Endocrine Abstracts

Introduction: X-linked hypo-phosphataemic rickets is characterized by hypophosphataemia, vitamin D deficiency, poor bone and dental mineralization. Mutations occur within the PHEX gene. Currently 329 mutations have been sequenced¹. We report a novel PHEX mutation in a female with hypophosphataemic rickets.

Case report: A 12-year-old girl presented with, genu varum, short stature and a previous dental abscess. Investigatons showed hypophosphataemia with a high urinary phosphate level, vitamin D deficiency, elevated parathyroid hormone, elevated alkaline phosphatase and normal calcium levels. Knee X-rays showed bilateral lucent lines and tibial growth plate defects. Dexa scan results were at the extreme lower limit of the expected range. The PHEX gene was analysed by Sanger sequence analysis of the coding and flanking intron regions by multiplex ligation-dependent probe amplification. Databases cross-referenced were: dbSNP, Exon Variant Server and locus specific database http://www.phexdb.mcgill.ca. DNA analysis of both parents was also performed. The patient was heterozygous for a novel, de novo PHEX mutation in the gene location c1501_1502ins24, exon 14 of PHEX gene. This resulted in an in-frame insertion of 8 novel amino acids in the protein p.Ala500Asp501ins8(p.A500_D501ins8).

Discussion: PHEX encodes an endopeptidase homolog mainly expressed in bone and teeth^2,3. It has been proposed that PHEX acts directly or indirectly on fibroblast growth factor 23 (FGF23)^4,5. FGF23 is produced by osteocytes^6,7 and acts on the sodium dependent phosphate transporters within the renal proximal tubules to reduce phosphate reabsorption⁸. FGF23 also inhibits1-α-hydroxylase activity causing vitamin D deficiency⁹. PHEX mutations result in failure to cleave FGF23 to an inactive form, resulting in renal phosphate leak and low vitamin D levels^4,10. FGF23 is considered a hormone, under the influence of PHEX as part of the bone-renal axis of phosphate homeostasis.

References:: 1. PHEX Locus specific database http://www.phexdb.mcgill.ca

2. The HYP Consortium. A gene (PEX) with homologies to endopeptidases is mutataed in patients with X-linked hypo-phosphataemic rickets. Nat Genet 1995 11 130–136.

3. Ruchon AF, Marcinkiewicz M, Siegfried G, Tenenhouse HS, Des-Groseillers L, Crine P, et al. Pex mRNA is localized in developing mouse osteoblasts and odontoblasts. J Histochem Cytochem 1998 46 459–468.

4. Bowe AE, Finnegan R, Jan de Beur SM, Cho J, Levine MA, Kumar R, et al. FGF-23 inhibits renal tubular phosphate transport and is a PHEX substrate. Biochem Biophys Res Commun 2001 284 977–981.

5. Campos M, Couture C, Hirata IY, Juliano MA, Loisel TP, Crine P, et al. Human recombinant endopeptidase PHEX has a strict s1’specificity for acidic residues and cleaves peptides derived from fibroblast growth factor-23 and matrix extracellular phosphoglycoprotein. Biochem J 2003 373 271–279.

6. Mirams M, Robinson BG, Mason RS & Nelson AE. Bone as a source of FGF23: regulation by phosphate? Bone 2004 35 1192–1999.

7. Liu S, Zhou J, Thang W, Jiang X, Rowe DW & Quarles LD. Pathogenic role of fgf23 in Hyp mice. Am J Physiol Endocrinol Metab 2006 291 E38-E49.

8. Murer H, Hernando N, Forster I & Biber J. Proximal tubular phosphate reabsorption: Molecular mechanisms. Physiol Rev 2000 80 1373–1409.

9. Shimada T, Hasegawa H, Yamazaki Y, Muto T, Hino R, Takeuchi Y, et al. FGF-23 is a potent regulator of vitamin D metabolism and phosphate homeostasis. J Bone Miner Res 2004 19 429–435.

10. Shimada T, Muto T, Urakawa I, Yoneya T, Yamazaki Y, Okawa K, et al. Mutant FGF-23 responsible for autosomal dominant hypophosphataemic rickets is resistant to cleavage and causes hypophosphataemia in vivo. Endocrinology 2002 143 3179–3182.