PHEX – X-linked Hypophosphatemic Rickets

X-linked hypophosphatemic rickets (XLH) is a phosphate-wasting disorder caused by loss-of-function mutations in the PHEX gene, leading to renal phosphate wasting, impaired bone mineralization, and elevated circulating fibroblast growth factor 23 (X-linked hypophosphatemic rickets). Affected individuals present with hypophosphatemia, rickets, short stature, bone deformities, and dental anomalies.

Genetic Evidence

XLH is inherited in an X-linked dominant manner, with both familial segregation and de novo events reported. Over 460 distinct PHEX mutations—including nonsense, missense, splice-site, insertions, and deletions—have been described in more than 500 probands from over 100 unrelated families, with consistent co-segregation of variants and phenotype ([PMID:11004247]; [PMID:18625346]). Functional loss is confirmed in multiple pedigrees with early onset bowing, waddling gait, and disproportionate short stature.

Variant Spectrum

Reported variants encompass truncating mutations (nonsense and frameshift), splice-site alterations, and missense changes affecting key metalloprotease domains. A representative pathogenic allele is c.1586_1586+1delAG (p.Glu529GlyfsTer41), which abolishes endopeptidase activity and leads to protein truncation in exon 14 ([PMID:19429806]). Both recurrent and private mutations occur across all 22 exons without a predominant hotspot, underscoring the need for complete gene sequencing and copy-number analysis.

Functional Evidence

PHEX protein is a Zn²⁺-dependent endopeptidase expressed in osteocytes. In vitro assays demonstrate that wild-type PHEX degrades phosphaturic factors and regulates FGF23 levels, whereas disease-causing mutants lack proteolytic activity and fail to traffic to the plasma membrane ([PMID:11409890]; [PMID:12727977]). Hyp mouse models and rescue experiments highlight that Phex deficiency elevates Fgf23 expression, induces phosphate wasting, and recapitulates XLH bone phenotypes.

Integration and Clinical Utility

Genetic confirmation of PHEX mutations enables early diagnosis, informs monitoring of renal phosphate reabsorption, and guides initiation of phosphate and active vitamin D therapy. Functional assays and animal models affirm haploinsufficiency as the primary mechanism. Novel intronic and deep intronic variants identified by RNA-first approaches further refine molecular diagnostics.

Key Take-home: PHEX mutation analysis offers definitive diagnosis of XLH, supports genetic counseling for X-linked inheritance, and underpins targeted therapeutic strategies.

References

• Pediatric Research • 2000 • Three novel PHEX gene mutations in Japanese patients with X-linked hypophosphatemic rickets PMID:11004247
• Bone • 2008 • Mutational survey of the PHEX gene in patients with X-linked hypophosphatemic rickets PMID:18625346
• Biochemical and Biophysical Research Communications • 2001 • FGF-23 inhibits renal tubular phosphate transport and is a PHEX substrate PMID:11409890
• The Journal of Clinical Endocrinology & Metabolism • 2003 • Structure and function of disease-causing missense mutations in the PHEX gene PMID:12727977

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