Thorough Analyses Needed to Prevent Misdiagnosis of XLH Patients, Case Study Asserts

Complete clinical and genetic analyses are needed to correctly diagnose X-linked hypophosphatemia (XLH), according to the case study of a woman whose disease was misdiagnosed as osteoporosis for years.

The case report, “Low Bone Mineral Density Does Not Equal Osteoporosis: The Finding of XLHR with a Novel Phex Mutation,” published in the Journal of the Endocrine Society, was to be presented at the ENDO 2020 meeting, which was cancelled due to the COVID-19 pandemic.

XLH, the most common type of hypophosphatemic rickets, is caused by mutations in the PHEX gene, which lead to abnormally high levels of a bone-derived hormone called fibroblast growth factor 23 (FGF23) in the blood.

Excessive FGF23 levels prevent the kidneys from reabsorbing phosphate, an important bone component, into the bloodstream. This leads to chronic hypophosphatemia (low blood levels of phosphate), defective bone mineralization, and osteomalacia — the abnormal softening of bones, making them more prone to deformities and fractures.

While XLH mainly affects children, “in some cases, it can be missed and not diagnosed until later in life,” researchers wrote.

A team from Phoenix, Arizona, reported the case of a 59-year-old, post-menopausal woman with XLH who had been misdiagnosed with osteoporosis for more than a decade.

She was admitted to the hospital due to the worsening of a fracture in the femur (the long bone in the upper leg) and the need for surgery. The woman had been diagnosed with osteoporosis at age 45 and had a history of multiple femur fractures from low-impact trauma.

Similar to XLH, osteoporosis is characterized by impaired bone mineralization and increased risk for bone fractures. Women are at a higher risk for osteoporosis after menopause.

Despite bisphosphonate therapy, a common bone-strengthening medicinal treatment for osteoporosis, she continued to have recurrent fractures. While she had no family history of early osteoporosis, her mother was diagnosed with rickets as a child.

Additional bloodwork to better understand the cause of the woman’s condition revealed no abnormalities other than sustained excessive levels of alkaline phosphatase, a liver enzyme that can indicate liver or bone problems, and phosphate deficiency.

Such results raised the possibility of Paget’s disease, a chronic bone disorder characterized by high levels of alkaline phosphatase and an abnormal bone structure. However, a bone scan revealed no such structure.

The team then evaluated whether the woman’s bone weakness and low phosphate levels could be due to abnormally high levels of FGF23, which were confirmed with further blood analysis.

The finding narrowed diagnosis to two possible conditions characterized by low phosphate and high FGF23 levels: tumor-induced osteomalacia and XLH. Additional imaging analyses detected no tumors, so the woman underwent genetic testing, which identified a previously reported PHEX mutation and confirmed a XLH diagnosis.

She was given 2 grams per day of phosphate supplements and 0.25 micrograms of once daily calcitriol (the active form of vitamin D), which normalized her phosphate and vitamin D levels. After one month of treatment, the woman reported significantly less bone pain and her bone mineral density (assessed with dual-energy X-ray absorptiometry) was stable for the following four years.

“We present a post-menopausal female that was misdiagnosed with osteoporosis for many years until complete work up was done, and she was found to have osteomalacia due to hypophosphatemia,” the researchers wrote.

“Recognition of the correct diagnosis is prudent to providing correct treatment,” they concluded.