RARE DISEASE
Hypophosphatemic rickets
Hypophosphatemic rickets
Hypophosphatemic rickets
Drug discovery
1
drug
With orphan designation
Overview
A genetic disorder characterized by renal phosphate wasting due to impaired tubular reabsorption, leading to hypophosphatemia and defective bone mineralization. Most commonly caused by X-linked dominant mutations in PHEX, resulting in elevated fibroblast growth factor-23 (FGF-23) levels. Clinical features include skeletal deformities (bowed legs, craniosynostosis), growth impairment, dental abscesses, and osteomalacia. Diagnosis involves hypophosphatemia, elevated alkaline phosphatase, and genetic testing. First-line treatment for XLH is burosumab, an anti-FGF-23 monoclonal antibody [1][4][6][18].
Categories: rare bone diseases, rare developmental anomalies during embryogenesis, rare endocrine diseases, rare genetic diseases, rare renal diseases
Research Papers
818 drug discovery papers about Hypophosphatemic rickets, with 1 first-in-class and 4 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
818 drug discovery papers about Hypophosphatemic rickets, with 1 first-in-class and 4 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
2026-08-04 | A Diagnostic Dilemma: Hypophosphatemic Rickets Unmasking Tyrosinemia Type 1: A Case Report.
A 7.5-year-old Pakistani girl was misdiagnosed with hypophosphatemic rickets. Progressive skeletal deformities, hepatomegaly, and renal tubular dysfunction were detected despite standard treatment. Due to the atypical findings, genetic testing was performed and confirmed the diagnosis of Hereditary tyrosinemia Type 1. Her survival without liver failure remains atypical for Pakistan.
2026-08-01 | Recent advances in the diagnosis and treatment of X-linked hypophosphatemic rickets
X-linked hypophosphatemic rickets (XLH) is a skeletal mineralization disorder characterized by hypophosphatemia, caused by pathogenic variants in the PHEX gene that lead to elevated levels of fibroblast growth factor 23 (FGF23), which in turn inhibits renal phosphate reabsorption. In children, XLH primarily manifests as lower limb-predominant skeletal deformities, growth retardation, short stature, bone and joint pain, and dental abscesses.The traditional treatment regimen for XLH consists of neutral phosphate combined with calcitriol. In 2018, burosumab was approved for the treatment of patients with XLH. Burosumab targets and binds to FGF23 to inhibit its activity, increases renal phosphate reabsorption, reduces urinary phosphate excretion, promotes intestinal phosphate absorption, elevates serum phosphorus levels, and improves skeletal mineralization function. It has gradually become the first-line treatment for XLH. However, XLH is currently incurable, and existing treatment regimens struggle to maintain normal serum phosphorus levels. Even after treatment, patients generally still have a shorter final height. Additionally, due to various issues including its high cost, burosumab is rarely used in China, and clinicians have limited understanding of the advances in the diagnosis and treatment of XLH. Currently, several drugs targeting FGFR, α-Klotho, and other molecules, that aim to inhibit the effects of elevated FGF23 levels, are under development and are expected to provide new therapeutic options for XLH. This article reviews the cutting-edge advances in the diagnosis and treatment of XLH to help readers grasp the current status and future directions of this field.
2026-07-28 | Successful Transition in Rare Metabolic Bone Diseases: One-Year Outcomes of a Multidisciplinary Pediatric-Adult Program.
Background and Objectives: Pediatric-onset metabolic bone diseases, including osteogenesis imperfecta (OI), hypophosphatemic rickets (XLH), hypoparathyroidism, and McCune-Albright syndrome (MAS), require lifelong follow-up because of persistent skeletal fragility, biochemical abnormalities, and functional morbidity extending into adulthood. However, evidence regarding structured transition from pediatric to adult care in these rare disorders remains limited. This study evaluated one-year outcomes of a multidisciplinary transition program for adolescents and young adults with rare metabolic bone diseases. Materials and Methods: This retrospective cohort study included 20 patients aged ≥17 years who underwent evaluation through a structured transition pathway consisting of multidisciplinary team meetings, a joint pediatric-adult transition clinic, and subsequent follow-up in adult endocrinology. Demographic, clinical, treatment, and transition-related data were extracted from medical records. The primary outcome was successful transition, defined as at least one adult endocrinology visit within 12 months. Secondary outcomes included attendance at the transition clinic, follow-up continuity, and treatment modifications. Results: All patients underwent multidisciplinary evaluation, and 85% attended the joint transition clinic. Successful transfer to adult endocrinology was achieved in 90% (18/20), while regular follow-up during the first year was maintained in 75%. Retention was highest in patients with OI, MAS, XLH, vitamin D-dependent rickets, and DiGeorge syndrome (100%). Greater variability was observed in postoperative and primary hypoparathyroidism. Treatment adjustments were required in 40% of patients, including optimization of phosphate/calcitriol replacement and reassessment of bisphosphonate or burosumab therapy. Three patients were lost to follow-up. No acute transition-related complications were observed. Conclusions: In this small exploratory cohort, implementation of a structured multidisciplinary transition pathway was feasible and was accompanied by high transfer and one-year retention rates. Observed differences across diagnostic subgroups should be interpreted cautiously, and larger multicenter comparative studies are needed to evaluate the effectiveness of structured transition frameworks.
2026-07-22 | Autosomal dominant hypophosphatemic rickets caused by a novel pathogenic variant in FGF23.
We report a child with autosomal dominant hypophosphatemic rickets (ADHR) due to a novel pathogenic variant in fibroblast growth factor 23 (FGF23). A 1 year 10 month old girl was referred for rickets that did not respond to a single mega dose of vitamin D (600 000 IU orally). Laboratory work-up revealed: calcium, 9.8 mg/dL (2.5 mmol/L) [reference range (ref.) 8-11 mg/dL (2-2.7 mmol/L)]; phosphorus, 2.1 mg/dL (0.7 mmol/L) [ref. 2.5-4.5 mg/dL (0.8-1.5 mmol/L)]; alkaline phosphatase, 1453 IU/L (24.2 µkat/L) [ref. 142-335 U/L (2.4-5.6 µkat/L)]; 25-hydroxyvitamin D, 20.6 ng/mL (51.4 nmol/L) [ref. 30-100 ng/mL (74.8 -249.6 nmol/L)]; 1,25-dihydroxyvitamin D, 47 pg/mL (117.3 pmol/L) [ref. 31-87 pg/mL (77.4 -217.2 pmol/L)]; parathyroid hormone, 54.2 pg/mL (54.2 ng/L) [ref. 18 -80 pg/mL (18-80 ng/L)]. Tubular reabsorption of phosphate was 61.2%. Whole-exome sequencing identified a novel de novo heterozygous in-frame deletion variant, c.515_529 del (p.(Pro172_Arg176del)) in exon 3 of FGF23 confirming the diagnosis of ADHR and the variant was submitted to ClinVar. She was started on phosphate and calcitriol with clinical and biochemical improvement. She had mild iron deficiency anemia and iron supplementation (2 mg/kg/day) was initiated, allowing further reduction in phosphate supplementation.
2026-06-15 | FROM CLINICAL PRESENTATION TO GENETIC DIAGNOSIS: A CASE REPORT OF ADULT X-LINKED HYPOPHOSPHATEMIC RICKETS
The article presents a clinical case of stepwise diagnosis of a rare orphan disease, X-linked hypophosphatemic rickets (XLH), confirmed by genetic testing. X-linked dominant hypophosphatemic rickets (XLH) is a hereditary orphan disorder characterized by impaired bone mineralization due to renal phosphate wasting caused by mutations in the PHEX gene.
proteins
2026-08-13 | Regulation of Proximal Tubule Phosphate Transport: New Partners, New Pathways.
