Abstract
The authors present a stereotypical case presentation of X-linked hypophosphatemia (XLH) and provide a review of the pathophysiology and related pharmacology of this condition, primarily focusing on the FDA-approved medication burosumab. XLH is a renal phosphate wasting disorder caused by loss of function mutations in the PHEX gene (phosphate-regulating gene with homologies to endopeptidases on the X chromosome). Typical biochemical findings include elevated serum levels of bioactive/intact fibroblast growth factor 23 (FGF23) which lead to (i) low serum phosphate levels, (ii) increased fractional excretion of phosphate, and (iii) inappropriately low or normal 1,25-dihydroxyvitamin D (1,25-vitD). XLH is the most common form of heritable rickets and short stature in patients with XLH is due to chronic hypophosphatemia. Additionally, patients with XLH experience joint pain and osteoarthritis from skeletal deformities, fractures, enthesopathy, spinal stenosis, and hearing loss. Historically, treatment for XLH was limited to oral phosphate supplementation, active vitamin D supplementation, and surgical intervention for cases of severe bowed legs. In 2018, the United States Food and Drug Administration (FDA) approved burosumab for the treatment of XLH and this medication has demonstrated substantial benefit compared with conventional therapy. Burosumab binds circulating intact FGF23 and blocks its biological effects in target tissues, resulting in increased serum inorganic phosphate (Pi) concentrations and increased conversion of inactive vitamin D to active 1,25-vitD.
Highlights
College of Osteopathic Medicine Division of Biomedical Science, Marian University, 3200 Cold Spring Rd., Bone & Muscle Research Group, Marian University, 3200 Cold Spring Rd., Indianapolis, IN 46222, USA
Regulating gene with homologies to endopeptidases on the X chromosome) which led to a diagnosis of the metabolic bone disease X-linked hypophosphatemia (XLH)
Prior to the approval of burosumab, management options for XLH focused on treatment of electrolyte abnormalities with oral phosphate replacement and 1,25-vitD supplementation, whereas burosumab is able to target and block the pathway that is overexpressed in patients with XLH directly treating the underlying condition [20]
Summary
XLH is the most common form of heritable rickets and its diagnosis is generally based on physical exam, biochemical analyses of serum and/or plasma, imaging tests, and family history. XLH is a renal phosphate wasting disorder caused by loss of function mutations in the PHEX gene [1,2,3]. Mutation in the PHEX gene product leads to increased serum levels of FGF23. Other biochemical findings typically include elevated low serum phosphate levels, increased fractional excretion of phosphate, normocalcemia and inappropriately low or normal 1,25-vitD [5]. FGF23 was initially identified through gain-of-function mutations in a different form of rickets, the rare heritable disorder autosomal dominant hypophosphatemia rickets (ADHR) [9]. Prior to this discovery, phosphate homeostasis was thought to be maintained through. FGF23 suppresses the transcription of the genes encoding sodium-phosphate cotransporters [1]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
