X-Linked Hypophosphatemia

Clinical characteristics: The phenotypic spectrum of X-linked hypophosphatemia (XLH) ranges from isolated hypophosphatemia to severe lower extremity bowing and/or craniosynostosis, usually involving the sagittal suture with consequent scaphocephaly. XLH typically manifests in the first two years of life with lower extremity bowing due to the onset of weight-bearing; however, it sometimes does not manifest until adulthood, as previously unevaluated short stature. Adults may present with calcification of the tendons, ligaments, and joint capsules, joint pain, fatigue, insufficiency fractures, and impaired mobility. Persons with XLH are prone to spontaneous dental abscesses; sensorineural hearing loss has also been reported. Rarely, individuals with XLH can suffer from spinal stenosis, Chiari I malformation, syringomyelia, and/or raised intracranial pressure.

Diagnosis/testing: The diagnosis is established in a proband with characteristic clinical, biochemical, and radiographic findings by identification of a hemizygous PHEX pathogenic variant in a male proband or a heterozygous PHEX pathogenic variant in a female proband on molecular genetic testing.

Management: Targeted therapy: Burosumab, a monoclonal antibody against FGF23. If burosuman is unavailable, conventional treatment with oral phosphate and active vitamin D analogues (alfacalcidol or calcitriol) to improve pain, promote fracture healing, and, in growing children, to correct and/or prevent bone deformation. Dental health may also improve with pharmacologic therapy.

Supportive care: Craniosynostosis treatment by craniofacial specialists; persistent lower extremity bowing and/or torsion resulting in misalignment of the lower extremity may require surgery; total hip or knee arthroplasty as needed for degenerative joint disease; rehabilitation, physiotherapy, and analgesics for musculoskeletal pain; surgical treatment for those with tertiary hyperparathyroidism; good oral hygiene with flossing, regular dental care, fluoride treatments, and sealants to prevent dental abscesses; standard treatment of sensorineural hearing loss; education and psychosocial support; standard treatment of cardiovascular comorbidities; consider physical medicine and rehabilitation, analgesics as needed, and evaluation for sleep apnea in those with fatigue.

Surveillance: For individuals on burosumab therapy, regular monitoring of serum concentrations of phosphate, calcium, creatinine, alkaline phosphatase, and intact parathyroid hormone. For those on conventional treatment with active vitamin D and phosphate supplementation, additional testing includes urinary calcium and creatinine to assess for hypercalciuria; periodic renal ultrasound examination to assess for nephrocalcinosis. For all individuals, assess growth and lower limb alignment at each visit throughout childhood; craniofacial examination at each visit throughout infancy; clinical assessment of joint mobility and pain at each visit; imaging of painful areas to assess for calcifications, pseudofractures, and/or insufficiency fractures; dental evaluation every six months; hearing evaluation and evaluation for Chiari I malformation performed based on clinical suspicion; assess psychosocial impact, fatigue, sleep issues, and quality of life at each visit; monitor weight, blood pressure, and cardiovascular risk factors at each visit.

Agents/circumstances to avoid: Treatment with phosphate without 1,25-dihydroxyvitamin D, because of the increased risk for secondary hyperparathyroidism. Although 1,25-dihydroxyvitamin D has been used as a single agent, this may increase the risk for hypercalcemia, hypercalciuria, and nephrocalcinosis. Bisphosphonates or osteoporosis medications may cause deterioration of osteomalacia in some individuals.

Evaluation of relatives at risk: Molecular genetic testing (if the PHEX pathogenic variant has been identified in the family) or biochemical testing of first-degree relatives at risk to ensure early treatment for optimal outcome.

Pregnancy management: There is generally no need for additional fetal monitoring or cesarean sections in pregnant women with XLH. Burosumab is not recommended during pregnancy. The benefit of phosphate and active vitamin D analogs in pregnant women who have XLH remains debated. Most women with XLH who are on oral phosphate and active vitamin D therapy at the time of conception are continued on treatment throughout the pregnancy with vigilant monitoring of urinary calcium-to-creatinine ratios to detect hypercalciuria early in order to modify treatment accordingly.

Genetic counseling: XLH is inherited in an X-linked manner; hemizygous males and heterozygous females are similarly affected. Affected males transmit the PHEX pathogenic variant to all of their daughters (who will be heterozygotes and will be affected) and none of their sons. Affected females have a 50% chance of transmitting the pathogenic variant to each child: male and female offspring who inherit the pathogenic variant will be affected. The severity of manifestations can differ among family members who inherit a PHEX pathogenic variant; intrafamilial clinical variability does not correlate with the sex of the affected family member. If the PHEX pathogenic variant has been identified in an affected family member, prenatal and preimplantation genetic testing for XLH are possible.