X-linked hypophosphatemia

Key words: X-linked hypophosphatemia, PHEX gene, Vitamin D metabolites, Nephrocalcinosis, Burosumab, FGF23

X-linked hypophosphatemia (XLH) is an X-linked disorder with dominant penetration, caused by mutations in the PHEX gene, which encodes for an endopeptidase that is predominantly expressed in osteoblasts, osteocytes and odontoblasts. PHEX mutations cause increased production of fibroblast growth factor 23 (FGF23) that in turn leads to hypophosphatemia by causing inhibition of the renal phosphate reabsorption and of the synthesis of active 1,25-dihydroxyvitamin D. In children XLH is characterised by rickets, bone pain, physical dysfunction, impaired growth, disproportionate short stature, lowerlimb deformities, pathological fractures, dental malposition and dental abscesses. Although phenotype may be variable in severity, early diagnosis and treatment are critical to improve outcome. Laboratory tests show hypophosphatemia associated with hyperphosphaturia and elevated alkaline phosphatase, while parathormone and calcium levels are normal. For decades, patients have been treated with conventional therapy, including active vitamin D supplementation and fractionated daily doses of oral phosphate salts. However, these therapies rarely normalise the phenotype. More recently, burosumab, a recombinant human IgG1 monoclonal antibody against FGF-23, has been introduced for the treatment of XLH. In phase 2 trials, burosumab has been shown to improve significantly clinical symptoms, as well as biological and radiological signs of rickets.