 mRNA. WT mice on a low-iron diet maintained normal serum intact Fgf23 and phosphate metabolism, with elevated serum C-terminal Fgf23 fragments. In contrast, the ADHR mice on the low-iron diet had elevated intact and C-terminal Fgf23 with hypophosphatemic osteomalacia. We used in vitro iron chelation to isolate the effects of iron deficiency on Fgf23 expression. We found that iron chelation in vitro resulted in a significant increase in Fgf23 mRNA that was dependent upon Mapk. Thus, unlike other syndromes of elevated FGF23, our findings support the concept that late-onset ADHR is the product of gene-environment interactions whereby the combined presence of an Fgf23-stabilizing mutation and iron deficiency can lead to ADHR.

Iron Modifies Plasma FGF23 Differently in Autosomal Dominant Hypophosphatemic Rickets and Healthy Humans

In autosomal dominant hypophosphatemic rickets (ADHR), fibroblast growth factor 23 (FGF23) resists cleavage, causing increased plasma FGF23 levels. The clinical phenotype includes variable onset during childhood or adulthood and waxing/waning of hypophosphatemia. Delayed onset after puberty in females suggests iron status may be important. Studies were performed to test the hypothesis that plasma C-terminal and intact FGF23 concentrations are related to serum iron concentrations in ADHR. Cross-sectional and longitudinal studies of ADHR and a cross-sectional study in healthy subjects were conducted at an academic medical center. Participants included 37 subjects with ADHR mutations from four kindreds and 158 healthy adult controls. The relationships of serum iron concentrations with plasma C-terminal and intact FGF23 concentrations were evaluated. Serum phosphate and 1,25-dihydroxyvitamin D correlated negatively with C-terminal FGF23 and intact FGF23 in ADHR but not in controls. Serum iron was negatively correlated to both C-terminal FGF23 (r = -0.386; P < 0.05) and intact FGF23 (r = -0.602; P < 0.0001) in ADHR. However, control subjects also demonstrated a negative relationship of serum iron with C-terminal FGF23 (r = -0.276; P < 0.001) but no relationship with intact FGF23. Longitudinally in ADHR subjects, C-terminal FGF23 and intact FGF23 concentrations changed negatively with iron concentrations (P < 0.001 and P = 0.055, respectively), serum phosphate changed negatively with C-terminal FGF23 and intact FGF23 (P < 0.001), and there was a positive relationship between serum iron and phosphate (P < 0.001). Low serum iron is associated with elevated FGF23 in ADHR. However, in controls, low serum iron was also associated with elevated C-terminal FGF23, but not intact FGF23, suggesting cleavage maintains homeostasis despite increased FGF23 expression.

FGF23 analysis of a Chinese family with autosomal dominant hypophosphatemic rickets

Autosomal dominant hypophosphatemic rickets (ADHR; MIM 193100) is a hereditary disorder characterized by isolated renal phosphate wasting, hypophosphatemia, and inappropriately normal 1,25-dihydroxyvitamin D(3) levels. Recent studies have shown that the fibroblast growth factor 23 (FGF23) gene is responsible for this disease. FGF23 protein is a phosphaturic factor that is elevated in several diseases associated with hypophosphatemia and rickets but varies with disease status in ADHR. In the present study we observed a Chinese family of Han ethnic origin diagnosed with ADHR. The proband is a 30-year-old woman with no history of rickets but with multiple tooth abscesses as a young adult. She presented with progressive painful swelling of the left ankle after a blunt trauma at 26years of age. She developed back pain, generalized weakness, and fatigue, and she could barely walk at age 27. She was found to have severe hypophosphatemia, low ratio of phosphorus tubule maximum (TmP) to glomerular filtration rate (GFR) (TmP/GFR), and elevated alkaline phosphatase at age 28. Her brother, 26years old, presented with fatigue at 24years of age and is normophosphatemic. The parents of this family had no history of rickets or hypophosphatemia. Direct sequence analysis of genomic DNA demonstrated a single heterozygous c.527G>A (p.R176Q) mutation in the FGF23 gene in three family members, including the proband, her brother, and their mother. Intact FGF23 assay of seven time points during the oral phosphate loading test showed no significant relationship between intact FGF23 and serum phosphorus levels of the subject with ADHR and a control. It is probably the first report of a Chinese family with ADHR.

