RARE DISEASE
X-linked hypophosphatemia
X-linked hypophosphatemia
X-linked hypophosphatemia
Synonyms: X-linked hypophosphatemic rickets, XLH
Synonyms: X-linked hypophosphatemic rickets, XLH
Synonyms: X-linked hypophosphatemic rickets, XLH
Drug discovery
4
drugs
With orphan designations
Overview
X-linked hypophosphatemia (XLH) is a rare genetic disorder caused by PHEX gene mutations, leading to excessive fibroblast growth factor 23 (FGF23) secretion, renal phosphate wasting, and hypophosphatemia. It manifests as rickets in children and osteomalacia in adults, with skeletal deformities, dental abscesses, enthesopathy, and chronic pain. Treatment includes phosphate/calcitriol supplementation and FGF23-targeted therapy (burosumab) to address metabolic defects and complications [1][5][11].
Therapies
Conventional: Oral phosphate + active vitamin D (calcitriol/alfacalcidol) to mitigate skeletal complications [1][8].
Targeted: Burosumab (anti-FGF23 monoclonal antibody) improves phosphate retention and reduces disease burden in patients ≥6 months old [3][5][11].
Adjunctive: Orthopedic surgery, dental interventions, and physical therapy for symptom management [1][7][14].
Categories: rare bone diseases, rare developmental anomalies during embryogenesis, rare endocrine diseases, rare genetic diseases, rare renal diseases
Research Papers
616 drug discovery papers about X-linked hypophosphatemia, with 3 first-in-class and 5 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
616 drug discovery papers about X-linked hypophosphatemia, with 3 first-in-class and 5 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
categories:
Small molecules
small molecules
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.
2026-07-03 | X-Linked Hypophosphatemia: A Review of Pathophysiology, Clinical Manifestations, Current Management, and Emerging Therapeutic Strategies
X-linked hypophosphatemia (XLH) is one of the most common inherited phosphate-wasting disorders, caused by pathogenic variants in the PHEX gene that result in excess fibroblast growth factor 23 (FGF23) and chronic hypophosphatemia. Historically considered a pediatric disease characterized by rickets and growth impairment, XLH is now recognized as a lifelong condition with substantial adult morbidity including osteomalacia, fractures, enthesopathy, osteoarthritis, and reduced quality of life. The discovery of FGF23 as the central mediator of phosphate wasting transformed understanding of disease pathophysiology and enabled development of burosumab, a monoclonal antibody that neutralizes FGF23 and restores phosphate homeostasis. While burosumab represents a paradigm shift in therapy, accumulating evidence indicates that XLH involves FGF23-independent mechanisms, including osteopontin accumulation, ASARM peptide generation, and pyrophosphate dysregulation, which contribute to persistent skeletal abnormalities despite biochemical correction. This review integrates current insights into the molecular genetics, pathophysiology, and lifelong clinical features of XLH, with particular attention to emerging concepts involving local bone matrix abnormalities and their impact on therapeutic innovation. We trace the transition from conventional phosphate and active vitamin D supplementation to targeted FGF23 inhibition, highlight the limitations of existing treatment strategies, and explore future directions such as small‑molecule inhibitors, anti‑sclerostin therapy, gene-based approaches, and ultimately PHEX‑focused repair. A comprehensive understanding of XLH as both a systemic endocrine disorder and an intrinsic defect of osteocyte biology is critical for optimizing patient care and steering the development of curative therapies.
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.
2026-04-01 | Sclerotic enthesopathy in X-linked hypophosphatemia: An atypical radiological mimic of sclerosing bone disorders
ABSTRACT A 26-year-old woman presented with progressive bilateral hip and leg pain and worsening gait difficulty over 5 years. She had lower-limb bowing since childhood, without a family history of skeletal deformities. Examination revealed genu varum and poor dentition. Biochemical evaluation showed hypophosphatemia (1.92 mg/dL), normal corrected calcium (9.7 mg/dL), elevated alkaline phosphatase (212 IU/L), vitamin D insufficiency (25-hydroxyvitamin D: 22 ng/mL), and normal parathyroid hormone (48 pg/mL). Vitamin D deficiency was corrected before assessment of tubular phosphate handling. Tubular maximum for phosphate reabsorption per glomerular filtration rate was reduced (0.6 mmol/L), confirming renal phosphate wasting. Serum intact fibroblast growth Factor (FGF) 23 was inappropriately elevated (108 pg/mL; reference range: 23.2–95.4 pg/mL; electrochemiluminescence immunoassay), supporting an FGF23-mediated process. Radiographs demonstrated interosseous membrane calcification, femoral pseudofracture, diffuse skeletal sclerosis, and enthesopathic changes of the femur and pelvis. There was no history of excess fluoride exposure, renal function was normal, and imaging showed no evidence of malignancy, excluding fluorosis, chronic kidney disease, and tumor-induced osteomalacia. Although genetic confirmation was not available, the clinical, biochemical, and radiological features strongly supported X-linked hypophosphatemia (XLH). Treatment with phosphate and calcitriol improved symptoms. This case highlights an atypical sclerotic phenotype of XLH mimicking sclerosing bone disorders.
2026-03-04 | Impact of oral phosphate supplements and active vitamin D treatment on dentoalveolar features of X-linked hypophosphatemia.
