Variant Synonymizer: Platform to identify mutations defined in different ways is available now!
Over 2,000 gene–disease validation summaries are now available—no login required!
X-linked dominant hypophosphatemic rickets (XLH) is a heritable phosphate-wasting disorder caused by pathogenic variants in the phosphate-regulating endopeptidase homolog X-linked, PHEX. Inheritance is X-linked dominant with complete penetrance in both sexes, leading to hypophosphatemia, rickets, osteomalacia, and growth retardation. The hallmark biochemical profile comprises renal phosphate wasting, elevated alkaline phosphatase, normal serum calcium, and inappropriately normal or elevated parathyroid hormone and FGF23 levels.
Extensive genetic studies have identified over 166 unique loss-of-function PHEX variants in 261 XLH patients, including nonsense, frameshift, splice-site, and large deletion mutations, with consistent segregation in multigenerational families ([PMID:20578943]). De novo mutations account for a significant fraction of sporadic cases. One example is the recurrent nonsense mutation c.286G>T (p.Glu96Ter), which segregates with disease in a mother–daughter pair of Indian ancestry and abolishes PHEX enzymatic activity ([PMID:20664300]).
Segregation analyses in kindreds of up to 13 affected individuals across four generations confirm robust co-segregation of PHEX variants with disease. No PHEX variants are detected in unaffected male relatives, supporting full penetrance. Recurrent hotspot mutations (e.g., R20X) further underscore the importance of PHEX in XLH pathogenesis ([PMID:10737991]).
Functional studies demonstrate abundant PHEX mRNA expression in the parathyroid gland and endopeptidase homology to the M13 family, implicating PHEX in PTH regulation. In a 5-year-old girl with primary hyperparathyroidism prior to therapy, elevated PHEX expression parallels Pi-induced PTH release, suggesting a direct role in phosphate–PTH homeostasis ([PMID:10460513]). Mouse models harboring Phex mutations replicate hypophosphatemia, rickets, and osteomalacia, confirming loss of function as a disease mechanism.
At the molecular level, PHEX loss of function impairs proteolytic degradation of FGF23 and disrupts downstream phosphate reabsorption in renal proximal tubules, leading to elevated circulating FGF23, reduced 1,25(OH)2D, and defective bone mineralization. The convergence of human genetic and murine functional data establishes haploinsufficiency of PHEX as the core mechanism driving XLH.
Key take-home: PHEX variants cause definitive XLH via an X-linked dominant loss-of-function mechanism, with clear diagnostic utility for genetic testing, family counseling, and targeted therapies such as anti-FGF23 antibodies.
Gene–Disease AssociationDefinitiveWidespread identification of PHEX loss-of-function variants in hundreds of individuals from >100 families over two decades, consistent segregation and functional data Genetic EvidenceStrongOver 166 unique PHEX mutations identified in 261 patients; multiple family segregation, de novo variants and consistent phenotype across cohorts Functional EvidenceModeratePHEX knockout and functional studies demonstrate loss-of-function phenotype in parathyroid gland and mouse models with hypophosphatemia and rickets |