Inherited Fanconi renotubular syndromes: unveiling the intricacies of hypophosphatemic rickets/osteomalacia.

INTRODUCTION: Fanconi renotubular syndromes (FRTS) are a rare group of inherited phosphaturic disorders with limited Indian as well as global data on this condition. Here, we describe the experience of a single Endocrinology center from Western India on FRTS. MATERIALS AND METHODS: Comprehensive clinical, biochemical, radiological, management, and genetic details of FRTS patients managed between 2010 and 2023 were collected and analyzed. RESULTS: FRTS probands had mutations (eight novel) in six genes [CLCN5 (n = 4), SLC2A2 (n = 2), GATM, EHHADH, HNF4A, and OCRL (1 each)]. Among 15 FRTS patients (11 families), rickets/osteomalacia was the most common (n = 14) presentation with wide inter- and intra-familial phenotypic variability. Delayed diagnosis (median: 8.8 years), initial misdiagnosis (8/11 probands), and syndrome-specific discriminatory features (8/11 probands) were commonly seen. Hypophosphatemia, elevated alkaline phosphatase, normal parathyroid hormone (median: 36 pg/ml), high-normal/elevated 1,25(OH)2D (median: 152 pg/ml), hypercalciuria (median spot urinary calcium to creatinine ratio: 0.32), and variable proximal tubular dysfunction(s) were observed. Elevated C-terminal fibroblast growth factor 23 in two probands was misleading, till the genetic diagnosis was reached. Novel observations in our FRTS cohort were preserved renal function (till sixth decade) and enthesopathy in FRTS1 and FRTS3 families, respectively. CONCLUSION: Our findings underscore frequent under- and misdiagnosis of FRTS; hence, a high index of suspicion for FRTS in phosphopenic rickets/osteomalacia, with early consideration of genetic testing is essential to ensure timely diagnosis of FRTS. The novel variants and phenotypic manifestations described here expand the disease spectrum of FRTS.

[Retrospective study on the diagnosis, treatment, and follow-up of 85 cases of hypophosphatemic rickets in children]. / 85ä¾‹ä½Žè¡€ç£·æ€§ä½å»ç— æ‚£å„¿è¯Šæ–­ã€æ²»ç–—ä¸Žéšè®¿çš„å›žé¡¾æ€§ç ”ç©¶.

OBJECTIVES: To study the diagnosis, treatment, and complications of hypophosphatemic rickets (HR) in children, explore effectiveness evaluation indicators for the disease, and understand the pattern in height growth among these patients. METHODS: A retrospective analysis of the initial clinical data and five-year follow-up data of 85 children with HR treated at Children's Hospital of Nanjing Medical University from January 2008 to December 2022. RESULTS: Among the 85 children with HR, there were 46 males (54%) and 39 females (46%). The age at initial diagnosis ranged from 6 months to 13 years and 9 months, with a median age of 2.75 years. The average height standard deviation score was -2.0±1.1. At initial diagnosis, children exhibited reduced blood phosphate levels and elevated alkaline phosphatase (ALP), with 99% (84/85) presenting with lower limb deformities. The positive rate for PHEX gene mutations was 93% (55/59). One year post-treatment, there was a significant reduction in ALP levels and the gap between the lower limbs (P<0.05). The fastest height growth occurred in the first year after treatment, at 8.23 cm/year, with a peak height velocity (PHV) phase lasting about two years during puberty. The height increased by 9-20 cm in male children during the PHV stage and 10-15 cm in female children. Major complications included nephrocalcinosis and hyperparathyroidism. The incidence rate of nephrocalcinosis in the first year after treatment was 55% (22/40), which increased with the duration of the disease (P<0.001); an increased urinary phosphate/creatinine ratio was positively associated with a higher risk of nephrocalcinosis (OR=1.740, P<0.001). The incidence of hyperparathyroidism in the first year after treatment was 64% (27/42). CONCLUSIONS: For children presenting with lower limb deformities, short stature, and slow growth, early testing for blood levels of phosphate, calcium, and ALP, along with imaging examinations of the lower limbs, can aid in the early diagnosis of HR. Genetic testing may be utilized for definitive confirmation when necessary. ALP combined with improvements in skeletal deformities and annual height growth can serve as indicators of therapeutic effectiveness for HR. Compared to normal children, children with HR demonstrate a lower height increase during the PHV phase, necessitating close follow-up and timely adjustment of treatment plans Citation:Chinese Journal of Contemporary Pediatrics, 2024, 26(7): 677-682.

