ESPE Yearbook of Paediatric Endocrinology

In brief: This observational analysis, based on data from the Global Hypophosphatasia Registry, reports the clinical profiles, prior to initiation of asfotase alfa enzyme replacement therapy, in a large cohort of children with hypophosphatasia (n=151), by age (<6 months vs 6 months to 18 years) and geographic region (USA/Canada, Europe, and Japan).

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). Clinical manifestations vary widely, especially with age, with perinatal and infantile forms being the most severe and potentially life-threatening.

Enzyme replacement therapy with asfotase alfa has led to improvements in the various manifestations of the disease and is now approved in the US/Canada and Europe. However, there are no global treatment guidelines for the initiation of asfotase alfa, and recommendations for the initiation of this treatment may vary from country to country. Given the wide clinical variability of the disease, a precise description of the signs and symptoms of HPP is needed to specify the indication and effects of treatment with asfotase alfa.

This observational study provides a precise description of the frequency of the various manifestations, both skeletal and extraskeletal, particularly as a function of age. In particular, it is reported that children with HPP are more likely to have skeletal, renal and respiratory manifestations at first presentation at <6 months of age, whereas dental, muscular and pain manifestations are more common in those aged 6 months to 18 years at first presentation. Evaluation and follow-up of clinical data may shed light on the emergence of associations between phenotypic features, the regional differences, and the impact of enzyme replacement therapy on the natural history of HPP, including treatment outcomes that are relevant to routine clinical practice.