🧬 X-linked hypophosphataemic rickets (XLH) is the most common inherited form of rickets.
It results from excess fibroblast growth factor-23 (FGF23), causing chronic renal phosphate wasting, impaired vitamin D activation, and defective bone mineralisation.
Children develop rickets, while adults develop osteomalacia.
📖 Overview
- XLH is a genetic phosphate-wasting disorder inherited in an X-linked dominant pattern.
- The disease leads to reduced renal tubular phosphate reabsorption and reduced production of active vitamin D.
- Unlike nutritional rickets, patients typically have:
- ↓ serum phosphate
- Normal calcium
- Normal or mildly low vitamin D
- Chronic hypophosphataemia impairs hydroxyapatite formation, causing defective bone mineralisation.
🧬 Pathophysiology
- PHEX gene mutation (Xp22.1) → impaired degradation of FGF23.
- Excess FGF23 causes:
- Reduced phosphate reabsorption in the proximal renal tubule.
- Suppression of renal 1-α hydroxylase.
- Reduced production of 1,25-dihydroxyvitamin D.
- The resulting hypophosphataemia causes defective mineralisation of osteoid.
🩺 Clinical Features
- Children:
- Growth delay and short stature 📏
- Bowing of the legs (genu varum) or knock knees
- Delayed walking
- Bone pain and waddling gait
- Dental abscesses due to enamel defects
- Adults:
- Bone pain
- Stress fractures or pseudofractures
- Enthesopathy (calcification of tendon insertions)
- Early osteoarthritis
- Reduced mobility and fatigue
🔎 Investigations
- Blood tests
- ↓ Serum phosphate (hallmark)
- Normal serum calcium
- ↑ Alkaline phosphatase
- PTH may be mildly elevated
- 25-hydroxyvitamin D usually normal
- ↓ or inappropriately normal 1,25-dihydroxyvitamin D
- Urine studies
- Increased urinary phosphate excretion
- Reduced TmP/GFR indicating renal phosphate wasting
- Genetic testing
- PHEX mutation confirms diagnosis
- Imaging
- X-rays in children show classical rickets changes (cupping, fraying, metaphyseal widening).
- Adults may show Looser’s zones (pseudofractures).
🧾 Differential Diagnosis
- Nutritional vitamin D deficiency rickets
- Autosomal dominant hypophosphataemic rickets (ADHR)
- Renal tubular disorders (Fanconi syndrome)
- Tumour-induced osteomalacia (FGF23-secreting tumours)
💊 Management
- Conventional therapy
- Oral phosphate supplements (divided doses throughout the day).
- Active vitamin D analogues (calcitriol or alfacalcidol).
- Targeted therapy
- Burosumab – monoclonal antibody against FGF23.
- Improves phosphate levels, bone mineralisation, and growth.
- Supportive management
- Orthopaedic management of limb deformities.
- Dental care for recurrent abscesses.
- Physiotherapy and pain management.
⚠️ Monitoring and Complications
- Secondary hyperparathyroidism
- Nephrocalcinosis from long-term phosphate therapy
- Persistent skeletal deformities
- Chronic pain and reduced mobility
📝 Exam Tip
XLH classic biochemical pattern:
Low phosphate + Normal calcium + High ALP + Renal phosphate wasting.
📚 References
