RARE DISEASE
Hypophosphatemic rickets
Hypophosphatemic rickets
Hypophosphatemic rickets
Drug discovery
1
drug
With orphan designation
Overview
A genetic disorder characterized by renal phosphate wasting due to impaired tubular reabsorption, leading to hypophosphatemia and defective bone mineralization. Most commonly caused by X-linked dominant mutations in PHEX, resulting in elevated fibroblast growth factor-23 (FGF-23) levels. Clinical features include skeletal deformities (bowed legs, craniosynostosis), growth impairment, dental abscesses, and osteomalacia. Diagnosis involves hypophosphatemia, elevated alkaline phosphatase, and genetic testing. First-line treatment for XLH is burosumab, an anti-FGF-23 monoclonal antibody [1][4][6][18].
Categories: rare bone diseases, rare developmental anomalies during embryogenesis, rare endocrine diseases, rare genetic diseases, rare renal diseases
Research Papers
818 drug discovery papers about Hypophosphatemic rickets, with 1 first-in-class and 4 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
818 drug discovery papers about Hypophosphatemic rickets, with 1 first-in-class and 4 next-in-class emerging drug candidates forecasted to outperform the average preclinical success rate. Recent publications:
2026-08-13 | Regulation of Proximal Tubule Phosphate Transport: New Partners, New Pathways.
Disorders of phosphate homeostasis are common but difficult to treat. The major organ systems responsible for phosphate homeostasis are the intestine, bone, kidney, and parathyroid gland. Overall, kidney handling of phosphate is the major regulator of both serum phosphate levels and overall phosphate homeostasis. However, our ability to manipulate kidney phosphate handling has been very limited. Npt2a has been more thoroughly investigated than Npt2c, but recent studies identifying the role of Npt2c in human disease have uncovered key differences in the role of Npt2c in mice and humans. Recent studies have identified new proteins, such as TMEM174 and RGS14, that are involved in the regulation of the major sodium-dependent phosphate transporters in the kidney. Additionally, newer chemical agents to alter the function of these transporters have been developed. The purpose of this review is to highlight these new advances, place them in the context of our current knowledge of phosphate homeostasis, and explore potential new approaches to abnormalities of phosphate homeostasis. The recent discoveries suggest potential therapeutic targets for hyperphosphatemic conditions, such as chronic kidney disease and tumoral calcinosis, as well as for hypophosphatemic states, such as Fanconi syndrome, hypophosphatemic rickets, or transporter mutations.
2026-08-04 | A Diagnostic Dilemma: Hypophosphatemic Rickets Unmasking Tyrosinemia Type 1: A Case Report.
A 7.5-year-old Pakistani girl was misdiagnosed with hypophosphatemic rickets. Progressive skeletal deformities, hepatomegaly, and renal tubular dysfunction were detected despite standard treatment. Due to the atypical findings, genetic testing was performed and confirmed the diagnosis of Hereditary tyrosinemia Type 1. Her survival without liver failure remains atypical for Pakistan.
2026-08-01 | Recent advances in the diagnosis and treatment of X-linked hypophosphatemic rickets
X-linked hypophosphatemic rickets (XLH) is a skeletal mineralization disorder characterized by hypophosphatemia, caused by pathogenic variants in the PHEX gene that lead to elevated levels of fibroblast growth factor 23 (FGF23), which in turn inhibits renal phosphate reabsorption. In children, XLH primarily manifests as lower limb-predominant skeletal deformities, growth retardation, short stature, bone and joint pain, and dental abscesses.The traditional treatment regimen for XLH consists of neutral phosphate combined with calcitriol. In 2018, burosumab was approved for the treatment of patients with XLH. Burosumab targets and binds to FGF23 to inhibit its activity, increases renal phosphate reabsorption, reduces urinary phosphate excretion, promotes intestinal phosphate absorption, elevates serum phosphorus levels, and improves skeletal mineralization function. It has gradually become the first-line treatment for XLH. However, XLH is currently incurable, and existing treatment regimens struggle to maintain normal serum phosphorus levels. Even after treatment, patients generally still have a shorter final height. Additionally, due to various issues including its high cost, burosumab is rarely used in China, and clinicians have limited understanding of the advances in the diagnosis and treatment of XLH. Currently, several drugs targeting FGFR, α-Klotho, and other molecules, that aim to inhibit the effects of elevated FGF23 levels, are under development and are expected to provide new therapeutic options for XLH. This article reviews the cutting-edge advances in the diagnosis and treatment of XLH to help readers grasp the current status and future directions of this field.
