Hypophosphatasia: classification, diagnosis and management

Abstract

Hypophosphatasia (HPP) is a rare inherited metabolic bone disorder caused by reduced activity of tissue non-specific alkaline phosphatase (TNSALP). Deficient TNSALP activity results in the accumulation of its natural substrates, predominantly inorganic pyrophosphate, leading to impaired bone mineralization, dental problems and multi-system involvement. Clinical manifestations are heterogeneous, ranging from life-threatening perinatal disease to milder musculoskeletal phenotypes that present in adulthood or with pure dental involvement only. The rarity of HPP, alongside many symptoms being non-specific, contributes to frequent diagnostic delay. For the orthopaedic surgeon, recognising HPP is critical when evaluating patients with recurrent metatarsal stress fractures, atypical femoral fractures and delayed bone healing. This review outlines the pathophysiology, diagnostic criteria, assessment and both medical and orthopaedic treatment, including the use of enzyme replacement therapy.