Makindo Medical Notes

Related Subjects: |Vitamin D Replacement |Osteomalacia-Rickets-Vitamin D |Vitamin D resistant rickets |Vitamin D (25 OH D) Testing |X linked Hypophosphataemic rickets |Osteoporosis

🦴 In Hypophosphatemic Rickets, defective renal phosphate reabsorption causes chronic phosphate wasting and hypophosphatemia. Unlike nutritional rickets, patients typically do not respond to standard Vitamin D therapy.

📖 About

• Hypophosphatemic Rickets (also called Vitamin D–Resistant Rickets) is a disorder of mineral metabolism caused by renal phosphate wasting.
• Inheritance is most commonly X-linked dominant (mutation in the PHEX gene). Autosomal recessive and sporadic forms exist.
• Most patients present in childhood with rickets that fails to improve despite Vitamin D supplementation.

🧬 Renal Tubular (RT) Forms

• Type I: Defect in renal 1-alpha-hydroxylase, leading to inadequate conversion of 25(OH)D → 1,25(OH)₂D.
• Type II: End-organ resistance to active Vitamin D (1,25(OH)₂D).
• Both are treated with high doses of calcitriol (active Vitamin D).

⚙️ Aetiology & Pathophysiology

• 🧪 Defective phosphate reabsorption in the proximal renal tubules → urinary phosphate wasting.
• ⬇️ Serum phosphate → impaired bone mineralisation → rickets/osteomalacia.
• Frequently associated with elevated FGF23 (fibroblast growth factor-23), a hormone that suppresses phosphate reabsorption and 1-alpha-hydroxylase activity.

🩺 Clinical Features

• 👶 Presents in infancy or early childhood.
• 📏 Short stature & growth failure.
• 🦵 Bowed legs (genu varum) or knock knees (genu valgum).
• 🦷 Dental problems: delayed dentition, spontaneous abscesses.
• Other possible features:
  • 👂 Deafness
  • 🧠 Chiari malformation
  • 💀 Craniosynostosis
  • 🪨 Calcification of ligaments, tendons, and joint capsules
  • 🪥 Renal stones or nephrocalcinosis

🔎 Investigations

• ⬇️ Serum phosphate
• ⬆️ Alkaline phosphatase (ALP)
• ⬆️ Urinary phosphate excretion
• ⬇️ or normal calcium
• ⬆️ Parathyroid hormone (secondary hyperparathyroidism)
• Normal 25(OH)D but impaired 1,25(OH)₂D
• Renal USS: may reveal nephrocalcinosis or stones
• Genetic testing for PHEX mutation in suspected familial cases

⚕️ Management

• 💊 Oral phosphate supplements (divided doses to minimise GI upset).
• 💊 Calcitriol or alfacalcidol (active Vitamin D) to bypass renal conversion defects.
• 🧬 Burosumab (anti-FGF23 monoclonal antibody): NICE-approved for X-linked hypophosphatemia, improves phosphate reabsorption and bone health.
• 📈 Growth hormone therapy in selected cases with severe growth retardation.
• 💧 Amiloride or thiazides: may help reduce calcium excretion and prevent nephrocalcinosis.
• 🦴 Supportive: orthopaedic surgery for severe deformities, dental surveillance.

💡 Exam Pearls

• 🧪 Distinguish from nutritional rickets: here, Vitamin D is normal but phosphate is low.
• 🧬 X-linked dominant inheritance – fathers cannot pass to sons, but all daughters are affected.
• 🦵 Persistent bowed legs despite Vitamin D therapy is a red flag.
• 🌟 Burosumab is a game-changer in modern management.

📚 References

• NHS – Vitamin D Resistant Rickets
• Carpenter TO. X-linked hypophosphatemia. J Bone Miner Res. 2012;27(10):1983–1998.
• NICE Guidance (TA581): Burosumab for treating X-linked hypophosphataemia in children and young people.