X-linked hypophosphatemia (XLH), the most common form of genetic rickets (1/20000 births), results in the disruption of skeletal and dental mineralization. Oral features include dentinomalacia, spontaneous dental abscesses, and a high susceptibility to periodontitis. The association of phosphate supplementation and active vitamin D analogs (PO4/VitD) aims to counteract the consequences of FGF23 excess and the impaired production of active vitamin D. Despite a significant improvement in the long bone phenotype, the impact on dentoalveolar tissues remains poorly documented. Here, we aimed to determine whether the PO4/VitD treatment improves dental features in the Hyp mouse model of XLH and in XLH patients. Hyp mice were treated with oral phosphate supplementation and calcitriol injections from 3 wk to 3 mo and were compared with untreated Hyp and WT mice. Histological analyses were also performed on teeth from patients with XLH treated with PO4/VitD and on control teeth. Micro-CT analyses showed that the PO4/VitD treatment did not significantly correct dentin/cementum volume and density, pulp chamber enlargement, and alveolar bone parameters in Hyp mice. Histological analyses also revealed that dentinomalacia and periodontal attachment were not rescued by the treatment. Remarkably, permanent teeth from XLH patients treated with PO4/VitD during childhood displayed a significant reduction in predentin thickness and a thinner layer of globular dentin. Taken together, our data show that the PO4/VitD treatment does not significantly improve dentoalveolar features in Hyp mice treated at the prepubertal stage. However, the impact observed on dentin in human teeth supports the interest of this treatment regarding the occurrence of spontaneous dental abscesses.
proteins
2026-07-07 | When X Does Not Mark the Spot: Autosomal Dominant and Recessive Forms of Renal Hypophosphatemic Rickets and Osteomalacia.
Conditions resulting in elevated fibroblast growth factor 23 (FGF23) cause hypophosphatemic rickets and osteomalacia. The most common of these is X-linked hypophosphatemia. In this review we will broadly discuss the other less common and clinically distinct forms of renal hypophosphatemia, with a focus on the autosomal dominant and autosomal recessive types. Variants in multiple genes cause dominant (FGF23, SGK3, FGFR1), recessive (DMP1, ENPP1, FAM20C, INPPL1) or even somatic (NRAS, HRAS, GNAS, gene fusions) conditions of FGF23 excess, with important phenotypic differences. For example, in autosomal dominant hypophosphatemic rickets due to FGF23 variants, iron deficiency drives the phenotype, while ENPP1 variants cause phenotypes ranging from severe neonatal vascular calcifications to rickets or osteoporosis. Other gene abnormalities cause FGF23-independent hypophosphatemia, often involving kidney disease. Recognizing the different mechanisms and phenotypes of hypophosphatemic conditions is critical to prognosis, management and to developing more effective therapies.
2026-06-26 | X-linked Hypophosphatemic Rickets Revealed by Exome Sequencing: A Pediatric Case Report of a PHEX Pathogenic Variant.
X-linked hypophosphatemic rickets (XLH) is the most common form of hereditary vitamin-resistant rickets, caused by inactivating mutations of the PHEX (phosphate-regulating endopeptidase homolog, X-linked) gene, leading to elevated fibroblast growth factor 23 (FGF23) and chronic hypophosphatemia secondary to renal phosphate wasting. We report the case of a 3.5-year-old boy presenting with bilateral varus deformity of the lower limbs, frontal bossing, rachitic rosary, and growth retardation (-2.5 SD). Laboratory investigations revealed hypophosphatemia (0.88 mmol/L) with severely reduced urinary phosphate excretion (196.8 mg/24 h), elevated alkaline phosphatase (521 IU/L), and normal serum calcium and vitamin D levels. Exome sequencing identified a hemizygous pathogenic variant in PHEX: c.2192T>G (p.Phe731Cys), confirming the diagnosis of XLH. This case illustrates the decisive contribution of exome sequencing in confirming vitamin-resistant rickets and the importance of early diagnosis to prevent irreversible orthopedic sequelae.
2025-12-31 | Biochemical evaluation of X-linked hypophosphatemia and tumor-induced osteomalacia: insights into diagnosis and management.
X-linked hypophosphatemia (XLH) and tumor-induced osteomalacia (TIO) are characterized by alterations in phosphate metabolism due to elevated levels of fibroblast growth factor 23 (FGF23). These conditions cause significant morbidity due to chronic hypophosphatemia and resulting musculoskeletal disorders. This study aims to provide clinical strategies for supporting the diagnosis and management of the biochemical profile of patients with XLH and TIO, addressing key considerations beyond the hypophosphatemia and hyperphosphaturia commonly observed in these conditions and addressing the variability and limitations of current biochemical marker detection methods. A literature search focused on studies published in the last ten years. A multidisciplinary team analyzed the data to integrate the findings into clinical best practices. The proposed approach emphasizes correctly performing and interpreting tests for serum phosphate, phosphaturia, FGF23, alkaline phosphatase (ALP), parathyroid hormone (PTH), vitamin D, serum calcium, and the calcium-corrected excretion rate. More standardization in screening methods is needed, which affects diagnostic accuracy and management. The recommendations include detailed protocols for patient preparation, sample collection, and interpretation of results. The recommendations for performing biochemical screening for XLH and TIO promote better clinical practices in patient diagnosis and management. Future research should focus on validating diagnostic methods in diverse populations and standardizing biochemical tests. Multidisciplinary approach to the diagnosis of these patients through the close collaboration of professionals of laboratory medicine and clinical specialties would be pivotal.
2025-11-12 | Proof-of-principle for enhanced dentoalveolar mineralization using exogenous tissue-nonspecific alkaline phosphatase in the Hyp mouse model of X-linked hypophosphatemia.