Mutational analysis of PHEX, FGF23 and DMP1 in a cohort of patients with hypophosphatemic rickets

X-linked hypophosphatemic rickets, autosomal dominant hypophosphatemic rickets and autosomal recessive hypophosphatemic rickets make up a group of renal phosphate wasting disorders with common clinical and biochemical characteristics. These three types of rickets are related to mutations in PHEX, FGF23 and dentin matrix protein 1 (DMP1), respectively. The objective of the study was to evaluate the frequency of mutations that occur in these three genes associated with hypophosphatemic rickets. In this study, we sequenced these genes in 76 members of 46 kindreds from a large hypophosphatemic rickets cohort. Forty-two individuals from 27 kindreds were found to have mutations in PHEX; 16 of which were novel. One subject had an FGF23 mutation. No individuals were found to have mutations in DMP1 consistent with the presence of recessive hypophosphatemic rickets. Our data highlight the wide spectrum of genetic variation that can be seen in PHEX, FGF23 and DMP1 when screening a large cohort with hypophosphatemic rickets.

The Cooperation of FGF Receptor and Klotho Is Involved in Excretory Canal Development and Regulation of Metabolic Homeostasis in Caenorhabditis elegans

FGFs have traditionally been associated with cell proliferation, morphogenesis, and development; yet, a subfamily of FGFs (FGF19, -21, and -23) functions as hormones to regulate glucose, lipid, phosphate, and vitamin D metabolism with impact on energy balance and aging. In mammals, Klotho and beta-Klotho are type 1 transmembrane proteins that function as obligatory co-factors for endocrine FGFs to bind to their cognate FGF receptors (FGFRs). Mutations in Klotho/beta-Klotho or fgf19, -21, or -23 are associated with a number of human diseases, including autosomal dominant hypophosphatemic rickets, premature aging disorders, and diabetes. The Caenorhabditis elegans genome contains two paralogues of Klotho/beta-Klotho, klo-1, and klo-2. klo-1 is expressed in the C. elegans excretory canal, which is structurally and functionally paralogous to the vertebrate kidney. KLO-1 associates with EGL-15/FGFR, suggesting a role for KLO-1 in the fluid homeostasis phenotype described previously for egl-15/fgfr mutants. Altered levels of EGL-15/FGFR signaling lead to defects in excretory canal development and function in C. elegans. These results suggest an evolutionarily conserved function for the FGFR-Klotho complex in the development of excretory organs such as the mammalian kidney and the worm excretory canal. These results also suggest an evolutionarily conserved function for the FGFR-Klotho axis in metabolic regulation.

