X-linked hypophosphataemia (XLH) is the most common form of inherited hypophosphataemic rickets, caused by loss-of-function mutations in the gene encoding phosphate-regulating endopeptidase homologue X-linked (PHEX), resulting in excess circulating fibroblast growth factor 23 (FGF-23).1,2 In children, clinical features include delayed walking, waddling gait, leg bowing, pain, spontaneous dental abscesses and growth failure. Current therapies do not treat the underlying cause of the disease,2 resulting in persistence of rickets, growth impairment, and gastrointestinal side effects.3 Burosumab is a novel, fully human anti-FGF-23 immunoglobulin G1 monoclonal antibody that binds and inhibits FGF-23 activity.4,5 Here, we describe the clinical and biochemical features of XLH in four paediatric patients treated with burosumab.
Patients (one male, three females) were aged 211.5 years at diagnosis. Physical symptoms included leg bowing in all patients; three patients had dental caries, two patients presented with a larger head circumference (≥95th percentile), and one patient had craniosynostosis. Other physical symptoms included short stature and wide wrists. Baseline biochemical investigations revealed low phosphate (PO4) levels in all patients (0.850.90 mmol/L), elevated parathyroid hormone (PTH) levels of 3.0716.06 pmol/L, high alkaline phosphatase (ALP) levels of 376937 U/L and low renal tubular maximum reabsorption rate of phosphate to glomerular filtration rate (TmP/GFR) of 0.610.81. Intact FGF-23 levels ranged from 77 to 139 RU/mL, with highly elevated levels in three patients. Genetic testing confirmed PHEX mutation in all patients. Despite receiving PO4 supplementation and a vitamin D analogue (alfacalcidiol), clinical signs of rickets did not improve, therefore burosumab was considered. Prior therapies were stopped 1 week before treatment initiation with burosumab (s.c.) and serum PO4 was measured every 2 weeks for the first month, monthly for 2 months and then every 3 months as appropriate after injection.
Burosumab treatment increased PO4 levels in all patients after the first injection and after 3 months, all patients had levels within the reference range (11.95 mmol/L). Mean serum ALP levels decreased from baseline in all patients after 3 months of treatment, and PTH levels were stable throughout the treatment period. TmP/GFR increased from baseline in all patients after 3 months of burosumab treatment (increase of 0.170.51).
In four paediatric cases of XLH, burosumab treatment increased serum PO4, decreased mean serum ALP, and improved TmP/GFR. No adverse effects were observed. These cases confirm previous findings3 that burosumab is effective in treating paediatric patients in whom conventional therapy had limited success.
19 - 21 Sep 2019
European Society for Paediatric Endocrinology