These findings expand the mutation spectrum of PHEX and may help us to understand the molecular basis of XLHR in order to facilitate genetic counseling.
Thus, the complex re-arrangement including a deletion of coding exons 8 to 11 of the PHEX can be regarded as the cause of XLH in the patient reported here.
The seminal observations leading to these discoveries were the following: 1) mutations in FGF23 cause ADHR by limiting cleavage of the bioactive intact molecule, at a subtilisin-like protein convertase (SPC) site, resulting in increased circulating FGF23 levels and hypophosphatemia; 2) mutations in DMP1 cause ARHR, not only by increasing serum FGF23, albeit by enhanced production and not limited cleavage, but also by limiting production of the active DMP1 component, the C-terminal fragment, resulting in dysregulated production of DKK1 and β-catenin, which contributes to impaired bone mineralization; and 3) mutations in PHEX cause XLH both by altering FGF23 proteolysis and production and causing dysregulated production of DKK1 and β-catenin, similar to abnormalities in ADHR and ARHR, but secondary to different central pathophysiological events.
X-linked dominant hypophosphatemic rickets (XLHR) is the most prevalent genetic type of hypophosphatemic rickets and is caused by germ line mutations in the PHEX-gene.
X-linked hypophosphatemia is the most common of the phosphate-wasting disorders mediated by elevated fibroblast growth factor 23 (FGF23) and occurs as a consequence of inactivating mutations of the PHEX gene product.
It is known that XLH in humans and in certain mouse models is caused by inactivating mutations in PHEX/Phex (phosphate-regulating gene with homologies to endopeptidases on the X chromosome).
Patients with clearly deleterious PHEX mutations had lower TRP and 1,25(OH)2D levels suggesting that the PHEX type of mutation might predict the XLHR phenotype severity.
In hypophosphatemic rickets, there are both inherited and acquired forms, where X-linked dominant hypophosphatemic rickets (XLH) is the most prevalent genetic form and caused by mutations in the phosphate-regulating endopeptidase (PHEX) gene.
We describe a patient with XLH caused by a novel missense mutation in the PHEX gene, who on treatment with alfacalcidol and oral phosphate had normal growth and minimal bone deformities, but who subsequently developed moderate nephrocalcinosis, significant hyperparathyroidism, hypercalcemia, renal failure, and hypertension.
Inactivating mutations in the gene encoding PHEX (phosphate-regulating gene with homologies to endopeptidases on the X chromosome) have been found to be associated with XLH.