Hypophosphataemic Rickets
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Direct answer
Hypophosphataemic rickets is a family of disorders of renal phosphate wasting, most commonly X-linked dominant hypophosphataemic rickets caused by PHEX mutations that raise FGF23 levels. Excess FGF23 causes phosphaturia and suppresses 1-alpha-hydroxylase, so children have low serum phosphate with normal calcium and normal vitamin D and develop bowed legs and short stature. Treatment is oral phosphate with active vitamin D, unlike nutritional rickets where calcium and vitamin D are deficient.
What you must remember
- Commonest form: X-linked dominant hypophosphataemic rickets, caused by PHEX mutations that increase FGF23 and waste phosphate in the kidney.
- Biochemistry: low or low-normal serum phosphate, normal calcium, normal 25-hydroxyvitamin D, raised alkaline phosphatase and reduced renal tubular reabsorption of phosphate.
- Clinical signs: bowed legs or knock knees, short stature, enthesopathy, and dental abscesses with enamel defects.
- Diagnostic trap: nutritional rickets shows low calcium or vitamin D with raised parathyroid hormone, whereas the X-linked form has normal calcium and vitamin D.
- Treatment: oral phosphate in several daily doses with active vitamin D such as calcitriol or alfacalcidol, titrated to alkaline phosphatase and radiological healing.
- Newer therapy: burosumab, an anti-FGF23 antibody, used in selected children in specialist centres.
A pathway from biochemical clue to genetic confirmation
The key reasoning is to recognise renal phosphate wasting and tie it to FGF23, because the treatment target is phosphate and active vitamin D.
- Recognise the biochemical pattern: rickets with low phosphate, normal calcium and raised alkaline phosphatase points to a phosphate-wasting disorder.
- Check renal phosphate handling: calculate tubular maximum reabsorption of phosphate relative to glomerular filtration rate; a low value confirms renal wasting.
- Measure FGF23: raised intact FGF23 supports FGF23-mediated disease such as X-linked hypophosphataemia and tumour-induced osteomalacia.
- Confirm genetics: PHEX sequencing for X-linked dominant disease, with family screening, since affected mothers may have milder disease.
- Start treatment: oral phosphate with calcitriol or alfacalcidol, with doses adjusted by alkaline phosphatase, radiology and phosphate levels.
- Monitor complications: nephrocalcinosis, secondary hyperparathyroidism, growth and bone deformity, with orthopaedic referral for limb deformity. Growth should be plotted at every visit, since growth responds slowly and treatment is judged against height velocity. Adherence to several daily phosphate doses is the main practical challenge for families.
Where the exam tries to catch you
Rickets questions often separate the X-linked form from the nutritional form using calcium and vitamin D levels.
- Trap: labelling every rickets as nutritional Correct: normal calcium and vitamin D with low phosphate points to X-linked hypophosphataemia, which does not respond to vitamin D alone.
- Trap: giving calcium supplements for X-linked rickets Correct: calcium does not correct phosphate wasting; phosphate and active vitamin D do.
- Trap: using plain vitamin D alone Correct: plain vitamin D cannot correct the FGF23-driven loss of renal phosphate.
- Trap: ignoring nephrocalcinosis in treated children Correct: phosphate and active vitamin D raise urinary calcium, so ultrasound monitoring is needed.
Frequently asked questions
What is the main cause of X-linked hypophosphataemic rickets?
X-linked hypophosphataemic rickets is caused by mutations in the PHEX gene, which lead to raised FGF23 levels. Excess FGF23 causes renal phosphate wasting and suppresses active vitamin D production.
How does X-linked hypophosphataemic rickets differ from nutritional rickets?
X-linked hypophosphataemic rickets has low phosphate with normal calcium and vitamin D, while nutritional rickets shows deficiency of calcium or vitamin D with raised parathyroid hormone. Treatment differs, with phosphate and active vitamin D for the X-linked form and vitamin D and calcium for the nutritional form.
What is the standard treatment for hypophosphataemic rickets?
Oral phosphate given in several daily doses, combined with active vitamin D such as calcitriol or alfacalcidol, is the standard treatment for hypophosphataemic rickets. Doses are titrated to alkaline phosphatase, radiology and phosphate levels, with monitoring for nephrocalcinosis.
Why is nephrocalcinosis a concern in hypophosphataemic rickets?
Phosphate and active vitamin D increase urinary calcium excretion, which can deposit calcium in the kidney. Regular renal ultrasound helps detect nephrocalcinosis early in children with hypophosphataemic rickets.
What is burosumab used for in hypophosphataemic rickets?
Burosumab is an anti-FGF23 antibody used in selected children with X-linked hypophosphataemia, usually in specialist centres. It addresses the underlying FGF23 excess rather than only correcting the phosphate level.