Two dominant inherited disorders of phosphate homeostasis, X-linked hypophosphatemia (XLH), and ADHR are known to be caused by inactivating mutations in the PHEX gene or activating mutations in the FGF23 gene (fibroblast growth factor 23), respectively. Both diseases show a similar phenotype with renal phosphate wasting and inappropriately normal or low 1,25-(OH)2-Vitamin D3 serum levels, leading to hypophosphatemic rickets and osteomalacia. The differential diagnosis can be achieved by molecular genetic analysis of the involved genes.
The index patient presented at the age of 2 years with growth retardation (−3.1 SDS; 4 cm <3. Percentile), genua vara, severe rickets, and osteomalacia, leading to bone pain and restricted mobility. Serum phosphate levels were low (0.8 mmol/l; normal range 1.12.0 mmol/l), tubular phosphate reabsorption (58%) and tubular phosphate transport maximum (0.8 mmol/l; normal range 1.22.6 mmol/l) were decreased. Calcium, 1,25-(OH)2-Vitamin D3 and PTH levels were normal. Based on these findings, hypophosphatemic rickets was diagnosed and the boy was treated with phosphate (550 mg/d) and 1,25-(OH)2-Vitamin D3 (0.4 μg/d). During treatment, radiological signs of rickets and osteomalacia decreased. The growth rate improved, although body height at the age of 7 years remains low (3. Percentile).
Mutations in the PHEX gene were excluded, but analysis of the FGF23 gene revealed a novel heterozygous missense mutation in exon 3, resulting in the substitution of the amino acid arginine at position 176 by tryptophane (CGG>TGG, R176W). The mutation R176W affects the cleavage site of FGF23 that is formed by the 176RXXR179 motif, and is predicted to prevent proteolytic cleavage and inactivation of FGF23. In conclusion, in this patient genetic testing allowed for the reliable differentiation of ADHR and XLH.
03 - 07 May 2008
European Society of Endocrinology