A 49-year-old female had been diagnosed with rickets at 1 year old, but the detailed pathogenesis of the rickets in this patient was unclear. She showed delayed and disproportionate growth, delayed motor development and gait abnormalities, short stature, deformity of weightbearing limbs, tooth abscesses, and excessive dental caries in childhood. Because she firstly suffered a left tibial pseudofracture, she started medication with oral phosphate salt for her hypophosphatemic rickets at 4 years old. She underwent the left tibial osteotomy for deformities of the lower extremities when she was in junior high school. Thereafter, she stopped treatment by herself during her high school days. She suffered a right hip fracture 10 years ago (the fracture was healed by conservative treatment), and restarted medication with phosphate salt without active vitamin D agents. However, despite the treatment, she repeatedly suffered pseudofractures. Furthermore, she suffered from paraspinal ligament ossification, which led to a restricted range of movement, neurological symptoms, and chronic disability, therefore, she underwent the laminoplasty of the 2nd to the 7th cervical vertebrae 8 years ago. Her son presented to a pediatrician with a chief complaint of a delayed start of walking at 1 year and 6 months old. He was also diagnosed with hypophosphatemic rickets (family pedigree is shown in  Figure 1A ). Furthermore, an elevated serum full-length FGF23 level (127 pg/mL; measured by ELISA [reference range: 16-69 pg/mL]) in the son was revealed at 10 years old.
The patient was transferred to our hospital along with her son from his pediatrician. Her height was 140 cm, and her body weight was 49.0 kg (body mass index [BMI]: 25.0 kg/m2). While the serum phosphate level at 2 hours after taking phosphate salt (3.1 mg/dL) was maintained within the reference range (2.5-4.5 mg/dL) (the fasting serum phosphate level: 2.1 mg/dL) under conventional treatment with phosphate salt (1,700 mg/day) without active vitamin D agents, the serum full-length FGF23 level (measured by CLEIA [reference range: 19.9-52.9 pg/mL] was markedly elevated (5,100 pg/mL). The TmP/GFR was low ( Table 1 ). In addition, she also showed tertiary hyperparathyroidism (the serum albumin adjusted calcium level: 10.3 mg/dL, serum intact PTH level: 532 pg/mL) and CKD (the estimated GFR [eGFR]: 56.0 mL/min/1.73 m2) ( Table 1 ). The serum levels of alkaline phosphatase (ALP), bone-type ALP (BAP), 1,25-dihydroxyvitamin D [1,25(OH)2D], tartrate-resistant acid phosphatase 5b (TRACP-5b), 25-hydroxyvitamin D [25(OH)D], and urinary calcium/creatinine (Cr) ratio are shown in  Table 1 . Since vitamin D deficiency was revealed, she started native vitamin D supplementation.
At this stage, genetic testing for both the patient and her son revealed a previously reported mutation in PHEX (c.1645 C>T, p. Arg549X), which led to the definitive diagnosis of XLH ( Figure 1B ). The skeletal investigation showed deformities of the lower extremities ( Figure 1C ). In addition, she suffered from paraspinal ligament ossification ( Figure 1D ). There was no pseudofracture nor fracture at the time.
Since we attempted to stop the progression of tertiary hyperparathyroidism and CKD, and improve her adherence to therapy, burosumab treatment was started at 1.0 mg/kg body weight (50 mg) injected subcutaneously every 4 weeks according to the approval for adult XLH by Japanese regulatory agency, and conventional treatment with phosphate salt was stopped. As shown in  Table 1  and  Figure 2 , the patient's trough (at end of dosing interval) serum phosphate levels and TmP/GFR unexpectedly remained low even after starting burosumab treatment. While we also evaluated the peak serum phosphate level 2 weeks after administration of burosumab, she showed still hypophosphatemia (1.8 mg/dL). Although burosumab has been approved for doses of up to 2.0 mg/kg in tumor-induced osteomalacia (TIO), 1.0 mg/kg of burosumab is the maximum prescribed for adult XLH in Japan. At that time, we considered that her high level of PTH (532 pg/mL) due to tertiary hyperparathyroidism remained to suppress renal phosphate reabsorption even in the setting of burosumab treatment. Because she declined to undergo total parathyroidectomy, a calcimimetic, evocalcet, was added to inhibit PTH actions. By increasing the dose of evocalcet (1 to 6 mg/day) as shown in  Table 1  and  Figure 2 , the serum trough phosphate level started to increase 28 weeks after burosumab treatment, and the TmP/GFR also increased 36 weeks after the treatment ( Figure 2 ). Furthermore, the serum albumin adjusted calcium and intact PTH levels decreased in the same period ( Table 1 ). Conversely, there were no remarkable changes in the eGFR or serum levels of ALP, BAP, 1,25(OH)2D, TRACP-5b, or urinary calcium/Cr ratio during this period. In addition, she did not develop any injection site or general adverse events with burosumab treatment.