2026-07-28 | Successful Transition in Rare Metabolic Bone Diseases: One-Year Outcomes of a Multidisciplinary Pediatric-Adult Program.
Background and Objectives: Pediatric-onset metabolic bone diseases, including osteogenesis imperfecta (OI), hypophosphatemic rickets (XLH), hypoparathyroidism, and McCune-Albright syndrome (MAS), require lifelong follow-up because of persistent skeletal fragility, biochemical abnormalities, and functional morbidity extending into adulthood. However, evidence regarding structured transition from pediatric to adult care in these rare disorders remains limited. This study evaluated one-year outcomes of a multidisciplinary transition program for adolescents and young adults with rare metabolic bone diseases. Materials and Methods: This retrospective cohort study included 20 patients aged ≥17 years who underwent evaluation through a structured transition pathway consisting of multidisciplinary team meetings, a joint pediatric-adult transition clinic, and subsequent follow-up in adult endocrinology. Demographic, clinical, treatment, and transition-related data were extracted from medical records. The primary outcome was successful transition, defined as at least one adult endocrinology visit within 12 months. Secondary outcomes included attendance at the transition clinic, follow-up continuity, and treatment modifications. Results: All patients underwent multidisciplinary evaluation, and 85% attended the joint transition clinic. Successful transfer to adult endocrinology was achieved in 90% (18/20), while regular follow-up during the first year was maintained in 75%. Retention was highest in patients with OI, MAS, XLH, vitamin D-dependent rickets, and DiGeorge syndrome (100%). Greater variability was observed in postoperative and primary hypoparathyroidism. Treatment adjustments were required in 40% of patients, including optimization of phosphate/calcitriol replacement and reassessment of bisphosphonate or burosumab therapy. Three patients were lost to follow-up. No acute transition-related complications were observed. Conclusions: In this small exploratory cohort, implementation of a structured multidisciplinary transition pathway was feasible and was accompanied by high transfer and one-year retention rates. Observed differences across diagnostic subgroups should be interpreted cautiously, and larger multicenter comparative studies are needed to evaluate the effectiveness of structured transition frameworks.
2026-07-24 | Case Report: Deep intronic PHEX variant causing aberrant splicing identified by whole genome and targeted RNA sequencing in X-linked hypophosphatemia.
X-linked hypophosphatemia (XLH) is a rare, genetically determined disorder of phosphate metabolism, most commonly caused by mutations in the PHEX gene. These mutations lead to overexpression of the phosphaturic hormone FGF23, resulting in renal phosphate wasting and impaired bone mineralization. In up to 16% of clinically diagnosed cases, no causative variant can be identified using standard sequencing approaches. We report on a female patient with a clearly defined clinical XLH phenotype, in whom no causative mutation had been detected over several years despite extensive genetic testing. The aim was to identify a previously undetected genetic cause using extended DNA and RNA methods. After unremarkable short-read whole exome sequencing (WES), short-read whole genome sequencing (WGS) was performed. For confirmation of splice effect, RNA was extracted from peripheral blood, amplified via RT-PCR, and analyzed using Nanopore long-read sequencing. A novel deep intronic variant in the PHEX gene (c.2070 + 601C>T) was identified and confirmed as de novo. The variant caused two aberrant transcripts with pseudoexon inclusions, each leading to a premature stop codon. This aberrant splicing supports the pathogenicity of the variant in the context of a loss-of-function mechanism. Following molecular diagnosis, the patient was successfully initiated on Burosumab therapy, resulting in clinical improvement. This case highlights the diagnostic value of comprehensive genomic analysis and subsequent RNA sequencing for identifying and analyzing deep intronic variants in genetically unexplained cases of XLH. The findings expand the known PHEX mutation spectrum and emphasize the importance of re-evaluating patients with a strong clinical diagnosis but previously negative genetic results. In the future, such technologies may play a crucial role in improving diagnostics for rare monogenic diseases.
