Endocrine Abstracts

X-linked hypophosphatemic rickets (XLH) is associated with mutations in PHEX, upregulation of FGF23, leading to hypophosphatemia, abnormal bone development and short stature. H-MAB to FGF23, Burosumab, is the new therapy for XLH. Among PHEX mutations, c.1586+6T >C, partially destroying the splice-site, is presumably associated to a mild phenotype not described so far. We describe two siblings bearing the PHEX c.1586+6T >C variant. Case 1: A 52y men, 152 cm tall (-3.4SDS), father of two pediatric patients, was referred after testing positive for same PHEX mutation found in the proband. Family history of a similar condition was negative, except for his sister. At 47y, after investigation on his affected daughters, an orthopedic consultation concluded for active rickets. He presented impaired mobility, district arthrosis, tibia vara, hypodisplasia of tooth enamel, and bilateral perceptive hearing loss. Six minutes walking test(6 MWT) showed reduced functional capacity. IQOLA-SF-36 showed poor QOL. X-ray found diffuse spondylarthrosis, coxosclerosis, dysmorphism of proximal femoral epiphyses and curvature of the diaphysis. The MOC-DEXA compatible by gender and age. Case 2: A 47y woman, 143 cm tall (-3.34SDS). At 29y underwent surgery on right foot scaphoid bone and was diagnosed tibia vara. At 45y an orthopedic consultation concluded for active rickets. She showed skeletal malformations, waddling gait, diffuse polyarthrosis, hypodisplasia tooth enamel, and perceptive deep. 6 MWT showed reduced functional capacity. IQOLA-SF-36 showed poor QOL. They started conventional supplementation with active vitamin D, phosphate was added to calcitriol and suspended before Burosumab. Both patients started Burosumab (1 mg/Kg/die), after approval of the compassionate use since December 2020. Results: At start, case 1: showed: Ca 9.2 mg/dl, P 1.9 mg/dl, ALP 62U, PTH 31 pg/ml, vitD 44.1 ng/ml, Cau/24h 83 mg/24h, Pu/24h 512 mg/24h, after 1y of Burosumab, Ca 10,3 mg/dl, P 3,47 mg/dl PTH 63,5 pg/ml, 25OHVitD 7 ng/ml, Cau/24h 44 mg/24h, Pu/24h 86 mg/24. P increased of 46%, Pu/24h decreased of 84%. Case 2: showed Ca 9.2 mg/dl, P 1.9 mg/dl, ALP 62U/l, PTH 31 pg/ml, vit D 44.1 ng/ml, Cau/24h 83 mg/24h, Pu/24h 512 mg/24h, and after 12 months of Burosumab Ca 9,4 mg/dl, P 2,06 mg/dl, ALP 35U/l, PTH 33,6 pg/ml, 25OHVitD 10,6 ng/ml, Cau/24h 155 mg/24h, Pu/24h 75 mg/24h, P increased of 8%, Pu/24h decreased of 85%. After 1y of Burosumab they performed a IQOLA SF-36, and WOMAC showing a progressive and statistically significant improvement of physical, psychological condition. At 6 MWT the distance covered was significantly increased.

Conclusions: XLH due to c.1586+6T >C in PHEX is associated to a mild phenotype. Our data underline the importance of Burosumab treatment, capable to reduce a substantial disease burden also in adults.