Patients teaching doctors: hypophosphatemic rickets and the revelation of a novel phosphate homeostatic system
Familial hypophosphatemic rickets was recognized in the 1950s, when hypophosphatemia due to renal phosphate wasting was identified in individuals with rickets unresponsive to vitamin D therapy. X-linked dominant inheritance was evident in many cases, and the most common form of the disease is known as X-linked hypophosphatemia (XLH). A description of vitamin D-refractory rickets likely represents the first report of XLH (Albright F et al., Am J Dis Children 1937). After trials of phosphate therapy, and then with vitamin D, combination therapy using calcitriol together with phosphate salts eventually emerged as the standard of care for XLH in the 1980s. This therapy usually improves, but does not completely heal, rachitic deformities and short stature. Later complications include eventual development of osteophytes, paradoxical calcification of tendons and ligaments, and osteoarthritis, all of which are poorly understood. The mutated gene in XLH, PHEX, is a product of the osteocyte, but its role in the pathogenesis of phosphate wasting is poorly understood.
Study of XLH and its related disorders has led to the identification of a novel fibroblast growth factor family member, FGF23, a unique FGF with endocrine properties. Renal action of FGF23 leads to reduced expression of the type II sodium-phosphate co-transporters NaPi-IIa and NaPi-IIc which are instrumental in renal tubular phosphate reclamation, as well as to reduced expression of CYP27B1, which encodes the vitamin D 1α-hydroxylase enzyme. Selectivity of the renal tubular action of FGF23 is mediated by a transmembrane protein, klotho, an essential co-receptor for FGF23, converting generic FGF receptors to specific FGF23 receptors. The osteocyte is the primary source of FGF23; thus this novel phosphate regulatory system serves as a mechanism by which the mineralizing skeleton can communicate mineral abundance or demand to the kidney and thereby signal the excretion or conservation of this important component of the skeleton.