Outcome and follow-up

The pregnancy was relatively uneventful, except for threatened preterm labor at 33 weeks, which was managed conservatively. Serial ultrasonography revealed normal fetal growth with no skeletal anomalies. At 35 years and 4 months of age, because of the patient's history of recurrent fractures associated with XLH and concerns about muscle weakness resulting in prolonged or difficult labor, an elective cesarean section was scheduled at 37 weeks and 0 days to reduce mechanical stress on the maternal skeleton. A male infant weighing 2325 g was delivered with Apgar scores of 8 and 8 at 1 and 5 minutes, respectively. The placenta exhibited mild signs of villous immaturity but no calcification.

The neonate was admitted to the neonatal intensive care unit with apnea but quickly stabilized. On day 2 after birth, laboratory evaluation revealed an extremely high intact FGF23 level of 48 700 pg/mL (SI: 1933 pmol/L), along with serum phosphate of 4.2 mg/dL (SI: 1.36 mmol/L) (reference range for newborn, 5.0-7.7 mg/dL [SI: 1.61-2.49 mmol/L]) and 1,25-dihydroxyvitamin D of 57.8 pg/mL (SI: 139 pmol/L) (reference range, 20.0-70.0 pg/mL [SI: 48.1-168.3 pmol/L]) (Table 1). Skeletal radiographs revealed no signs of rickets or skeletal dysplasia (Fig. 2). The infant's serum intact FGF23 levels dropped rapidly to 546 pg/mL (SI: 21.6 pmol/L) after 3 months and then to 151 pg/mL (SI: 6.0 pmol/L) after 7 months. In both mother and infant, genetic analysis identified a long interspersed nuclear element-1 retrotransposon insertion near exon 9 of the PHEX gene (Fig. 3).

Figure 2: Radiographic findings of the infant. (A-C) Radiograph of the neonate on day 2. Despite extremely high serum FGF23 levels, there is no evidence of rickets or skeletal dysplasia. (D-E) Radiograph of the infant's hands at 1 month of age, revealing normal mineralization.

Figure 3: Genetic analysis of the PHEX gene. (A) Pedigree of the family at the time of birth of the affected infant (III-2). Filled symbols show individuals affected by XLH. The arrow denotes the proband (II-4). “PHEX+” indicates individuals in whom the identified PHEX insertion variant was confirmed by molecular testing. Deceased individuals are represented by a diagonal slash. Individual numbers are shown in the upper right corner of each symbol, and generation numbers are indicated on the left side of the pedigree. (B) PCR analysis of the PHEX gene. Gel electrophoresis reveals a wild-type band (393 bp) and a larger mutant band (approximately 1700 bp) in both the mother and infant, indicating a large insertion. (C) Nucleotide sequence of the PHEX insertion site determined using Sanger sequencing. PCR products spanning the insertion breakpoint were subjected to Sanger sequencing. A LINE-1-derived sequence was identified immediately downstream of exon 9 of the PHEX gene (chrX:22,099,040). A 14-base pair (bp) target site duplication (chrX:22,099,027-22,099,040) flanking the inserted sequence was observed. (D) Schematic representation of the PHEX gene mutation identified by long-read sequencing, showing a LINE-1 retrotransposon insertion near exon 9. Approx., approximately.

