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
631 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:
631 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
2026-09-24 | Exploring the Association of Angiotensin-(1-7) with Left Ventricular Mass Index in Youth with Hereditary Hypophosphatemia: A Pilot Study.
Fibroblast growth factor 23 (FGF23) regulates phosphate homeostasis and is associated with cardiovascular-kidney-metabolic syndrome in patients with chronic kidney disease in part mediated by angiotensin II. X-linked hypophosphatemia (XLH) is characterized by phosphate wasting due to excess FGF23 activity, but its associations with angiotensin peptides and cardiovascular disease remain unclear. We evaluated cross-sectional associations between angiotensin II, angiotensin-(1-7), and left ventricular mass index (LVMI) in youth with XLH. A pilot prospective cross-sectional study enrolled youth and young adults aged 2-24 years with XLH from nephrology and endocrinology clinics at one hospital. Individuals with acquired hypophosphatemia or inability to provide urine were excluded. LVMI was collected from echocardiograms while peptides were measured in blood and urine by radioimmunoassays. We assessed associations using Spearman correlation coefficients. Among seven participants, 71% were female and median age was 12.8 years [IQR 7.7-13.7]. Seventy-one percent had a pathologic PHEX variant. Median peptide values were Ang II 56.0 pg/ml [47.2-58.1] and Ang-(1-7) 23.2 pg/ml [13.1-30.2] in blood and Ang II 32.1 pg/ml [27.5-103.2] and Ang-(1-7) 48.5 pg/ml [37.9-74.6] in urine. Median LVMI was 26.0 g/m2.7 [21.0-28.0] and 43.9 g/BSA [39.6-47.9]. Blood and urine angiotensin peptides were not correlated with either LVMI measure (p > 0.05). In youth and young adults with XLH, blood and urine angiotensin peptide collection was feasible, but values were not associated with LVMI, suggesting ACE/Ang II and ACE2/Ang-(1-7) may not mediate FGF23-related cardiovascular-kidney-metabolic syndrome risk if confirmed. Larger studies are needed to determine if the renin-angiotensin-aldosterone system contributes to worse outcomes in FGF23-mediated XLH and should be targeted to improve cardiovascular-kidney-metabolic health.
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.
proteins
2026-09-03 | Role of 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 the pathophysiology of XLH. Particular attention was given to the role of 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 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.
2026-07-07 | 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.
2026-06-01 | Fifty Years of Misdiagnosis: Two Sisters with X-Linked Hypophosphatemia Misdiagnosed as Achondroplasia
X-linked hypophosphatemia (XLH) is the most common inherited form of hypophosphatemic rickets, caused by inactivating mutations in the phosphate-regulating endopeptidase homolog, X-linked (PHEX) gene. Despite its distinct clinical and biochemical features, XLH can be misdiagnosed as achondroplasia because of overlapping skeletal manifestations. Two sisters, aged 53 and 60 years, who were misdiagnosed with achondroplasia for more than 5 decades were later diagnosed with XLH. Both patients presented with diffuse bone pain, severe skeletal deformities, including coxa vara with shepherd’s crook deformity and femoral bowing and a history of spontaneous dental abscesses. Laboratory testing revealed hypophosphatemia with normocalcemia. Family history showed an X-linked dominant inheritance pattern, with an affected father, all 4 sisters affected, and 3 unaffected brothers—inconsistent with achondroplasia. Whole-exome sequencing identified a novel heterozygous PHEX variant, c.207_212del (p.K69_V70del), classified as a variant of uncertain significance (VUS) per American College of Medical Genetics (ACMG) guidelines. Notably, the first patient had undergone parathyroidectomy 24 years earlier, likely reflecting tertiary hyperparathyroidism as a long-term complication of undiagnosed XLH. This report highlights that careful evaluation of family history, combined with simple biochemical tests, can prevent decades of misdiagnosis and its associated morbidity. Cite this article as: Aydemir EE, Ertürk Ş., Leblebici CB, Karabulut HG, Demir. Fifty years of misdiagnosis: two sisters with X-linked hypophosphatemia misdiagnosed as achondroplasia. Endocrinol Res Pract. 2026;30(3):213-216.
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.
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
2026-09-23 | Real-World Effectiveness of Burosumab Versus Oral Phosphate and Active Vitamin D in Adults with X-Linked Hypophosphatemia (XLH): A 3-Year Follow-Up of the XLH Disease Monitoring Program.
