X linked hypophosphataemia

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X-Linked Hypophosphataemia (XLH)

Overview

X-linked hypophosphataemia (XLH), also known as X-linked hypophosphatemic rickets (XLHR), is the most common inherited form of hypophosphatemic rickets and osteomalacia, with a prevalence of approximately 1 in 20,000. It is inherited in an X-linked dominant pattern, affecting both males and females, though males tend to be more severely affected.

Goldman-Cecil Medicine, p. 2628

Genetics and Molecular Basis

Gene involved: PHEX (Phosphate-regulating gene with homologies to Endopeptidases on the X chromosome), located at Xp22.1.

PHEX encodes a zinc-dependent neutral endopeptidase expressed predominantly on the surface of osteocytes and mature osteoblasts. Loss-of-function mutations in PHEX result in elevated circulating FGF23 (fibroblast growth factor 23). Although it was initially thought PHEX directly cleaved FGF23, this is no longer supported - the exact mechanism by which PHEX inactivation raises FGF23 remains incompletely understood.

Key downstream effects of excess FGF23:

Inhibits apical expression of NaPi-2a (SLC34A1) and NaPi-2c (SLC34A3) in the proximal tubule → reduced renal phosphate reabsorption → phosphaturia and hypophosphataemia
Inhibits renal 1α-hydroxylase (CYP27B1) → suppressed synthesis of 1,25(OH)₂D (calcitriol) - this is paradoxical because hypophosphataemia normally stimulates calcitriol production
Reduced calcitriol → impaired intestinal phosphate absorption, compounding hypophosphataemia

The Hyp mouse (3' deletion in PHEX) is the standard animal model of XLH, and ablation of the FGF23 gene in this model reverses the hypophosphataemia, confirming FGF23 centrality.

Harrison's Principles of Internal Medicine 22E, p. 3307-3308
Katzung's Basic and Clinical Pharmacology 16e
National Kidney Foundation Primer on Kidney Diseases, 8e, p. 401

Pathophysiology Summary

PHEX mutation (X-linked dominant)
        ↓
  ↑ FGF23 from osteocytes
        ↓
  ↓ NaPi-2a / NaPi-2c in proximal tubule
        ↓
  Renal phosphate wasting → Hypophosphataemia
        +
  ↓ 1,25(OH)₂D production (↓ 1α-hydroxylase)
        ↓
  ↓ Intestinal phosphate absorption
        ↓
  Defective bone/cartilage mineralisation
  → RICKETS (children) / OSTEOMALACIA (adults)

Note: Other factors independent of FGF23 may also contribute to bone demineralisation in XLHR.

Clinical Features

In Children (Rickets)

Bowing of the legs (genu varum) - the most recognisable feature
Short stature - one of the hallmarks; epiphyseal growth disruption
Dental abscesses - spontaneous, without trauma, due to abnormal dentine mineralisation (odontoblast defect); this is pathognomonic of XLH
Frontal bossing, rachitic rosary, widened wrists/ankles
Delayed walking, waddling gait
Craniosynostosis (rare)
Enthesopathy - calcification of tendons and ligaments (more prominent in adults)

In Adults (Osteomalacia)

Bone pain, stress fractures, pseudo-fractures (Looser zones)
Enthesopathy causing spinal stenosis, hearing impairment
Persistent short stature
Osteoarthritis of knees and hips

Biochemical Profile

Parameter	Finding
Serum phosphate	Low (hypophosphataemia)
Serum calcium	Normal or low-normal
PTH	Normal or mildly elevated (secondary)
1,25(OH)₂D (calcitriol)	Low or inappropriately normal (key feature - should be high if phosphate is low)
25(OH)D	Normal
ALP	Elevated (marker of bone disease activity)
Urinary phosphate	Elevated (TmP/GFR low) - phosphaturia
FGF23	Elevated

The combination of hypophosphataemia + low/normal calcitriol (without secondary cause) is a diagnostic red flag for FGF23-mediated disease.

