**10. Conclusions**

HPP is a systemic skeletal disorder that is caused by TNAP deficiency. Human TNAP is one of the four isoenzymes of alkaline phosphatase and is expressed ubiquitously. The TNAP protein is linked to the outer membrane of cells via a GPI anchor and works as an enzyme in a homodimer state. TNAP is essential for biomineralization; it is located on the MV membrane and plays a role in the elongation of hydroxyapatite crystals into the extracellular space.

HPP is classified into six forms and clinical severity varies among the forms. Hypomineralization of hard tissues is a common feature of HPP. In the severe forms, patients show rickets and respiratory failure that cause death. Milder forms exhibit musculoskeletal disorder or teeth problems. Although low serum ALP activity and an elevated urine PEA value are characteristic of HPP, genetic diagnosis is the definitive diagnosis. ERT using a genetically modified enzyme (asfotase alfa) opens up a new vista in the therapy of HPP, especially for severe forms of HPP. Although asfotase alfa has drastically changed the treatment of HPP, there remain still several problems with its use that need to be resolved.