Age | Day 2 | Day 13 | Day 30 | 3 months | 7 months | 8 months | 12 months | 15 months | 20 months | Reference range
Treatment | None | Conventional | Conventional | Conventional | Conventional | Switch to burosumab (7 mg q2w) | Burosumab (10 mg q2w) | Burosumab (20 mg q2w) | Burosumab (20 mg q2w) | 
Serum Phosphatea | 4.2 mg/dL (1.36 mmol/L) | 3.8 mg/dL (1.23 mmol/L) | 4.4 mg/dL (1.42 mmol/L) | 3.2 mg/dL (1.03 mmol/L) | 3.9 mg/dL (1.26 mmol/L) | 3.3 mg/dL (1.07 mmol/L) | 3.9 mg/dL (1.26 mmol/L) | 3.2 mg/dL (1.03 mmol/L) | 3.6 mg/dL (1.16 mmol/L) | 3.9-6.2 mg/dL (1 26-2.0 mmol/L)at 1 year
Serum calciumb | 7.2 mg/dL (1.80 mmol/L) | 9.9 mg/dL (2.48 mmol/L) | 9.6 mg/dL (2.40 mmol/L) | 9.8 mg/dL (2.45 mmol/L) | 10.9 mg/dL (2.73 mmol/L) | 10.3 mg/dL (2.58 mmol/L) | 10.1 mg/dL (2.53 mmol/L) | 10.4 mg/dL (2.60 mmol/L) | 9.9 mg/dL (2.48 mmol/L) | 8.8-10.6 mg/dL (2.20-2.64 mmol/L) at 1 year
ALPc | 357 U/L(5.95 μkat/L) | 510 U/L(8.50 μkat/L) | 662 U/L(11.0 μkat/L) | 751 U/L(12.5 μkat/L) | 989 U/L(16.4 μkat/L) | 760 U/L(12.7 μkat/L) | 693 U/L(11.6 μkat/L) | 675 U/L(11.3 μkat/L) | 503 U/L(8.39 μkat/L) | 138-469 U/L(2.30-7.82 μkat/L)at 1 year
Intact PTH | 84 pg/mL (8.9 pmol/L) | — | — | 96 pg/mL (10.2 pmol/L) | 44 pg/mL (4.5 pmol/L) | — | — | — | — | 10-65 pg/mL (1.1-6.9 pmol/L)
Intact FGF23 | 48 700 pg/mL (1933 pmol/L) | — | — | 546 pg/mL (21.6 pmol/L) | 151 pg/mL (6.0 pmol/L) | — | — | — | — | 19.9-52.9 pg/mL (0.79-2.10 pmol/L)
TmP/GFR | 3.34 mg/dL (1.08 mmol/L) | 2.89 mg/dL (0.93 mmol/L) | 3.21 mg/dL (1.04 mmol/L) | 2.48 mg/dL (0.80 mmol/L) | 3.47 mg/dL (1.12 mmol/L) | 3.08 mg/dL (0.99 mmol/L) | 3.52 mg/dL (1.14 mmol/L) | 2.70 mg/dL (0.87 mmol/L) | 3.15 mg/dL (1.01 mmol/L) | 4.45-6.85 mg/dL (1.43-2.21 mmol/L) at 1 year
Urine Ca/Cr | 0.01 mg/mg (0.003 mmol/mmol) | 0.38 mg/mg (0.13 mmol/mmol) | 0.19 mg/mg (0.06 mmol/mmol) | 0.03 mg/mg (0.01 mmol/mmol) | 0.1 mg/mg (0.03 mmol/mmol) | 0.08 mg/mg (0.03 mmol/mmol) | 0.25 mg/mg (0.08 mmol/mmol) | 0.17 mg/mg (0.06 mmol/mmol) | 0.24 mg/mg (0.08 mmol/mmol) | <0.3 mg/mg (<0.1 mmol/mmol)
Height | 45.9 cm | 47 cm | 48 cm | 54.5 cm | 60.5 cm | 65 cm | 65.4 cm | 70.9 cm | 75.6 cm | 
Weight | 2.325 kg | 2.530 kg | 3.235 kg | 5.615 kg | 8.6 kg | 8.7 kg | 8.8 kg | 8.8 kg | 10.1 kg | 

During the neonatal period, alfacalcidol (0.125 mcg/day) and oral phosphate (200 mg/day) were administered as conventional therapy. However, at 8 months of age, the patient had an elevated alkaline phosphatase (ALP) level of 760 U/mL (SI: 12.7 μkat/L) (reference range at 1 year, 138-469 U/mL [SI: 2.30-7.82 μkat/L]) and a low serum phosphate level of 3.3 mg/dL (SI: 1.07 mmol/L) (reference range at 1 year, 3.9-6.2 mg/dL [SI: 1.26-2.0 mmol/L]) despite receiving alfacalcidol (0.25 mcg/day) and oral phosphate (200 mg/day). At 8 months of age, the infant began receiving burosumab treatment (7 mg every 2 weeks) (Table 1). One year after burosumab initiation, the child's height was 75.6 cm and weight was 10.1 kg. Growth was monitored using the Japanese standard growth chart [7], and no adverse events associated with prenatal burosumab exposure during pregnancy or subsequent treatment were observed.