X-linked hypophosphatemia (XLH) is caused by mutations in the PHEX gene, which leads to increased levels of fibroblast growth factor 23 and hypophosphatemia, contributing to rickets, osteomalacia, and dentoalveolar defects, including severe dentin hypomineralization, thin cementum, and alveolar bone osteomalacia. Current XLH treatment options appear to have limited efficacy on dentoalveolar tissues, suggesting underlying disease mechanisms that remain unchecked. Increased production of inorganic pyrophosphate (PPi) and osteopontin (OPN), both mineralization inhibitors, has been posited to contribute to mineralization defects in XLH. The enzyme, tissue-nonspecific alkaline phosphatase (TNAP) reduces PPi levels via hydrolysis and inactivates OPN by dephosphorylation. Our previous study showed improved alveolar bone socket healing in Hyp mice administered mineralized tissue-targeted TNAP (TNAP-Fc-D10). We hypothesized that increased TNAP would partially ameliorate developmental mineralization defects in XLH by dually reducing PPi levels and dephosphorylating and inactivating OPN. In a proof-of-principle study to investigate pathological mechanisms, we delivered systemic (subcutaneous injection) and local (submucosal injection to mandibles) TNAP-Fc-D10 injections to the Hyp mutant mouse model of XLH from 7 to 60 d postnatal (dpn). While systemic delivery was ineffective at improving dentin or bone properties, micro-CT and histology analyses demonstrated that local delivery of TNAP-Fc-D10 increased dentin thickness, root length, alveolar bone volume, alveolar bone proper (ABP) volume and density, PDL attachment, and acellular cementum thickness, compared to control Hyp mice receiving a sham injection. Dynamic mechanical testing confirmed partially improved mechanical properties in locally treated vs untreated Hyp mice, suggesting incompletely improved periodontal function. Quantitative PCR revealed increased Dspp expression in molars of treated Hyp mice. In conclusion, we found TNAP administration reduced dentoalveolar defects in Hyp mice when delivered locally into dentoalveolar structures, proof-of-principle pointing to a pathological contribution by PPi and/or OPN and highlighting a promising adjunctive approach considering limitations of current treatment modalities.
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.
gene therapies
2026-05-01 | Association of PHEX Gene Dosage With Meniere Disease and Related Audiovestibular Phenotypes in X-Linked Hypophosphatemia
Importance Meniere disease (MD) is a heterogenous disorder whose underlying etiologies remain poorly understood. A subtype of MD characterized by endolymphatic sac (ES) underdevelopment (ES hypoplasia), frequent bilateral disease, and male predominance—termed MD-hp—has emerged as a promising model for genetic investigation. Objective To test whether the PHEX gene underlies the association of XLH with MD-hp. Design, Setting, and Participants This prospective, cross-sectional, study was conducted at tertiary academic centers in the US (Boston, Massachusetts) and Switzerland (Zurich) from January 2021 to August 2024. Participants aged 18 years and older with XLH were recruited. Data were analyzed from October 2024 to August 2025. Exposure Diagnosis of XLH. Main Outcomes and Measures The primary outcome was co-occurrence of XLH and MD-hp as compared with population prevalences. MD-hp assessment included pure-tone audiometry and speech-intelligibility testing, vestibular function testing via caloric and video head-impulse testing, symptom history indicating definite MD criteria, high-resolution computed tomography assessment of ES hypoplasia (angular trajectory of the vestibular aqueduct ≥140°), delayed 3-dimensional fluid-attenuated inversion recovery magnetic resonance imaging for detection of endolymphatic hydrops, and PHEX pathway gene sequencing. Results Given population prevalences of XLH (approximately 0.005%), MD (approximately 0.2%), and MD-hp (approximately 30% of MD), random co-occurrence would be approximately 1 in 33 million. In this cohort of 33 patients (10 male; mean [SD] age, 53.1 [13.0] years and 23 female; mean [SD] age, 46.2 [17.6] years), 6 (18.2%) met bilateral MD-hp criteria (approximately 1 in 5.5 patients)—a more than 6 million–fold enrichment. All 6 case patients were hemizygous males (including 2 males with fluctuating-progressive sensorineural hearing loss but no vertigo). Two additional hemizygous males younger than 40 years displayed bilateral ES hypoplasia without clinical MD, and 2 males with mosaic or hypomorphic PHEX variants showed normal ES anatomy and no audiovestibular symptoms. No female carriers met MD-hp criteria; instead, 5 females exhibited mild to moderate, low- to mid-frequency sensorineural hearing loss without vertigo, and 2 females had isolated conductive hearing loss. Conclusions and Relevance These findings support an inner ear–specific PHEX gene-dosage threshold model for MD-hp penetrance; complete loss of function in hemizygous males leads to bilateral ES hypoplasia and MD, whereas mosaic or partial-loss variants in males—and heterozygosity in females—permit residual PHEX activity, resulting in milder or absent audiovestibular phenotypes. This genotype-endotype-phenotype linkage (complete PHEX loss, ES hypoplasia, and MD) enables early risk stratification and personalized surveillance and paves the way for targeted therapies in patients with XLH.
2026-04-17 | Association of PHEX Gene Dosage With Meniere Disease and Related Audiovestibular Phenotypes in X-Linked Hypophosphatemia.
Meniere disease (MD) is a heterogenous disorder whose underlying etiologies remain poorly understood. A subtype of MD characterized by endolymphatic sac (ES) underdevelopment (ES hypoplasia), frequent bilateral disease, and male predominance-termed MD-hp-has emerged as a promising model for genetic investigation. To test whether the PHEX gene underlies the association of XLH with MD-hp. This prospective, cross-sectional, study was conducted at tertiary academic centers in the US (Boston, Massachusetts) and Switzerland (Zurich) from January 2021 to August 2024. Participants aged 18 years and older with XLH were recruited. Data were analyzed from October 2024 to August 2025. Diagnosis of XLH. The primary outcome was co-occurrence of XLH and MD-hp as compared with population prevalences. MD-hp assessment included pure-tone audiometry and speech-intelligibility testing, vestibular function testing via caloric and video head-impulse testing, symptom history indicating definite MD criteria, high-resolution computed tomography assessment of ES hypoplasia (angular trajectory of the vestibular aqueduct ≥140°), delayed 3-dimensional fluid-attenuated inversion recovery magnetic resonance imaging for detection of endolymphatic hydrops, and PHEX pathway gene sequencing. Given population prevalences of XLH (approximately 0.005%), MD (approximately 0.2%), and MD-hp (approximately 30% of MD), random co-occurrence would be approximately 1 in 33 million. In this cohort of 33 patients (10 male; mean [SD] age, 53.1 [13.0] years and 23 female; mean [SD] age, 46.2 [17.6] years), 6 (18.2%) met bilateral MD-hp criteria (approximately 1 in 5.5 patients)-a more than 6 million-fold enrichment. All 6 case patients were hemizygous males (including 2 males with fluctuating-progressive sensorineural hearing loss but no vertigo). Two additional hemizygous males younger than 40 years displayed bilateral ES hypoplasia without clinical MD, and 2 males with mosaic or hypomorphic PHEX variants showed normal ES anatomy and no audiovestibular symptoms. No female carriers met MD-hp criteria; instead, 5 females exhibited mild to moderate, low- to mid-frequency sensorineural hearing loss without vertigo, and 2 females had isolated conductive hearing loss. These findings support an inner ear-specific PHEX gene-dosage threshold model for MD-hp penetrance; complete loss of function in hemizygous males leads to bilateral ES hypoplasia and MD, whereas mosaic or partial-loss variants in males-and heterozygosity in females-permit residual PHEX activity, resulting in milder or absent audiovestibular phenotypes. This genotype-endotype-phenotype linkage (complete PHEX loss, ES hypoplasia, and MD) enables early risk stratification and personalized surveillance and paves the way for targeted therapies in patients with XLH.
