Experts' consensus on the management and treatment of individuals with X-linked hypophosphatemia across lifespan

Abstract

Purpose: X-linked hypophosphatemia (XLH) is a rare hereditary skeletal disorder that may be very disabling and significantly impacting the quality of life throughout the lifespan. The aim of this document was to inform stakeholders about the lifelong impact, management, and treatment of individuals with XLH, especially focusing on the new therapeutic approach with burosumab.

Methods: From October 2023 to April 2024, a multidisciplinary working group of Italian experts on bone and mineral metabolism convened periodic online meetings. Statements were formulated identifying the most relevant studies, including randomized controlled trials, international guidelines based on GRADE criteria, and systematic reviews, and the experts' opinions.

Results: The panel of experts provided "consensus statements" on the clinical management of individuals with XLH across lifespan. Five main issues were identified: (1) clinical and biochemical diagnosis of individuals with XLH and monitoring of the progression of the disease; (2) effects of conventional treatment with phosphate supplements and active vitamin D metabolites; (3) effects of the treatment with burosumab; (4) multidisciplinary approach and management of individuals with XLH; (5) consensus statement for transition from pediatric to adult care in individuals with XLH.

Conclusion: Individuals with XLH often experience unmet needs throughout life; a multidisciplinary approach involving different specialists, is recommended. The new treatment with burosumab can provide an effective and safety therapeutic option in reducing the burden of the disease in both children and adults. Therefore, awareness about the XLH disease should be increased among stakeholders. The criteria and reimbursement policies of burosumab should be revised.

Keywords: Burosumab; Conventional treatment; FGF23; Osteomalacia; Rickets; XLH.

Fig. 1

Phenotype throughout the lifespan in individuals living with XLH. Note the progression and the occurrence of some symptoms along the life. Infant: 0–1 year; child: > 1–12 years; adolescent: > 12–17 years; adult: 18 + years; elderly: 65 + years. Possible complications caused by conventional treatment are not reported. The mechanisms of the development of overweight/obesity and hypertension are not defined, and it is not clear if they are related to conventional treatment or disease itself. *It may be associated with Arnold-Chiari malformation. Light grey arrow represents the transition phase from adolescence to young adulthood

Fig. 2

Typical phenotype and radiological lesions in children with XLH. a Severe short stature (−4.6 Z-score) with body disproportion and genu-varum in a 6.5-year-old male. b Severe short stature (−3.0 Z-score) with body disproportion, exaggerated lordotic posture to compensate for the anterior bowing of the lower limbs, and craniosynostosis in a 6-year-old male. c Spontaneous gingival fistulae (black arrows) corresponding to deciduous left and right maxillary lateral incisors in a 4.3-year-old male. d X-ray features of the wrist in a 1.8-year-old female: widening and fraying of the epiphyseal plate and metaphyseal concavity of the ulna. e X-ray features of the lower limbs in a 2.1-year-old female: genu-varum and distal medial femoral and tibial bowing with widening and fraying of the distal epiphyseal plate of the femur and tibia and of the proximal epiphyseal plate of fibula and medial epiphyseal plate of the tibia