X-linked dominant hypophosphatemia (XLH), the most common form of hereditary hypophosphatemic rickets/osteomalacia, is caused by loss-of-function phosphate-regulating endopeptidase homolog X-linked gene (PHEX) variants. However, synonymous PHEX variants are rare in XLH. We report a 7-year-old boy with hypophosphatemia, short stature, and lower limb deformity. Whole-exome sequencing, reverse transcription-polymerase chain reaction, and Sanger sequencing were performed to identify the pathogenicity of the variant. A novel synonymous PHEX variant (NM_000444.4:c.1530 C>T, p.Arg510Arg) was detected in the proband. Further analysis revealed a 58-bp deletion at the 5\' site of exon 14 during splicing. This study extends the genetic spectrum of XLH and confirms the rarity and significance of synonymous PHEX variants.

A decade ago, only two hormones, parathyroid hormone and 1,25(OH)2D, were widely recognized to directly affect phosphate homeostasis. Since the discovery of fibroblast growth factor 23 (FGF23) in 2000 (1), our understanding of the mechanisms of phosphate homeostasis and of bone mineralization has grown exponentially. FGF23 is the link between intestine, bone, and kidney together in phosphate regulation. However, we still do not know the complex mechanism of phosphate homeostasis and bone mineralization. The physiological role of FGF23 is to regulate serum phosphate. Secreted mainly by osteocytes and osteoblasts in the skeleton (2,3), it modulates kidney handling of phosphate reabsorption and calcitriol production. Genetic and acquired abnormalities in FGF23 structure and metabolism cause conditions of either hyper-FGF23 or hypo-FGF23. Hyper-FGF23 is related to hypophosphatemia, while hypo-FGF23 is related to hyperphosphatemia. Both hyper-FGF23 and hypo-FGF23 are detrimental to humans. In this review, we will discuss the pathophysiology of FGF23 and hyper-FGF23 related renal phosphate wasting disorders (4).