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.
antibodies
2026-08-16 | Three Generations of X-Linked Hypophosphataemia: The Inter-generational Impact of Burosumab Across the Lifespan.
X-linked hypophosphataemia (XLH) is a rare, lifelong heritable metabolic bone disorder characterized by fibroblast growth factor 23 (FGF23) excess, chronic hypophosphataemia, renal phosphate wasting, progressive skeletal deformities and impaired quality of life. Burosumab, targeted anti-FGF-23 therapy, is approved for use in XLH across the lifespan. Clinical trials have demonstrated benefit, although distinct outcomes in response to treatment vary depending on whether initiated during childhood, adolescence or adulthood. We uniquely describe three patients with XLH across three generations within a single family, each initiated on burosumab at different stages of life. This familial case study highlights the broad phenotypic spectrum of XLH, and differential efficacy profile of burosumab across various stages, such as pre- and post-growth plate closure or in the presence of established musculoskeletal morbidity. We also demonstrate the unique inter-generational impact of burosumab in XLH, as a targeted novel treatment available for patients with a dominantly inherited disorder across the lifespan.
2026-07-09 | 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.
2026-06-23 | Second interim analysis of the post-authorisation safety study (PASS) of burosumab in paediatric patients with X-linked hypophosphataemia.
X-linked hypophosphataemia (XLH) is a rare genetic disorder characterised by defective bone and tooth mineralisation. Burosumab is a recombinant, human, anti-fibroblast growth factor 23 monoclonal antibody approved for treating XLH. Due to the rarity of the disease, additional safety data for the treatment of XLH with burosumab are required. A post-authorisation safety study analysis of data for paediatric participants from the International X-linked Hypophosphataemia Registry. This study included standard diagnostic and monitoring clinical data at participating centres, regardless of treatment. This was a second interim analysis performed 5 years after study initiation in the paediatric population. Primary objectives assessed safety outcomes in children and adolescents with XLH. The secondary objective compared safety outcomes with burosumab vs phosphate and/or active vitamin D. In total, 340 participants were treated with ≥1 dose of burosumab, and 91 were treated with phosphate and/or active vitamin D. Overall, 37.4% and 22.0% of participants in the burosumab or phosphate and/or active vitamin D cohorts, respectively, experienced ≥1 adverse event. The proportions of participants with events were similar among children and adolescents. Forty-nine (14.4%) participants reported events possibly/probably related to burosumab. No events led to the withdrawal of burosumab. In both cohorts, no serious adverse events were considered related to treatment, and there were no deaths. Hospitalisations occurred in ∼71% of participants. Hyperphosphataemia, elevated parathyroid hormone, and ectopic mineralisation events were rare. The safety profile of burosumab was consistent with previous studies, and no new safety concerns were reported for children or adolescents.
2026-06-11 | Burosumab for X-linked Hypophosphataemia and Tumour-induced Osteomalacia in Adults.
X-linked hypophosphataemia and tumour-induced osteomalacia are rare, distinct metabolic conditions that can affect both children and adults, and result in elevated fibroblast growth factor-23 levels and subsequent low phosphate levels. This leads to severe musculoskeletal symptoms and complications, and these conditions carry significant disease burden and high levels of morbidity. In this article, we examine the conditions and analyse the use of burosumab, a recently developed monoclonal antibody treatment, in the care of adults with these conditions.
2026-06-10 | FGF23–GH Crosstalk in Phosphate Allocation and Growth Plate Biology
Phosphate is an essential element for energy metabolism, bone mineralization and chondrocyte function, particularly during growth. Its homeostasis involves complex interactions between dietary intake, renal excretion and hormonal regulation, notably through fibroblast growth factor 23 (FGF23) and growth hormone (GH). The intricate balance of phosphate and its interplay with FGF23 and GH are examined in the context of normal development and disorders such as X-linked hypophosphatemia (XLH) and chronic kidney disease (CKD), which disrupt this balance through mechanisms of hypophosphatemia or hyperphosphatemia. FGF23 emerges as a key regulator, mediating phosphate excretion and vitamin D metabolism, while GH exerts a counter-regulatory effect by promoting phosphate reabsorption and chondrocyte proliferation. This hormonal interaction maintains skeletal integrity but becomes dysregulated in pathological conditions, leading to impaired growth and mineralization. Recent insights into the molecular mechanisms of phosphate transporters and the role of the PHEX gene in FGF23 regulation provide promising avenues for therapeutic interventions. Emerging treatments, including phosphate binders, calcitriol supplementation and anti-FGF23 antibodies such as burosumab, offer potential to address the complications of phosphate dysregulation. However, challenges remain in optimizing therapies for pediatric populations and mitigating adverse effects like vascular calcification. Future research into phosphate homeostasis, transporter dynamics and gene-based approaches holds the promise of advancing clinical outcomes for phosphate-related disorders. This review explores the dual role of phosphate in skeletal growth, highlighting its critical contributions to chondrocyte maturation, apoptosis and hydroxyapatite formation during endochondral ossification.
small molecules
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.
