Hypophosphatasia is an inherited metabolic bone disease that affects the normal development of the bones and teeth. This genetic disease weakens and softens bones, causing skeletal abnormalities, closely resembling osteogenesis imperfecta. Hypophosphatasia results from low levels of alkaline phosphate (ALP) in the body. Specifically, the disease is caused by a mutation in the ALPL gene. The ALPL gene provides instructions for making the enzyme alkaline phosphatase, which plays an essential role in mineralization. Mineralization is a process in which minerals, such as calcium and phosphorus, are deposited in developing bones and teeth. This process is critical for the normal development of strong bones and teeth. Mutations of ALPL lead to the production of an abnormal version of the enzyme. This abnormal enzyme cannot participate in mineralization, therefore creating the abnormal development of bones and teeth. Severity varies from patient to patient. However, the most severe forms of the disorder tend to occur before birth and in early infancy. The different forms of the disease are named perinatal, infantile, childhood, or adult hypophosphophatasia, depending on the age at which the disease is first detected.


Radiographic signs of childhood (left) and adult (right) hypophosphatasia.

Symptoms of hypophosphatasia can appear at any time from infancy to adulthood. They include the appearance of blue sclera (whites of the eyes) during infancy and childhood, deformities in the arms, legs and chest, frequent occurrences of pneumonia which result from chest distortion, recurrent fractures, premature loss of teeth, and teeth that may have wide pulp chambers that predispose them to cavities. These symptoms vary depending on the age at which the disease occurs. The most severe cases of the disease result in the failure of the formation of a skeleton in the womb and eventually a stillbirth. In comparison, the most mildly affected patients show low levels of ALP in the blood, yet never suffer bone problems. Infants with this disorder can be born with short limbs, an abnormally shaped chest, and soft skull bones. Other symptoms of the disease in infants include poor feeding, failure to gain weight, respiratory problems, and hypercalcemia.

The forms of hypophosphatasia that occur in childhood and adulthood are less severe than infant forms of the disease. The first sign in children is loss of baby teeth. Children also may have a short stature with bowed legs of knock knees, enlarged wrists and ankle joints, and an abnormal skull shape. Adult forms include softening of the bones (osteomalacia), recurrent fractures in the foot and thigh bones, and loss of adult teeth prematurely. Adults are also at a higher risk for joint pain and inflammation. There is also a very mild form of this disease called odontohypophosphatasia. This condition only affects teeth. Symptoms include abnormal tooth development and premature tooth loss.

Premature tooth loss, a symptom of hypophosphatasia.

Severe forms of hypophosphatasia affect 1 in 100,000 newborns. These severe forms of the disease are inherited in an autosomal recessive pattern. Milder cases in children and adults occur more frequently and have an autosomal recessive or an autosomal dominant pattern of inheritance. This disorder is most common in Caucasian populations however, it has been reported worldwide and in people of all ethnicities and backgrounds. 1 out of every 300 individuals in the United States is thought to be a carrier for the disease. Gene testing has been recently made available in order to determine if a person is a carrier for the disease. There is no cure for hypophosphatasia and there is no established medical therapy for this disease. However, expert dental care and physical therapy are recommended. There is also an orthopedic procedure called, “rodding,” which has proven to be helpful for adults with recurrent fractures.


Hypophosphatasia. (2012, March 05). Retrieved from http://ghr.nlm.nih.gov/condition/hypophosphatasia

Oi issues: Hypophosphatasia. (2007). Retrieved from http://www.oif.org/site/PageServer?pagename=Hypophosphatasia

Hypophosphatasia. (2010, May 20). Retrieved from http://www.magicfoundation.org/www/docs/175/



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