X-linked hypophosphatemia (XLH) is a progressive disease in which excess FGF23 causes renal phosphate wasting, leading to hypophosphatemia. Consequences in adults include osteomalacia, fractures, pseudofractures, joint dysfunction, pain, and impaired mobility. Treatments for XLH are the anti-FGF23 antibody burosumab and active forms of vitamin D alone or in combination with oral phosphate (Pi/D). Randomized studies comparing burosumab with Pi/D in adults with XLH are lacking. We present a 3-yr follow-up analysis evaluating real-world effectiveness of burosumab versus Pi/D based on biochemistry and standardized symptom assessments (Western Ontario and McMaster Universities Osteoarthritis Index [WOMAC]) using data from the XLH Disease Monitoring Program (DMP; NCT03651505), a prospective, Americas-based study. Adults with XLH initiated burosumab between baseline and the year 1 visit (N = 54) or reported being on Pi/D therapy at enrollment (N = 55) were included. After adjusting for baseline differences using inverse probability of treatment weighting, the data showed a significantly higher mean (SD) change from baseline in serum phosphate with burosumab versus Pi/D (year 1: 0.8 [0.8] vs 0.1 [0.7] mg/dL; year 3: 0.6 [0.8] vs 0.1 [0.7] mg/dL, both p < .001). A higher proportion of burosumab versus Pi/D participants achieved serum phosphate levels above the lower limit of normal (2.5 mg/dL; year 1: 70.5% vs 18.8%; year 3: 60.8% vs 25.0%, both p < .001). At year 1, changes from baseline in WOMAC pain (-6.3 [27.7] vs 2.1 [22.4], p = .055), physical function (-6.4 [19.1] vs 0.1 [29.0], p = .122), and stiffness (-11.1 [32.1] vs -2.3 [33.7], p = .073) were not statistically significant between cohorts, but were significant at year 3 (pain: -9.8 [22.6] vs 3.3 [24.1], p < .001; physical function: -10.0 [25.7] vs 3.3 [24.7], p = .001; stiffness: -15.2 [29.5] vs -3.7 [31.4], p = .016). In this real-world analysis of adults with XLH over a 3-yr follow-up, burosumab treatment was associated with improved serum phosphate and patient-reported outcomes versus Pi/D.
2026-09-18 | Burosumab improves alkaline phosphatase and rickets severity in X-linked hypophosphatemia: 3-year SUNFLOWER analysis.
SUNFLOWER is a 10-year longitudinal observational cohort study of patients with X-linked hypophosphatemia (XLH) in Japan and South Korea. This report describes the 3-year cut-off of SUNFLOWER, including data from 1 year of burosumab administration (burosumab-treated group) and 1 year after providing informed consent (non-burosumab-treated group). The real-world effectiveness of burosumab and the associations between bone metabolism markers and quality of life (QoL)/patient-reported outcomes (PROs) and rickets severity scores (RSS)/height over 1 year in burosumab-treated patients with XLH were assessed. As burosumab had not been launched in South Korea at the time of cut-off, data from South Korea were not available. The main outcome measures were changes in serum parameters, and correlations between alkaline phosphatase (ALP) levels and RSS and height (children), and between ALP (children) or bone-specific ALP (BALP; adults) levels and QoL/PROs and motor functions. In total, 146 patients were enrolled, including 69 (47.3%) children and 77 (52.7%) adults. After 1 year of treatment, burosumab-treated patients (43 [62.3%] children, 29 [37.7%] adults) had improved serum phosphate levels, 1,25-dihydroxyvitamin D, and ALP/BALP compared with pre-treatment levels. In children, RSS changes significantly correlated with ALP changes (correlation coefficient: 0.806, p < 0.001), but height changes did not show significant correlation. There were no significant correlations between changes in ALP/BALP and QoL/PRO assessments or motor function. In conclusion, decreased ALP correlated with an improvement in rickets severity score in Japanese children with XLH, suggesting that ALP may be a useful marker for monitoring both the severity and improvement of rickets/osteomalacia. NCT03745521 and UMIN000031605.
2026-09-16 | Health-Related Quality of Life in Children with X-Linked Hypophosphatemia Treated with Burosumab: Real-World Data from a German-Swiss Study.
