Hypophosphatasia in children: From low alkaline phosphatase activity to diagnosis, genetic testing, and treatment options. A narrative review

Hypophosphatasia (HPP) is an inherited metabolic disorder caused by loss-of-function mutations in the ALPL gene encoding a tissue-nonspecific alkaline phosphatase (TNSALP). It has been classified based on age at first disease manifestation, including lethal perinatal, benign perinatal, infantile, juvenile, adult, and odontohypophosphatasia. Diagnosis is based on clinical presentation, alkaline phosphatase (ALP) assay and genetic testing. The main diagnostic clue is the low (for age and sex) ALP activity. In any patient with suspected HPP or skeletal/bone deformities/dysplasia, it is recommended to evaluate phospho-calcium metabolism, which is useful in differential diagnosis. Genetic diagnosis of HPP requires identification of a disease-causing variant(s) (pathogenic). In Europe, the most frequent ALPL variants are c.571G>A, c.407G>A and c.1250A>G, while the most frequently detected variants in the world are c.1250A>G, c.571G>A and c.1133A>T. Asfotase alfa, a recombinant human TNSALP enzyme replacement therapy, is now available for the treatment of HPP. The article provides an up-to-date overview of clinical, biochemical and molecular features of HPP. Treatment strategy in HPP was also described.