PHEX – Hypophosphatemic Rickets

PHEX loss-of-function mutations cause X-linked dominant hypophosphatemic rickets, the most common form of hereditary phosphate-wasting rickets. Affected individuals present in early childhood with hypophosphatemia, renal phosphate wasting, rickets, bone deformities and dental abscesses, reflecting impaired bone mineralization and phosphate homeostasis. Diagnosis relies on biochemical findings of low serum phosphate, elevated alkaline phosphatase, normal calcium and genetic confirmation.

Genetic evidence for PHEX in hypophosphatemic rickets is robust. In a cohort of 46 unrelated kindreds and 22 sporadic cases, 31 distinct PHEX mutations (nonsense, missense, splice site, insertions/deletions) were identified, with segregation in familial cases ([PMID:9768674]). Case reports describe a novel splice acceptor mutation c.934-1G>T at the intron 8/exon 9 junction ([PMID:24926462]) and a heterozygous missense variant c.1216T>C (p.Cys406Arg) in exon 11 associated with renal phosphate wasting ([PMID:24756041]).

The variant spectrum includes >140 unique PHEX alleles: 7 nonsense, 8 missense, 6 splice site, deletions and insertions disrupting protein length or catalytic domains. Segregation analyses across multiple pedigrees demonstrate co-segregation of PHEX alleles with disease phenotype in X-linked dominant fashion, confirming pathogenicity. The recurrent p.Gly579Arg allele has been observed in diverse populations.

Functional studies support a haploinsufficiency mechanism. Disease-causing missense mutations such as p.Gly579Arg and p.Cys85Arg interfere with ER exit and membrane targeting of PHEX, reducing endopeptidase activity ([PMID:11468271]). Transgenic Hyp mouse models lacking Phex expression in osteoblasts exhibit hypophosphatemia and rickets that cannot be rescued by osteoblast-specific Phex overexpression, underscoring extra-osteoblastic roles of Phex in phosphate homeostasis ([PMID:11713245]).

No convincing conflicting evidence has been reported. Both in vitro and in vivo assays consistently show loss of PHEX function leads to elevated FGF23 levels and phosphaturia. Further data from deep intronic variants and transcriptomic analyses extend the allele spectrum beyond canonical splice sites.

Key take-home: PHEX genetic testing should be implemented in patients with hypophosphatemic rickets to confirm diagnosis, guide management and enable accurate genetic counseling.

References

• The Journal of clinical endocrinology and metabolism • 1998 • Mutational analysis of PHEX gene in X-linked hypophosphatemia PMID:9768674
• Annals of pediatric endocrinology & metabolism • 2014 • A novel de novo mutation within PHEX gene in a young girl with hypophosphatemic rickets and review of literature PMID:24926462
• Journal of pediatric endocrinology & metabolism : JPEM • 2014 • Hypophosphatemic rickets caused by a novel PHEX gene mutation in an Indian girl PMID:24756041
• Human molecular genetics • 2001 • Disease-causing missense mutations in the PHEX gene interfere with membrane targeting of the recombinant protein PMID:11468271
• The Journal of biological chemistry • 2002 • Overexpression of Phex in osteoblasts fails to rescue the Hyp mouse phenotype PMID:11713245

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