2026-08-13 | Regulation of Proximal Tubule Phosphate Transport: New Partners, New Pathways.
Disorders of phosphate homeostasis are common but difficult to treat. The major organ systems responsible for phosphate homeostasis are the intestine, bone, kidney, and parathyroid gland. Overall, kidney handling of phosphate is the major regulator of both serum phosphate levels and overall phosphate homeostasis. However, our ability to manipulate kidney phosphate handling has been very limited. Npt2a has been more thoroughly investigated than Npt2c, but recent studies identifying the role of Npt2c in human disease have uncovered key differences in the role of Npt2c in mice and humans. Recent studies have identified new proteins, such as TMEM174 and RGS14, that are involved in the regulation of the major sodium-dependent phosphate transporters in the kidney. Additionally, newer chemical agents to alter the function of these transporters have been developed. The purpose of this review is to highlight these new advances, place them in the context of our current knowledge of phosphate homeostasis, and explore potential new approaches to abnormalities of phosphate homeostasis. The recent discoveries suggest potential therapeutic targets for hyperphosphatemic conditions, such as chronic kidney disease and tumoral calcinosis, as well as for hypophosphatemic states, such as Fanconi syndrome, hypophosphatemic rickets, or transporter mutations.
2026-08-04 | A Diagnostic Dilemma: Hypophosphatemic Rickets Unmasking Tyrosinemia Type 1: A Case Report.
A 7.5-year-old Pakistani girl was misdiagnosed with hypophosphatemic rickets. Progressive skeletal deformities, hepatomegaly, and renal tubular dysfunction were detected despite standard treatment. Due to the atypical findings, genetic testing was performed and confirmed the diagnosis of Hereditary tyrosinemia Type 1. Her survival without liver failure remains atypical for Pakistan.
2026-08-01 | Recent advances in the diagnosis and treatment of X-linked hypophosphatemic rickets
X-linked hypophosphatemic rickets (XLH) is a skeletal mineralization disorder characterized by hypophosphatemia, caused by pathogenic variants in the PHEX gene that lead to elevated levels of fibroblast growth factor 23 (FGF23), which in turn inhibits renal phosphate reabsorption. In children, XLH primarily manifests as lower limb-predominant skeletal deformities, growth retardation, short stature, bone and joint pain, and dental abscesses.The traditional treatment regimen for XLH consists of neutral phosphate combined with calcitriol. In 2018, burosumab was approved for the treatment of patients with XLH. Burosumab targets and binds to FGF23 to inhibit its activity, increases renal phosphate reabsorption, reduces urinary phosphate excretion, promotes intestinal phosphate absorption, elevates serum phosphorus levels, and improves skeletal mineralization function. It has gradually become the first-line treatment for XLH. However, XLH is currently incurable, and existing treatment regimens struggle to maintain normal serum phosphorus levels. Even after treatment, patients generally still have a shorter final height. Additionally, due to various issues including its high cost, burosumab is rarely used in China, and clinicians have limited understanding of the advances in the diagnosis and treatment of XLH. Currently, several drugs targeting FGFR, α-Klotho, and other molecules, that aim to inhibit the effects of elevated FGF23 levels, are under development and are expected to provide new therapeutic options for XLH. This article reviews the cutting-edge advances in the diagnosis and treatment of XLH to help readers grasp the current status and future directions of this field.
2026-07-28 | Successful Transition in Rare Metabolic Bone Diseases: One-Year Outcomes of a Multidisciplinary Pediatric-Adult Program.
