Hypophosphatasia

Hypophosphatasia (HPP) is a rare inherited metabolic disorder caused by loss-of-function mutations in the ALPL gene, which encodes tissue-nonspecific alkaline phosphatase (TNSALP). Deficiency of this enzyme leads to accumulation of its natural substrates, including inorganic pyrophosphate, which inhibits bone mineralization. The disease is characterized by defective mineralization of bones and teeth, resulting in a clinical spectrum that ranges from a lethal perinatal form with profound skeletal hypomineralization to a mild adult form presenting primarily with stress fractures and dental abnormalities. Common synonyms include phosphoethanolaminuria and Rathbun disease. The clinical features vary widely depending on the age of onset and severity. The perinatal lethal form presents with severe skeletal deformity, respiratory insufficiency due to hypoplastic lungs, and hypercalcemia. The infantile form typically manifests before six months of age with failure to thrive, rickets-like skeletal changes, craniosynostosis, hypercalcemia, and nephrocalcinosis. Childhood forms often present with premature loss of deciduous teeth (with intact roots), short stature, skeletal deformities, bone pain, and a waddling gait. The adult form may present with recurrent metatarsal stress fractures, chondrocalcinosis, osteomalacia, musculoskeletal pain, and premature loss of adult teeth. Odontohypophosphatasia refers to a form limited to dental manifestations. A hallmark biochemical finding across all forms is low serum alkaline phosphatase activity, with elevated levels of phosphoethanolamine, pyridoxal 5'-phosphate (vitamin B6), and inorganic pyrophosphate in blood and urine. Treatment has been transformed by the availability of asfotase alfa (Strensiq), a bone-targeted enzyme replacement therapy approved for the treatment of pediatric-onset hypophosphatasia. This therapy has demonstrated significant improvements in skeletal mineralization, respiratory function, and survival in severe forms. Supportive care includes management of hypercalcemia, respiratory support, dental care, physical therapy, and treatment of fractures. Non-steroidal anti-inflammatory drugs (NSAIDs) may help with bone pain. Importantly, bisphosphonates are contraindicated as they further inhibit mineralization. Genetic counseling is recommended for affected families.

Data sourced from FDA regulatory filings and ClinicalTrials.gov. Updated periodically.

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