In patients with HPP the predominant organs involved are the skeleton and teeth, which are hard tissues, even though there are high levels of TNSALP in many organs. Four of the five principal forms of HPP are based on age at diagnosis: perinatal, infantile, childhood, and adult, with earlier disease onset being more severe. The fifth form, which has dental manifestations only, is termed odonto-HPP. The most severe form is perinatal HPP, which presents in utero, with skeletal abnormalities at birth including extreme hypomineralization and short, deformed limbs. Life expectancy is short. Skeletal manifestations of infantile HPP present before 6 months of age and are inherited as an autosomal recessive trait. Clinical manifestations result from poor skeletal mineralization and include growth failure, rachitic deformities, hypercalcemia, and renal compromise from nephrocalcinosis. Cranial sutures appear widened but are representative of severe skull hypomineralization. Death occurs soon after initial clinical manifestations appear.

The childhood form occurs after 6 months of age and has a variable but more benign course. Premature loss of deciduous teeth, the most consistent clinical sign, is a result of hypoplasia of the cementum. Radiographs may reveal characteristic tongues, which are lucent projections from rachitic growth plates into abnormal metaphyses.

The adult form is the least severe and is clinically heterogeneous. It is inherited as an autosomal dominant trait with variable penetrance. There may be a childhood history of premature loss of deciduous teeth or of rachitic deformity but often young adult life is relatively normal. As the patient ages, multiple recurrent, poorly healing metatarsal fractures and femoral pseudofractures are common clinical features. Patients may have pseudogout with chondrocalcinosis. Total serum alkaline phosphatase level is well below normal in patients with adult HPP. Low levels of alkaline phosphatase can be seen in pregnancy, hypothyroidism, cleidocranial dysplasia, and severe osteogenesis imperfecta. Pyridoxal 5′-phosphate (PLP, vitamin B₆) is usually elevated and is a good marker for HPP. Serum 25(OH)D, 1,25(OH)D, and PTH values are typically normal.

There is no established treatment for HPP. Bone marrow transplant has been tried in infants. Teriparatide has been used with some success in several case reports. Enzyme replacement using a bone-targeted recombinant TNSALP is undergoing clinical trials.