2026-07-03 | X-Linked Hypophosphatemia: A Review of Pathophysiology, Clinical Manifestations, Current Management, and Emerging Therapeutic Strategies
X-linked hypophosphatemia (XLH) is one of the most common inherited phosphate-wasting disorders, caused by pathogenic variants in the PHEX gene that result in excess fibroblast growth factor 23 (FGF23) and chronic hypophosphatemia. Historically considered a pediatric disease characterized by rickets and growth impairment, XLH is now recognized as a lifelong condition with substantial adult morbidity including osteomalacia, fractures, enthesopathy, osteoarthritis, and reduced quality of life. The discovery of FGF23 as the central mediator of phosphate wasting transformed understanding of disease pathophysiology and enabled development of burosumab, a monoclonal antibody that neutralizes FGF23 and restores phosphate homeostasis. While burosumab represents a paradigm shift in therapy, accumulating evidence indicates that XLH involves FGF23-independent mechanisms, including osteopontin accumulation, ASARM peptide generation, and pyrophosphate dysregulation, which contribute to persistent skeletal abnormalities despite biochemical correction. This review integrates current insights into the molecular genetics, pathophysiology, and lifelong clinical features of XLH, with particular attention to emerging concepts involving local bone matrix abnormalities and their impact on therapeutic innovation. We trace the transition from conventional phosphate and active vitamin D supplementation to targeted FGF23 inhibition, highlight the limitations of existing treatment strategies, and explore future directions such as small‑molecule inhibitors, anti‑sclerostin therapy, gene-based approaches, and ultimately PHEX‑focused repair. A comprehensive understanding of XLH as both a systemic endocrine disorder and an intrinsic defect of osteocyte biology is critical for optimizing patient care and steering the development of curative therapies.
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.
2026-04-01 | Sclerotic enthesopathy in X-linked hypophosphatemia: An atypical radiological mimic of sclerosing bone disorders
ABSTRACT A 26-year-old woman presented with progressive bilateral hip and leg pain and worsening gait difficulty over 5 years. She had lower-limb bowing since childhood, without a family history of skeletal deformities. Examination revealed genu varum and poor dentition. Biochemical evaluation showed hypophosphatemia (1.92 mg/dL), normal corrected calcium (9.7 mg/dL), elevated alkaline phosphatase (212 IU/L), vitamin D insufficiency (25-hydroxyvitamin D: 22 ng/mL), and normal parathyroid hormone (48 pg/mL). Vitamin D deficiency was corrected before assessment of tubular phosphate handling. Tubular maximum for phosphate reabsorption per glomerular filtration rate was reduced (0.6 mmol/L), confirming renal phosphate wasting. Serum intact fibroblast growth Factor (FGF) 23 was inappropriately elevated (108 pg/mL; reference range: 23.2–95.4 pg/mL; electrochemiluminescence immunoassay), supporting an FGF23-mediated process. Radiographs demonstrated interosseous membrane calcification, femoral pseudofracture, diffuse skeletal sclerosis, and enthesopathic changes of the femur and pelvis. There was no history of excess fluoride exposure, renal function was normal, and imaging showed no evidence of malignancy, excluding fluorosis, chronic kidney disease, and tumor-induced osteomalacia. Although genetic confirmation was not available, the clinical, biochemical, and radiological features strongly supported X-linked hypophosphatemia (XLH). Treatment with phosphate and calcitriol improved symptoms. This case highlights an atypical sclerotic phenotype of XLH mimicking sclerosing bone disorders.
2026-03-04 | Impact of oral phosphate supplements and active vitamin D treatment on dentoalveolar features of X-linked hypophosphatemia.
X-linked hypophosphatemia (XLH), the most common form of genetic rickets (1/20000 births), results in the disruption of skeletal and dental mineralization. Oral features include dentinomalacia, spontaneous dental abscesses, and a high susceptibility to periodontitis. The association of phosphate supplementation and active vitamin D analogs (PO4/VitD) aims to counteract the consequences of FGF23 excess and the impaired production of active vitamin D. Despite a significant improvement in the long bone phenotype, the impact on dentoalveolar tissues remains poorly documented. Here, we aimed to determine whether the PO4/VitD treatment improves dental features in the Hyp mouse model of XLH and in XLH patients. Hyp mice were treated with oral phosphate supplementation and calcitriol injections from 3 wk to 3 mo and were compared with untreated Hyp and WT mice. Histological analyses were also performed on teeth from patients with XLH treated with PO4/VitD and on control teeth. Micro-CT analyses showed that the PO4/VitD treatment did not significantly correct dentin/cementum volume and density, pulp chamber enlargement, and alveolar bone parameters in Hyp mice. Histological analyses also revealed that dentinomalacia and periodontal attachment were not rescued by the treatment. Remarkably, permanent teeth from XLH patients treated with PO4/VitD during childhood displayed a significant reduction in predentin thickness and a thinner layer of globular dentin. Taken together, our data show that the PO4/VitD treatment does not significantly improve dentoalveolar features in Hyp mice treated at the prepubertal stage. However, the impact observed on dentin in human teeth supports the interest of this treatment regarding the occurrence of spontaneous dental abscesses.
proteins
2026-07-07 | When X Does Not Mark the Spot: Autosomal Dominant and Recessive Forms of Renal Hypophosphatemic Rickets and Osteomalacia.
