Endocrine Abstracts

Hypophosphatasia (HPP) is a rare inherited metabolic disorder characterized by deficient activity of tissue-nonspecific alkaline phosphatase (TNAP) caused by variants in the ALPL gene. Disease manifestations include: reduced skeletal mineralization, rickets, lung hypoplasia, vitamin B6-dependent neurological manifestations, craniosynostosis, premature loss of deciduous teeth, and muscle pain. The clinical presentation can comprise failure to thrive with muscular hypotonia, delayed motor development, and gait disturbances later in childhood. In adults, pseudofractures are a characteristic indicator of severely compromised enzyme activity. However, non-classical symptoms like generalized musculoskeletal pain, weakness, and fatigue, frequently accompanied by neuropsychiatric and gastrointestinal problems are increasingly recognized as key findings in patients with HPP. The diagnosis is based on clinical manifestations in combination with persistently low alkaline phosphatase (ALP) activity, elevated levels of ALP substrates, specifically inorganic pyrophosphate (PPi), pyridoxal 5’-phosphate (PLP) or urine phosphoethanolamine (PEA), and genetic confirmation of a causative ALPL variant. Considering the wide range of manifestations, treatment must be multimodal and tailored to individual needs. The multidisciplinary team for comprehensive management of HPP patients should include expertise to ensure disease state metabolic and musculoskeletal treatment, dental care, neurological and neurosurgical surveillance, pain management, physical therapy, and psychological care. Asfotase alfa as first-in-class enzyme replacement therapy (ERT) for HPP was shown to improve survival, rickets, and functional outcomes in severely affected children. However, we need to know more the effects of the enzyme replacement therapy on emerging manifestations of the disease. The understanding of the pathophysiology behind the diverse clinical manifestations of HPP is instrumental for improving the diagnostic process, working on novel means to substitute enzyme activity, and developing an integrative care of the HPP patient.