Infantile hypophosphatasia

Infantile hypophosphatasia (infantile HPP) is a severe form of hypophosphatasia, a rare inherited metabolic bone disease caused by mutations in the ALPL gene, which encodes tissue-nonspecific alkaline phosphatase (TNSALP). This enzyme plays a critical role in bone mineralization, and its deficiency leads to the accumulation of natural substrates, including inorganic pyrophosphate, which inhibits hydroxyapatite crystal formation. Infantile hypophosphatasia manifests between birth and six months of age and is distinguished from the perinatal lethal form by the presence of some mineralized bone at birth. The disease primarily affects the skeletal system, leading to progressive skeletal demineralization, rachitic changes of the chest and long bones, short stature, and widened cranial sutures with a bulging fontanelle. Affected infants frequently develop hypercalcemia and hypercalciuria, which can result in nephrocalcinosis and renal compromise. Respiratory insufficiency due to poorly mineralized ribs and a small thoracic cage is a major cause of morbidity and mortality. Additional features may include failure to thrive, irritability, periodic vomiting, and vitamin B6-responsive seizures due to impaired pyridoxal-5'-phosphate metabolism. Laboratory findings characteristically show markedly low serum alkaline phosphatase activity and elevated levels of phosphoethanolamine and pyridoxal-5'-phosphate in blood and urine. Historically, infantile hypophosphatasia carried a high mortality rate, with many affected children dying from respiratory failure within the first years of life. The treatment landscape was transformed by the approval of asfotase alfa (Strensiq), a bone-targeted enzyme replacement therapy that replaces the deficient TNSALP enzyme. Clinical trials demonstrated significant improvements in skeletal mineralization, respiratory function, and overall survival. Supportive care, including respiratory support, management of hypercalcemia, nutritional optimization, and vitamin B6 supplementation for seizures, remains an important component of management. Genetic counseling is recommended for affected families.

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