Alkaline phosphatase is contained in membrane-enclosed vesicles located at the sites of mineral deposition in bone matrix and cartilage. Alkaline phosphatase appears to act as a pyrophosphatase, which releases phosphate ions needed for calcification. Usually, serum levels of alkaline phosphatase in children are approximately three times those in adults because of an increase in the bone fraction that is associated with active bone growth.

Deficiency of alkaline phosphatase, termed hypophosphatasia, is characterized by faulty bone mineralization. Four currently recognized forms of the disorder vary in age of onset and clinical severity. All are associated with reduced serum levels of alkaline phosphatase and elevated levels of plasma and urinary pyridoxal-5′-phosphate, inorganic pyrophosphate, and phosphoethanolamine, which are natural substrates for the enzyme. Varying degrees of hypercalcemia and hypercalciuria occur. Mutations in the tissue-nonspecific alkaline phosphatase (TNSALP or ALPL) gene, located at chromosome 1p36.1-p34, show genotype-phenotype correlation with the differing forms of the disorder. Prenatal diagnosis is available for the severe forms.

The perinatal or lethal form of hypophosphatasia is the most severe and is expressed in utero. Polyhydramnios may occur. Almost complete lack of skeletal mineralization, shortened extremities, and severe craniotabes occur. Serum alkaline phosphatase levels are extremely low and often are less than 10% of the lower limit of normal for infants. Many affected individuals are stillborn, whereas others live a few days and then die in the immediate neonatal period of respiratory insufficiency.
Radiography will help to differentiate this disorder from other severe forms of bone dysplasia. This form of the disorder is inherited as an autosomal recessive trait.

The infantile form of hypophosphatasia is a severe, autosomal recessive disorder that presents within the first year of life with generalized skeletal demineralization. Shortened extremities, fractures, failure to thrive, hypercalcemia, hypercalciuria, nephrocalcinosis, premature synostosis of the skull, and respiratory infections are common. Serum alkaline phosphatase levels are moderately reduced, with levels usually less than 25% of the lower limit of normal for children. Initial treatment with calcitonin may correct elevated calcium levels. Long-term therapy with chlorothiazide has resulted in decreased hypercalciuria and may improve bone mineralization. Dietary reduction of vitamin D and calcium may be needed to control the hypercalcemia. Reduced exposure to sunlight and use of sunscreens also may be required. Importantly, however, children should receive between 200 and 400 IU of vitamin D daily to prevent secondary rickets from developing. Serial measurement of 25-hydroxyvitamin D levels will help to monitor intake. Premature synostosis may not be appreciated on routine radiography or computed tomography, owing to the demineralization. Increased intracranial pressure may require surgical correction. Although many children with the infantile form die during childhood, long-term survival is possible. Bone marrow transplantation resulted in clinical improvement in one reported patient.

The childhood form of hypophosphatasia is characterized by premature loss of deciduous teeth, short stature, and clinical features of rickets. Joint swelling and discomfort and a nonprogressive myopathy often occur. Affected patients have an increased incidence of scoliosis and fractures. Radiography shows demineralization and rachitic changes. Focal areas of radiolucency project from growth plates into the metaphyseal areas. Craniosynostosis has been reported. Serum alkaline phosphatase levels are variably reduced and range between 20% and 75% of the lower limit of normal for children. Hypercalcemia and hypercalciuria may occur. Treatment is similar to that for the infantile form of the disorder. This form may be inherited as an autosomal dominant or an autosomal recessive trait.

Patients with the relatively mild adult form of hypophosphatasia may have a history of early loss of deciduous teeth, repeated fractures, or “rickets” in infancy. Stress fractures, pseudofractures, and arthritis may occur. Serum alkaline phosphatase levels are low, but not as reduced as in the more severe forms, and they may be just under the lower limit of normal for age. Usually, significant hypercalcemia and hypercalciuria are not noted. In some patients, the disorder is detected on screening blood panels. This form of the disorder may be inherited as an autosomal dominant or an autosomal recessive trait.