Childhood-onset hypophosphatasia

Childhood-onset hypophosphatasia (childhood HPP) is a rare inherited metabolic bone disease caused by loss-of-function mutations in the ALPL gene, which encodes tissue-nonspecific alkaline phosphatase (TNSALP). This enzyme plays a critical role in bone and tooth mineralization. In childhood-onset hypophosphatasia, reduced TNSALP activity leads to accumulation of its natural substrates, including inorganic pyrophosphate, which inhibits normal mineralization of bones and teeth. The condition typically manifests after six months of age but before 18 years, distinguishing it from the more severe perinatal and infantile forms and the milder adult form. Key clinical features include skeletal abnormalities such as rickets-like changes in the growth plates, short stature, bowed legs or knock knees, delayed walking, a waddling gait, bone pain, and recurrent fractures. A hallmark feature is premature loss of deciduous (baby) teeth, often with intact roots, due to deficient cementum formation. Some children may also experience muscle weakness, joint pain, and impaired physical function. Laboratory findings characteristically show low serum alkaline phosphatase activity and elevated levels of phosphoethanolamine and pyridoxal 5'-phosphate (vitamin B6) in the blood. The primary body systems affected are the skeletal system and dentition, though secondary effects on muscle function and overall growth are common. Treatment has been transformed by the availability of asfotase alfa (Strensiq), an enzyme replacement therapy approved for hypophosphatasia, which targets the underlying enzyme deficiency and has been shown to improve skeletal mineralization, growth, and physical function. Supportive care includes dental management, orthopedic interventions, physical therapy, and pain management. Non-steroidal anti-inflammatory drugs (NSAIDs) may be used for bone pain, and careful monitoring of calcium and phosphate metabolism is important. Bisphosphonates are contraindicated as they can worsen the condition.

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