Disorders of phosphate homeostasis are common but difficult to treat. The major organ systems responsible for phosphate homeostasis are the intestine, bone, kidney, and parathyroid gland. Overall, kidney handling of phosphate is the major regulator of both serum phosphate levels and overall phosphate homeostasis. However, our ability to manipulate kidney phosphate handling has been very limited. Npt2a has been more thoroughly investigated than Npt2c, but recent studies identifying the role of Npt2c in human disease have uncovered key differences in the role of Npt2c in mice and humans. Recent studies have identified new proteins, such as TMEM174 and RGS14, that are involved in the regulation of the major sodium-dependent phosphate transporters in the kidney. Additionally, newer chemical agents to alter the function of these transporters have been developed. The purpose of this review is to highlight these new advances, place them in the context of our current knowledge of phosphate homeostasis, and explore potential new approaches to abnormalities of phosphate homeostasis. The recent discoveries suggest potential therapeutic targets for hyperphosphatemic conditions, such as chronic kidney disease and tumoral calcinosis, as well as for hypophosphatemic states, such as Fanconi syndrome, hypophosphatemic rickets, or transporter mutations.
2025-12-25 | Six cases of ENPP1 pathogenic variants causing autosomal recessive hypophosphatemic rickets type 2 and generalized arterial calcification of infancy.
Autosomal recessive hypophosphatemic rickets type 2 (ARHR2) and generalized arterial calcification of infancy (GACI) occur secondary to biallelic ectonucleotide pyrophosphate/phosphodiesterase 1 (ENPP1) loss-of-function pathogenic variants. GACI is a life-threatening condition, often presenting in the neonatal period with heart failure and hypertension, caused by calcification of the media in large- and medium-sized arteries. ARHR2 typically manifests later in life. Children with ARHR2 commonly exhibit short stature, rachitic skeletal changes, progressive deformities of the lower limbs, skeletal fragility and bone/muscle pain. We present six cases of homozygous pathogenic variants in the ENPP1 gene causing ARHR2 and/or GACI. Case 1: Presented with lower limb deformities and pain with radiological evidence of rickets. Subsequent investigations displayed aortic and pulmonary arterial calcification. Case 2: Presented with lower limb deformities and knee pain. Confirmatory testing was undertaken following her brother's (Case 1) diagnosis. Case 3: The diagnosis was made antenatally. Bisphosphonate treatment was instituted in both the pre- and post-natal periods due to the presence of extensive arterial calcifications. Rickets were noted by two years of age. Case 4: Presented with lower limb deformities and pain. There is neither any current evidence of arterial calcification nor hypertension. Case 5: Presented at 3 mo of age in cardiogenic shock with widespread calcification of large and medium-sized arteries. Bisphosphonate treatment was instituted. Case 6: Presented at 2 wk of age with right shoulder discomfort, with evidence of glenohumeral joint calcification. Further imaging revealed aortic, mediastinal, sternoclavicular joint and vertebral spinous process calcification. Case 1 and 2 were also found to have a heterozygous pathogenic ALPL variant consistent with hypophosphatasia. Clinical features, biochemistry, imaging and genetic analyses assist in the diagnosis of ARHR2 and GACI. Conventional therapy, oral phosphate and calcitriol for ARHR2 and bisphosphonates for GACI, have been utilized for many years. ENPP1 replacement treatment remains an exciting prospect for future management of ARHR2 and GACI secondary to loss of function of ENPP1.
2025-11-02 | Autosomal recessive hypophosphatemic rickets type 2 (ARHR2): Is phosphate supplementation safe?
Autosomal recessive hypophosphatemic rickets type 2 (ARHR2) is an ultra-rare disorder characterized by renal phosphate wasting and patients may exhibit an increased risk of vascular calcification. Phosphate supplementation, a standard treatment for hypophosphatemic rickets, may further increase this risk by elevating the calcium-phosphate product. To expand the phenotypic spectrum of ARHR2 and heterozygous ENPP1 variant carriers and to review safety concerns related to phosphate supplementation in affected individuals. We describe an 11-year follow-up of a pediatric patient with ARHR2, focusing on skeletal and extraskeletal manifestations, particularly the response to a brief period of phosphate supplementation. Additionally, we present a phenotypic analysis of four heterozygous family members, highlighting potential implications of carrier status. The patient was homozygous for the ENPP1 variant c.2677G > T, p.(Glu893*), exhibited progressive skeletal symptoms, and developed vascular calcifications following phosphate supplementation. Heterozygous family members showed mild alterations in bone and phosphate metabolism, suggesting a possible subclinical phenotype. This case highlights the complexity of ARHR2 management, the importance of accurate genetic diagnosis, and concerns regarding the safety of phosphate supplementation. Close cardiovascular monitoring is essential, and future therapies should aim to correct phosphate imbalance without increasing calcification risk-potentially through combined treatment strategies or enzyme replacement therapy.
2025-10-08 | Targeted Alkaline Phosphatase Therapy Enhances Alveolar Bone Healing in X-Linked Hypophosphatemia in Mice.
X-linked Hypophosphatemia (XLH), caused by PHEX mutations, hinders skeletal and dental mineralization and contributes to tooth loss. While XLH is associated with dental implant-related complications, no clinical or preclinical studies have investigated socket healing. XLH secondarily disrupts local mineral metabolism by increasing levels of the mineralization inhibitors, osteopontin (OPN) and inorganic pyrophosphate (PPi). Tissue-nonspecific alkaline phosphatase (TNAP) promotes mineralization by dephosphorylating OPN and hydrolyzing PPi. In this proof-of-principle study, we hypothesized that alveolar bone socket healing defects in the Hyp mouse model of XLH would be improved by exogenous TNAP. Maxillary first molars were extracted from wild-type (WT) and Hyp mice at 6 weeks, and collagen gel ± mineral-targeted TNAP (TNAP-Fc-D10; asfotase alfa) was placed in sockets. Submucosal injections of TNAP-Fc-D10 or saline were delivered at 7 and 14 days post-procedure (dpp) in some mice. Maxillae were collected at 21 dpp for micro-computed tomography, histology, and RT-qPCR. Untreated Hyp mice showed impaired socket healing compared to WT mice in bone volume and density. TNAP delivered at the time of extraction was unable to improve healing in Hyp mice. However, additional local TNAP delivery increased both alveolar bone volume and density in Hyp mice. Histology indicated repeated TNAP increased both woven and mature bone in Hyp mouse sockets. Immunostaining for osteopontin and bone sialoprotein suggested partial resolution of osteoid accumulation. TNAP enhanced socket healing in Hyp mice, overcoming inherent bone healing defects in XLH. These results provide new insights into bone healing with implications beyond alveolar bone in XLH.
2025-10-01 | A Case of Chronic Hypophosphatemia Leading to Identification of a Rare Mutation
Introduction: Hypophosphatemia occurs not infrequently in the inpatient setting. Inherited causes should be suspected when it is accompanied by musculoskeletal symptoms or extra-skeletal calcification. Case Description: A 47-year-old Asian man was referred for evaluation of chronic hypophosphatemia. His history included congenital bilateral conductive hearing loss, congenital hip dysplasia requiring childhood surgery and hip arthroplasty at age 39, and ossification of the posterior longitudinal ligament (OPLL) s/p numerous spinal surgeries since age 38. He had a bicuspid aortic valve with moderate calcification and severe stenosis. His brother also had chronic hypophosphatemia and OPLL requiring spinal surgery. Our patient had asymptomatic chronic mild-moderate hypophosphatemia. Further outpatient work-up revealed renal phosphate wasting (TMP/GFR 1.78 mg/dL, ref: >4.2), normal serum calcium and creatinine, elevated FGF23(129 pg/mL, ref:<59), PTH (111 pg/mL, ref: 25-105) and Alkphos (163 U/L, ref: 40-150)). Genetic testing ultimately identified a novel homozygous mutation in Ectonucleotide pyrophosphatase/phosphodiesterase 1(ENPP1) c.1437+1G>C (splice donor). Discussion: ENPP1 hydrolyzes extracellular ATP to pyrophosphate, an endogenous inhibitor of hydroxyapatite formation. It regulates soft tissue mineralization and vascular endothelial proliferation, while inhibiting extra-skeletal calcification. ENPP1 deficiency results in phenotypes ranging from generalized arterial calcification of infancy to autosomal recessive hypophosphatemic rickets type 2 (ARHR2), and OPLL. Clinically, ARHR2 resembles the more common X-linked hypophosphatemia (XLH) with FGF23-mediated renal phosphate wasting, but diagnosis is often delayed, and treatment differs significantly: Burosumab, a monoclonal antibody inhibiting FGF23 approved for XLH, can potentially exacerbate extra-skeletal calcification in ARHR2. Recombinant ENPP1-Fc enzyme replacement therapy showed promising results in mouse models of ARHR2 and vascular calcification in CKD, and is being studied in humans with ARHR2 and calciphylaxis. In summary, ARHR2 from ENPP1 deficiency causes significant multi-system morbidities, including hypophosphatemia, musculoskeletal complications like rickets and OPLL, and early-onset vascular calcification. Diagnosis requires high clinical suspicion and prompt genetic testing, and burosumab should be avoided in affected patients.
antibodies
2026-07-24 | Case Report: Deep intronic PHEX variant causing aberrant splicing identified by whole genome and targeted RNA sequencing in X-linked hypophosphatemia.