Fibroblast Growth Factor, A Review

The recent identification of fibroblast growth factor (FGF)23 has filled in the gaps of our understanding of calcium– phosphate regulation. Together with its cofactor Klotho, FGF-23 is a phosphaturic factor that influences vitamin D metabolism and renal re-absorption of phosphorus in order to maintain serum phosphate levels within the normal range. In chronic kidney disease (CKD), FGF-23 levels rise in parallel with declining kidney function before any significant rise is perceived in serum phosphate concentration. Increased serum FGF-23 levels in CKD patients were found to be independently associated with ventricular hypertrophy and endothelial dysfunction after correcting for traditional markers of calcium–phosphate metabolism. FGF-23 has been implicated in various human diseases including autosomal dominant hypophosphatemic rickets (ADHR), X-linked hypophosphatemia (XLH), tumor induced osteomalacia and familial tumoral calcinosis. Lastly, in prospective studies, elevated serum FGF-23 levels predicted rapid disease progression in non-dialysis dependent CKD patients and increased mortality in chronic hemodialysis patients. The growing knowledge and understanding of FGF-23 may provide potential answers with regards to prevention and management of CKD [1]. The FGF family is comprised of polypeptides that share a common region of amino peptide residues. Seven human FGF subfamilies have been identified; FGF-23 belongs to the FGF19 subgroup including FGF 19, 21 and 23 having very different physiological functions despite sharing a similar disulphide bond which is absent in most other families. FGF23 is a central regulator of phosphate homeostasis, enhancing phosphorus excretion and suppressing1-alpha hydroxylase activity in the kidney [2, 3], whereas FGF-19 is involved in bile acid synthesis and FGF-21 stimulates insulinindependent glucose uptake in adipocytes and reduces triglyceride levels. The active form of FGF-23 is an approximately 32-kD (251 amino acids) protein with its gene located on chromosome 12 [4, 5]. It is mainly expressed in osteocytes [6, 7], and also expressed in pericyte-like cells around the venous sinuses, the ventrolateral thalamic nucleus, and in the thymus. The contribution of sites other than bone to circulating FGF-23 levels is still unclear. It is clear, however that there are high levels of expression in the osteocytes and that because osteocytes are the most abundant cell in bone, this suggests that the serum levels of FGF-23 are derived mainly from bone [8]. FGF-23 exerts its biological effects through activation of FGF receptors in a Klotho dependent manner, as a Klotho/ FGF-Receptor complex binds to FGF-23. Klotho is a transmembrane protein, the gene expression of which was detected in distal renal tubular cells, parathyroid gland, the pituitary gland, ovary, testis, skeletal muscle, duodenum, pancreas and choroid plexus. It is unclear why Klotho is G. C. Chibesakunda (*) :C. S. Brecklin Department of Medicine/Section of Nephrology, University of Illinois Medical Center at Chicago, 820 S Wood Street (MC 793), Chicago, IL 60612, USA e-mail: gracecc@uic.edu

Hereditary disorders of renal phosphate wasting

Inherited diseases of renal phosphate handling lead to urinary phosphate wasting and depletion of total body phosphorus stores. Clinical sequelae of inherited disorders that are associated with increased urinary phosphate excretion are deleterious and can lead to abnormal skeletal growth and deformities. This Review describes hereditary disorders of renal phosphate wasting taking into account developments in our understanding of renal phosphate handling from the last decade. The cloning of genes involved in these disorders and further studies on their pathophysiological mechanisms have given important insights in to how phosphatonins, such as FGF-23, regulate renal phosphate reabsorption in health and disease. X-linked dominant hypophosphatemic rickets results from mutation of a metalloprotease (PHEX) that has an unidentified role in FGF-23 degradation. Mutation of an RXXR proteolytic cleavage site in FGF-23 prevents degradation and increases circulating levels of FGF-23 in autosomal dominant hypophosphatemic rickets. FGF-23 acts to remove sodium phosphate co-transporters from the luminal membrane of proximal tubular cells with resultant renal phosphate wasting. Loss of function mutations in genes encoding the transporters NaPi-IIc and NaPi-IIa also result in renal phosphate wasting and rickets.

Tumour-induced osteomalacia: a curable condition

Osteomalacia is a condition characterised by failure of bone mineralisation. While abnormalities of vitamin D supply, metabolism or action are the most common and well-known causes, chronic phosphate deficiency, due to either insufficient input (intake or absorption) or renal losses are also important causes of rickets or osteomalacia.1 Hypophosphataemia also commonly co-exists with vitamin D deficiency, pursuant to secondary hyperparathyroidism. Other causes include chronic calcium deficiency, hypophosphatasia, fluoride and aluminium excess. In respect of chronic hypophosphataemia-associated rickets/ osteomalacia, the commonest aetiology is X-linked dominant hypophosphataemia, XLH, (1:20000 births).1 Others include Fanconi syndrome, autosomal dominant hypophosphataemic rickets (ADHR) and tumour-induced osteomalacia (TIO).2