Family and infrequently hypophosphatemic rickets: clinical and molecular findings.

Abstract

Human disorders of phosphate handling and skeletal mineralization can result from inactivating mutations in PHEX, an X linked dominant disorder (XLH). Autosomal-dominant hypophosphatemic rickets (ADHR) is a rare disorder caused by mutation in the FGF23 gene, which, in contrast to XLH, displays incomplete penetrance and variable age of onset. We studied genomic DNA of 13 Argentinean families in order to characterize these genes. We studied 29 patients and their relatives (n=12) with hypophosphatemic rickets and osteomalacia, belonging to 13 families. FGF23 was analyzed by bidirectional complete sequencing of the exons 3. For the evaluation of the PHEX gene all 22 exons and introns/exons boundaries were analyzed by SSCP/HD and bidirectional complete sequencing of regions with abnormal migration patterns was performed. We found five sporadic cases. Six patients had been diagnosed in early childhood. FGF23 missense mutation was identified in 4 affected members of a family (G>A, R179Q, in exon 3). Four novel PHEX gene mutations were detected. Family III: two patients, presented c.552 ins G+1 of intron 3-4 in splice donor. Family IV: three members, had a silence mutation c.401 C>A pos 11 exon 3. Family VII: two patients had a codon stop mutation, c.1241 C>G pos 105 exon 9. A single girl with healthy parents showed silence mutation c.2260 T>G in pos 93 exon 20. Patients with XLRH have more severe skeletal disease. We describe 4 novel mutations in the PHEX gene. In contrast, we detected only one family with ADHR where we could observe different clinical manifestations. PHEX mutations were detected also in sporadic cases.