X-linked hypophosphatemia (XLH) is a genetic disorder affecting the bones, which presents with a wide spectrum of clinical severity, ranging from simple low blood phosphate levels to severe bowlegs.
While most commonly identified in childhood, namely, in the first two years, once weight-bearing begins, sometimes it remains occult until the abnormally short adult height is evaluated, or it may present as enthesopathy, arthralgia and reduced joint mobility.
Children may also show signs of rickets, such as the typical rachitic rosary of swollen rib cartilages, Harrison’s sulcus at the lower margin of the ribcage due to the pull of the diaphragm on the excessively soft lower ribs, epiphyseal swelling and craniotabes.
Other manifestations in adults include dental abscesses without obvious cause and sensorineural deafness.
The diagnosis is based upon the following features:
Low serum phosphate
Reduced tubular resorption of phosphate after correction is made for the glomerular filtration rate
Absence of the normal reactive rise in 1,25 dihydroxy vitamin D following low serum phosphate levels
Normal serum calcium and 25 hydroxy vitamin D
Normal or somewhat raised parathyroid hormone (PTH)
High serum alkaline phosphate (SAP) in childhood, notably during rapid growth periods, but normal SAP in adult life
Genetic testing for a PHEX mutation to confirm the diagnosis – this may be by serial testing of single genes, multi-gene panel testing or genome testing
Management of the condition is primarily focused on correcting the hypophosphatemia. In early cases, regular oral supplementation of phosphate and calcitriol at high dosage can prevent the bowing of the long bones of the lower limbs. A full evaluation should be done to detect other skeletal complications.
In cases of later diagnosis, the same therapy is given to control the pain and reduce the bowing of the legs. The duration of therapy is typically until the cessation of long bone growth. In adults, the same treatment is given in case of bone pain, or in anticipation of orthopedic surgery, if the bones are abnormally calcium deficient (osteomalacia) and the SAP is high, or if there are repeated stress fractures or pseudo-fractures. Surgical correction of severe deformity of the lower limb due to bowing or twisting of the bone shaft is required in some cases. Preventive dental hygiene will help prevent dental abscesses.
Regular monitoring of various serum parameters, such as calcium, phosphate, SAP, and PTH, as well as urinary loss of calcium, phosphate and urine creatinine assessment are necessary to detect hyperparathyroidism in patients who are taking calcitriol and phosphate. X-rays of the lower limbs, ultrasound scans of the kidneys to rule out renal stones, and dental checkups, should also be carried out regularly. Phosphate without calcitriol supplementation may result in secondary hyperparathyroidism.
Genetic counseling is necessary if the PHEX mutation is present, to ensure infants in the family who are at risk are diagnosed and treated early. This is transmitted by the X chromosome, so any affected male will pass it on to all of his daughters, but to none of the sons, whereas a woman with XLH may pass it on to half of her children, whether boys or girls.
A new agent called KRN23 is now being used in research trials. It is a recombinant human monoclonal antibody and targets the fibroblast growth factor 23 (FGF-23).