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:
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.
2026-08-01 | 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.
2026-07-09 | 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.
2026-07-07 | 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.
2026-07-03 | 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.
2026-08-16 | 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.
2026-08-01 | 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.
2026-07-09 | 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.
2026-07-07 | 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.
2026-07-03 | 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.
Access all drug discovery papers and probability of success in trials forecasts:
Access all drug discovery papers and probability of success in trials forecasts:
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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