X-linked hypophosphatemia (XLH) is a rare, genetically determined disorder of phosphate metabolism, most commonly caused by mutations in the PHEX gene. These mutations lead to overexpression of the phosphaturic hormone FGF23, resulting in renal phosphate wasting and impaired bone mineralization. In up to 16% of clinically diagnosed cases, no causative variant can be identified using standard sequencing approaches. We report on a female patient with a clearly defined clinical XLH phenotype, in whom no causative mutation had been detected over several years despite extensive genetic testing. The aim was to identify a previously undetected genetic cause using extended DNA and RNA methods. After unremarkable short-read whole exome sequencing (WES), short-read whole genome sequencing (WGS) was performed. For confirmation of splice effect, RNA was extracted from peripheral blood, amplified via RT-PCR, and analyzed using Nanopore long-read sequencing. A novel deep intronic variant in the PHEX gene (c.2070 + 601C>T) was identified and confirmed as de novo. The variant caused two aberrant transcripts with pseudoexon inclusions, each leading to a premature stop codon. This aberrant splicing supports the pathogenicity of the variant in the context of a loss-of-function mechanism. Following molecular diagnosis, the patient was successfully initiated on Burosumab therapy, resulting in clinical improvement. This case highlights the diagnostic value of comprehensive genomic analysis and subsequent RNA sequencing for identifying and analyzing deep intronic variants in genetically unexplained cases of XLH. The findings expand the known PHEX mutation spectrum and emphasize the importance of re-evaluating patients with a strong clinical diagnosis but previously negative genetic results. In the future, such technologies may play a crucial role in improving diagnostics for rare monogenic diseases.
2026-06-04 | Non-nutritional rickets: Approach, precision medicine, and outcomes
Rickets are chronic bone disorders marked by impaired mineralization of the growing skeleton.While most cases arise from nutritional deficiencies, non-nutritional forms are frequently underrecognized.Subtle signs such as alopecia in vitamin D dependent rickets type 2A, cataract in Lowe syndrome, dental abscesses or sensorineural hearing loss in Xlinked hypophosphatemia can prompt timely diagnosis and referral.A structured approach combining growth and skeletal assessment, targeted biochemistry (calcium, phosphate, alkaline phosphatase, parathyroid hormone, 25-hydroxyvitamin D, 1,25dihydroxyvitamin D), radiography, and early genetic testing once nutritional deficiency or renal failure are excluded improves diagnostic accuracy.Molecular confirmation enables precise subclassification into hypophosphatemic and calciopenic rickets, supporting genotype-directed therapy, including burosumab for X-linked hypophosphatemia.Early, tailored treatment enhances radiographic healing, growth, and function.Emerging genotype-phenotype correlations further inform genetic counselling and prognosis, strengthening the multidisciplinary management of these complex disorders.
2026-05-29 | Interaction Between Local Growth Plate Mechanisms and Systemic Endocrine Signals in X-Linked Hypophosphatemia (XLH) Impaired Linear Growth
Background/Objectives: X-linked hypophosphatemia (XLH), the most frequent heritable cause of hypophosphatemic rickets, is characterized by impaired linear growth and skeletal deformities, that can lead to disproportionate short stature. Linear growth depends on the coordinated regulation of systemic endocrine signals and local growth plate regulatory mechanisms controlling chondrocyte proliferation, differentiation, and apoptosis. This review critically discusses the molecular processes underlying growth impairment in XLH, with particular emphasis on growth plate dysfunction. Methods: A narrative review of experimental and clinical studies was conducted, focusing on growth plate biology, and on pathophysiology of XLH. Particular attention was given to the interaction between systemic phosphate-regulating hormones, local paracrine factors, and intracellular signaling pathways, as well as the effects of current therapeutic strategies on linear growth. Results: Excess fibroblast growth factor 23 (FGF23) in XLH disrupts phosphate homeostasis and vitamin D metabolism, impairing skeletal mineralization and growth plate signaling. Beyond FGF23-related dysregulation, additional FGF23-independent mechanisms directly affect growth plate chondrocyte function and extracellular matrix composition, further contributing to growth plate disorganization. Current therapeutic approaches, including conventional phosphate and active vitamin D supplementation, FGF23 inhibition with human monoclonal antibody, and combination with recombinant human growth hormone, exert heterogeneous effects on linear growth through distinct biological mechanisms. Conclusions: Growth impairment in XLH reflects the combined impact of alteration of calcium-phosphate metabolism, systemic endocrine dysregulation, and intrinsic growth plate dysfunctions. A better understanding of these mechanisms may facilitate the development of targeted therapeutic strategies, improving growth outcomes in individuals with XLH.
2026-05-15 | Hypophosphatemic rickets: diagnosis and treatment.
Hypophosphatemicrickets (HR) represents a heterogeneous group of disorders characterized by renal phosphate wasting, impaired bone mineralization, and skeletal deformities. This narrative review provides an overview of phosphate homeostasis and the molecular mechanisms underlying HR, focusing on the role of Fibroblast Growth Factor 23 (FGF23) in regulating renal phosphate use and vitamin D metabolism. The clinical, biochemical, and genetic features of both FGF23-dependent and -independent forms of HR are discussed, including X-linked hypophosphatemia (XLH), autosomal dominant hypophosphatemic rickets (ADHR), autosomal recessive hypophosphatemic rickets (ARHR), tumor-induced osteomalacia (TIO), hereditary hypophosphatemic rickets with hypercalciuria (HHRH), and Fanconi syndrome. Advances in understanding these mechanisms have led to the development of targeted therapies, such as burosumab, which are redefining the clinical management of affected individuals.
2026-05-04 | Fibroblast growth factor 23 at the crossroads of mineral metabolism and bone disease.
Fibroblast growth factor 23 (FGF23) is an endocrine regulator of phosphate homeostasis produced by bone. This review aims to examine the role of FGF23 in bone biology, with a focus on its contributions to skeletal abnormalities in hereditary hypophosphatemia and chronic kidney disease (CKD). In hereditary hypophosphatemic disorders, FGF23 excess leads to renal phosphate wasting and impaired bone mineralization. Therapies targeting FGF23 demonstrated clear clinical benefits in restoring phosphate levels and improving skeletal defects. Recent evidence indicates that FGF23 may also exert direct effects on osteoblast differentiation independent of phosphate levels. In CKD, preclinical studies suggest that reducing FGF23 improves bone outcomes, but the contribution of FGF23 to altered osteoblast differentiation and bone loss in CKD remains to be tested directly. FGF23 contributes to bone disease both indirectly by regulating phosphate homeostasis and directly by inhibiting osteoblast differentiation. Targeting FGF23 represents a promising therapeutic approach, but in CKD, strategies blocking FGF23 must be carefully balanced against the risk of further disrupting phosphate balance. A better understanding of the mechanisms underlying the direct effects of FGF23 on bone is essential for the development of safe and effective treatments.
gene therapies
2025-10-31 | Treatment with Minicircle DNA Expressing a FGF23 Fragment in a Clinically relevant Mouse Model of X-Linked Hypophosphatemic Rickets.
