Treatment of Rickets in X-Linked Hypophosphatemia (PHEX Mutation) with FGF23-Mediated Renal Phosphate Wasting in Children Under 18
X-linked hypophosphatemia (XLH) is a genetic cause of rickets arising from mutations in the PHEX gene. These mutations drive increased FGF23 expression in bone, producing chronic renal phosphate wasting and reduced calcitriol levels — the core pathophysiological basis of rickets in this population. This protocol addresses paediatric patients (under 18 years) presenting in this specific context.
Clinical Scenario
Rickets in a child with confirmed X-linked hypophosphatemia due to a PHEX mutation, characterised by FGF23-mediated renal phosphate wasting. Other poorly understood alterations beyond FGF23 and calcitriol dysregulation are also recognised in XLH.
Treatment Approach
Two distinct treatment strategies are used in XLH-related rickets: a conventional approach combining oral phosphate supplementation with an active vitamin D analogue, and a biologic alternative targeting the underlying FGF23 excess. The complete regimen — including which approach to use, how to initiate it, and how to adjust over time — is in the full protocol.
Clinical Targets
Treatment goals include improvement or normalisation of serum alkaline phosphatase, maintenance of fasting serum phosphate in the lower end of the normal reference range for age, PTH levels within the normal range, absence of hypercalciuria, and improvement of TmP/GFR as a measure of renal phosphate handling.
References
- X-linked hypophosphatemia is due to mutations in PHEX resulting in increased expression of FGF23 in bone and consecutive renal phosphate wasting and reduced calcitriol levels, as well as other so far poorly understood alterations.
- Patients with XLH can either be treated with oral supplements of inorganic phosphate salts in combination with active vitamin D ("conventional treatment") or with burosumab.
- Treatment with phosphate should always be done in combination with active vitamin D (either with calcitriol or alphacalcidiol) in XLH patients, as this prevents the development of secondary hyperparathyroidism as seen in patients treated with phosphate salts alone, which further promotes renal phosphate wasting and can result in autonomous (tertiary) hyperparathyroidism.
- Thus, in XLH patients on conventional treatment, improvement/normalization of serum ALP is the main biochemical surrogate indicating adequate treatment.
- By contrast, burosumab treatment is primarily tailored according to fasting serum phosphate levels, which should be kept in the lower age-related normal range.
- In addition, monitoring of renal phosphorus threshold concentration (TmP/GFR) is recommended in these patients, in order to confirm improvement of renal phosphate wasting.
- Dosages need to be adjusted in order to keep PTH levels in the normal range and to avoid hypercalciuria.
DOI: 10.1007/s00467-022-05505-5
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