FGF23 contains two distinct high-affinity binding sites enabling bivalent interactions with α-Klotho.

The three members of the endocrine-fibroblast growth factor (FGF) family, FGF19, 21, and 23 are circulating hormones that regulate critical metabolic processes. FGF23 stimulates the assembly of a signaling complex composed of α-Klotho (KLA) and FGF receptor (FGFR) resulting in kinase activation, regulation of phosphate homeostasis, and vitamin D levels. Here we report that the C-terminal tail of FGF23, a region responsible for KLA binding, contains two tandem repeats, repeat 1 (R1) and repeat 2 (R2) that function as two distinct ligands for KLA. FGF23 variants with a single KLA binding site, FGF23-R1, FGF23-R2, or FGF23-wild type (WT) with both R1 and R2, bind to KLA with similar binding affinity and stimulate FGFR1 activation and MAPK response. R2 is flanked by two cysteines that form a disulfide bridge in FGF23-WT; disulfide bridge formation in FGF23-WT is dispensable for KLA binding and for cell signaling via FGFRs. We show that FGF23-WT stimulates dimerization and activation of a chimeric receptor molecule composed of the extracellular domain of KLA fused to the cytoplasmic domain of FGFR and employ total internal reflection fluorescence microscopy to visualize individual KLA molecules on the cell surface. These experiments demonstrate that FGF23-WT can act as a bivalent ligand of KLA in the cell membrane. Finally, an engineered Fc-R2 protein acts as an FGF23 antagonist offering new pharmacological intervention for treating diseases caused by excessive FGF23 abundance or activity.

Successful treatment with MEK-inhibitor in a patient with NRAS-related cutaneous skeletal hypophosphatemia syndrome.

Cutaneous skeletal hypophosphatemia syndrome (CSHS) is caused by somatic mosaic NRAS variants and characterized by melanocytic/sebaceous naevi, eye, and brain malformations, and FGF23-mediated hypophosphatemic rickets. The MEK inhibitor Trametinib, acting on the RAS/MAPK pathway, is a candidate for CSHS therapy. A 4-year-old boy with seborrheic nevus, eye choristoma, multiple hamartomas, brain malformation, pleural lymphangioma and chylothorax developed severe hypophosphatemic rickets unresponsive to phosphate supplementation. The c.182A > G;p.(Gln61Arg) somatic NRAS variant found in DNA from nevus biopsy allowed diagnosing CSHS. We administered Trametinib for 15 months investigating the transcriptional effects at different time points by whole blood RNA-seq. Treatment resulted in prompt normalization of phosphatemia and phosphaturia, catch-up growth, chylothorax regression, improvement of bone mineral density, reduction of epidermal nevus and hamartomas. Global RNA sequencing on peripheral blood mononucleate cells showed transcriptional changes under MEK inhibition consisting in a strong sustained downregulation of signatures related to RAS/MAPK, PI3 kinase, WNT and YAP/TAZ pathways, reverting previously defined transcriptomic signatures. CSHS was effectively treated with a MEK inhibitor with almost complete recovery of rickets and partial regression of the phenotype. We identified "core" genes modulated by MEK inhibition potentially serving as surrogate markers of Trametinib action.

[Value of serum fibroblast growth factor 23 in diagnosis of hypophosphatemic rickets in children]. / è¡€æ¸ æˆçº¤ç»´ç»†èƒžç”Ÿé•¿å› å­23å¯¹å„¿ç«¥ä½Žè¡€ç£·æ€§ä½å»ç— çš„è¯Šæ–­ä»·å€¼ç ”ç©¶.

