X-linked hypophosphatemia results from pathogenic variants in the PHEX gene, which maps to the X chromosome. PHEX encodes phosphate-regulating endopeptidase homolog X-linked, a protein involved in the regulation of fibroblast growth factor 23 (FGF23). Loss-of-function variants in PHEX lead to elevated circulating FGF23 levels, which impair renal phosphate reabsorption and suppress renal 1-alpha-hydroxylase activity, producing hypophosphatemia and inappropriately low or normal concentrations of calcitriol. The resulting phosphate deficiency disrupts normal bone and tooth mineralization and generates the characteristic skeletal and dental manifestations of the disease. The condition follows an X-linked dominant inheritance pattern, with documented complete penetrance (100%) in both affected males and females. The pathophysiological centrality of FGF23 dysregulation is reflected in the mechanism of action of the approved targeted therapy, burosumab, which acts by blocking FGF23.

Diagnosis of X-linked hypophosphatemia is established through the combination of clinical, radiographic, laboratory, and family history assessment, as described in the GeneReviews diagnostic criteria. Suggestive clinical findings in children include signs of rickets resistant to treatment with standard vitamin D supplementation, progressive lower extremity bowing, decreased height velocity after the onset of ambulation, epiphyseal swelling, and Harrison groove. Obligate laboratory abnormalities include hypophosphatemia and elevated alkaline phosphatase, both documented in the linked phenotype dataset as present in 100% of affected individuals. Molecular genetic testing demonstrating a pathogenic or likely pathogenic variant in the PHEX gene confirms the diagnosis. Because clinical presentation is variable and can range from isolated biochemical hypophosphatemia to severe skeletal disease, some individuals are not diagnosed until adulthood. Penetrance is complete in both sexes. GeneReviews documentation describes multidisciplinary team evaluation at tertiary referral centers as the standard management approach for XLH.

Burosumab (Crysvita; burosumab-twza), a monoclonal antibody targeting FGF23, received FDA approval on April 17, 2018, and is listed as the sole FDA-approved treatment for XLH in the disease packet. Burosumab acts by blocking elevated FGF23 activity, thereby restoring renal phosphate reabsorption and normalizing 1,25-dihydroxyvitamin D concentrations. GeneReviews clinical trial documentation indicates that burosumab improved radiographic signs of rickets, corrected lower limb deformity, and improved height z-scores in children compared with conventional therapy using oral phosphate supplementation with active vitamin D; a statistically significant improvement in height was documented at 64 weeks but not at 40 weeks. Management guidelines described in GeneReviews identify the aim of targeted therapy as improving osteomalacia and rickets, reducing pain, promoting fracture healing, and—in children—stimulating growth and correcting or preventing bone deformation, while also minimizing complications of therapy. An investigational compound, KK8123, is being evaluated in a Phase 1 first-in-human study in adults with XLH (NCT06525636; sponsor: Kyowa Kirin Co., Ltd.).

X-linked hypophosphatemia is a chronic, lifelong condition with clinical features evolving from childhood rickets and growth impairment through adult-onset enthesopathy, joint pain, pseudofractures, and dental disease. GeneReviews documentation characterizes health-related quality-of-life impairment as substantial, exceeding that reported in comparator chronic musculoskeletal conditions such as axial spondylarthritis. Penetrance is complete, meaning all individuals carrying pathogenic PHEX variants are expected to develop clinical manifestations. The availability of burosumab as a targeted therapy since 2018 has introduced the potential to alter the natural history trajectory for individuals treated during childhood, with documented improvements in skeletal and growth parameters in clinical trials. Long-term outcomes under targeted therapy are being assessed in ongoing registry and observational studies, including the XLH Disease Monitoring Program (NCT03651505, Ultragenyx Pharmaceutical) and a patient registry sponsored by Kyowa Kirin (NCT03193476). Adult outcomes across the full natural history arc, particularly for individuals diagnosed and managed prior to the availability of targeted therapy, continue to be characterized in the literature.

Eight active clinical trials are registered for X-linked hypophosphatemia as of the packet generation date, encompassing natural history registry studies, pharmacokinetic and dosing investigations of burosumab, observational outcome studies in adult populations, and a Phase 1 investigation of a novel compound (KK8123, NCT06525636, Kyowa Kirin Co., Ltd.). Industry sponsors active in the XLH clinical trial landscape include Kyowa Kirin, Ultragenyx Pharmaceutical, and Novo Nordisk. A classified research landscape derived from 136 publications identifies epidemiology and natural history as the dominant research focus. The landscape additionally documents publications addressing gene therapy approaches and biomarker research, as well as recent clinical trial–related publications. Thirty-four review articles and 14 case reports are represented in the classified corpus. One additional orphan drug designation has been granted to an investigational antisense oligonucleotide compound (Aptacure Therapeutics Limited) for the treatment of X-linked hypophosphatemia, reflecting ongoing interest in expanded therapeutic development beyond the current approved agent.