Effect of Mutation Type on Ectopic Ossification Among Adult Patients With X-Linked Hypophosphatemia

Causative factors for ectopic ossifications in X-linked hypophosphatemia (XLH) remain to be elucidated.

This work aimed to investigate the genotype-phenotype correlations between the phosphate-regulating endopeptidase homologue, X-linked gene (PHEX) and ectopic ossifications in XLH.

Biochemical data, spinal computed tomography scans, and x-rays of hip/knee joints were retrospectively reviewed. Genetic analysis and the measurement of plasma inorganic pyrophosphate (PP_i)-a potent inhibitor of tissue calcification-were performed. The effect of PHEX mutations on protein function was predicted using nonsense-mediated decay (NMD) and 3-dimensional structure modeling. The index of ossification of the anterior/posterior longitudinal ligament and yellow ligament (OA/OP/OY index) and the sum of the OA/OP/OY index (OS index) were used to quantify the severity of spinal ligament ossification. The severity of the hip/knee osteoarthritis was evaluated by the Kellgren-Lawrence classification.

We examined 24 distinct pathogenic PHEX variants in 28 patients from a study population of 33 individuals in 27 unrelated, nonconsanguineous families. Among the 31 patients whose plasma samples were analyzed for PP_i, 14 patients (45%) showed decreased plasma PP_i concentrations; however, PP_i concentrations did not correlate with mutation type or ectopic ossification. Fibroblast growth factor 23 levels in women with NMD-insensitive mutations trended lower than in men with NMD-sensitive mutations but failed to reach statistical significance. Both models revealed no correlations between PHEX pathogenic variant and ectopic ossification.

Neither modeling found correlates between PHEX pathogenic variants and ectopic ossification. The effects of PP_i on ectopic ossifications in adults with XLH revealed trends that should be investigated with a large sample size.