Bone Abstracts

Background: Defects in 1-α-hydroxylase enzyme activity result in reduced activity of 1,25(OH)₂D causing vitamin D dependent rickets. Physiologically FGF23 levels are stimulated by a rise in 1,25(OH)₂D which in turn suppresses 1-α-hydroxylase expression to complete the feedback loop.

Presenting problem: A 15-month-old Irish Caucasian girl was referred by her GP for failure to weight bear. She was born at term via elective section, and was bottle fed with no dietary or absorption issues. She had prominent swelling of her wrists, femora and tibiae but no genu valgum or varum, talipes or spinal anomalies. X-rays demonstrated metaphyseal flaring of all long bones suggestive of rickets. Skeletal biochemistry confirmed this with raised alkaline phosphatase, low-normal calcium and low phosphorus. Serum 25OHD was raised while 1,25(OH)₂D was inappropriately low. Subsequent genetic testing identified a heterozygous mutation in the 1-α-hydroxylase gene considered to be pathogenic because it creates a frameshift mutation changing the amino acid sequence from position 387 with a premature truncation. The mutation is paternally inherited.

Clinical management: The girl was commenced on calcium supplementation with 1-α replacement resulting in improvements in serum PTH, alkaline phosphatase, calcium and phosphorus over subsequent months. FGF23 levels were measured at initial assessment and during recovery and are persistently raised (range 127–190 RU/ml, reference range <100) despite persistent low phosphorus levels thought to be secondary to the raised PTH level. Clinically, her demeanour has improved from initial treatment and after 6 months she began weight bearing without difficulty and showing interest in walking.

Discussion: The phenotype of this girl reflects the diagnosis of a 1-α-hydroxylase mutation albeit with the identification of only one affected allele. Blunted activity of 1,25(OH)₂D and hypophosphataemia should both result in the lowering of FGF23 levels yet counter intuitively the levels remain high. Is this a cause or consequence of therapy?