Background and Objectives: Pediatric-onset metabolic bone diseases, including osteogenesis imperfecta (OI), hypophosphatemic rickets (XLH), hypoparathyroidism, and McCune-Albright syndrome (MAS), require lifelong follow-up because of persistent skeletal fragility, biochemical abnormalities, and functional morbidity extending into adulthood. However, evidence regarding structured transition from pediatric to adult care in these rare disorders remains limited. This study evaluated one-year outcomes of a multidisciplinary transition program for adolescents and young adults with rare metabolic bone diseases. Materials and Methods: This retrospective cohort study included 20 patients aged ≥17 years who underwent evaluation through a structured transition pathway consisting of multidisciplinary team meetings, a joint pediatric-adult transition clinic, and subsequent follow-up in adult endocrinology. Demographic, clinical, treatment, and transition-related data were extracted from medical records. The primary outcome was successful transition, defined as at least one adult endocrinology visit within 12 months. Secondary outcomes included attendance at the transition clinic, follow-up continuity, and treatment modifications. Results: All patients underwent multidisciplinary evaluation, and 85% attended the joint transition clinic. Successful transfer to adult endocrinology was achieved in 90% (18/20), while regular follow-up during the first year was maintained in 75%. Retention was highest in patients with OI, MAS, XLH, vitamin D-dependent rickets, and DiGeorge syndrome (100%). Greater variability was observed in postoperative and primary hypoparathyroidism. Treatment adjustments were required in 40% of patients, including optimization of phosphate/calcitriol replacement and reassessment of bisphosphonate or burosumab therapy. Three patients were lost to follow-up. No acute transition-related complications were observed. Conclusions: In this small exploratory cohort, implementation of a structured multidisciplinary transition pathway was feasible and was accompanied by high transfer and one-year retention rates. Observed differences across diagnostic subgroups should be interpreted cautiously, and larger multicenter comparative studies are needed to evaluate the effectiveness of structured transition frameworks.
2026-07-24 | Case Report: Deep intronic PHEX variant causing aberrant splicing identified by whole genome and targeted RNA sequencing in X-linked hypophosphatemia.
X-linked hypophosphatemia (XLH) is a rare, genetically determined disorder of phosphate metabolism, most commonly caused by mutations in the PHEX gene. These mutations lead to overexpression of the phosphaturic hormone FGF23, resulting in renal phosphate wasting and impaired bone mineralization. In up to 16% of clinically diagnosed cases, no causative variant can be identified using standard sequencing approaches. We report on a female patient with a clearly defined clinical XLH phenotype, in whom no causative mutation had been detected over several years despite extensive genetic testing. The aim was to identify a previously undetected genetic cause using extended DNA and RNA methods. After unremarkable short-read whole exome sequencing (WES), short-read whole genome sequencing (WGS) was performed. For confirmation of splice effect, RNA was extracted from peripheral blood, amplified via RT-PCR, and analyzed using Nanopore long-read sequencing. A novel deep intronic variant in the PHEX gene (c.2070 + 601C>T) was identified and confirmed as de novo. The variant caused two aberrant transcripts with pseudoexon inclusions, each leading to a premature stop codon. This aberrant splicing supports the pathogenicity of the variant in the context of a loss-of-function mechanism. Following molecular diagnosis, the patient was successfully initiated on Burosumab therapy, resulting in clinical improvement. This case highlights the diagnostic value of comprehensive genomic analysis and subsequent RNA sequencing for identifying and analyzing deep intronic variants in genetically unexplained cases of XLH. The findings expand the known PHEX mutation spectrum and emphasize the importance of re-evaluating patients with a strong clinical diagnosis but previously negative genetic results. In the future, such technologies may play a crucial role in improving diagnostics for rare monogenic diseases.
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
1 orphan drug designation for Hypophosphatemic rickets.
1 orphan drug designation for Hypophosphatemic rickets.
Drug | Therapy type | Regulator | Orphan designation | Approval | Sponsor |
|---|---|---|---|---|---|
Secalciferol | small molecules | FDA | 1993-07-26 | — | Teva Pharmaceuticals USA |
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