ESPE Abstracts

Introduction: X-linked hypophosphataemic rickets (XLH), due to mutations in the PHEX (Phosphate-regulating Endopeptidase homolog; X-linked) gene, causes reduced bone and dentin mineralisation and decreased renal phosphate reabsorption. Mosaic PHEX mutations are reported only in a few case reports.We report three male cases, with mosaic pathogenic PHEX variants, showing importance of considering this in the diagnosis of XLH.Case 1 presented at 4 years, with marked bowing of the legs, hypophosphataemia and low tubular reabsorption of phosphate (TRP). He commenced conventional treatment (alfacalcidol/phosphate) but did not tolerate phosphate, continuing to have rickets and bone deformities. Initially, no mutations were found in PHEX/FGF23, but the UK 100,000-genome project then suggested a PHEX variant. Reanalysis with Sanger-sequencing confirmed this, showing a low-level (35%) de novo mosaic pathological splice site variant: c.1173+5G>C in peripheral blood mononuclear cells (PMBCs), predicted to cause skipping of exon 10. This was originally missed by Sanger and next generation sequencing due to failure to recognise its pathogenicity and low-level mosaicism. Five years after diagnosis, he was then eligible for burosumab. Currently, aged 10 years, he is on 0.5mg/kg/dose burosumab, with healing rickets and height of -1.65SDS.Case 2 presented at 6 years, with mild tibial bowing. He had rickets, hypophosphataemia and reduced TRP. He was initially given conventional treatment; then burosumab. Sanger-sequencing of PHEX showed a mosaic splice site variant (30% mosaicism in PBMCs): c.1645+1G>A, causing skipping of exon 15 and likely nonsense mediated mRNA decay. At 13 years, he is on 0.7mg/kg/dose burosumab, with height of 1SDS.Case 3 presented at 11 months with macrocephaly, scaphocephaly and short stature. Biochemistry and X-rays suggested XLH. He had a truncating mutation in PHEX: c.1157G>A;p.(Trp386*), with 59% level mosaicism in PMBCs. He is currently on burosumab 1.3mg/kg/dose with height of -2.65 SDS, at 5 years.

Discussion: The splice site and frameshift variants have been found before in XLH; however, this is the first time they have been found as mosaic variants. The cases suggest that mosaic PHEX variants may not be extremely rare, and give similar phenotypes as non-mosaic mutations. Interestingly, only boys with mosaic PHEX variants have been described, whereas XLH in girls is not always rescued by X-chromosome inactivation.

Case 1 had difficulty with conventional therapy and delayed diagnosis meant initial ineligibility for burosumab treatment. This shows the importance to consider mosaicism and splice site variants when there is high clinical suspicion of XLH but genetic analysis is negative.