X-linked hypophosphatemic rickets (XLHR) is a rare X-linked dominant skeletal dysplasia caused by phosphate regulating endopeptidase homolog X-linked (PHEX) gene mutation. Until now, the pathogenic role of PHEX has not been fully determined, and there has been no radical cure for XLHR. In the previous study, a novel PHEX variant (c.T1349C; p.L450P) is identified in a child with XLHR. The present study aims to reveal its pathogenic role and evaluate the therapeutic effects of the minicircle (MC)-DNA in XLHR. In vitro, the wildtype and mutant plasmids are introduced into HEK293 cells. In vivo, a new knock-in XLHR mouse model carrying the novel variant is established. Furthermore, this study makes the first attempt to perform gene therapy using a MC-DNA vector expressing a fragment of FGF23 (amino acids 180-251) in the Phex-T1349C mice. The new mouse model demonstrates the clinical manifestations of XLHR seen in the patient, including a gene dosage effect. Furthermore, MC-DNA is found to slightly increase blood phosphorus levels, significantly decrease serum alkaline phosphatase levels, and improve bone mineralization without apparent adverse effects for at least 6 weeks. This study suggests MC-DNA as a promisingly safe and effective therapeutic strategy to treat XLHR.
2025-06-22 | First case of preimplantation genetic testing of X-linked dominantly inherited hypophosphatemia family lines using next-generation sequencing technology.
A 30-year-old female was prenatally diagnosed with X-linked hypophosphatemia (XLH) due to a nonsense variant in the phosphate-regulating endopeptidase homolog X-linked (PHEX) gene. Using the coding region of the PHEX gene as the target region, multiplex polymerase chain reaction (PCR) and next-generation sequencing (NGS) were performed, and615 informative single-nucleotide polymorphism (SNP) loci were selected as genetic linkage markers within 1 Mb on both sides of the pathogenic variant. After whole-genome amplification of trophoblast cells via biopsy, Sanger sequencing, NGS-based SNP linkage analysis, and low sequencing depth copy number variation (CNV) analysis were used to directly detect the pathogenic PHEX gene variant, identify the high-risk chromosome and screen for aneuploidy, respectively. Embryos E2 and E4 are both euploid and have a wild-type PHEX status. Embryos E12, E8 and E7, which are three euploid embryos, each carry the single heterozygous pathogenic PHEX gene variant. Embryo E13 had an abnormal X chromosome, so SNP detection upstream and downstream of the gene revealed abnormalities. Embryos E4 was selected for frozen-thawed embryo transfer, and at mid-pregnancy, invasive prenatal diagnosis revealed that the fetus was not a carrier of the PHEX pathogenic gene variant or chromosomal abnormality, resulting in the full-term delivery of a healthy baby girl. This is the first report of the successful delivery of an infant with PHEX-related XLH detected by PGT-M. The successful utilization of PGT-M in the family demonstrates its potential as a strategy for assisted reproduction and genetic counselingto manage the inheritance of XLH.
2024-08-31 | X-linked hypophosphataemia.
X-linked hypophosphataemia is a genetic disease caused by defects in the phosphate regulating endopeptidase homolog X-linked (PHEX) gene and is characterised by X-linked dominant inheritance. The main consequence of PHEX deficiency is increased production of the phosphaturic hormone fibroblast growth factor 23 (FGF23) in osteoblasts and osteocytes. Chronic exposure to circulating FGF23 is responsible for renal phosphate wasting and decreased synthesis of calcitriol, which decreases intestinal phosphate absorption. These mechanisms result in lifelong hypophosphataemia, impaired growth plate and bone matrix mineralisation, and diverse manifestations in affected children and adults, including some debilitating morbidities and possibly increased mortality. Important progress has been made in disease knowledge and management over the past decade; in particular, targeting FGF23 is a therapeutic approach that has substantially improved outcomes. However, patients affected by this complex disease need lifelong care and innovative treatment strategies, such as gene repair of PHEX, are necessary to further limit the disease burden.
2023-11-09 | FGF23 directly inhibits osteoprogenitor differentiation in Dmp1-knockout mice
Fibroblast growth factor 23 (FGF23) is a phosphate (Pi)-regulating hormone produced by bone. Hereditary hypophosphatemic disorders are associated with FGF23 excess, impaired skeletal growth and osteomalacia. Blocking FGF23 became an effective therapeutic strategy in X-linked hypophosphatemia, but testing remains limited in autosomal recessive hypophosphatemic rickets (ARHR). This study investigates the effects of Pi repletion and bone specific deletion of Fgf23 on bone and mineral metabolism in the Dmp1 knockout (Dmp1KO) mouse model of ARHR.At 12 weeks, Dmp1KO mice showed increased serum FGF23 and PTH levels, hypophosphatemia, impaired growth, rickets and osteomalacia. Six weeks of dietary Pi supplementation exacerbated FGF23 production, hyperparathyroidism, renal Pi excretion and osteomalacia. In contrast, osteocyte-specific deletion of Fgf23 resulted in a partial correction of FGF23 excess, which was sufficient to fully restore serum Pi levels, but only partially corrected the bone phenotype. In vitro, we show that FGF23 directly impairs osteoprogenitors differentiation and that DMP1 deficiency contributes to impaired mineralization independently of FGF23 or Pi levels.
2021-11-29 | X-linked hypophosphatemia: The medical expert's challenges and the patient's concerns on their journey with the disease.
X-linked hypophosphatemia (XLH) is a rare inheritable disorder of phosphate handling due to loss of function mutations of the PHEX gene, associated with increased production of FGF23 and impaired bone mineralization. In children, the disease's most common manifestations are bowing deformities of the lower limbs, short stature, and spontaneous dental abscesses. In adults, these are osteomalacia, insufficiency fractures, and enthesopathies associated with bone and joint pain. The XLH patient's journey with the disease may be difficult, reflecting concerns and experiences globally common to all patients with rare genetic diseases. Delays in diagnosis often preclude an optimal treatment outcome. Under-treatment is common as treating physicians, particularly those not familiar with the disease, tend to err on the side of caution, often choosing safety over efficacy. Physical abnormalities, pain, diminished function, and impaired mobility tend not only to isolate the XLH patient from his peers but also to have a significant psychological effect, eventually leading to significant impairment in quality of life. Significant advances in understanding the pathophysiology of XLH, the availability of a very comprehensive Evidence-based Guideline for the diagnosis and management of XLH, and the successful development of an effective and safe disease-specific novel therapy for XLH, have paved the way for a significant improvement in the management of this rare disorder of phosphate metabolism, heralding a significant improvement in the disease's outcome measures. Additional data from long-term observational studies and randomized controlled trials are eagerly awaited to consolidate these promising developments in the field of this rare disease.
other
2024-04-01 | Familial cases with adult-onset FGF23-related hypophosphatemic osteomalacia -A PHEX 3'-UTR change as a possible cause.
Excessive actions of FGF23 cause several kinds of hypophosphatemic rickets/osteomalacia. It is possible that there still remain unknown causes or mechanisms for FGF23-related hypophosphatemic diseases. We report two male cousins who had been suffering form FGF23-related hypophosphatemic osteomalacia. Sequencing of exons and exon-intron junctions of known causative genes for FGF23-related hypophosphatemic diseases and whole genome sequencing were conducted. Luciferase assay was used to evaluate the effect of a detected nucleotide change on mRNA stability. Two cousins showed hypophosphatemia with impaired proximal tubular phosphate reabsorption and high FGF23. Serum phosphate of their mothers was within the reference range. Exome sequencing of the proband detected no mutations. Whole genome sequencing of the patients and their mothers identified a nucleotide change in the 3'-UTR of phosphate-regulating gene with homologies to endopeptidases on the X chromosome (PHEX) gene (c.*1280_*1287dupGTGTGTGT) which is heterozygous in the mothers and hemizygous in the patients. While sixteen is the most prevalent number of GT repeats, this family had twenty repeats. Luciferase assay indicated that mRNA with 3'-UTR of PHEX with 20 GT repeats was more unstable than that with 16 repeats. Sequencing of exons and exon-intron junctions of known causative genes for FGF23-related hypophosphatemic diseases cannot identify all the genetic causes. Our results strongly suggest that changes of PHEX expression by a nucleotide change in the 3'-UTR is a novel mechanism of FGF23-related hypophosphatemic osteomalacia.
small molecules
2026-08-04 | A Diagnostic Dilemma: Hypophosphatemic Rickets Unmasking Tyrosinemia Type 1: A Case Report.
