Mineralized tissues in hypophosphatemic rickets
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EDUCATIONAL REVIEW
Mineralized tissues in hypophosphatemic rickets Marie-Eve Robinson 1 & Haitham AlQuorain 1 & Monzur Murshed 1 & Frank Rauch 1 Received: 29 January 2019 / Revised: 3 June 2019 / Accepted: 6 June 2019 # IPNA 2019
Abstract Hypophosphatemic rickets is caused by renal phosphate wasting that is most commonly due to X-linked dominant mutations in PHEX. PHEX mutations cause hypophosphatemia indirectly, through the increased expression of fibroblast growth factor 23 (FGF23) by osteocytes. FGF23 decreases renal phosphate reabsorption and thereby increases phosphate excretion. The lack of phosphate leads to a mineralization defect at the level of growth plates (rickets), bone tissue (osteomalacia), and teeth, where the defect facilitates the formation of abscesses. The bone tissue immediately adjacent to osteocytes often remains unmineralized (“periosteocytic lesions”), highlighting the osteocyte defect in this disorder. Common clinical features of XLH include deformities of the lower extremities, short stature, enthesopathies, dental abscesses, as well as skull abnormalities such as craniosynostosis and Chiari I malformation. For the past four decades, XLH has been treated by oral phosphate supplementation and calcitriol, which improves rickets and osteomalacia and the dental manifestations, but often does not resolve all aspects of the mineralization defects. A newer treatment approach using inactivating FGF23 antibodies leads to more stable control of serum inorganic phosphorus levels and seems to heal rickets more reliably. However, the long-term benefits of FGF23 antibody treatment remain to be elucidated. Keywords Bone . Hypophosphatemia . Mineralization . Phosphate . Rickets . Vitamin D
Introduction Hypophosphatemic rickets is, as the name says, a skeletal disorder that is characterized by hypophosphatemia. As phosphate is essential for mineralization, hypophosphatemia leads to a mineralization deficit. This primarily affects the tissues where mineralization physiologically occurs—bones, teeth, and growth plate cartilage. In growing children, the mineralization defect affects all three tissues. The growth plate abnormalities are responsible for the main skeletal manifestations of rickets—deformities of the lower extremities and slow growth [1–3]. In adults, where the growth plates have fused, the mineralization defect still affects bone tissue and teeth. Hypophosphatemic rickets is caused by renal phosphate wasting that is most commonly due to dominant mutations in the phosphate-regulating endopeptidase gene (PHEX). As
* Frank Rauch [email protected] 1
Shriners Hospital for Children and McGill University, 1003 Boulevard Decarie, Montreal, Québec H4A 0A9, Canada
PHEX is located on the X chromosome, mutations in this gene lead to the X-linked form of hypophosphatemic rickets (XLH), which has a prevalence of about 1 in 20,000 [4–6]. Mutations in other genes are much rarer causes of hypophosphatemic rickets (Table 1) [7–9, 3]. Very rarely, the clinical picture of hypophosphatemic rickets ca
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