Burosumab is effective in improving rickets in children with X-linked hypophosphatemia (XLH). Predictors of health-related quality of life (HRQoL) in pediatric XLH patients treated with burosumab are unknown. In this cross-sectional analysis of a prospective binational observational study, we investigated HRQoL in 64 pediatric XLH patients (36 female) on burosumab treatment, using the KIDSCREEN-52 questionnaire and qualitative interviews. Associations between HRQoL and clinical findings were analysed using multiple regression and receiver operating characteristics (ROC) curve analyses. Median age at investigation and duration of burosumab treatment were 13.1 (IQR 10.4; 14.8) and 2.8 (IQR 1.4; 3.8) years, respectively; 54.7% of patients received secondary burosumab treatment following prior active vitamin D and phosphate. Overall, HRQoL scores were comparable to national reference values. Caregivers rated Physical Well-Being, Moods & Emotions, and Bullying lower than the patients themselves. Burosumab dose was significantly associated with Physical Well-Being, Psychological Well-Being, and Self-Perception in self-report, and with total T-values and Physical Well-Being in proxy questionnaires. The duration of prior treatment with active vitamin D and phosphate was significantly associated with the dimension of Autonomy in self-report and proxy reports. A burosumab dosage above 0.6 mg/kg was associated with a good Physical Well-Being (above the mean of the general population) with a sensitivity and specificity of 75% and 70% in self-report, and 67% and 70% in proxy questionnaires, respectively. In this real-world study, HRQoL in burosumab-treated children with XLH was comparable to that of the general population and associated with burosumab dosage.
2026-09-14 | Hypophosphataemia in adults: approach to diagnosis and management.
Hypophosphataemia is a common electrolyte disorder which can have clinically significant consequences for bone, muscle, neurological and haematological function. Its causes range from transient transcellular shifts in hospitalised patients to chronic renal phosphate-wasting disorders mediated by fibroblast growth factor 23 (FGF23). A stepwise diagnostic approach enables identification of the underlying aetiology and guides management. While most cases are managed with removal of causative factors and phosphate supplementation, burosumab has revolutionised the treatment of patients with chronic FGF23-mediated hypophosphataemia. This review provides a practical framework for the evaluation and management of hypophosphataemia in adults, with focussed discussion of iron infusion-associated hypophosphataemia, X-linked hypophosphataemia and tumour-induced osteomalacia.
2026-09-04 | Fibroblast growth factor 23 (FGF23): From synthesis to cleavage.
Fibroblast growth factor 23 (FGF23) maintains phosphate and vitamin D homeostasis. In the kidney, recognition of FGF23 is mediated by fibroblast growth factor receptors (FGFRs), α-Klotho, and heparan sulfate. Structural studies indicate that an FGF23-FGFR-α-Klotho recognition unit recruits a second FGFR with assistance from heparan sulfate to form an asymmetric 1:2:1:1 complex that activates Ras-mitogen-activated protein kinase (MAPK) signaling. Circulating intact FGF23 reflects transcription, post-translational processing, secretion, and clearance. In FGF23-producing cells, polypeptide N-acetylgalactosaminyltransferase 3 (GALNT3)-mediated O-glycosylation at Thr178 protects the cleavage site, whereas phosphorylation of Ser180 by FAM20C, a Golgi-associated secretory pathway kinase, limits this protection. Furin and related proprotein convertases cleave FGF23 within the secretory pathway, although their in vivo contributions remain unresolved. In cell-free experiments, tissue-type and urokinase-type plasminogen activators directly cleave recombinant FGF23; mouse data also implicate the plasminogen activator inhibitor-1 axis, but its quantitative contribution to the human circulating pool is unknown. Receptor availability further shapes signaling. Although osteocytes and osteoblasts are the principal endocrine sources, human skin cells express and secrete FGF23 in vitro. Their response to 1,25-dihydroxyvitamin D3 depends partly on the vitamin D receptor, but whether skin contributes to circulating FGF23 remains undefined. Chronic kidney disease, autosomal dominant hypophosphatemic rickets, hyperphosphatemic familial tumoral calcinosis, X-linked hypophosphatemia, Raine syndrome, and ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) deficiency illustrate the relationships among FGF23 processing, bone-matrix signaling, and pyrophosphate homeostasis. This review integrates these mechanisms and evaluates burosumab, selective FGFR inhibition, C-terminal peptides, small-molecule antagonists, and ENPP1 enzyme replacement according to current evidence.
small molecules
2026-09-24 | Exploring the Association of Angiotensin-(1-7) with Left Ventricular Mass Index in Youth with Hereditary Hypophosphatemia: A Pilot Study.