Conditions resulting in elevated fibroblast growth factor 23 (FGF23) cause hypophosphatemic rickets and osteomalacia. The most common of these is X-linked hypophosphatemia. In this review we will broadly discuss the other less common and clinically distinct forms of renal hypophosphatemia, with a focus on the autosomal dominant and autosomal recessive types. Variants in multiple genes cause dominant (FGF23, SGK3, FGFR1), recessive (DMP1, ENPP1, FAM20C, INPPL1) or even somatic (NRAS, HRAS, GNAS, gene fusions) conditions of FGF23 excess, with important phenotypic differences. For example, in autosomal dominant hypophosphatemic rickets due to FGF23 variants, iron deficiency drives the phenotype, while ENPP1 variants cause phenotypes ranging from severe neonatal vascular calcifications to rickets or osteoporosis. Other gene abnormalities cause FGF23-independent hypophosphatemia, often involving kidney disease. Recognizing the different mechanisms and phenotypes of hypophosphatemic conditions is critical to prognosis, management and to developing more effective therapies.
2026-06-26 | X-linked Hypophosphatemic Rickets Revealed by Exome Sequencing: A Pediatric Case Report of a PHEX Pathogenic Variant.
X-linked hypophosphatemic rickets (XLH) is the most common form of hereditary vitamin-resistant rickets, caused by inactivating mutations of the PHEX (phosphate-regulating endopeptidase homolog, X-linked) gene, leading to elevated fibroblast growth factor 23 (FGF23) and chronic hypophosphatemia secondary to renal phosphate wasting. We report the case of a 3.5-year-old boy presenting with bilateral varus deformity of the lower limbs, frontal bossing, rachitic rosary, and growth retardation (-2.5 SD). Laboratory investigations revealed hypophosphatemia (0.88 mmol/L) with severely reduced urinary phosphate excretion (196.8 mg/24 h), elevated alkaline phosphatase (521 IU/L), and normal serum calcium and vitamin D levels. Exome sequencing identified a hemizygous pathogenic variant in PHEX: c.2192T>G (p.Phe731Cys), confirming the diagnosis of XLH. This case illustrates the decisive contribution of exome sequencing in confirming vitamin-resistant rickets and the importance of early diagnosis to prevent irreversible orthopedic sequelae.
2025-12-31 | Biochemical evaluation of X-linked hypophosphatemia and tumor-induced osteomalacia: insights into diagnosis and management.
X-linked hypophosphatemia (XLH) and tumor-induced osteomalacia (TIO) are characterized by alterations in phosphate metabolism due to elevated levels of fibroblast growth factor 23 (FGF23). These conditions cause significant morbidity due to chronic hypophosphatemia and resulting musculoskeletal disorders. This study aims to provide clinical strategies for supporting the diagnosis and management of the biochemical profile of patients with XLH and TIO, addressing key considerations beyond the hypophosphatemia and hyperphosphaturia commonly observed in these conditions and addressing the variability and limitations of current biochemical marker detection methods. A literature search focused on studies published in the last ten years. A multidisciplinary team analyzed the data to integrate the findings into clinical best practices. The proposed approach emphasizes correctly performing and interpreting tests for serum phosphate, phosphaturia, FGF23, alkaline phosphatase (ALP), parathyroid hormone (PTH), vitamin D, serum calcium, and the calcium-corrected excretion rate. More standardization in screening methods is needed, which affects diagnostic accuracy and management. The recommendations include detailed protocols for patient preparation, sample collection, and interpretation of results. The recommendations for performing biochemical screening for XLH and TIO promote better clinical practices in patient diagnosis and management. Future research should focus on validating diagnostic methods in diverse populations and standardizing biochemical tests. Multidisciplinary approach to the diagnosis of these patients through the close collaboration of professionals of laboratory medicine and clinical specialties would be pivotal.
2025-11-12 | Proof-of-principle for enhanced dentoalveolar mineralization using exogenous tissue-nonspecific alkaline phosphatase in the Hyp mouse model of X-linked hypophosphatemia.
X-linked hypophosphatemia (XLH) is caused by mutations in the PHEX gene, which leads to increased levels of fibroblast growth factor 23 and hypophosphatemia, contributing to rickets, osteomalacia, and dentoalveolar defects, including severe dentin hypomineralization, thin cementum, and alveolar bone osteomalacia. Current XLH treatment options appear to have limited efficacy on dentoalveolar tissues, suggesting underlying disease mechanisms that remain unchecked. Increased production of inorganic pyrophosphate (PPi) and osteopontin (OPN), both mineralization inhibitors, has been posited to contribute to mineralization defects in XLH. The enzyme, tissue-nonspecific alkaline phosphatase (TNAP) reduces PPi levels via hydrolysis and inactivates OPN by dephosphorylation. Our previous study showed improved alveolar bone socket healing in Hyp mice administered mineralized tissue-targeted TNAP (TNAP-Fc-D10). We hypothesized that increased TNAP would partially ameliorate developmental mineralization defects in XLH by dually reducing PPi levels and dephosphorylating and inactivating OPN. In a proof-of-principle study to investigate pathological mechanisms, we delivered systemic (subcutaneous injection) and local (submucosal injection to mandibles) TNAP-Fc-D10 injections to the Hyp mutant mouse model of XLH from 7 to 60 d postnatal (dpn). While systemic delivery was ineffective at improving dentin or bone properties, micro-CT and histology analyses demonstrated that local delivery of TNAP-Fc-D10 increased dentin thickness, root length, alveolar bone volume, alveolar bone proper (ABP) volume and density, PDL attachment, and acellular cementum thickness, compared to control Hyp mice receiving a sham injection. Dynamic mechanical testing confirmed partially improved mechanical properties in locally treated vs untreated Hyp mice, suggesting incompletely improved periodontal function. Quantitative PCR revealed increased Dspp expression in molars of treated Hyp mice. In conclusion, we found TNAP administration reduced dentoalveolar defects in Hyp mice when delivered locally into dentoalveolar structures, proof-of-principle pointing to a pathological contribution by PPi and/or OPN and highlighting a promising adjunctive approach considering limitations of current treatment modalities.
