Hypophosphatasia – Recent Advances in Diagnosis and Treatment

Abstract

Hypophosphatasia (HP) is a rare inborn error of bone and mineral metabolism transmitted as an autosomal- recessive trait. It is characterized by a reduced activity of the tissue-nonspecific isoenzyme of alkaline phosphatase (TNSAP) and elevated concentrations of its substrates including pyrophosphates. Clinical symptoms include defective bone mineralisation with bone deformities, fractures and recently defined chronic non-bacterial osteomyelitis. Renal damage due to calcification, dental abnormalities with premature loss of dentition and craniosynostosis are further symptoms. Knowledge on the mechanisms underlying cell activation leading to inflammation and tissue destruction is still limited in HP. Recent investigations have provided evidence that calcium pyrophosphate crystals are essentially involved in activating inflammatory signal transduction pathways via different receptors of the innate immune system. Further studies are needed to improve our understanding of the pathophysiological mechanisms leading to inflammation and tissue destruction associated with deposition of microcrystals. They might support the development of new therapeutic strategies for crystal-induced inflammation. Laboratory assays, genetic analysis and radiographic imaging can confirm the diagnosis. Since clinical symptoms are highly variable patients should be followed by a HP-experienced multidisciplinary team (paediatrician, radiologist, orthopedic surgeon, neurosurgeon, dentist, nutritional specialist). At the moment symptomatic treatment is most important because curative or causative therapies, like gene transfer or enzyme replacement therapy, are not yet available.