Fibroblast growth factor 23 (FGF23) regulates phosphate homeostasis and is associated with cardiovascular-kidney-metabolic syndrome in patients with chronic kidney disease in part mediated by angiotensin II. X-linked hypophosphatemia (XLH) is characterized by phosphate wasting due to excess FGF23 activity, but its associations with angiotensin peptides and cardiovascular disease remain unclear. We evaluated cross-sectional associations between angiotensin II, angiotensin-(1-7), and left ventricular mass index (LVMI) in youth with XLH. A pilot prospective cross-sectional study enrolled youth and young adults aged 2-24 years with XLH from nephrology and endocrinology clinics at one hospital. Individuals with acquired hypophosphatemia or inability to provide urine were excluded. LVMI was collected from echocardiograms while peptides were measured in blood and urine by radioimmunoassays. We assessed associations using Spearman correlation coefficients. Among seven participants, 71% were female and median age was 12.8 years [IQR 7.7-13.7]. Seventy-one percent had a pathologic PHEX variant. Median peptide values were Ang II 56.0 pg/ml [47.2-58.1] and Ang-(1-7) 23.2 pg/ml [13.1-30.2] in blood and Ang II 32.1 pg/ml [27.5-103.2] and Ang-(1-7) 48.5 pg/ml [37.9-74.6] in urine. Median LVMI was 26.0 g/m2.7 [21.0-28.0] and 43.9 g/BSA [39.6-47.9]. Blood and urine angiotensin peptides were not correlated with either LVMI measure (p > 0.05). In youth and young adults with XLH, blood and urine angiotensin peptide collection was feasible, but values were not associated with LVMI, suggesting ACE/Ang II and ACE2/Ang-(1-7) may not mediate FGF23-related cardiovascular-kidney-metabolic syndrome risk if confirmed. Larger studies are needed to determine if the renin-angiotensin-aldosterone system contributes to worse outcomes in FGF23-mediated XLH and should be targeted to improve cardiovascular-kidney-metabolic health.
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.
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2026-09-03 | Role of 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 the pathophysiology of XLH. Particular attention was given to the role of 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 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.
2026-07-07 | 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.
2026-06-01 | Fifty Years of Misdiagnosis: Two Sisters with X-Linked Hypophosphatemia Misdiagnosed as Achondroplasia
X-linked hypophosphatemia (XLH) is the most common inherited form of hypophosphatemic rickets, caused by inactivating mutations in the phosphate-regulating endopeptidase homolog, X-linked (PHEX) gene. Despite its distinct clinical and biochemical features, XLH can be misdiagnosed as achondroplasia because of overlapping skeletal manifestations. Two sisters, aged 53 and 60 years, who were misdiagnosed with achondroplasia for more than 5 decades were later diagnosed with XLH. Both patients presented with diffuse bone pain, severe skeletal deformities, including coxa vara with shepherd’s crook deformity and femoral bowing and a history of spontaneous dental abscesses. Laboratory testing revealed hypophosphatemia with normocalcemia. Family history showed an X-linked dominant inheritance pattern, with an affected father, all 4 sisters affected, and 3 unaffected brothers—inconsistent with achondroplasia. Whole-exome sequencing identified a novel heterozygous PHEX variant, c.207_212del (p.K69_V70del), classified as a variant of uncertain significance (VUS) per American College of Medical Genetics (ACMG) guidelines. Notably, the first patient had undergone parathyroidectomy 24 years earlier, likely reflecting tertiary hyperparathyroidism as a long-term complication of undiagnosed XLH. This report highlights that careful evaluation of family history, combined with simple biochemical tests, can prevent decades of misdiagnosis and its associated morbidity. Cite this article as: Aydemir EE, Ertürk Ş., Leblebici CB, Karabulut HG, Demir. Fifty years of misdiagnosis: two sisters with X-linked hypophosphatemia misdiagnosed as achondroplasia. Endocrinol Res Pract. 2026;30(3):213-216.
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.
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.
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2026-09-23 | Real-World Effectiveness of Burosumab Versus Oral Phosphate and Active Vitamin D in Adults with X-Linked Hypophosphatemia (XLH): A 3-Year Follow-Up of the XLH Disease Monitoring Program.
