Diagnostic Process for Hypophosphatemic Rickets Lengthy, Report Says

People with hypophosphatemic rickets (HR) may experience yearslong delays in getting a confirmed diagnosis of their condition, undergoing a multitude of clinical visits and evaluations, according to a report detailing eight patient cases.

The report also describes two cases in which tumors caused hypophosphatemic rickets. The researchers believe that treatments currently used for X-linked hypophosphatemia (XLH), the most common form of HR, may help treat these and other patients with hypophosphatemic rickets caused by conditions other than XLH.

Titled “The Difficult Diagnosis of Hypophosphatemic Rickets-A Review of 8 Clinical Cases,” the study was published in the journal Clinical Medicine Research.

HR is characterized by softening and weakening of bones due to low levels of phosphate in the blood (hypophosphatemia).

XLH is caused by the increased activity of protein fibroblast growth factor 23 (FGF23), which leads to more phosphate being excreted in urine and lower blood phosphate levels.

Researchers in Bulgaria and Japan described eight cases of HR they had diagnosed and treated over the past two decades. Patients ranged in age from 18 to 52 years; three were women and five were men.

In all eight cases, patients experienced long diagnostic delays — averaging about two to three years. The process generally involved many clinical visits, laboratory evaluations, and imaging studies, largely used to rule out other conditions.

Ultimately, five patients were diagnosed with XLH, showing typical impairments in calcium and phosphate metabolism, as well as changed levels of parathyroid hormone and vitamin D. High FGF23 activity supported the diagnosis.

Another patient was diagnosed with Fanconi syndrome, a kidney disorder, exhibiting low FGF23 levels.

In the remaining two cases, the underlying disease was a tumor. These two patients were diagnosed with tumor-induced osteomalacia (TIO) — meaning a tumor caused bone and muscle weakness, as well as fatigue. Laboratory tests revealed increased FGF23 activity in both patients.

In one case involving a 26-year-old man, a tumor in the leg was identified and removed surgically. This led to a substantial decrease in FGF23 activity within three months after surgery.

A lung tumor was identified and removed in the second TIO case, a 60-year-old man, leading to higher phosphate levels and markedly improved motor function. However, FGF23 activity continued to increase.

The researchers hypothesized that this patient might benefit from treatments that target FGF23, namely Crysvita (burosumab). Crysvita is approved to treat XLH in the U.S. and European Union, as well as TIO in the U.S.

“The opportunity to treat him with anti-FGF23 monoclonal antibodies could give us time to find the probable tumor source of FGF23 that we have been searching for two years now,” the researchers wrote, adding that Crysvita “could postpone the progression of hypophosphatemia and give us time to find the underlying [cancer].”

“The progression of clinical trials with [Crysvita] for the treatment of XLH and its recent availability for clinical use may have potential for treating other conditions associated with FGF23 overactivity,” they concluded.