Hypophosphataemic Rickets

Hypophosphataemic rickets is characterised by growth retardation, rickets or osteomalacia, hypophosphataemia, and renal defects in phosphate reabsorption and in vitamin D metabolism.^[1] The X-linked form (X-linked dominant) is the most common with a defect in phosphate transport in the proximal tubule leading to persistent hypophosphataemia and high levels of phosphate in the urine. Much rarer autosomal dominant, recessive, and sporadic forms also occur.

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Epidemiology

• Rare.
• The degree of bone involvement is much less severe in heterozygous females. However, there is often a maternal as well as paternal family history of short stature.^[2]

Presentation^[2]

• Slow growth rate in the first year of life.
• Reluctance to weight-bear when beginning to stand or walk.
• Late dentition, multiple dental abscesses.
• Intellectual development is unaffected.
• Widened joint spaces and flaring at the knees may become apparent in children by their first birthday, particularly in boys.
• When a child begins to stand and walk, bowing of the weight-bearing long bones develops quickly.

Differential diagnosis

• Cystinosis.
• Tyrosinaemia.
• Renal tubular acidosis.
• Hereditary hypophosphataemic rickets with hypocalciuria.
• Fanconi's syndrome.
• Vitamin D-deficient rickets.
• Pseudohypoparathyroidism.

Investigations

• Urinary loss of phosphate is increased because of decreased renal tubular reabsorption of phosphate.
• Blood tests for serum calcium, phosphate, alkaline phosphatase and parathyroid hormone:
  • Serum calcium levels may be normal or slightly low.
  • Phosphate levels are low.
  • Alkaline phosphatase levels are increased.
  • Parathyroid hormone level is normal or slightly raised.
• X-rays of the wrists, knees, ankles, and long bones: no pathognomonic signs distinguish hypophosphataemic rickets from any other aetiology.
• Periodic renal ultrasound is important to monitor for development of nephrocalcinosis.
• Monitoring the ratio of calcium to creatinine in the urine is also important (a urinary ratio of calcium to creatinine more than 0.25:1 requires reduction of the vitamin D dosage to avoid nephrocalcinosis).
• Patients under treatment should be carefully monitored for evidence of hyperparathyroidism.

Management

• Calcitriol (1,25-dihydroxycholecalciferol) - standard vitamin D preparations are not effective.
• In some poorly growing patients, long-term growth hormone therapy given with conventional treatment improves linear growth.^[3]
• Calcitriol reduces but does not eliminate the risk of hypercalcaemic episodes, which may be frequent with vitamin D treatment.^[2]
• Amiloride and hydrochlorothiazide are given to increase calcium reabsorption and reduce the risk of nephrocalcinosis.^[2]
• Phosphate replacement is required because of the large urinary phosphate loss.
• Osteotomy may be necessary for children whose diagnosis was delayed or whose initial treatment was inadequate.
• Skull deformity may require treatment for synostosis.
• Dental abscesses often require dental treatment.

Complications

• Short stature, which is disproportionate, resulting from deformity and growth retardation of lower extremities.
• Acute hypercalcaemia may occur during treatment.
• Nephrocalcinosis, which does not usually progress to renal failure.
• Hypertension may occur as a result of persistent hyperparathyroidism.

Prognosis

• X-linked hypophosphataemic rickets is frequently associated with short stature, even when treatment is provided for a long time.^[3]
• Apart from the short stature, the prognosis is usually good with a normal lifespan.