A 7.5-year-old Pakistani girl was misdiagnosed with hypophosphatemic rickets. Progressive skeletal deformities, hepatomegaly, and renal tubular dysfunction were detected despite standard treatment. Due to the atypical findings, genetic testing was performed and confirmed the diagnosis of Hereditary tyrosinemia Type 1. Her survival without liver failure remains atypical for Pakistan.
2026-08-01 | Recent advances in the diagnosis and treatment of X-linked hypophosphatemic rickets
X-linked hypophosphatemic rickets (XLH) is a skeletal mineralization disorder characterized by hypophosphatemia, caused by pathogenic variants in the PHEX gene that lead to elevated levels of fibroblast growth factor 23 (FGF23), which in turn inhibits renal phosphate reabsorption. In children, XLH primarily manifests as lower limb-predominant skeletal deformities, growth retardation, short stature, bone and joint pain, and dental abscesses.The traditional treatment regimen for XLH consists of neutral phosphate combined with calcitriol. In 2018, burosumab was approved for the treatment of patients with XLH. Burosumab targets and binds to FGF23 to inhibit its activity, increases renal phosphate reabsorption, reduces urinary phosphate excretion, promotes intestinal phosphate absorption, elevates serum phosphorus levels, and improves skeletal mineralization function. It has gradually become the first-line treatment for XLH. However, XLH is currently incurable, and existing treatment regimens struggle to maintain normal serum phosphorus levels. Even after treatment, patients generally still have a shorter final height. Additionally, due to various issues including its high cost, burosumab is rarely used in China, and clinicians have limited understanding of the advances in the diagnosis and treatment of XLH. Currently, several drugs targeting FGFR, α-Klotho, and other molecules, that aim to inhibit the effects of elevated FGF23 levels, are under development and are expected to provide new therapeutic options for XLH. This article reviews the cutting-edge advances in the diagnosis and treatment of XLH to help readers grasp the current status and future directions of this field.
2026-07-28 | Successful Transition in Rare Metabolic Bone Diseases: One-Year Outcomes of a Multidisciplinary Pediatric-Adult Program.
Background and Objectives: Pediatric-onset metabolic bone diseases, including osteogenesis imperfecta (OI), hypophosphatemic rickets (XLH), hypoparathyroidism, and McCune-Albright syndrome (MAS), require lifelong follow-up because of persistent skeletal fragility, biochemical abnormalities, and functional morbidity extending into adulthood. However, evidence regarding structured transition from pediatric to adult care in these rare disorders remains limited. This study evaluated one-year outcomes of a multidisciplinary transition program for adolescents and young adults with rare metabolic bone diseases. Materials and Methods: This retrospective cohort study included 20 patients aged ≥17 years who underwent evaluation through a structured transition pathway consisting of multidisciplinary team meetings, a joint pediatric-adult transition clinic, and subsequent follow-up in adult endocrinology. Demographic, clinical, treatment, and transition-related data were extracted from medical records. The primary outcome was successful transition, defined as at least one adult endocrinology visit within 12 months. Secondary outcomes included attendance at the transition clinic, follow-up continuity, and treatment modifications. Results: All patients underwent multidisciplinary evaluation, and 85% attended the joint transition clinic. Successful transfer to adult endocrinology was achieved in 90% (18/20), while regular follow-up during the first year was maintained in 75%. Retention was highest in patients with OI, MAS, XLH, vitamin D-dependent rickets, and DiGeorge syndrome (100%). Greater variability was observed in postoperative and primary hypoparathyroidism. Treatment adjustments were required in 40% of patients, including optimization of phosphate/calcitriol replacement and reassessment of bisphosphonate or burosumab therapy. Three patients were lost to follow-up. No acute transition-related complications were observed. Conclusions: In this small exploratory cohort, implementation of a structured multidisciplinary transition pathway was feasible and was accompanied by high transfer and one-year retention rates. Observed differences across diagnostic subgroups should be interpreted cautiously, and larger multicenter comparative studies are needed to evaluate the effectiveness of structured transition frameworks.
2026-07-22 | Autosomal dominant hypophosphatemic rickets caused by a novel pathogenic variant in FGF23.
We report a child with autosomal dominant hypophosphatemic rickets (ADHR) due to a novel pathogenic variant in fibroblast growth factor 23 (FGF23). A 1 year 10 month old girl was referred for rickets that did not respond to a single mega dose of vitamin D (600 000 IU orally). Laboratory work-up revealed: calcium, 9.8 mg/dL (2.5 mmol/L) [reference range (ref.) 8-11 mg/dL (2-2.7 mmol/L)]; phosphorus, 2.1 mg/dL (0.7 mmol/L) [ref. 2.5-4.5 mg/dL (0.8-1.5 mmol/L)]; alkaline phosphatase, 1453 IU/L (24.2 µkat/L) [ref. 142-335 U/L (2.4-5.6 µkat/L)]; 25-hydroxyvitamin D, 20.6 ng/mL (51.4 nmol/L) [ref. 30-100 ng/mL (74.8 -249.6 nmol/L)]; 1,25-dihydroxyvitamin D, 47 pg/mL (117.3 pmol/L) [ref. 31-87 pg/mL (77.4 -217.2 pmol/L)]; parathyroid hormone, 54.2 pg/mL (54.2 ng/L) [ref. 18 -80 pg/mL (18-80 ng/L)]. Tubular reabsorption of phosphate was 61.2%. Whole-exome sequencing identified a novel de novo heterozygous in-frame deletion variant, c.515_529 del (p.(Pro172_Arg176del)) in exon 3 of FGF23 confirming the diagnosis of ADHR and the variant was submitted to ClinVar. She was started on phosphate and calcitriol with clinical and biochemical improvement. She had mild iron deficiency anemia and iron supplementation (2 mg/kg/day) was initiated, allowing further reduction in phosphate supplementation.
2026-06-15 | FROM CLINICAL PRESENTATION TO GENETIC DIAGNOSIS: A CASE REPORT OF ADULT X-LINKED HYPOPHOSPHATEMIC RICKETS
The article presents a clinical case of stepwise diagnosis of a rare orphan disease, X-linked hypophosphatemic rickets (XLH), confirmed by genetic testing. X-linked dominant hypophosphatemic rickets (XLH) is a hereditary orphan disorder characterized by impaired bone mineralization due to renal phosphate wasting caused by mutations in the PHEX gene.
proteins
2026-08-13 | Regulation of Proximal Tubule Phosphate Transport: New Partners, New Pathways.
Disorders of phosphate homeostasis are common but difficult to treat. The major organ systems responsible for phosphate homeostasis are the intestine, bone, kidney, and parathyroid gland. Overall, kidney handling of phosphate is the major regulator of both serum phosphate levels and overall phosphate homeostasis. However, our ability to manipulate kidney phosphate handling has been very limited. Npt2a has been more thoroughly investigated than Npt2c, but recent studies identifying the role of Npt2c in human disease have uncovered key differences in the role of Npt2c in mice and humans. Recent studies have identified new proteins, such as TMEM174 and RGS14, that are involved in the regulation of the major sodium-dependent phosphate transporters in the kidney. Additionally, newer chemical agents to alter the function of these transporters have been developed. The purpose of this review is to highlight these new advances, place them in the context of our current knowledge of phosphate homeostasis, and explore potential new approaches to abnormalities of phosphate homeostasis. The recent discoveries suggest potential therapeutic targets for hyperphosphatemic conditions, such as chronic kidney disease and tumoral calcinosis, as well as for hypophosphatemic states, such as Fanconi syndrome, hypophosphatemic rickets, or transporter mutations.
