Diagnostic assessment

The diagnosis was made clinically based on rickets history and biochemical results. Prior to pregnancy, the patient received genetic counseling as part of her marriage, followed by genetic testing.

Since 16 genes cause hereditary hypophosphatemic rickets, short-read next-generation sequencing was performed as a panel test. This revealed a disruption of sequencing reads at chrX:22,099,026 within the PHEX gene, raising suspicion of a heterozygous deletion/insertion (indel) variant originating at this locus; however, a definitive molecular diagnosis could not be established using this method. The clinical response to burosumab (50 mg subcutaneously every 4 weeks) was robust; within 7 months, her bone pain subsided, and she no longer needed a cane. Serum phosphate was normalized to 3.2 mg/dL (SI: 1.03 mmol/L) with an improvement in TmP/GFR (2.80 mg/dL [SI: 0.90 mmol/L]). Prior to conception, the patient received multidisciplinary counseling regarding pregnancy and burosumab treatment. She was informed that there were limited safety data on burosumab use during pregnancy and that current guidelines generally recommend conventional therapy during pregnancy. The discussion also included the possibility of transplacental transfer of burosumab as an IgG1 monoclonal antibody as well as the 50% risk of transmitting the PHEX variant to the offspring, with the possibility that fetal exposure to burosumab could have different consequences depending on whether the fetus inherited XLH. After understanding these uncertainties, the patient expressed a strong desire to continue burosumab therapy if pregnancy occurred. The pregnancy was confirmed at 34 years and 9 months of age, 20 months after starting burosumab. The patient expressed strong concern about symptom recurrence and potential loss of mobility if treatment was discontinued and expressed a strong preference to continue receiving burosumab.