Hypophosphatasia

Hypophosphatasia is a rare inherited disorder characterized by defective mineralization of bone and teeth. It results from loss-of-function mutations in the ALPL gene, which encodes tissue-nonspecific alkaline phosphatase (TNSALP). The resulting deficiency leads to accumulation of inorganic pyrophosphate, a mineralization inhibitor, causing a spectrum of skeletal and dental symptoms.

Clinical features vary by age and form. Perinatal and infantile forms present with severe skeletal hypomineralization, bowed limbs, chest deformities, respiratory difficulties, and short stature; some affected infants survive with medical management. Childhood forms include rickets-like changes, delayed walking, bone pain, and premature loss of teeth. Odontohypophosphatasia affects teeth with early loss due to defective cementum, while adults may experience stress fractures, bone pain, and premature tooth loss despite otherwise preserved stature. Dental abnormalities often predominate in milder cases.

Genetically, hypophosphatasia can follow autosomal recessive or autosomal dominant inheritance, depending on the mutations. There is marked clinical and biochemical variability, even within families.

Diagnosis typically involves low serum alkaline phosphatase activity as a key clue, supported by elevated substrates such as phosphoethanolamine and pyridoxal 5'-phosphate in blood or urine. Radiographs reveal hypomineralized bones with metaphyseal-epiphyseal abnormalities. Genetic testing of ALPL confirms the diagnosis.

Treatment is multidisciplinary and supportive, addressing fractures, mobility, dental care, and growth. A recombinant enzyme replacement therapy, asfotase alfa, is approved for the pediatric-onset forms and has improved skeletal outcomes and survival in many patients. Management plans are individualized based on disease severity and trajectory.