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.
gene therapies
2026-05-01 | Association of PHEX Gene Dosage With Meniere Disease and Related Audiovestibular Phenotypes in X-Linked Hypophosphatemia
Importance Meniere disease (MD) is a heterogenous disorder whose underlying etiologies remain poorly understood. A subtype of MD characterized by endolymphatic sac (ES) underdevelopment (ES hypoplasia), frequent bilateral disease, and male predominance—termed MD-hp—has emerged as a promising model for genetic investigation. Objective To test whether the PHEX gene underlies the association of XLH with MD-hp. Design, Setting, and Participants This prospective, cross-sectional, study was conducted at tertiary academic centers in the US (Boston, Massachusetts) and Switzerland (Zurich) from January 2021 to August 2024. Participants aged 18 years and older with XLH were recruited. Data were analyzed from October 2024 to August 2025. Exposure Diagnosis of XLH. Main Outcomes and Measures The primary outcome was co-occurrence of XLH and MD-hp as compared with population prevalences. MD-hp assessment included pure-tone audiometry and speech-intelligibility testing, vestibular function testing via caloric and video head-impulse testing, symptom history indicating definite MD criteria, high-resolution computed tomography assessment of ES hypoplasia (angular trajectory of the vestibular aqueduct ≥140°), delayed 3-dimensional fluid-attenuated inversion recovery magnetic resonance imaging for detection of endolymphatic hydrops, and PHEX pathway gene sequencing. Results Given population prevalences of XLH (approximately 0.005%), MD (approximately 0.2%), and MD-hp (approximately 30% of MD), random co-occurrence would be approximately 1 in 33 million. In this cohort of 33 patients (10 male; mean [SD] age, 53.1 [13.0] years and 23 female; mean [SD] age, 46.2 [17.6] years), 6 (18.2%) met bilateral MD-hp criteria (approximately 1 in 5.5 patients)—a more than 6 million–fold enrichment. All 6 case patients were hemizygous males (including 2 males with fluctuating-progressive sensorineural hearing loss but no vertigo). Two additional hemizygous males younger than 40 years displayed bilateral ES hypoplasia without clinical MD, and 2 males with mosaic or hypomorphic PHEX variants showed normal ES anatomy and no audiovestibular symptoms. No female carriers met MD-hp criteria; instead, 5 females exhibited mild to moderate, low- to mid-frequency sensorineural hearing loss without vertigo, and 2 females had isolated conductive hearing loss. Conclusions and Relevance These findings support an inner ear–specific PHEX gene-dosage threshold model for MD-hp penetrance; complete loss of function in hemizygous males leads to bilateral ES hypoplasia and MD, whereas mosaic or partial-loss variants in males—and heterozygosity in females—permit residual PHEX activity, resulting in milder or absent audiovestibular phenotypes. This genotype-endotype-phenotype linkage (complete PHEX loss, ES hypoplasia, and MD) enables early risk stratification and personalized surveillance and paves the way for targeted therapies in patients with XLH.
2026-04-17 | Association of PHEX Gene Dosage With Meniere Disease and Related Audiovestibular Phenotypes in X-Linked Hypophosphatemia.
Meniere disease (MD) is a heterogenous disorder whose underlying etiologies remain poorly understood. A subtype of MD characterized by endolymphatic sac (ES) underdevelopment (ES hypoplasia), frequent bilateral disease, and male predominance-termed MD-hp-has emerged as a promising model for genetic investigation. To test whether the PHEX gene underlies the association of XLH with MD-hp. This prospective, cross-sectional, study was conducted at tertiary academic centers in the US (Boston, Massachusetts) and Switzerland (Zurich) from January 2021 to August 2024. Participants aged 18 years and older with XLH were recruited. Data were analyzed from October 2024 to August 2025. Diagnosis of XLH. The primary outcome was co-occurrence of XLH and MD-hp as compared with population prevalences. MD-hp assessment included pure-tone audiometry and speech-intelligibility testing, vestibular function testing via caloric and video head-impulse testing, symptom history indicating definite MD criteria, high-resolution computed tomography assessment of ES hypoplasia (angular trajectory of the vestibular aqueduct ≥140°), delayed 3-dimensional fluid-attenuated inversion recovery magnetic resonance imaging for detection of endolymphatic hydrops, and PHEX pathway gene sequencing. Given population prevalences of XLH (approximately 0.005%), MD (approximately 0.2%), and MD-hp (approximately 30% of MD), random co-occurrence would be approximately 1 in 33 million. In this cohort of 33 patients (10 male; mean [SD] age, 53.1 [13.0] years and 23 female; mean [SD] age, 46.2 [17.6] years), 6 (18.2%) met bilateral MD-hp criteria (approximately 1 in 5.5 patients)-a more than 6 million-fold enrichment. All 6 case patients were hemizygous males (including 2 males with fluctuating-progressive sensorineural hearing loss but no vertigo). Two additional hemizygous males younger than 40 years displayed bilateral ES hypoplasia without clinical MD, and 2 males with mosaic or hypomorphic PHEX variants showed normal ES anatomy and no audiovestibular symptoms. No female carriers met MD-hp criteria; instead, 5 females exhibited mild to moderate, low- to mid-frequency sensorineural hearing loss without vertigo, and 2 females had isolated conductive hearing loss. These findings support an inner ear-specific PHEX gene-dosage threshold model for MD-hp penetrance; complete loss of function in hemizygous males leads to bilateral ES hypoplasia and MD, whereas mosaic or partial-loss variants in males-and heterozygosity in females-permit residual PHEX activity, resulting in milder or absent audiovestibular phenotypes. This genotype-endotype-phenotype linkage (complete PHEX loss, ES hypoplasia, and MD) enables early risk stratification and personalized surveillance and paves the way for targeted therapies in patients with XLH.
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.
antibodies
2026-08-16 | Three Generations of X-Linked Hypophosphataemia: The Inter-generational Impact of Burosumab Across the Lifespan.