Diagnosis

Clinical history - family history (X-linked dominant pedigree), characteristic features in childhood
Biochemistry - as above; measure fasting phosphate (significant diurnal variation otherwise)
FGF23 level - elevated (intact FGF23 assay)
PHEX gene sequencing - confirms diagnosis; identifies mutation in ~70-80% of cases
Radiology - rickets changes at growth plates (metaphyseal irregularity, cupping, fraying); Looser zones in adults
TmP/GFR ratio - low, confirming renal phosphate wasting

Differential diagnosis of FGF23-mediated hypophosphataemia:

Autosomal dominant hypophosphatemic rickets (ADHR) - FGF23 gain-of-function mutations
Autosomal recessive hypophosphatemic rickets (ARHR) types 1-3 - DMP1, ENPP1, FAM20C mutations
Tumor-induced osteomalacia (TIO) - acquired FGF23 excess from mesenchymal tumours

Treatment

Traditional Therapy (prior to burosumab)

Oral phosphate supplements - 1-3 g/day in divided doses (to limit GI side effects and secondary hyperparathyroidism)
Calcitriol (1,25(OH)₂D) - 0.25-2 mcg/day
Rationale: correct the two downstream consequences of FGF23 excess
Limitations:
- Prolonged use leads to secondary/tertiary hyperparathyroidism
- Nephrocalcinosis with phosphate + calcitriol combination
- Symptoms and deformities not fully corrected
- Does not address the primary pathophysiology (elevated FGF23)

Burosumab (Crysvita) - Anti-FGF23 Monoclonal Antibody

Burosumab is a fully human IgG1 monoclonal antibody that directly neutralises excess FGF23. It is the first disease-modifying treatment for XLH.

Approved for: Children and adults with XLH

Dosing:

Children: 0.8-2 mg/kg subcutaneous injection every 2 weeks, adjusted based on serum phosphate
Adults: 1 mg/kg SC every 4 weeks, up to a maximum of 90 mg, adjusted based on serum phosphate

Efficacy:

Corrects hypophosphataemia
Improves bone mineralisation and reduces rickets severity
Reduces fractures and pseudo-fractures
Improves pain and physical functioning
Does not cause secondary hyperparathyroidism (unlike phosphate + calcitriol)

Recent evidence: Two 2024 meta-analyses (PMIDs 39211452 and 39008126) confirm burosumab's efficacy and safety in children. A 2025 systematic review (PMID 39715351) evaluated outcomes important to adult patients with XLH on medical therapy.

Note: Burosumab should not be used concurrently with oral phosphate/calcitriol in most protocols - this can cause hyperphosphataemia.

Orthopaedic Considerations

Corrective osteotomy for severe limb deformity (after biochemical control is achieved)
Growth hormone has been used in some cases to improve final height

Monitoring

Serum phosphate, calcium, ALP, PTH, creatinine
Urine calcium:creatinine ratio (renal calcification risk)
Renal ultrasound for nephrocalcinosis
Bone radiographs for healing
FGF23 levels if on burosumab

Comparison: XLH vs Other Hypophosphatemic Disorders

Feature	XLH	ADHR	TIO
Inheritance	X-linked dominant	Autosomal dominant	Acquired
Gene	PHEX	FGF23	Mesenchymal tumour
FGF23	Elevated	Elevated	Elevated
Key mechanism	PHEX loss → ↑ FGF23	Resistant-to-cleavage FGF23	Tumour FGF23 secretion
Treatment	Burosumab / phosphate+calcitriol	Similar	Tumour resection

Sources:

Harrison's Principles of Internal Medicine 22E, pp. 3307-3308
Goldman-Cecil Medicine, p. 2628
Katzung's Basic and Clinical Pharmacology 16e
National Kidney Foundation Primer on Kidney Diseases 8e, pp. 400-401

Recent systematic reviews:

Wang K et al. (2024) - burosumab in children with XLH [PMID 39211452]
Kiafzezi D et al. (2024) - burosumab real-world data [PMID 39008126]
Ali DS et al. (2025) - medical therapy outcomes in adult XLH [PMID 39715351]

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