2025-12-25 | Six cases of ENPP1 pathogenic variants causing autosomal recessive hypophosphatemic rickets type 2 and generalized arterial calcification of infancy.
Autosomal recessive hypophosphatemic rickets type 2 (ARHR2) and generalized arterial calcification of infancy (GACI) occur secondary to biallelic ectonucleotide pyrophosphate/phosphodiesterase 1 (ENPP1) loss-of-function pathogenic variants. GACI is a life-threatening condition, often presenting in the neonatal period with heart failure and hypertension, caused by calcification of the media in large- and medium-sized arteries. ARHR2 typically manifests later in life. Children with ARHR2 commonly exhibit short stature, rachitic skeletal changes, progressive deformities of the lower limbs, skeletal fragility and bone/muscle pain. We present six cases of homozygous pathogenic variants in the ENPP1 gene causing ARHR2 and/or GACI. Case 1: Presented with lower limb deformities and pain with radiological evidence of rickets. Subsequent investigations displayed aortic and pulmonary arterial calcification. Case 2: Presented with lower limb deformities and knee pain. Confirmatory testing was undertaken following her brother's (Case 1) diagnosis. Case 3: The diagnosis was made antenatally. Bisphosphonate treatment was instituted in both the pre- and post-natal periods due to the presence of extensive arterial calcifications. Rickets were noted by two years of age. Case 4: Presented with lower limb deformities and pain. There is neither any current evidence of arterial calcification nor hypertension. Case 5: Presented at 3 mo of age in cardiogenic shock with widespread calcification of large and medium-sized arteries. Bisphosphonate treatment was instituted. Case 6: Presented at 2 wk of age with right shoulder discomfort, with evidence of glenohumeral joint calcification. Further imaging revealed aortic, mediastinal, sternoclavicular joint and vertebral spinous process calcification. Case 1 and 2 were also found to have a heterozygous pathogenic ALPL variant consistent with hypophosphatasia. Clinical features, biochemistry, imaging and genetic analyses assist in the diagnosis of ARHR2 and GACI. Conventional therapy, oral phosphate and calcitriol for ARHR2 and bisphosphonates for GACI, have been utilized for many years. ENPP1 replacement treatment remains an exciting prospect for future management of ARHR2 and GACI secondary to loss of function of ENPP1.
2025-11-02 | Autosomal recessive hypophosphatemic rickets type 2 (ARHR2): Is phosphate supplementation safe?
Autosomal recessive hypophosphatemic rickets type 2 (ARHR2) is an ultra-rare disorder characterized by renal phosphate wasting and patients may exhibit an increased risk of vascular calcification. Phosphate supplementation, a standard treatment for hypophosphatemic rickets, may further increase this risk by elevating the calcium-phosphate product. To expand the phenotypic spectrum of ARHR2 and heterozygous ENPP1 variant carriers and to review safety concerns related to phosphate supplementation in affected individuals. We describe an 11-year follow-up of a pediatric patient with ARHR2, focusing on skeletal and extraskeletal manifestations, particularly the response to a brief period of phosphate supplementation. Additionally, we present a phenotypic analysis of four heterozygous family members, highlighting potential implications of carrier status. The patient was homozygous for the ENPP1 variant c.2677G > T, p.(Glu893*), exhibited progressive skeletal symptoms, and developed vascular calcifications following phosphate supplementation. Heterozygous family members showed mild alterations in bone and phosphate metabolism, suggesting a possible subclinical phenotype. This case highlights the complexity of ARHR2 management, the importance of accurate genetic diagnosis, and concerns regarding the safety of phosphate supplementation. Close cardiovascular monitoring is essential, and future therapies should aim to correct phosphate imbalance without increasing calcification risk-potentially through combined treatment strategies or enzyme replacement therapy.
2025-10-08 | Targeted Alkaline Phosphatase Therapy Enhances Alveolar Bone Healing in X-Linked Hypophosphatemia in Mice.
X-linked Hypophosphatemia (XLH), caused by PHEX mutations, hinders skeletal and dental mineralization and contributes to tooth loss. While XLH is associated with dental implant-related complications, no clinical or preclinical studies have investigated socket healing. XLH secondarily disrupts local mineral metabolism by increasing levels of the mineralization inhibitors, osteopontin (OPN) and inorganic pyrophosphate (PPi). Tissue-nonspecific alkaline phosphatase (TNAP) promotes mineralization by dephosphorylating OPN and hydrolyzing PPi. In this proof-of-principle study, we hypothesized that alveolar bone socket healing defects in the Hyp mouse model of XLH would be improved by exogenous TNAP. Maxillary first molars were extracted from wild-type (WT) and Hyp mice at 6 weeks, and collagen gel ± mineral-targeted TNAP (TNAP-Fc-D10; asfotase alfa) was placed in sockets. Submucosal injections of TNAP-Fc-D10 or saline were delivered at 7 and 14 days post-procedure (dpp) in some mice. Maxillae were collected at 21 dpp for micro-computed tomography, histology, and RT-qPCR. Untreated Hyp mice showed impaired socket healing compared to WT mice in bone volume and density. TNAP delivered at the time of extraction was unable to improve healing in Hyp mice. However, additional local TNAP delivery increased both alveolar bone volume and density in Hyp mice. Histology indicated repeated TNAP increased both woven and mature bone in Hyp mouse sockets. Immunostaining for osteopontin and bone sialoprotein suggested partial resolution of osteoid accumulation. TNAP enhanced socket healing in Hyp mice, overcoming inherent bone healing defects in XLH. These results provide new insights into bone healing with implications beyond alveolar bone in XLH.
2025-10-01 | A Case of Chronic Hypophosphatemia Leading to Identification of a Rare Mutation
Introduction: Hypophosphatemia occurs not infrequently in the inpatient setting. Inherited causes should be suspected when it is accompanied by musculoskeletal symptoms or extra-skeletal calcification. Case Description: A 47-year-old Asian man was referred for evaluation of chronic hypophosphatemia. His history included congenital bilateral conductive hearing loss, congenital hip dysplasia requiring childhood surgery and hip arthroplasty at age 39, and ossification of the posterior longitudinal ligament (OPLL) s/p numerous spinal surgeries since age 38. He had a bicuspid aortic valve with moderate calcification and severe stenosis. His brother also had chronic hypophosphatemia and OPLL requiring spinal surgery. Our patient had asymptomatic chronic mild-moderate hypophosphatemia. Further outpatient work-up revealed renal phosphate wasting (TMP/GFR 1.78 mg/dL, ref: >4.2), normal serum calcium and creatinine, elevated FGF23(129 pg/mL, ref:<59), PTH (111 pg/mL, ref: 25-105) and Alkphos (163 U/L, ref: 40-150)). Genetic testing ultimately identified a novel homozygous mutation in Ectonucleotide pyrophosphatase/phosphodiesterase 1(ENPP1) c.1437+1G>C (splice donor). Discussion: ENPP1 hydrolyzes extracellular ATP to pyrophosphate, an endogenous inhibitor of hydroxyapatite formation. It regulates soft tissue mineralization and vascular endothelial proliferation, while inhibiting extra-skeletal calcification. ENPP1 deficiency results in phenotypes ranging from generalized arterial calcification of infancy to autosomal recessive hypophosphatemic rickets type 2 (ARHR2), and OPLL. Clinically, ARHR2 resembles the more common X-linked hypophosphatemia (XLH) with FGF23-mediated renal phosphate wasting, but diagnosis is often delayed, and treatment differs significantly: Burosumab, a monoclonal antibody inhibiting FGF23 approved for XLH, can potentially exacerbate extra-skeletal calcification in ARHR2. Recombinant ENPP1-Fc enzyme replacement therapy showed promising results in mouse models of ARHR2 and vascular calcification in CKD, and is being studied in humans with ARHR2 and calciphylaxis. In summary, ARHR2 from ENPP1 deficiency causes significant multi-system morbidities, including hypophosphatemia, musculoskeletal complications like rickets and OPLL, and early-onset vascular calcification. Diagnosis requires high clinical suspicion and prompt genetic testing, and burosumab should be avoided in affected patients.
antibodies
2026-07-24 | Case Report: Deep intronic PHEX variant causing aberrant splicing identified by whole genome and targeted RNA sequencing in X-linked hypophosphatemia.