X-linked hypophosphatemia (XLH) is a progressive disease in which excess FGF23 causes renal phosphate wasting, leading to hypophosphatemia. Consequences in adults include osteomalacia, fractures, pseudofractures, joint dysfunction, pain, and impaired mobility. Treatments for XLH are the anti-FGF23 antibody burosumab and active forms of vitamin D alone or in combination with oral phosphate (Pi/D). Randomized studies comparing burosumab with Pi/D in adults with XLH are lacking. We present a 3-yr follow-up analysis evaluating real-world effectiveness of burosumab versus Pi/D based on biochemistry and standardized symptom assessments (Western Ontario and McMaster Universities Osteoarthritis Index [WOMAC]) using data from the XLH Disease Monitoring Program (DMP; NCT03651505), a prospective, Americas-based study. Adults with XLH initiated burosumab between baseline and the year 1 visit (N = 54) or reported being on Pi/D therapy at enrollment (N = 55) were included. After adjusting for baseline differences using inverse probability of treatment weighting, the data showed a significantly higher mean (SD) change from baseline in serum phosphate with burosumab versus Pi/D (year 1: 0.8 [0.8] vs 0.1 [0.7] mg/dL; year 3: 0.6 [0.8] vs 0.1 [0.7] mg/dL, both p < .001). A higher proportion of burosumab versus Pi/D participants achieved serum phosphate levels above the lower limit of normal (2.5 mg/dL; year 1: 70.5% vs 18.8%; year 3: 60.8% vs 25.0%, both p < .001). At year 1, changes from baseline in WOMAC pain (-6.3 [27.7] vs 2.1 [22.4], p = .055), physical function (-6.4 [19.1] vs 0.1 [29.0], p = .122), and stiffness (-11.1 [32.1] vs -2.3 [33.7], p = .073) were not statistically significant between cohorts, but were significant at year 3 (pain: -9.8 [22.6] vs 3.3 [24.1], p < .001; physical function: -10.0 [25.7] vs 3.3 [24.7], p = .001; stiffness: -15.2 [29.5] vs -3.7 [31.4], p = .016). In this real-world analysis of adults with XLH over a 3-yr follow-up, burosumab treatment was associated with improved serum phosphate and patient-reported outcomes versus Pi/D.
2026-09-18 | Burosumab improves alkaline phosphatase and rickets severity in X-linked hypophosphatemia: 3-year SUNFLOWER analysis.
SUNFLOWER is a 10-year longitudinal observational cohort study of patients with X-linked hypophosphatemia (XLH) in Japan and South Korea. This report describes the 3-year cut-off of SUNFLOWER, including data from 1 year of burosumab administration (burosumab-treated group) and 1 year after providing informed consent (non-burosumab-treated group). The real-world effectiveness of burosumab and the associations between bone metabolism markers and quality of life (QoL)/patient-reported outcomes (PROs) and rickets severity scores (RSS)/height over 1 year in burosumab-treated patients with XLH were assessed. As burosumab had not been launched in South Korea at the time of cut-off, data from South Korea were not available. The main outcome measures were changes in serum parameters, and correlations between alkaline phosphatase (ALP) levels and RSS and height (children), and between ALP (children) or bone-specific ALP (BALP; adults) levels and QoL/PROs and motor functions. In total, 146 patients were enrolled, including 69 (47.3%) children and 77 (52.7%) adults. After 1 year of treatment, burosumab-treated patients (43 [62.3%] children, 29 [37.7%] adults) had improved serum phosphate levels, 1,25-dihydroxyvitamin D, and ALP/BALP compared with pre-treatment levels. In children, RSS changes significantly correlated with ALP changes (correlation coefficient: 0.806, p < 0.001), but height changes did not show significant correlation. There were no significant correlations between changes in ALP/BALP and QoL/PRO assessments or motor function. In conclusion, decreased ALP correlated with an improvement in rickets severity score in Japanese children with XLH, suggesting that ALP may be a useful marker for monitoring both the severity and improvement of rickets/osteomalacia. NCT03745521 and UMIN000031605.
2026-09-16 | Health-Related Quality of Life in Children with X-Linked Hypophosphatemia Treated with Burosumab: Real-World Data from a German-Swiss Study.
