Bone Abstracts

Hypophosphatasia is a recessively inherited disorder with a wide phenotypic manifestation ranging from lethality in neonates to asymptomatic in adults. The severity of the phenotype is largely determined by the nature of the ALPL mutations. We describe a previously asymptomatic adult whose phenotype dramatically changed after he developed renal failure. A 50-year-old man was diagnosed with IgA nephropathy. At age 52 (eGFR 50 ml/min) he suffered his first metatarsal fracture. A DXA scan showed osteopenia, and he was prescribed alendronate. His renal failure progressed and he began dialysis (CAPD) at age 55. Prior to and after starting CAPD he suffered multiple non-traumatic fractures affecting metatarsals, vertebrae and ribs. Alendronate treatment was stopped. Further investigation showed low serum PTH levels 1.8–5.2 pmol/l (N 1–7) and discordance between the bone formation markers alkaline phosphatase (ALP) 56 U/l (N 40–120) and procollagen–1 N-peptide 180 μg/l (N 20–85). The ALP levels had been low (26–32 U/l) before starting alendronate. A bone biopsy showed osteomalacia, reduced cellular activity and negative staining for aluminium. Genetic analysis showed compound heterozygosity for missense mutations in ALPL (T117H and G438S). Expression plasmids for the mutant ALPs fused to green fluorescent protein were transfected into COS7 cells, and the cell lysates were harvested to assay enzymatic activity. The T117H mutant had almost no enzymatic activity, but the G438S mutant retained similar activity to wild-type ALP. Six months treatment with teriparatide produced an increase in ALP activity and histological improvement in bone, but significant side effects. After the restoration of renal function by transplantation there was complete symptomatic and histological resolution. It is probable that as the patient developed renal failure, phosphate retention inhibited his residual ALP enzyme activity, resulting in a marked clinical deterioration – an interesting example of a reversible genotype-environment interaction affecting phenotype.