X-linked hypophosphatemia (XLH) is a rare, genetically determined disorder of phosphate metabolism, most commonly caused by mutations in the PHEX gene. These mutations lead to overexpression of the phosphaturic hormone FGF23, resulting in renal phosphate wasting and impaired bone mineralization. In up to 16% of clinically diagnosed cases, no causative variant can be identified using standard sequencing approaches. We report on a female patient with a clearly defined clinical XLH phenotype, in whom no causative mutation had been detected over several years despite extensive genetic testing. The aim was to identify a previously undetected genetic cause using extended DNA and RNA methods. After unremarkable short-read whole exome sequencing (WES), short-read whole genome sequencing (WGS) was performed. For confirmation of splice effect, RNA was extracted from peripheral blood, amplified via RT-PCR, and analyzed using Nanopore long-read sequencing. A novel deep intronic variant in the PHEX gene (c.2070 + 601C>T) was identified and confirmed as de novo. The variant caused two aberrant transcripts with pseudoexon inclusions, each leading to a premature stop codon. This aberrant splicing supports the pathogenicity of the variant in the context of a loss-of-function mechanism. Following molecular diagnosis, the patient was successfully initiated on Burosumab therapy, resulting in clinical improvement. This case highlights the diagnostic value of comprehensive genomic analysis and subsequent RNA sequencing for identifying and analyzing deep intronic variants in genetically unexplained cases of XLH. The findings expand the known PHEX mutation spectrum and emphasize the importance of re-evaluating patients with a strong clinical diagnosis but previously negative genetic results. In the future, such technologies may play a crucial role in improving diagnostics for rare monogenic diseases.
2026-06-04 | Non-nutritional rickets: Approach, precision medicine, and outcomes
Rickets are chronic bone disorders marked by impaired mineralization of the growing skeleton.While most cases arise from nutritional deficiencies, non-nutritional forms are frequently underrecognized.Subtle signs such as alopecia in vitamin D dependent rickets type 2A, cataract in Lowe syndrome, dental abscesses or sensorineural hearing loss in Xlinked hypophosphatemia can prompt timely diagnosis and referral.A structured approach combining growth and skeletal assessment, targeted biochemistry (calcium, phosphate, alkaline phosphatase, parathyroid hormone, 25-hydroxyvitamin D, 1,25dihydroxyvitamin D), radiography, and early genetic testing once nutritional deficiency or renal failure are excluded improves diagnostic accuracy.Molecular confirmation enables precise subclassification into hypophosphatemic and calciopenic rickets, supporting genotype-directed therapy, including burosumab for X-linked hypophosphatemia.Early, tailored treatment enhances radiographic healing, growth, and function.Emerging genotype-phenotype correlations further inform genetic counselling and prognosis, strengthening the multidisciplinary management of these complex disorders.
2026-05-29 | Interaction Between Local Growth Plate Mechanisms and Systemic Endocrine Signals in X-Linked Hypophosphatemia (XLH) Impaired Linear Growth
Background/Objectives: X-linked hypophosphatemia (XLH), the most frequent heritable cause of hypophosphatemic rickets, is characterized by impaired linear growth and skeletal deformities, that can lead to disproportionate short stature. Linear growth depends on the coordinated regulation of systemic endocrine signals and local growth plate regulatory mechanisms controlling chondrocyte proliferation, differentiation, and apoptosis. This review critically discusses the molecular processes underlying growth impairment in XLH, with particular emphasis on growth plate dysfunction. Methods: A narrative review of experimental and clinical studies was conducted, focusing on growth plate biology, and on pathophysiology of XLH. Particular attention was given to the interaction between systemic phosphate-regulating hormones, local paracrine factors, and intracellular signaling pathways, as well as the effects of current therapeutic strategies on linear growth. Results: Excess fibroblast growth factor 23 (FGF23) in XLH disrupts phosphate homeostasis and vitamin D metabolism, impairing skeletal mineralization and growth plate signaling. Beyond FGF23-related dysregulation, additional FGF23-independent mechanisms directly affect growth plate chondrocyte function and extracellular matrix composition, further contributing to growth plate disorganization. Current therapeutic approaches, including conventional phosphate and active vitamin D supplementation, FGF23 inhibition with human monoclonal antibody, and combination with recombinant human growth hormone, exert heterogeneous effects on linear growth through distinct biological mechanisms. Conclusions: Growth impairment in XLH reflects the combined impact of alteration of calcium-phosphate metabolism, systemic endocrine dysregulation, and intrinsic growth plate dysfunctions. A better understanding of these mechanisms may facilitate the development of targeted therapeutic strategies, improving growth outcomes in individuals with XLH.
2026-05-15 | Hypophosphatemic rickets: diagnosis and treatment.
Hypophosphatemicrickets (HR) represents a heterogeneous group of disorders characterized by renal phosphate wasting, impaired bone mineralization, and skeletal deformities. This narrative review provides an overview of phosphate homeostasis and the molecular mechanisms underlying HR, focusing on the role of Fibroblast Growth Factor 23 (FGF23) in regulating renal phosphate use and vitamin D metabolism. The clinical, biochemical, and genetic features of both FGF23-dependent and -independent forms of HR are discussed, including X-linked hypophosphatemia (XLH), autosomal dominant hypophosphatemic rickets (ADHR), autosomal recessive hypophosphatemic rickets (ARHR), tumor-induced osteomalacia (TIO), hereditary hypophosphatemic rickets with hypercalciuria (HHRH), and Fanconi syndrome. Advances in understanding these mechanisms have led to the development of targeted therapies, such as burosumab, which are redefining the clinical management of affected individuals.
2026-05-04 | Fibroblast growth factor 23 at the crossroads of mineral metabolism and bone disease.
Fibroblast growth factor 23 (FGF23) is an endocrine regulator of phosphate homeostasis produced by bone. This review aims to examine the role of FGF23 in bone biology, with a focus on its contributions to skeletal abnormalities in hereditary hypophosphatemia and chronic kidney disease (CKD). In hereditary hypophosphatemic disorders, FGF23 excess leads to renal phosphate wasting and impaired bone mineralization. Therapies targeting FGF23 demonstrated clear clinical benefits in restoring phosphate levels and improving skeletal defects. Recent evidence indicates that FGF23 may also exert direct effects on osteoblast differentiation independent of phosphate levels. In CKD, preclinical studies suggest that reducing FGF23 improves bone outcomes, but the contribution of FGF23 to altered osteoblast differentiation and bone loss in CKD remains to be tested directly. FGF23 contributes to bone disease both indirectly by regulating phosphate homeostasis and directly by inhibiting osteoblast differentiation. Targeting FGF23 represents a promising therapeutic approach, but in CKD, strategies blocking FGF23 must be carefully balanced against the risk of further disrupting phosphate balance. A better understanding of the mechanisms underlying the direct effects of FGF23 on bone is essential for the development of safe and effective treatments.
gene therapies
2025-10-31 | Treatment with Minicircle DNA Expressing a FGF23 Fragment in a Clinically relevant Mouse Model of X-Linked Hypophosphatemic Rickets.
