X-linked hypophosphatemia (XLH) is the most common hereditary form of rickets, caused by loss-of-function mutations in PHEX, a phosphate-regulating endopeptidase. PHEX deficiency leads to elevated FGF23 levels, causing renal phosphate wasting and impaired 1,25-dihydroxyvitamin D synthesis. This results in chronic hypophosphatemia, rickets/osteomalacia, short stature, and dental abnormalities. Burosumab (Crysvita), an anti-FGF23 antibody, is approved for treatment.
name: X-Linked Hypophosphatemia
creation_date: '2026-02-13T00:31:42Z'
updated_date: '2026-02-16T20:19:38Z'
category: Mendelian
description: >
X-linked hypophosphatemia (XLH) is the most common hereditary form of rickets,
caused by loss-of-function mutations in PHEX, a phosphate-regulating endopeptidase.
PHEX deficiency leads to elevated FGF23 levels, causing renal phosphate wasting
and impaired 1,25-dihydroxyvitamin D synthesis. This results in chronic
hypophosphatemia, rickets/osteomalacia, short stature, and dental abnormalities.
Burosumab (Crysvita), an anti-FGF23 antibody, is approved for treatment.
disease_term:
preferred_term: X-linked dominant hypophosphatemic rickets
term:
id: MONDO:0010619
label: X-linked dominant hypophosphatemic rickets
parents:
- Metabolic Bone Disorders
inheritance:
- name: X-linked Dominant
description: >
X-linked dominant inheritance with variable expressivity. Males
are generally more severely affected than females. The PHEX gene
is located on Xp22.1.
evidence:
- reference: PMID:7550339
supports: SUPPORT
snippet: "X-linked hypophosphatemic rickets (HYP) is a dominant disorder characterised by impaired phosphate uptake in the kidney"
explanation: "Confirms X-linked dominant inheritance pattern of XLH."
pathophysiology:
- name: Renal Phosphate Wasting via FGF23 Excess
description: >
Loss-of-function mutations in PHEX lead to elevated circulating FGF23
(fibroblast growth factor 23), a phosphaturic hormone produced by
osteocytes. Elevated FGF23 acts on the kidney to downregulate sodium-
phosphate cotransporters (NaPi-IIa/IIc) in the proximal tubule, causing
renal phosphate wasting. FGF23 also suppresses 1-alpha-hydroxylase
(CYP27B1), reducing conversion of 25-hydroxyvitamin D to active
1,25-dihydroxyvitamin D, further impairing phosphate absorption.
biological_processes:
- preferred_term: Phosphate Ion Homeostasis
term:
id: GO:0055062
label: phosphate ion homeostasis
- preferred_term: Vitamin D Metabolism
term:
id: GO:0042359
label: vitamin D metabolic process
cell_types:
- preferred_term: Osteocyte
term:
id: CL:0000137
label: osteocyte
- preferred_term: Kidney Proximal Tubule Cell
term:
id: CL:0002306
label: epithelial cell of proximal tubule
evidence:
- reference: PMID:29947083
supports: SUPPORT
snippet: "inherited loss-of-function mutations in the PHEX gene cause excess circulating levels of fibroblast growth factor 23 (FGF23), leading to lifelong renal phosphate wasting and hypophosphatemia"
explanation: "Directly describes the FGF23-mediated phosphate wasting mechanism in XLH."
- reference: PMID:7550339
supports: SUPPORT
snippet: "impaired phosphate uptake in the kidney, which is likely to be caused by abnormal regulation of sodium phosphate cotransport in the proximal tubules"
explanation: "Early evidence linking PHEX to renal proximal tubule phosphate transport defect."
- reference: PMID:11062477
supports: PARTIAL
snippet: "We identified missense mutations in a gene encoding a new member of the fibroblast growth factor (FGF) family, FGF23"
explanation: "Discovery of FGF23 as the phosphaturic factor, providing the mechanistic link between PHEX and phosphate wasting."
- name: Defective Bone Mineralization
description: >
Chronic hypophosphatemia results in insufficient phosphate for
hydroxyapatite crystal formation. This causes rickets at the
growth plate in children (disorganized hypertrophic zone, widened
physis) and osteomalacia in adults (undermineralized osteoid).