OBJECTIVES: To study the value of serum fibroblast growth factor 23 (FGF23) in the diagnosis of hypophosphatemic rickets in children. METHODS: A total of 28 children who were diagnosed with hypophosphatemic rickets in Children's Hospital of Nanjing Medical University from January 2016 to June 2021 were included as the rickets group. Forty healthy children, matched for sex and age, who attended the Department of Child Healthcare of the hospital were included as the healthy control group. The serum level of FGF23 was compared between the two groups, and the correlations of the serum FGF23 level with clinical characteristics and laboratory test results were analyzed. The value of serum FGF23 in the diagnosis of hypophosphatemic rickets was assessed. RESULTS: The rickets group had a significantly higher serum level of FGF23 than the healthy control group (P<0.05). In the rickets group, the serum FGF23 level was positively correlated with the serum alkaline phosphatase level (rs=0.38, P<0.05) and was negatively correlated with maximum renal tubular phosphorus uptake/glomerular filtration rate (rs=-0.64, P<0.05), while it was not correlated with age, height Z-score, sex, and parathyroid hormone (P>0.05). Serum FGF23 had a sensitivity of 0.821, a specificity of 0.925, an optimal cut-off value of 55.77 pg/mL, and an area under the curve of 0.874 in the diagnosis of hypophosphatemic rickets (P<0.05). CONCLUSIONS: Serum FGF23 is of valuable in the diagnosis of hypophosphatemic rickets in children, which providing a theoretical basis for early diagnosis of this disease in clinical practice.

Mutation update: Variants of the ENPP1 gene in pathologic calcification, hypophosphatemic rickets, and cutaneous hypopigmentation with punctate keratoderma.

ENPP1 encodes ENPP1, an ectonucleotidase catalyzing hydrolysis of ATP to AMP and inorganic pyrophosphate (PPi), and an endogenous plasma protein physiologically preventing ectopic calcification of connective tissues. Mutations in ENPP1 have been reported in association with a range of human genetic diseases. In this mutation update, we provide a comprehensive review of all the pathogenic variants, likely pathogenic variants, and variants of unknown significance in ENPP1 associated with three autosomal recessive disorders-generalized arterial calcification of infancy (GACI), autosomal recessive hypophosphatemic rickets type 2 (ARHR2), and pseudoxanthoma elasticum (PXE), as well as with a predominantly autosomal dominant disorder-Cole disease. The classification of all variants is determined using the latest ACMG guidelines. A total of 140 ENPP1 variants were curated consisting of 133 previously reported variants and seven novel variants, with missense variants being the most prevalent (70.0%, 98/140). While the pathogenic variants are widely distributed in the ENPP1 gene of patientsgen without apparent genotype-phenotype correlation, eight out of nine variants associated with Cole disease are confined to the somatomedin-B-like (SMB) domains critical for homo-dimerization of the ENPP1 protein.

Bone Deformities and Kidney Failure: Coincidence of PHEX-Related Hypophosphatemic Rickets and m.3243A>G Mitochondrial Disease.

X-linked hypophosphatemic rickets (XLH) and m.3243A>G mitochondrial disease share several clinical findings, including short stature, hearing impairment (HI), nephropathy, and hypertension. Here, we report on a case with the rare coincidence of these two genetic conditions. In early childhood, the patient presented with hypophosphatemia and bone deformities and was clinically diagnosed with XLH. This was genetically verified in adulthood with the identification of a de novo pathogenic deletion in phosphate-regulating endopeptidase homolog X-linked (PHEX). In addition, the patient developed HI and hypertension and when his mother was diagnosed with m.3243A>G, subsequent genetic testing confirmed the patient to carry the same variant. Over the next two decades, the patient developed progressive renal impairment however without nephrocalcinosis known to associate with XLH which could indicate an m.3243A>G-related kidney disease. Parallel with the progression of renal impairment, the patient developed hyperphosphatemia and secondary hyperparathyroidism. In conclusion, this case represents a complex clinical phenotype with the reversal of hypo- to hyperphosphatemia in XLH potentially mediated by the development of an m.3243A>G-associated nephropathy.

Rickets guidance: part II-management.