Burosumab is effective in improving rickets in children with X-linked hypophosphatemia (XLH). Predictors of health-related quality of life (HRQoL) in pediatric XLH patients treated with burosumab are unknown. In this cross-sectional analysis of a prospective binational observational study, we investigated HRQoL in 64 pediatric XLH patients (36 female) on burosumab treatment, using the KIDSCREEN-52 questionnaire and qualitative interviews. Associations between HRQoL and clinical findings were analysed using multiple regression and receiver operating characteristics (ROC) curve analyses. Median age at investigation and duration of burosumab treatment were 13.1 (IQR 10.4; 14.8) and 2.8 (IQR 1.4; 3.8) years, respectively; 54.7% of patients received secondary burosumab treatment following prior active vitamin D and phosphate. Overall, HRQoL scores were comparable to national reference values. Caregivers rated Physical Well-Being, Moods & Emotions, and Bullying lower than the patients themselves. Burosumab dose was significantly associated with Physical Well-Being, Psychological Well-Being, and Self-Perception in self-report, and with total T-values and Physical Well-Being in proxy questionnaires. The duration of prior treatment with active vitamin D and phosphate was significantly associated with the dimension of Autonomy in self-report and proxy reports. A burosumab dosage above 0.6 mg/kg was associated with a good Physical Well-Being (above the mean of the general population) with a sensitivity and specificity of 75% and 70% in self-report, and 67% and 70% in proxy questionnaires, respectively. In this real-world study, HRQoL in burosumab-treated children with XLH was comparable to that of the general population and associated with burosumab dosage.
2026-09-14 | Hypophosphataemia in adults: approach to diagnosis and management.
Hypophosphataemia is a common electrolyte disorder which can have clinically significant consequences for bone, muscle, neurological and haematological function. Its causes range from transient transcellular shifts in hospitalised patients to chronic renal phosphate-wasting disorders mediated by fibroblast growth factor 23 (FGF23). A stepwise diagnostic approach enables identification of the underlying aetiology and guides management. While most cases are managed with removal of causative factors and phosphate supplementation, burosumab has revolutionised the treatment of patients with chronic FGF23-mediated hypophosphataemia. This review provides a practical framework for the evaluation and management of hypophosphataemia in adults, with focussed discussion of iron infusion-associated hypophosphataemia, X-linked hypophosphataemia and tumour-induced osteomalacia.
2026-09-04 | Fibroblast growth factor 23 (FGF23): From synthesis to cleavage.
Fibroblast growth factor 23 (FGF23) maintains phosphate and vitamin D homeostasis. In the kidney, recognition of FGF23 is mediated by fibroblast growth factor receptors (FGFRs), α-Klotho, and heparan sulfate. Structural studies indicate that an FGF23-FGFR-α-Klotho recognition unit recruits a second FGFR with assistance from heparan sulfate to form an asymmetric 1:2:1:1 complex that activates Ras-mitogen-activated protein kinase (MAPK) signaling. Circulating intact FGF23 reflects transcription, post-translational processing, secretion, and clearance. In FGF23-producing cells, polypeptide N-acetylgalactosaminyltransferase 3 (GALNT3)-mediated O-glycosylation at Thr178 protects the cleavage site, whereas phosphorylation of Ser180 by FAM20C, a Golgi-associated secretory pathway kinase, limits this protection. Furin and related proprotein convertases cleave FGF23 within the secretory pathway, although their in vivo contributions remain unresolved. In cell-free experiments, tissue-type and urokinase-type plasminogen activators directly cleave recombinant FGF23; mouse data also implicate the plasminogen activator inhibitor-1 axis, but its quantitative contribution to the human circulating pool is unknown. Receptor availability further shapes signaling. Although osteocytes and osteoblasts are the principal endocrine sources, human skin cells express and secrete FGF23 in vitro. Their response to 1,25-dihydroxyvitamin D3 depends partly on the vitamin D receptor, but whether skin contributes to circulating FGF23 remains undefined. Chronic kidney disease, autosomal dominant hypophosphatemic rickets, hyperphosphatemic familial tumoral calcinosis, X-linked hypophosphatemia, Raine syndrome, and ectonucleotide pyrophosphatase/phosphodiesterase 1 (ENPP1) deficiency illustrate the relationships among FGF23 processing, bone-matrix signaling, and pyrophosphate homeostasis. This review integrates these mechanisms and evaluates burosumab, selective FGFR inhibition, C-terminal peptides, small-molecule antagonists, and ENPP1 enzyme replacement according to current evidence.
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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 | Orphan designation | Clinical trial status | Sponsor |
|---|---|---|---|---|
fibroblast growth factor 23-C tail | peptides | FDA | — | 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 | — | Aptacure Therapeutics Limited |
Recombinant human monoclonal IgG1 antibody for fibroblast growth factor 23 [CRYSVITA] | antibodies | EMA | Approved | Kyowa Kirin Holdings B.V. |
burosumab-twza [Crysvita] | antibodies | FDA | Approved | Kyowa Kirin, Inc. |
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