Hypophosphatasia (HPP) is a rare inborn metabolic disorder due to ALPL gene (1p36.12) mutations leading to deficient activity of the Tissue Non-Specific Alkaline Phosphatase (TNSALP), a homodimeric cell surface phosphohydrolase expressed in multiple tissues. Autosomal recessive or dominant inheritance of more than 300 different loss-of-function mutations cause accumulation of TNSALP substrates, including inorganic pyrophosphate (PPi), a potent inhibitor of mineralization, Pyridoxal 5-phosphate, the major circulating form of Vitamin B6 and Phosphoethanolamine (PEA). The clinical spectrum of disease manifestations both in terms of severity and organ involvement is remarkably broad, ranging from stillbirth and perinatal/infantile life-threatening symptoms, including chest and lung hypoplasia and pyridoxine-dependent seizures over premature loss of deciduous teeth and rachitic bone deformities in early childhood to unspecific musculoskeletal issues with rheumatoid/inflammatory pain, muscular weakness and fatigue along with compromised physical performance and recurrent, sometimes poorly healing fractures and bone marrow lesions. Beyond assessment family and individual medical history and clinical examination, diagnostic workup includes laboratory evaluation with Alkaline Phosphatase activity below age/sex adjusted normal range, elevated substrate levels (PLP in serum/plasma and urinary PEA) and eventually genetic testing for ALPL-Gene mutations, even though is to be considered that available evidence does not support the idea of a reproducible or meaningful genotype-phenotype correlation. Treatment is always multidisciplinary, including different medical specialties depending on prevailing organ manifestations and has to be tailored to individual needs. Following multinational approval of Asfotase alfa, a recombinant bone anchoring human alkaline phosphatase, enzyme replacement therapy (ERT) is available in Europe to treat bone manifestations of the disease in patients with childhood onset HPP. Study data on ERT clearly shows significantly improved survival of treated children as compared to a historical cohort. Further treatment modalities in addition and for less severely affected patients include analgesic medication with NSAIDs, supportive care with physiotherapy and phosphate reduced diet or phosphate binders and interventions to improve bone health including moderate Vitamin D supplementation and osteoanabolic treatment on an individual per-case decision, while avoiding bisphosphonates which appear to aggravate HPP-associated bone manifestation.
19 - 22 May 2018
European Society of Endocrinology