Here, we discuss the management of different forms of rickets, including new therapeutic approaches based on recent guidelines. Management includes close monitoring of growth, the degree of leg bowing, bone pain, serum phosphate, calcium, alkaline phosphatase as a surrogate marker of osteoblast activity and thus degree of rickets, parathyroid hormone, 25-hydroxyvitamin D3, and calciuria. An adequate calcium intake and normal 25-hydroxyvitamin D3 levels should be assured in all patients. Children with calcipenic rickets require the supplementation or pharmacological treatment with native or active vitamin D depending on the underlying pathophysiology. Treatment of phosphopenic rickets depends on the underlying pathophysiology. Fibroblast-growth factor 23 (FGF23)-associated hypophosphatemic rickets was historically treated with frequent doses of oral phosphate salts in combination with active vitamin D, whereas tumor-induced osteomalacia (TIO) should primarily undergo tumor resection, if possible. Burosumab, a fully humanized FGF23-antibody, was recently approved for treatment of X-linked hypophosphatemia (XLH) and TIO and shown to be superior for treatment of XLH compared to conventional treatment. Forms of hypophosphatemic rickets independent of FGF23 due to genetic defects of renal tubular phosphate reabsorption are treated with oral phosphate only, since they are associated with excessive 1,25-dihydroxyvitamin D production. Finally, forms of hypophosphatemic rickets caused by Fanconi syndrome, such as nephropathic cystinosis and Dent disease require disease-specific treatment in addition to phosphate supplements and active vitamin D. Adjustment of medication should be done with consideration of treatment-associated side effects, including diarrhea, gastrointestinal discomfort, hypercalciuria, secondary hyperparathyroidism, and development of nephrocalcinosis or nephrolithiasis.

Advances in understanding of phosphate homeostasis and related disorders.

Inorganic phosphate (Pi) in the mammalian body is balanced by its influx and efflux through the intestines, kidneys, bones, and soft tissues, at which several sodium/Pi co-transporters mediate its active transport. Pi homeostasis is achieved through the complex counter-regulatory feedback balance between fibroblast growth factor 23 (FGF23), 1,25-dihydroxyvitamin D (1,25(OH)2D), and parathyroid hormone. FGF23, which is mainly produced by osteocytes in bone, plays a central role in Pi homeostasis and exerts its effects by binding to the FGF receptor (FGFR) and αKlotho in distant target organs. In the kidneys, the main target, FGF23 promotes the excretion of Pi and suppresses the production of 1,25(OH)2D. Deficient and excess FGF23 result in hyperphosphatemia and hypophosphatemia, respectively. FGF23-related hypophosphatemic rickets/osteomalacia include tumor-induced osteomalacia and various genetic diseases, such as X-linked hypophosphatemic rickets. Coverage by the national health insurance system in Japan for the measurement of FGF23 and the approval of burosumab, an FGF23-neutralizing antibody, have had a significant impact on the diagnosis and treatment of FGF23-related hypophosphatemic rickets/osteomalacia. Some of the molecules responsible for genetic hypophosphatemic rickets/osteomalacia are highly expressed in osteocytes and function as local regulators of FGF23 production. A number of systemic factors also regulate FGF23 levels. Although the mechanisms responsible for Pi sensing in mammals have not yet been elucidated in detail, recent studies have suggested the involvement of FGFR1. The further clarification of the mechanisms by which osteocytes detect Pi levels and regulate FGF23 production will lead to the development of better strategies to treat hyperphosphatemic and hypophosphatemic conditions.

Twin girls with hypophosphataemic rickets and papilloedema.

A 7 year-old twin girl with hypophosphataemic rickets was evaluated for a recent onset of mild strabismus.She was a homozygous twin sister with hypophosphataemic rickets diagnosed at the age of 2 years, with a mutation in intron 21 of the PHEX gene, which was also present in her sister.The girls' clinical histories were remarkable for an important lower limb varus that progressively improved after starting phosphate supplementation with a galenical solution (Joulies solution 1 mmol phosphate/ml) and vitamin D 1,25 OH.During the examinations, both girls were in good general condition. Physical examinations were unremarkable, except for tibial varus, bilateral fifth finger clinodactyly and bilateral syndactyly of the third and fourth foot fingers. No major head shape abnormalities were noticeable except for a high forehead.One patient presented with a slight strabismus, normal isochoric isocyclic and reactive pupils, no signs of cranial nerve deficit, and no alterations in the rest of the neurological examination. An ophthalmological evaluation showed bilateral papilloedema. A cerebral MRI scan was then performed, suspecting elevated intracranial pressure (figure 1). The same examination was performed on the asymptomatic sister which also demonstrated papilloedema with similar findings on cranial MRI too.

Molecular analysis of enthesopathy in a mouse model of hypophosphatemic rickets.

