Hypophosphatasia in adults: how not to overlook a rare disease?

Abstract

Hypophosphatasia (HPP) is a rare hereditary disease characterized by reduced activity of tissue-nonspecific alkaline phosphatase (TNSALP) encoded by ALPL gene, defective mineralization of bone (osteomalacia) and various musculoskeletal manifestations, such as bone deformity, teeth loss, recurrent fractures, chronic bone and muscle pain, reduced muscular strength, etc. Deficiency of TNSALP activity leads to the extracellular accumulation of its substrates, including inorganic pyrophosphate that inhibits bone mineralization. Homozygous and compound heterozygous mutations of the ALPL gene are associated with a lower TNSALP activity and HPP severity. However, heterozygous dominant negative variants can also result in clinical manifestations. The authors present two adult patients with HPP and discuss diverse clinical features of the disease and the efficacy of asfotase alpha, the human recombinant enzyme-replacement therapy that replaces deficient TNSALP. In adults and adolescents with pediatric-onset HPP, treatment with asfotase alfa was associated with improved functional abilities and health-related quality of life.