The mineralization defect persists despite growth plate closure
in adults.
biological_processes:
- preferred_term: Ossification
term:
id: GO:0001503
label: ossification
cell_types:
- preferred_term: Osteoblast
term:
id: CL:0000062
label: osteoblast
evidence:
- reference: PMID:29947083
supports: PARTIAL
snippet: "fractures, and pseudofractures due to osteomalacia"
explanation: "Pseudofractures and fractures reflect defective mineralization (osteomalacia) in adults with XLH."
phenotypes:
- name: Rickets
description: >
Rachitic changes at the growth plate, bowing of lower extremities
(genu varum), and metaphyseal irregularities. Typically presents
in the first two years of life when the child begins weight-bearing.
phenotype_term:
preferred_term: Rickets
term:
id: HP:0002748
label: Rickets
evidence:
- reference: PMID:31104833
supports: SUPPORT
snippet: "X-linked hypophosphataemia in children is characterised by elevated serum concentrations of fibroblast growth factor 23 (FGF23), hypophosphataemia, rickets, lower extremity bowing, and growth impairment"
explanation: "Phase 3 trial confirms rickets and lower extremity bowing as cardinal pediatric features of XLH."
- reference: PMID:11062477
supports: SUPPORT
snippet: "characterized by low serum phosphorus concentrations, rickets, osteomalacia, lower extremity deformities, short stature, bone pain and dental abscesses"
explanation: "Rickets listed as core clinical feature of phosphate wasting disorders."
- name: Short Stature
description: >
Disproportionate short stature with relatively short lower limbs.
Adult height is typically -2 to -3 SD below mean.
phenotype_term:
preferred_term: Short stature
term:
id: HP:0004322
label: Short stature
evidence:
- reference: PMID:29947083
supports: SUPPORT
snippet: "Adults with XLH present with chronic musculoskeletal pain and stiffness, short stature, lower limb deformities"
explanation: "Short stature confirmed as characteristic adult XLH feature."
- reference: PMID:11062477
supports: SUPPORT
snippet: "rickets, osteomalacia, lower extremity deformities, short stature, bone pain and dental abscesses"
explanation: "Short stature listed as core clinical feature."
- name: Lower Limb Bowing
description: >
Progressive bowing of the legs (genu varum), worse with ambulation.
May require surgical correction (osteotomy).
phenotype_term:
preferred_term: Genu varum
term:
id: HP:0002970
label: Genu varum
evidence:
- reference: PMID:29947083
supports: SUPPORT
snippet: "short stature, lower limb deformities, fractures, and pseudofractures due to osteomalacia"
explanation: "Lower limb deformities confirmed as characteristic feature in adults with XLH."
- reference: PMID:29460029
supports: SUPPORT
snippet: "Orthopaedic involvement requiring surgical intervention (osteotomy) was frequent"
explanation: "Confirms that lower limb bowing frequently requires surgical correction in adult XLH patients."
- name: Dental Abscesses
description: >
Spontaneous dental abscesses and periapical lucencies from
defective dentin mineralization, without caries. May be the
presenting feature.
phenotype_term:
preferred_term: Tooth abscess
term:
id: HP:0030757
label: Tooth abscess
evidence:
- reference: PMID:29947083
supports: SUPPORT
snippet: "accelerated osteoarthritis, dental abscesses, and enthesopathy"
explanation: "Dental abscesses confirmed as characteristic adult XLH feature."
- reference: PMID:29460029
supports: SUPPORT
snippet: "Dental disease (63%), nephrocalcinosis (42%), and hearing impairment (14%) were also common"
explanation: "63% prevalence of dental disease in adult XLH cohort."
- reference: PMID:11062477
supports: SUPPORT
snippet: "rickets, osteomalacia, lower extremity deformities, short stature, bone pain and dental abscesses"
explanation: "Dental abscesses listed as core clinical feature of phosphate wasting disorders."
- name: Enthesitis
description: >
Calcification and ossification of tendons, ligaments, and joint
capsules in adults. Progressive and often disabling, affecting
spine and major joints.
phenotype_term:
preferred_term: Enthesitis
term:
id: HP:0100686
label: Enthesitis
evidence:
- reference: PMID:29947083
supports: SUPPORT
snippet: "dental abscesses, and enthesopathy"
explanation: "Enthesopathy confirmed as characteristic adult XLH feature."
- reference: PMID:29460029
supports: PARTIAL
snippet: "Joint replacement and decompressive laminectomy were observed in those older than 40 years"
explanation: "Progressive enthesopathy leads to need for joint replacement and spinal surgery in older adults."
- name: Hypophosphatemia
description: >
Chronic low serum phosphate due to renal phosphate wasting.
The biochemical hallmark of the disease.
phenotype_term:
preferred_term: Hypophosphatemia
term:
id: HP:0002148
label: Hypophosphatemia
evidence:
- reference: PMID:29460029
supports: SUPPORT
snippet: "X-linked hypophosphatemia (XLH) is the most common monogenic disorder causing hypophosphatemia"
explanation: "XLH confirmed as the most common hereditary cause of hypophosphatemia."
