ESPE Yearbook of Paediatric Endocrinology

In brief: This systematic review, conducted by an international group of experts, provides an overview of the phenotype of patients with hypophosphatasia and proposes updated diagnostic criteria for this disease in children and adults.

Commentary: Hypophosphatasia (HPP) is a rare genetic disorder caused by loss-of-function mutations in the alkaline phosphatase (ALPL) gene, which encodes the tissue nonspecific alkaline phosphatase (TNSALP) enzyme. Low alkaline phosphatase activity is associated with impaired mineralisation of the skeleton, manifested by signs of rickets and osteomalacia, as well as extraskeletal manifestations (such as failure to thrive, seizures, muscle weakness, gross motor delay, abnormal gait, pain, early loss of primary teeth, and other dental problems).

Diagnosis of HPP is based on a combination of clinical and radiographic signs, laboratory profile and the identification of a pathogenic or likely pathogenic variant in the ALPL gene. Its presentation can be extremely variable and the diagnosis is often delayed, in both children and adults, with a median time to diagnosis of 5.7 years from the onset of first signs and symptoms. During this time, individuals may experience complications of the disease and may also be misdiagnosed and/or mistreated with drugs such as bisphosphonates, which may further impair the underlying skeletal mineralisation defect. Therefore, it is important to establish precise diagnostic criteria to allow early diagnosis and appropriate evaluation and treatment of the multisystem complications of HPP. In addition, an accurate description of the disease is important to identify phenotype-genotype correlations.