X-Linked Hypophosphataemia

X-linked hypophosphataemia is an X-linked dominant disorder caused by inactivating variants of PHEX, leading to raised fibroblast growth factor 23 (FGF23), renal phosphate wasting, rickets in children and osteomalacia in adults.

It is the commonest inherited cause of rickets, with a prevalence of about 1 in 20,000 to 25,000. Both sexes are affected, and about one third of cases are new variants.

Disease expression varies within families. Adults have osteomalacia, enthesopathy, osteoarthritis, hearing loss and dental disease.

Pathophysiology.

PHEX loss of function raises FGF23 by effects on osteocytes and bone matrix proteins. FGF23 reduces proximal tubular phosphate reabsorption and 1-alpha hydroxylase activity, causing low phosphate and inappropriately low calcitriol.

Chronic low phosphate impairs bone and dental mineralisation. Conventional treatment can stimulate FGF23 further.

• Children: bowed legs, short stature, waddling gait, delayed walking, craniosynostosis and dental abscesses.
• Adults: bone and joint pain, pseudofractures, fractures, enthesopathy, spinal stenosis, hearing loss, fatigue and muscle weakness.
• Hypertension and nephrocalcinosis can follow treatment.

Red flags.

• Neurological deficits from spinal stenosis or Chiari malformation.
• Fragility fracture or pseudofracture.

• Fasting phosphate low, calcium normal, alkaline phosphatase raised, parathyroid hormone normal or mildly raised, and calcitriol low or inappropriately normal.
• Tubular maximum reabsorption of phosphate to glomerular filtration rate low (under 0.8 mmol/L in adults). FGF23 raised or inappropriately normal.
• PHEX sequencing and family testing. Radiographs for rickets, pseudofractures and enthesopathy.
• Renal ultrasound for nephrocalcinosis.

Differential diagnosis.

• Other FGF23 mediated and FGF23 independent hypophosphataemic disorders.
• Tumour induced osteomalacia in a patient with late adult onset and no family history.
• Nutritional rickets, Fanconi syndrome and hypophosphatasia.

• Children: elemental phosphorus 20 to 40 mg/kg daily in 4 to 5 divided doses with calcitriol 20 to 30 nanograms/kg daily in two divided doses; or burosumab 0.8 mg/kg subcutaneously every 2 weeks, adjusted to fasting phosphate and up to 2 mg/kg (90 mg) every 2 weeks.
• Adults with symptoms: burosumab 1 mg/kg (maximum 90 mg) every 4 weeks, or elemental phosphorus 1 to 3 g daily in 3 to 5 divided doses with calcitriol 0.5 to 1.5 micrograms daily. Treat asymptomatic adults only for planned surgery or fracture healing.
• Before burosumab stop phosphate and active vitamin D for 1 week. Do not use with fasting phosphate over the normal range or with eGFR under 30 mL/min.
• Dental care, physiotherapy and analgesia. Orthopaedic surgery for deformity after bone healing. Consider hearing review.
• Avoid excess phosphate and calcitriol to limit nephrocalcinosis and hyperparathyroidism.

Special groups. Pregnancy: continue conventional therapy at the lowest effective dose and monitor calcium and phosphate. Data on burosumab are limited. Genetic counselling: each child of an affected parent has a 50% chance of inheriting the variant.

Monitoring. Phosphate, calcium, alkaline phosphatase, parathyroid hormone and urine calcium every 3 months (children) or 6 months (adults). Renal ultrasound yearly. Blood pressure, growth, hearing and dental review.

Referral and escalation. Paediatric or adult endocrinology or metabolic bone service; nephrology for kidney complications; neurosurgery for spinal cord compression.