The bone tendon attachment site known as the enthesis comprises a transitional zone between bone and tendon, and plays an important role in enabling movement at this site. X-linked hypophosphatemia (XLH) is characterized by impaired activation of vitamin D, elevated serum FGF23 levels and low serum phosphate levels, which impair bone mineralization. Paradoxically, an important complication of XLH is mineralization of the enthesis (enthesopathy). Studies were undertaken to identify the cellular and molecular pathways important for normal post-natal enthesis maturation and to examine their role during the development of enthesopathy in mice with XLH (Hyp). The Achilles tendon entheses of Hyp mice demonstrate an expansion of hypertrophic-appearing chondrogenic cells by P14. Post-natally, cells in wild-type and Hyp entheses similarly descend from scleraxis- and Sox9-expressing progenitors; however, Hyp entheses exhibit an expansion of Sox9-expressing cells, and enhanced BMP and IHH signaling. These results support a role for enhanced BMP and IHH signaling in the development of enthesopathy in XLH.

Hypophosphatasia in Adults: Clinical Spectrum and Its Association With Genetics and Metabolic Substrates.

BACKGROUND: Hypophosphatasia (HPP) is a rare metabolic bone disorder caused by mutations in the alkaline phosphatase (ALPL) gene, and characterized by low circulating alkaline phosphatase (ALP) levels and bone, muscle, dental and systemic manifestations. In this case series we investigate the clinical spectrum, genetic and biochemical profile of adult HPP patients from the University Hospitals Leuven, Belgium. METHODOLOGY: Adults with HPP were identified through medical record review. Inclusion criteria were: (1) age ≥ 16 yr; (2) consecutively low ALP levels not explained by secondary causes; (3) one or more of the following supporting criteria: biochemical evidence of elevated enzyme substrates; subtrochanteric fractures, metatarsal fractures or other typical clinical features; family history of HPP; a known or likely pathogenic ALPL mutation. RESULTS: Nineteen patients met our inclusion criteria (n = 2 infantile, n = 6 childhood, n = 10 adult-onset HPP and one asymptomatic carrier). Fractures and dental abnormalities were the most reported symptoms. Fatigue was reported in n = 7/19 patients (37%), three of which had previously been misdiagnosed as having chronic fatigue syndrome and/or fibromyalgia. Empirical pyridoxine therapy in four patients (without seizures) did not provide symptomatic relief. N = 7/19 patients (37%) were inappropriately treated or planned to be treated with antiresorptive treatment. Two patients developed atypical femoral fractures following exposure to bisphosphonates and/or denosumab. Patients detected by screening were less severely affected, while patients with homozygous or compound heterozygous mutations had the most severe symptoms, significantly lower circulating ALP levels (p = 0.013) and significantly higher pyridoxal-5'-phosphate (p = 0.0018) and urinary phosphoethanolamine (p = 0.0001) concentrations. CONCLUSIONS: Screening may detect mainly less severely affected individuals, which may nevertheless avoid misdiagnosis and inappropriate antiresorptive drug exposure. Patients with biallelic mutations had more severe symptoms, significantly lower ALP and higher substrate levels. Whether the latter finding has implications for the classification and treatment of HPP should be investigated further in larger cohorts.

Hypophosphatemic rickets: A rare complication of congenital melanocytic nevus syndrome.

We report the case of a child who presented with a giant melanocytic nevus with numerous satellite nevi at birth and developed hypophosphatemic rickets due to excessive secretion of the FGF23 hormone. A NRAS c.182A>G (Q61R) mutation was identified in the lesional skin. The functional outcome was favorable with medical treatment.

Nutritional hypophosphatemic rickets secondary to Neocate® use.

Elemental formula is commonly used in children with feeding intolerance. We describe two, medically complex and feeding tube dependent, patients exclusively fed with Neocate® who subsequently developed hypophosphatemic rickets. Both patients had gross motor decline and pain with physical touch. They were found to have low serum phosphorus, normal calcium, and vitamin D studies, with elevated alkaline phosphatase suggestive of nutritional hypophosphatemia. Both courses were complicated by hypocalcemia following formula change and phosphorus supplementation, highlighting the need for careful management of phosphate repletion in affected individuals. Diligent serial electrolyte monitoring as well as attention to bone health is needed in conjunction with elemental nutrition. Formula change led to restoration of calcium and phosphorus homeostasis and radiographic improvement in these patients.

Renal Fanconi Syndrome and Hypophosphatemic Rickets in the Absence of Xenotropic and Polytropic Retroviral Receptor in the Nephron.

