X-linked hypophosphatemia (XLH) is a congenital bone disorder caused by the renal excretion of phosphate, preventing proper mineralization of the bone.

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In adults, diagnosis includes an evaluation of painful skeletal sites by x-rays to rule out enthesopathy as well as the occurrence of stress fractures, as well as dental and hearing tests

Once a diagnosis of XLH is established, the individual needs to be fully evaluated to outline the extent of the disease as well as the treatment needs. In children, this includes:

• Assessment of bone growth by measures such as the skeletal age
• Survey of the degree to which the bones have been affected (by x-rays of the lower limb and wrists)
• Evidence of craniosynostosis
• Dental and hearing examinations

For patients who complain of headache with vertigo at any age, the Chiari malformation (in which part of the cerebellum protrudes into the upper spinal canal through the foramen magnum at the base of the skull, because of skull abnormalities) must be ruled out.

For all patients, genetic counseling should be offered for issues related to possible inheritance or transmission of the trait.

Pharmacological management

The aims of medicinal treatments for XLH are to reduce pain associated with faulty bone growth and correct any related deformities.

If XLH is diagnosed in childhood, oral phosphate supplementation coupled with high doses of active vitamin D3 are provided and continued until skeletal growth is completed. Vitamin D3 promotes mineralization of the bone, while phosphate prevents secondary hyperparathyroidism.

Both low and high doses of calcitriol are used initially, and low doses are continued until the end of skeletal growth.

The endpoints measured in this treatment include:

• Reduced alkaline phosphatase in serum
• Better musculoskeletal performance
• Correction of rickets-related bone changes
• A more normal bone growth velocity if growth potential still exists
• Rule out secondary hyperparathyroidism, hypercalciuria, and calcium calculi in the kidneys, often by over-supplementation of phosphate

In adults, treatment is meant to correct bone pain or, in the presence of osteomalacia as shown by a high alkaline phosphatase, to improve prognosis, and to assess the  development of stress fractures or pseudofractures.

Because of the variation in the vitamin D receptor promoter, different patients may require different regimens depending on their response to vitamin D.

Orthopedic management

Persistent bowing of the lower limbs may require surgical correction, perhaps due to lack of adequate adherence to prescribed pharmacological therapy in the growing period. Various techniques are used, such as stapling or the use of toggle plates at the epiphysis in children, and in adults, distraction to promote bone lengthening or intramedullary nailing with or without external or internal fixation for acute correction.

Enthesopathy and irreversible joint damage may sometimes require hip and knee replacements. Correction of dental abnormalities using oral hygiene measures as well as fluoride supplementation are keys to prevent dental abscesses. The standard drug regimen, however, may also be helpful in adults.

Surveillance and other measures

Hearing loss should be treated as required. Regular follow-ups are mandatory to screen for secondary hyperparathyroidism. This involves testing for parathyroid hormone levels, serum calcium, and other renal markers of phosphate excretion and renal function (corrected by adjusting the doses of phosphate or calcitriol).

Tertiary hyperparathyroidism should be identified and surgical treatment should be offered. If serum and urinary calcium is high, calcitriol doses need to be lowered accordingly. Following a baseline examination, screening for renal calculi should be performed via ultrasound scans every 1-5 years depending on the risk .

Family members who are in their growing years should be tested to allow early treatment to be given. Molecular genetic testing and biochemical testing may be performed, and the latter should be repeated at intervals of two to three months until the child is a year old, even if the test results appear initially appear normal.

Novel agents

At present, newer therapies are being investigated, such as a recombinant human monoclonal antibody which is directed at FGF23 which can increase the renal threshold for phosphate reabsorption, thus improving serum phosphate levels and renal vitamin D production.