- reference: PMID:29947083
supports: SUPPORT
snippet: "leading to lifelong renal phosphate wasting and hypophosphatemia"
explanation: "Lifelong hypophosphatemia confirmed as the biochemical hallmark."
- name: Craniosynostosis
description: >
Premature cranial suture fusion occurs in a subset of patients,
particularly those with more severe disease.
phenotype_term:
preferred_term: Craniosynostosis
term:
id: HP:0001363
label: Craniosynostosis
genetic:
- name: PHEX Mutations
association: Causative
notes: >
Loss-of-function mutations in PHEX (phosphate-regulating endopeptidase
homolog, X-linked) on Xp22.1. Over 300 mutations described including
missense, nonsense, splice-site, and large deletions. The precise
mechanism by which PHEX deficiency elevates FGF23 remains incompletely
understood.
evidence:
- reference: PMID:7550339
supports: SUPPORT
snippet: "By positional cloning, we have isolated a candidate gene from the HYP region in Xp22.1. This gene exhibits homology to a family of endopeptidase genes"
explanation: "Original cloning of the PHEX gene from Xp22.1 with endopeptidase homology."
- reference: PMID:7550339
supports: SUPPORT
snippet: "Intragenic non-overlapping deletions from four different families and three mutations (two splice sites and one frameshift) have been detected in HYP patients"
explanation: "Early evidence of diverse mutation types in PHEX causing XLH."
- reference: PMID:29460029
supports: SUPPORT
snippet: "XLH is associated with a large number of private mutations; 37 different mutations in the PHEX gene were identified in this cohort"
explanation: "37 distinct PHEX mutations in a single cohort confirms extensive allelic heterogeneity."
- reference: PMID:11062477
supports: SUPPORT
snippet: "Inactivating mutations of the gene PHEX, encoding a member of the neutral endopeptidase family of proteins, are responsible for XLH"
explanation: "Confirms inactivating PHEX mutations as the cause of XLH."
treatments:
- name: Burosumab (Crysvita)
description: >
Anti-FGF23 monoclonal antibody. Directly targets the pathogenic
mechanism by neutralizing excess FGF23, normalizing phosphate
homeostasis. FDA approved 2018 for pediatric and adult XLH.
Administered subcutaneously every 2-4 weeks.
evidence:
- reference: PMID:29947083
supports: SUPPORT
snippet: "Burosumab, a fully human monoclonal antibody, binds and inhibits FGF23 to correct hypophosphatemia"
explanation: "Describes burosumab mechanism as anti-FGF23 antibody."
- reference: PMID:29947083
supports: SUPPORT
snippet: "94.1% of burosumab-treated participants attained mean serum phosphate concentration above the lower limit of normal compared with 7.6% of those receiving placebo"
explanation: "Phase 3 adult trial demonstrates robust phosphate normalization with burosumab."
- reference: PMID:29947083
supports: SUPPORT
snippet: "43.1% (burosumab) and 7.7% (placebo) of baseline active fractures were fully healed; the odds of healed fracture in the burosumab group was 16.8-fold greater than that in the placebo group"
explanation: "Burosumab dramatically improves fracture healing in adults with XLH."
- reference: PMID:31104833
supports: SUPPORT
snippet: "Significantly greater clinical improvements were shown in rickets severity, growth, and biochemistries among children with X-linked hypophosphataemia treated with burosumab compared with those continuing conventional therapy"
explanation: "Phase 3 pediatric trial confirms burosumab superiority over conventional therapy for rickets, growth, and biochemistry."
- name: Conventional Therapy (Phosphate/Calcitriol)
description: >
Oral phosphate supplementation combined with active vitamin D
(calcitriol or alfacalcidol). Previously standard of care but
limited by GI side effects, secondary hyperparathyroidism, and
nephrocalcinosis risk.
evidence:
- reference: PMID:29460029
supports: PARTIAL
snippet: "Dental disease (63%), nephrocalcinosis (42%), and hearing impairment (14%) were also common"
explanation: "42% nephrocalcinosis rate reflects a known complication of conventional phosphate/calcitriol therapy."
- name: Orthopedic Management
description: >
Corrective osteotomies for significant lower limb deformity.
Timing typically after optimization of medical therapy and
near completion of growth.
treatment_term:
preferred_term: surgical procedure
term:
id: MAXO:0000004
label: surgical procedure
located_in:
preferred_term: hindlimb
term:
id: UBERON:0002103
label: hindlimb
evidence:
- reference: PMID:29460029
supports: SUPPORT
snippet: "Orthopaedic involvement requiring surgical intervention (osteotomy) was frequent. Joint replacement and decompressive laminectomy were observed in those older than 40 years"
explanation: "Confirms frequent need for osteotomy and joint replacement in adult XLH patients."
datasets: []