Tight control of extracellular and intracellular inorganic phosphate (Pi) levels is critical to most biochemical and physiologic processes. Urinary Pi is freely filtered at the kidney glomerulus and is reabsorbed in the renal tubule by the action of the apical sodium-dependent phosphate transporters, NaPi-IIa/NaPi-IIc/Pit2. However, the molecular identity of the protein(s) participating in the basolateral Pi efflux remains unknown. Evidence has suggested that xenotropic and polytropic retroviral receptor 1 (XPR1) might be involved in this process. Here, we show that conditional inactivation of Xpr1 in the renal tubule in mice resulted in impaired renal Pi reabsorption. Analysis of Pi transport in primary cultures of proximal tubular cells or in freshly isolated renal tubules revealed that this Xpr1 deficiency significantly affected Pi efflux. Further, mice with conditional inactivation of Xpr1 in the renal tubule exhibited generalized proximal tubular dysfunction indicative of Fanconi syndrome, characterized by glycosuria, aminoaciduria, calciuria, and albuminuria. Dramatic alterations in the renal transcriptome, including a significant reduction in NaPi-IIa/NaPi-IIc expression, accompanied these functional changes. Additionally, Xpr1-deficient mice developed hypophosphatemic rickets secondary to renal dysfunction. These results identify XPR1 as a major regulator of Pi homeostasis and as a potential therapeutic target in bone and kidney disorders.

[Analysis of PHEX gene mutations in three pedigrees affected with hypophosphatemic rickets].

OBJECTIVE: To explore the molecular basis for three pedigrees affected with hypophosphatemia vitamin D resistant rickets (X-linked hypophosphatemia, XLH). METHODS: Peripheral blood samples from the three pedigrees were collected. Following DNA extraction, the 11 exons and flanking regions of the PHEX gene were subjected to PCR amplification and direct sequencing. Pathogenicity of identified mutations was evaluated through genotype-phenotype correlation. RESULTS: For pedigrees 1 and 2, pathogenic mutations were respectively identified in exon 8 (c.871C>T, p.R291X) and exon 15 (c.1601C>T, p.P534L) of the PHEX gene. For pedigree 3, a novel mutation (c.1234delA, p.S412Vfs*12) was found in exon 11 of the PHEX gene, which caused shift the reading frame and premature termination of protein translation. CONCLUSION: The three mutations probably account for the XLH in the affected pedigrees. The discovery of novel mutations has enriched the spectrum of PHEX gene mutations.

[Mutation analysis of four pedigrees affected with hypophosphatemic rickets through targeted next-generation sequencing].

OBJECTIVE: To detect potential mutations of PHEX gene in four pedigrees affected with hypophosphatemic rickets (HR) and provide prenatal diagnosis for a fetus at 13th gestational week. METHODS: The coding regions and exon/intron boundaries of PHEX, FGF23, DMP1, ENPP1, CLCN5 and SLC34A3 genes of the probands were analyzed by targeted next-generation sequencing (NGS). Suspected mutations were verified by Sanger sequencing among unaffected relatives and 200 unrelated healthy individuals. Deletions were confirmed by multiplex ligation-dependent probe amplification (MLPA) detection of probands, unaffected relatives and 20 unrelated healthy individuals. Prenatal diagnosis for a fetus with high risk was carried out through MLPA analysis. RESULTS: Four PHEX mutations were respectively detected in the pedigrees, which included c.850-3C>G, exon 11 deletion, exon 13 deletion and c.1753G>A (p.G585R). Among these, exon 11 deletion, exon 13 deletion and c.1753G>A (p.G585R) were novel mutations and not found among unaffected relatives and healthy controls. In pedigree 3, the same mutation was not found in the fetus. CONCLUSION: Mutations of the PHEX gene probably underlies the disease among the four pedigrees. NGS combined with Sanger sequencing and/or MLPA detection can ensure accurate diagnosis for this disease.

[Rickets/Osteomalacia. FGF23-related hypophosphatemic rickets/osteomalacia.]

FGF23 is a hormone that reduces blood phosphate level. Excessive actions of FGF23 result in several kinds of hypophosphatemic rickets/osteomalacia such as X-linked hypophosphatemic rickets and tumor-induced osteomalacia. It is not clear how excessive actions of FGF23 are induced in these diseases. The inhibition of excessive FGF23 actions is a promising new treatment for FGF23-related hypophosphatemic rickets/osteomalacia.