Hypophosphataemic Rickets

Hypophosphataemic rickets is defective mineralisation of the growth plate and bone in children caused by chronic renal phosphate wasting. It is a group of inherited disorders, and acquired forms also occur.

X-linked hypophosphataemia (PHEX) is the commonest, at about 1 in 20,000 births. Rarer forms are autosomal dominant (FGF23), autosomal recessive (DMP1, ENPP1) and hereditary hypophosphataemic rickets with hypercalciuria (SLC34A3).

Most forms raise fibroblast growth factor 23. Hypercalciuric disease is FGF23 independent. Acquired causes are Fanconi syndrome, tumour induced osteomalacia and some drugs.

Pathophysiology.

Raised FGF23 reduces sodium phosphate cotransporter expression in the proximal tubule and suppresses calcitriol synthesis, so phosphate is lost and intestinal absorption falls. Low phosphate impairs apoptosis of hypertrophic chondrocytes and bone matrix mineralisation.

In the hypercalciuric form calcitriol is high, and intestinal calcium absorption rises, giving hypercalciuria.

• Delayed walking, waddling gait, bowed legs or knock knees, short stature, widened wrists and knees, rachitic rosary and frontal bossing.
• Bone pain, dental abscesses without trauma, craniosynostosis and, in adults, osteomalacia and enthesopathy.

Red flags.

• Hypocalcaemic seizure or tetany (suggests nutritional rickets instead).
• Hypercalciuria with nephrocalcinosis or kidney stones.
• Glycosuria, aminoaciduria or acidosis (Fanconi syndrome).

• Fasting phosphate low for age, calcium normal, alkaline phosphatase raised, parathyroid hormone normal or mildly raised, 25-hydroxyvitamin D normal, and calcitriol low or inappropriately normal (high in hypercalciuric disease).
• Tubular maximum reabsorption of phosphate to glomerular filtration rate low for age, and FGF23 raised or inappropriately normal.
• Radiographs of the wrists and knees: widened, frayed and cupped growth plates.
• Urine calcium, glucose, amino acids and bicarbonate to exclude Fanconi syndrome.
• Genetic testing (PHEX, FGF23, DMP1, ENPP1, SLC34A3) and family history.

Differential diagnosis.

• Nutritional rickets and vitamin D dependent rickets (calcium low, parathyroid hormone high).
• Fanconi syndrome and renal tubular acidosis.
• Hypophosphatasia (alkaline phosphatase low) and tumour induced osteomalacia.
• Metaphyseal dysplasia.

• FGF23 mediated forms: 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. Burosumab when conventional therapy is inadequate or not tolerated.
• Burosumab in children from 1 year: 0.8 mg/kg subcutaneously every 2 weeks, titrated to fasting phosphate in the age range, to a maximum of 2 mg/kg (90 mg) every 2 weeks. Stop oral phosphate and calcitriol 1 week before starting, and do not use if eGFR is under 30 mL/min or fasting phosphate is over the age range.
• Hypercalciuric form: phosphate alone, without calcitriol or vitamin D analogues.
• Side effects of conventional therapy: diarrhoea, secondary or tertiary hyperparathyroidism and nephrocalcinosis. Keep phosphate doses divided and calcitriol at the lowest effective dose.
• Orthopaedic correction of deformity after healing. Dental review twice yearly.

Special groups. Adolescents: continue treatment until growth ends and decide on adult treatment by symptoms. Pregnancy: use conventional therapy at the lowest dose.

Monitoring. Every 3 months in childhood: growth, phosphate, calcium, alkaline phosphatase, parathyroid hormone, urine calcium to creatinine ratio. Renal ultrasound yearly. Head shape, blood pressure and dental review.

Referral and escalation. Paediatric endocrinology or metabolic bone service for all children; nephrology for nephrocalcinosis or Fanconi syndrome.