X-linked hypophosphatemic rickets (XLHR) is a rare X-linked dominant skeletal dysplasia caused by phosphate regulating endopeptidase homolog X-linked (PHEX) gene mutation. Until now, the pathogenic role of PHEX has not been fully determined, and there has been no radical cure for XLHR. In the previous study, a novel PHEX variant (c.T1349C; p.L450P) is identified in a child with XLHR. The present study aims to reveal its pathogenic role and evaluate the therapeutic effects of the minicircle (MC)-DNA in XLHR. In vitro, the wildtype and mutant plasmids are introduced into HEK293 cells. In vivo, a new knock-in XLHR mouse model carrying the novel variant is established. Furthermore, this study makes the first attempt to perform gene therapy using a MC-DNA vector expressing a fragment of FGF23 (amino acids 180-251) in the Phex-T1349C mice. The new mouse model demonstrates the clinical manifestations of XLHR seen in the patient, including a gene dosage effect. Furthermore, MC-DNA is found to slightly increase blood phosphorus levels, significantly decrease serum alkaline phosphatase levels, and improve bone mineralization without apparent adverse effects for at least 6 weeks. This study suggests MC-DNA as a promisingly safe and effective therapeutic strategy to treat XLHR.
2025-06-22 | First case of preimplantation genetic testing of X-linked dominantly inherited hypophosphatemia family lines using next-generation sequencing technology.
A 30-year-old female was prenatally diagnosed with X-linked hypophosphatemia (XLH) due to a nonsense variant in the phosphate-regulating endopeptidase homolog X-linked (PHEX) gene. Using the coding region of the PHEX gene as the target region, multiplex polymerase chain reaction (PCR) and next-generation sequencing (NGS) were performed, and615 informative single-nucleotide polymorphism (SNP) loci were selected as genetic linkage markers within 1 Mb on both sides of the pathogenic variant. After whole-genome amplification of trophoblast cells via biopsy, Sanger sequencing, NGS-based SNP linkage analysis, and low sequencing depth copy number variation (CNV) analysis were used to directly detect the pathogenic PHEX gene variant, identify the high-risk chromosome and screen for aneuploidy, respectively. Embryos E2 and E4 are both euploid and have a wild-type PHEX status. Embryos E12, E8 and E7, which are three euploid embryos, each carry the single heterozygous pathogenic PHEX gene variant. Embryo E13 had an abnormal X chromosome, so SNP detection upstream and downstream of the gene revealed abnormalities. Embryos E4 was selected for frozen-thawed embryo transfer, and at mid-pregnancy, invasive prenatal diagnosis revealed that the fetus was not a carrier of the PHEX pathogenic gene variant or chromosomal abnormality, resulting in the full-term delivery of a healthy baby girl. This is the first report of the successful delivery of an infant with PHEX-related XLH detected by PGT-M. The successful utilization of PGT-M in the family demonstrates its potential as a strategy for assisted reproduction and genetic counselingto manage the inheritance of XLH.
2024-08-31 | X-linked hypophosphataemia.
X-linked hypophosphataemia is a genetic disease caused by defects in the phosphate regulating endopeptidase homolog X-linked (PHEX) gene and is characterised by X-linked dominant inheritance. The main consequence of PHEX deficiency is increased production of the phosphaturic hormone fibroblast growth factor 23 (FGF23) in osteoblasts and osteocytes. Chronic exposure to circulating FGF23 is responsible for renal phosphate wasting and decreased synthesis of calcitriol, which decreases intestinal phosphate absorption. These mechanisms result in lifelong hypophosphataemia, impaired growth plate and bone matrix mineralisation, and diverse manifestations in affected children and adults, including some debilitating morbidities and possibly increased mortality. Important progress has been made in disease knowledge and management over the past decade; in particular, targeting FGF23 is a therapeutic approach that has substantially improved outcomes. However, patients affected by this complex disease need lifelong care and innovative treatment strategies, such as gene repair of PHEX, are necessary to further limit the disease burden.
2023-11-09 | FGF23 directly inhibits osteoprogenitor differentiation in Dmp1-knockout mice
Fibroblast growth factor 23 (FGF23) is a phosphate (Pi)-regulating hormone produced by bone. Hereditary hypophosphatemic disorders are associated with FGF23 excess, impaired skeletal growth and osteomalacia. Blocking FGF23 became an effective therapeutic strategy in X-linked hypophosphatemia, but testing remains limited in autosomal recessive hypophosphatemic rickets (ARHR). This study investigates the effects of Pi repletion and bone specific deletion of Fgf23 on bone and mineral metabolism in the Dmp1 knockout (Dmp1KO) mouse model of ARHR.At 12 weeks, Dmp1KO mice showed increased serum FGF23 and PTH levels, hypophosphatemia, impaired growth, rickets and osteomalacia. Six weeks of dietary Pi supplementation exacerbated FGF23 production, hyperparathyroidism, renal Pi excretion and osteomalacia. In contrast, osteocyte-specific deletion of Fgf23 resulted in a partial correction of FGF23 excess, which was sufficient to fully restore serum Pi levels, but only partially corrected the bone phenotype. In vitro, we show that FGF23 directly impairs osteoprogenitors differentiation and that DMP1 deficiency contributes to impaired mineralization independently of FGF23 or Pi levels.
2021-11-29 | X-linked hypophosphatemia: The medical expert's challenges and the patient's concerns on their journey with the disease.
X-linked hypophosphatemia (XLH) is a rare inheritable disorder of phosphate handling due to loss of function mutations of the PHEX gene, associated with increased production of FGF23 and impaired bone mineralization. In children, the disease's most common manifestations are bowing deformities of the lower limbs, short stature, and spontaneous dental abscesses. In adults, these are osteomalacia, insufficiency fractures, and enthesopathies associated with bone and joint pain. The XLH patient's journey with the disease may be difficult, reflecting concerns and experiences globally common to all patients with rare genetic diseases. Delays in diagnosis often preclude an optimal treatment outcome. Under-treatment is common as treating physicians, particularly those not familiar with the disease, tend to err on the side of caution, often choosing safety over efficacy. Physical abnormalities, pain, diminished function, and impaired mobility tend not only to isolate the XLH patient from his peers but also to have a significant psychological effect, eventually leading to significant impairment in quality of life. Significant advances in understanding the pathophysiology of XLH, the availability of a very comprehensive Evidence-based Guideline for the diagnosis and management of XLH, and the successful development of an effective and safe disease-specific novel therapy for XLH, have paved the way for a significant improvement in the management of this rare disorder of phosphate metabolism, heralding a significant improvement in the disease's outcome measures. Additional data from long-term observational studies and randomized controlled trials are eagerly awaited to consolidate these promising developments in the field of this rare disease.
other
2024-04-01 | Familial cases with adult-onset FGF23-related hypophosphatemic osteomalacia -A PHEX 3'-UTR change as a possible cause.
Excessive actions of FGF23 cause several kinds of hypophosphatemic rickets/osteomalacia. It is possible that there still remain unknown causes or mechanisms for FGF23-related hypophosphatemic diseases. We report two male cousins who had been suffering form FGF23-related hypophosphatemic osteomalacia. Sequencing of exons and exon-intron junctions of known causative genes for FGF23-related hypophosphatemic diseases and whole genome sequencing were conducted. Luciferase assay was used to evaluate the effect of a detected nucleotide change on mRNA stability. Two cousins showed hypophosphatemia with impaired proximal tubular phosphate reabsorption and high FGF23. Serum phosphate of their mothers was within the reference range. Exome sequencing of the proband detected no mutations. Whole genome sequencing of the patients and their mothers identified a nucleotide change in the 3'-UTR of phosphate-regulating gene with homologies to endopeptidases on the X chromosome (PHEX) gene (c.*1280_*1287dupGTGTGTGT) which is heterozygous in the mothers and hemizygous in the patients. While sixteen is the most prevalent number of GT repeats, this family had twenty repeats. Luciferase assay indicated that mRNA with 3'-UTR of PHEX with 20 GT repeats was more unstable than that with 16 repeats. Sequencing of exons and exon-intron junctions of known causative genes for FGF23-related hypophosphatemic diseases cannot identify all the genetic causes. Our results strongly suggest that changes of PHEX expression by a nucleotide change in the 3'-UTR is a novel mechanism of FGF23-related hypophosphatemic osteomalacia.
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Drug Discovery Landscape
1 orphan drug designation for Hypophosphatemic rickets.
1 orphan drug designation for Hypophosphatemic rickets.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
Secalciferol | small molecules | FDA | 1993-07-26 | — | Teva Pharmaceuticals USA |
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