X-linked hypophosphataemia (XLH) is a rare, lifelong heritable metabolic bone disorder characterized by fibroblast growth factor 23 (FGF23) excess, chronic hypophosphataemia, renal phosphate wasting, progressive skeletal deformities and impaired quality of life. Burosumab, targeted anti-FGF-23 therapy, is approved for use in XLH across the lifespan. Clinical trials have demonstrated benefit, although distinct outcomes in response to treatment vary depending on whether initiated during childhood, adolescence or adulthood. We uniquely describe three patients with XLH across three generations within a single family, each initiated on burosumab at different stages of life. This familial case study highlights the broad phenotypic spectrum of XLH, and differential efficacy profile of burosumab across various stages, such as pre- and post-growth plate closure or in the presence of established musculoskeletal morbidity. We also demonstrate the unique inter-generational impact of burosumab in XLH, as a targeted novel treatment available for patients with a dominantly inherited disorder across the lifespan.
2026-07-09 | 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.
2026-06-23 | Second interim analysis of the post-authorisation safety study (PASS) of burosumab in paediatric patients with X-linked hypophosphataemia.
X-linked hypophosphataemia (XLH) is a rare genetic disorder characterised by defective bone and tooth mineralisation. Burosumab is a recombinant, human, anti-fibroblast growth factor 23 monoclonal antibody approved for treating XLH. Due to the rarity of the disease, additional safety data for the treatment of XLH with burosumab are required. A post-authorisation safety study analysis of data for paediatric participants from the International X-linked Hypophosphataemia Registry. This study included standard diagnostic and monitoring clinical data at participating centres, regardless of treatment. This was a second interim analysis performed 5 years after study initiation in the paediatric population. Primary objectives assessed safety outcomes in children and adolescents with XLH. The secondary objective compared safety outcomes with burosumab vs phosphate and/or active vitamin D. In total, 340 participants were treated with ≥1 dose of burosumab, and 91 were treated with phosphate and/or active vitamin D. Overall, 37.4% and 22.0% of participants in the burosumab or phosphate and/or active vitamin D cohorts, respectively, experienced ≥1 adverse event. The proportions of participants with events were similar among children and adolescents. Forty-nine (14.4%) participants reported events possibly/probably related to burosumab. No events led to the withdrawal of burosumab. In both cohorts, no serious adverse events were considered related to treatment, and there were no deaths. Hospitalisations occurred in ∼71% of participants. Hyperphosphataemia, elevated parathyroid hormone, and ectopic mineralisation events were rare. The safety profile of burosumab was consistent with previous studies, and no new safety concerns were reported for children or adolescents.
2026-06-11 | Burosumab for X-linked Hypophosphataemia and Tumour-induced Osteomalacia in Adults.
X-linked hypophosphataemia and tumour-induced osteomalacia are rare, distinct metabolic conditions that can affect both children and adults, and result in elevated fibroblast growth factor-23 levels and subsequent low phosphate levels. This leads to severe musculoskeletal symptoms and complications, and these conditions carry significant disease burden and high levels of morbidity. In this article, we examine the conditions and analyse the use of burosumab, a recently developed monoclonal antibody treatment, in the care of adults with these conditions.
2026-06-10 | FGF23–GH Crosstalk in Phosphate Allocation and Growth Plate Biology
Phosphate is an essential element for energy metabolism, bone mineralization and chondrocyte function, particularly during growth. Its homeostasis involves complex interactions between dietary intake, renal excretion and hormonal regulation, notably through fibroblast growth factor 23 (FGF23) and growth hormone (GH). The intricate balance of phosphate and its interplay with FGF23 and GH are examined in the context of normal development and disorders such as X-linked hypophosphatemia (XLH) and chronic kidney disease (CKD), which disrupt this balance through mechanisms of hypophosphatemia or hyperphosphatemia. FGF23 emerges as a key regulator, mediating phosphate excretion and vitamin D metabolism, while GH exerts a counter-regulatory effect by promoting phosphate reabsorption and chondrocyte proliferation. This hormonal interaction maintains skeletal integrity but becomes dysregulated in pathological conditions, leading to impaired growth and mineralization. Recent insights into the molecular mechanisms of phosphate transporters and the role of the PHEX gene in FGF23 regulation provide promising avenues for therapeutic interventions. Emerging treatments, including phosphate binders, calcitriol supplementation and anti-FGF23 antibodies such as burosumab, offer potential to address the complications of phosphate dysregulation. However, challenges remain in optimizing therapies for pediatric populations and mitigating adverse effects like vascular calcification. Future research into phosphate homeostasis, transporter dynamics and gene-based approaches holds the promise of advancing clinical outcomes for phosphate-related disorders. This review explores the dual role of phosphate in skeletal growth, highlighting its critical contributions to chondrocyte maturation, apoptosis and hydroxyapatite formation during endochondral ossification.
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Drug Discovery Landscape
4 orphan drug designations for X-linked hypophosphatemia, including 2 approved therapies.
4 orphan drug designations for X-linked hypophosphatemia, including 2 approved therapies.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
fibroblast growth factor 23-C tail | peptides | FDA | 2024-09-09 | — | Andaraix Pharmaceuticals, Inc. |
DNA, (Cm-Gm-Gm-Gm-G-T-G-T-G-G-G-T-T-C-G-T-C-G-T-T-A-G-C-T-T-G-A-T-T-T-G-G-C-A-G-C-Um-Gm-Cm-Cm-(5'->3')-idT), 5'-ester with (29S)-29-carboxy-8,17,26,31-tetraoxo-10,13,19,22-tetraoxa-7,16,25,30-tetraazaoctatetracontan-48-oic acid | antibodies | FDA | 2024-02-21 | — | Aptacure Therapeutics Limited |
Recombinant human monoclonal IgG1 antibody for fibroblast growth factor 23 [CRYSVITA] | antibodies | EMA | 2014-10-15 | 2018-02-21 | Kyowa Kirin Holdings B.V. |
burosumab-twza [Crysvita] | antibodies | FDA | 2009-12-14 | 2018-04-17 | Kyowa Kirin, Inc. |
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