Approach to Hypophosphatemic Rickets

Abstract

Hypophosphatemic rickets typically presents in infancy or early childhood with skeletal deformities and growth plate abnormalities. The most common causes are genetic (such as X-linked hypophosphatemia), and these typically will result in lifelong hypophosphatemia and osteomalacia. Knowledge of phosphate metabolism, including the effects of fibroblast growth factor 23 (FGF23) (an osteocyte produced hormone that downregulates renal phosphate reabsorption and 1,25-dihydroxyvitamin-D (1,25(OH)2D) production), is critical to determining the underlying genetic or acquired causes of hypophosphatemia and to facilitate appropriate treatment. Serum phosphorus should be measured in any child or adult with musculoskeletal complaints suggesting rickets or osteomalacia. Clinical evaluation incudes thorough history, physical examination, laboratory investigations, genetic analysis (especially in the absence of a guiding family history), and imaging to establish etiology and to monitor severity and treatment course. The treatment depends on the underlying cause, but often includes active forms of vitamin D combined with phosphate salts, or anti-FGF23 antibody treatment (burosumab) for X-linked hypophosphatemia. The purpose of this article is to explore the approach to evaluating hypophosphatemic rickets and its treatment options.

Keywords: X-linked hypophosphatemia; burosumab; fibroblast growth factor 23; hypophosphatemia; rickets.

Figure 1.

Algorithm for assessing causes of hypophosphatemic rickets. Note that before applying this algorithm, the calciopenic causes of rickets (such as vitamin D deficiency, etc., must first be excluded). The calciopenic forms are often marked by hypocalcemia along with marked elevation of PTH. Once calciopenic forms are excluded, evaluation for causes of hypophosphatemia is pursued beginning with TmP/GFR. ^aConsider genetic causes even without family history. ^bIron deficiency itself triggers hypophosphatemia in ADHR. ^cIron infusions especially iron carboxymaltose or polymaltose can also trigger hypophosphatemia, likely through impaired cleavage of FGF23. ^dFGF23 may be high in hyperparathyroidism. ^eHypercalciuria may not always be present in tubulopathies. ^fNon-FGF23–mediated causes of hypophosphatemia may still result in high FGF23 concentrations if moderate to severe chronic kidney disease develops.